Isolated polypeptide, protein fusion and their application, T cell isolated epitope, expression vector, host cell, method for the stimulation and/ or multiplication of T cells, isolated T cell population, a compound and its application as well as isolated

Description of the invention

The invention relates to an isolated polypeptide, a fusion protein and its use, an isolated T cell epitope, an expression vector, a host cell, a method of stimulating and / or proliferating T cells, an isolated population of T cells, the composition and use thereof, and isolated T cells.

The present invention relates generally to the treatment and diagnosis of cancer, such as prostate cancer. More particularly, the invention relates to polypeptides comprising at least a portion of a prostate cancer protein and to polynucleotides encoding such polypeptides. Such polypeptides and polynucleotides can be used in vaccines and pharmaceutical compositions for the prevention and treatment of prostate cancer, and for the diagnosis and monitoring of such tumors.

Background of the invention

Prostate cancer is the most common type of cancer in men, occurring in an estimated 30% of men over the age of 50. The influx of clinical data shows that human prostate cancer has the property of bone metastasis and the disease appears to inevitably progress from androgen dependent to androgen resistant, leading to increased mortality in patients. This widespread disease now ranks second as the cause of cancer death in US men.

Despite extensive research into a treatment for this disease, prostate cancer remains difficult to treat. Usually treatment is based on surgery and / or radiation therapy, but these methods are ineffective in a significant percentage of cases. Two previously identified prostate specific proteins - prostate specific antigen (PSA) and prostate specific phosphatase (PAP) have limited therapeutic and diagnostic potential. For example, PSA levels do not always correlate well with the presence of prostate cancer, being positive in a percentage of non-prostate cancer cases, including bening prostatic hyperplasmia (BPH). Moreover, PSA measurements correlate with prostate volume and do not indicate the level of metastasis.

Despite extensive research into the treatment of these and other cancers, prostate cancer remains difficult to diagnose and treat effectively. Accordingly, there is a need in the art for improved methods of detecting and treating such neoplasms. The present invention meets these needs and provides further related advantages.

Summary of the invention

The invention relates to an isolated polypeptide consisting of a sequence fragment from SEQ. ID NO: 113, wherein the fragment comprises at least the T-cell epitope sequence of SEQ ID NO: 337.

The invention also relates to an isolated T-cell epitope consisting of the amino acid sequence of SEQ. ID NO .: 337.

Furthermore, the invention relates to an expression vector containing a polynucleotide encoding a polypeptide of the invention operably linked to an expression control sequence.

The invention also relates to a host cell transformed or transfected with an expression vector according to the invention and a fusion protein containing a polypeptide according to the invention.

The invention also relates to the use of a polypeptide or fusion protein of the invention in the manufacture of a medicament for stimulating a prostate tumor protein specific immune response.

The invention further relates to a method of stimulating and / or proliferating prostate cancer specific T cells comprising contacting the T cells with one or more of:

(i) a polypeptide of the invention;

(ii) a polynucleotide encoding the polypeptide of (i); and / or (iii) kc ^ rmź ^ r ^^ antigen presenters that express the pollpeptide ο ^ έ ^ ην in (i); under conditions and for a sufficient time to allow T cells to be stimulated and / or multiplied.

The invention furthermore relates to an isolated population of T cells comprising T cells prepared according to the method of the invention.

The invention also relates to a composition comprising a first component selected from the group consisting of physiologically acceptable carriers and immunostimulating agents and a second active agent component, the second component being selected from the group consisting of:

a) a polypeptide according to the invention;

b) an isolated T-cell epitope of the invention;

c) a fusion protein according to the invention;

PL 200 772 B1

d) the T cell population of the invention; and

e) antigen presenting cells that express a polypeptide of the invention.

The invention further relates to the use of a composition according to the invention for the manufacture of a medicament for the stimulation of an immune response and for the treatment of cancer.

The invention also relates to isolated T cells propagated by: incubating CD4 + and / or CD8 + T cells isolated from a patient with at least one component selected from the group consisting of (i) a polypeptide of the invention;

(ii) an isolated T-cell epitope of the invention;

(iii) antigen presenting cells that express a polypeptide of the invention; and (iv) the fusion protein of the invention; such that T cells proliferate;

for use in the manufacture of a medicament for inhibiting cancer growth.

Briefly, compositions and methods for the diagnosis and treatment of cancer such as prostate cancer are disclosed herein. Polypeptides containing at least a portion of a prostate tumor protein, or variants thereof, have been described. Certain parts or other variants are immunogenic, such that the ability of the variant to react with the antigen-specific antiserum is not significantly reduced. The polypeptides described herein contain at least an immunogenic portion of a prostate cancer protein, or a variant thereof, wherein the prostate cancer protein comprises an amino acid sequence that is encoded by a polynucleotide sequence selected from the group consisting of (a) the sequences shown in any one of SEQ. ID NO .: 1-111, 115-171, 173-175, 177, 179-305, 307-315, 326, 328, 330, 332-335, 340-375, 381, 382 or 384-472; (b) sequences that hybridize to any of the above sequences under moderately stringent conditions; (c) the complement of any one of the sequences of (a) or (b). Such polypeptides contain at least a portion or variant of a prostate cancer protein that comprises an amino acid sequence selected from the group consisting of the sequences set out in any one of SEQ. ID NO .: 112-114, 172, 176, 178, 327, 329, 331, 336, 339, 376-380, and 383.

Also described herein are polynucleotides that encode a polypeptide as described above or a portion thereof (such as a portion encoding at least 15 amino acid residues in a prostate cancer protein), expression vectors containing such polynucleotides, and host cells transformed or transfected with such expression vectors.

Pharmaceutical compositions comprising a polypeptide or polynucleotide as described above and a physiologically acceptable carrier and vaccines are also discussed. Such vaccines contain a polypeptide or polynucleotide as described above and a non-specific immune response enhancer.

Also disclosed herein are pharmaceutical compositions which comprise: (a) an antibody, or antigen-binding fragment thereof, that binds specifically to a prostate cancer protein, and (b) a physiologically acceptable carrier. Also described are pharmaceutical compositions comprising: (a) antigen presenting cells that express the polypeptide as described above, and (b) pharmaceutically acceptable carrier or excipient. Antigen presenting cells include dendritic cells, macrophages, monocytes, fibroblasts, and B cells.

Also described herein are vaccines which contain: (a) antigen presenting cells that express a polypeptide as described above, and (b) a non-specific immune response enhancer. In addition, fusion proteins that contain at least one polypeptide as described above, as well as polynucleotides encoding such fusion proteins, are also described.

Also disclosed are pharmaceutical compositions comprising a fusion protein or a polynucleotide encoding such a fusion protein in combination with a non-specific immune response enhancer, as well as vaccines that contain the fusion protein or a polynucleotide encoding such a fusion protein in combination with a non-specific immune response enhancer.

Also described below are methods for inhibiting tumor growth in a patient that include administering to the patient a pharmaceutical composition or vaccine as set out above. Further, disclosed are methods of removing tumor cells from a biological sample, comprising contacting the biological sample with T cells that react specifically with a prostate tumor protein, the contacting step being performed under conditions and in a time sufficient to allow removal of the cells expressing the protein from the sample. Other methods of braking

In order to develop a tumor in a patient, the procedure involves administering to the patient a biological sample treated as described above.

Further described are methods of stimulating and / or propagating prostate tumor specific T cells comprising contacting the T cells with one or more (i) polypeptides as described above; (ii) polynucleotides encoding such a polypeptide; and / or (iii) antigen presenting cells that express such a polypeptide; under conditions and at a time sufficient to stimulate and / or proliferate T cells. Isolated T cell populations containing T cells prepared as described above are also provided.

Also described are methods for inhibiting cancer development in a patient comprising administering to the patient an effective amount of the T cell population as described above.

Disclosed herein are methods for inhibiting cancer development in a patient comprising the steps of: (a) incubating CD4 + and / or CD8 + T cells isolated from the patient with one or more: (i) polypeptides comprising at least an immunogenic portion of a prostate cancer protein; (ii) polynucleotides encoding such a polypeptide; and / or (iii) antigen presenting cells that express such a polypeptide; and (b) administering to the patient an effective amount of the expanded T cells, thereby inhibiting tumor growth in the patient. The expanded cells may or may not be cloned prior to administration to the patient.

Further described are methods for determining the presence or absence of a tumor in a patient comprising: (a) contacting a biological sample taken from the patient with a binding agent that binds to a polypeptide as set out above; (b) detecting the amount of polypeptide in the sample that binds to the binding agent; and (c) comparing the amount of polypeptide to a predetermined cutoff and determining the presence or absence of a tumor in the patient therefrom. An exemplary binding agent is an antibody, in particular a monoclonal antibody. The cancer may be prostate cancer.

The solutions disclosed herein enable the monitoring of tumor development in a patient. Such methods include the steps of: (a) contacting a biological sample from the patient with a binding agent that binds to the polypeptide as set out above; (b) detecting in the sample the amount of polypeptide that binds to the binding agent and (c) repeating steps (a) and (b) using a biological sample obtained from the patient at a subsequent time point and (d) comparing the amount of polypeptide detected in step (c) ) with the amount detected in step (b) and thereby monitoring the tumor development in the patient.

It is also possible to determine the presence or absence of a tumor in a patient by: (a) contacting a biological sample from the patient with an oligonucleotide that hybridizes to a polynucleotide that encodes a prostate tumor protein; (b) detecting the level of a polynucleotide, preferably mRNA, in the sample that hybridizes to the oligonucleotide; and (c) comparing the level of the polynucleotide that hybridizes to the oligonucleotide with a predetermined cut-off value and then determining the presence or absence of a tumor in the patient. The amount of mRNA can be detected by the polymerase chain reaction using, for example, at least one oligonucleotide primer that hybridizes to a polynucleotide that encodes a polypeptide as set forth above or a sequence complementary to such a polynucleotide. The amount of mRNA can also be detected using an oligonucleotide probe hybridization technique that hybridizes to a polynucleotide that encodes a polypeptide as set forth above or a sequence complementary to such a polynucleotide.

Also described herein are methods of monitoring cancer development in a patient, comprising the steps of (a) contacting a biological sample from the patient with an oligonucleotide that hybridizes to a polynucleotide that encodes a prostate cancer protein; (b) detecting in the sample the amount of polypeptide that hybridizes to the oligonucleotide; (c) repeating steps (a) and (b) using a biological sample obtained from the patient at the next time point; and (d) comparing the amount of polynucleotide detected in step (c) with the amount detected in step (b) thereby monitoring tumor development in the patient.

Also described herein are antibodies, such as monoclonal antibodies, that bind to a polypeptide as described above, as well as diagnostic kits containing such antibodies. Also provided are diagnostic kits containing one or more oligonucleotide probes or primers as described above.

PL 200 772 B1

These and other aspects of the present invention will become apparent with reference to the following detailed description and accompanying drawings. All references disclosed herein are incorporated herein by reference in their entirety as if each were included individually.

Brief description of the drawings and sequence identifiers

Figure 1 shows the ability of T cells to kill fibroblasts expressing a representative prostate tumor polypeptide P502S compared to control fibroblasts. The percentage of lysis is shown as a series of target cell ratios as indicated.

Figures 2A and 2B show the ability of T cells to recognize fibroblasts expressing a representative prostate cancer polypeptide P502S. In each case, the number of γ interferon spots is shown for a different number of responses. In Figure 2A, data is shown for fibroblasts pulsed with P2S-12 peptide compared to fibroblasts treated with control E75 peptide. In fig. 2B, data are shown for P502S expressing fibroblasts compared to HER-2 / neu expressing fibroblasts.

Fig. 3 is a competition assay showing that P501S-derived P1S # 10 peptide binds HLA-A2. Peptide P1S # 10 inhibits the HLA-A2 restricted presentation of the fluM58 peptide to the D150M58 CTL clone in a TNF release bioassay. D150M58 CTL is specific for HLA-A2 binding fluM58 peptide from influenza virus matrix.

Fig. 4 shows the ability of T cell lines generated from P1S # 10 immunized mice to specifically lyse P1S # 10 pulsed and P501S transduced Jurkat A2Kb target cells as compared to EGFP transduced Jurkat A2Kb cells. The percentage of lysis is shown as a series of the effector to target cell ratio as indicated.

Fig. 5 depicts the ability of a T cell clone to recognize and specifically lyse Jurkat A2Kb cells expressing a representative prostate cancer polypeptide P501S, showing that P1S # 10 peptide can be a natural tumor epitope processed of the PS01S polypeptide.

Figures 6A and 6B are graphs showing the specificity of the CD8 + cell line (3A-1) for a representative prostate cancer polypeptide (P501S). Fig. 6A shows the results of the release test⁵¹Cr. The percentage of specific lysis is shown as a series of effector: target cell ratios as indicated. Fig. 6B shows interferon-gamma production by 3A-1 cells stimulated with autologous P501S transduced B-LCL at different target cell effector ratios as indicated.

KNOT. ID NO: 1 is the fixed cDNA sequence for F1-13

KNOT. ID NO: 2 is the fixed 3 'cDNA sequence for F1-12

KNOT. ID NO: 3 is the fixed 5 'cDNA sequence for F1-12

KNOT. ID NO: 4 is the fixed 3 'cDNA sequence for F1-16

KNOT. 5 is the fixed 3 'cDNA sequence for H1-1

KNOT. ID NO: 6 is the fixed 3 'cDNA sequence for H1-9

KNOT. ID NO: 7 is the fixed 3 'cDNA sequence for H1-4

KNOT. ID NO: 8 is the fixed 3 'cDNA sequence for J1-17

KNOT. ID NO: 9 is the fixed 5 'cDNA sequence for J1-17

KNOT. ID NO: 10 is the fixed 3 'cDNA sequence for L1-12

KNOT. 11 is the fixed 5 'cDNA sequence for L1-12

KNOT. ID NO: 12 is the fixed 3 'cDNA sequence for N1-1862

KNOT. ID NO: 13 is the fixed 5 'cDNA sequence for N1-1862

KNOT. ID NO: 14 is the fixed 3 'cDNA sequence for J1-13

KNOT. ID NO: 15 is the fixed 5 'cDNA sequence for J1-13

KNOT. ID NO: 16 is the fixed 3 'cDNA sequence for J1-19

KNOT. ID NO: 17 is the fixed 5 'cDNA sequence for J1-19

KNOT. ID NO: 18 is the fixed 3 'cDNA sequence for J1-25

KNOT. 19 is the fixed 5 'cDNA sequence for J1-25

KNOT. ID NO: 20 is the fixed 5 'cDNA sequence for J1-24

KNOT. ID NO: 21 is the fixed 3 'cDNA sequence for J1-24

KNOT. ID NO: 22 is the fixed 5 'cDNA sequence for K1-58

KNOT. ID NO: 23 is the fixed 3 'cDNA sequence for K1-58

KNOT. ID NO: 24 is the fixed 5 'cDNA sequence for K1-63

KNOT. ID NO: 25 is the fixed 3 'cDNA sequence for K1-63

KNOT. ID NO: 26 is the fixed 5 'cDNA sequence for L1-4

KNOT. ID NO: 27 is the fixed 3 'cDNA sequence for L1-4

PL 200 772 B1

KNOT. 28 is the fixed 5 'cDNA sequence for L1-14 of SEQ. ID NO: 29 is the fixed 3 'cDNA sequence for L1-14 of SEQ. ID NO: 30 is the fixed 3 'cDNA sequence for L1-12 of SEQ. ID NO: 31 is the fixed 3 'cDNA sequence for J1-16 of SEQ. ID NO: 32 is the fixed 3 'cDNA sequence for J1-21 of SEQ. ID NO: 33 is the fixed 3 'cDNA sequence for K1-48 of SEQ. 34 is the fixed 3 'cDNA sequence for K1 -55 SEQ. 35 is the fixed 3 'cDNA sequence for L1-2 of SEQ. ID NO: 36 is the fixed 3 'cDNA sequence for L1-6 of SEQ. ID NO: 37 is the fixed 3 'cDNA sequence for N1-1858 of SEQ. 38 is the fixed 3 'cDNA sequence for N1-1860 of SEQ. No. 39 is the fixed 3 'cDNA sequence for N1-1861 of SEQ. 40 is the fixed 3 'cDNA sequence for N1-1864 of SEQ. P5 SEQ ID NO: 41 is the fixed cDNA sequence. SEQ ID NO: 42 is the fixed cDNA sequence for P8. P9 SEQ ID NO: 43 is the fixed cDNA sequence. ID NO: 44 is the fixed cDNA sequence for P18 of SEQ. 45 is the fixed cDNA sequence for P20 SEQ. 46 is the fixed cDNA sequence for P29 of SEQ. ID NO: 47 is the fixed cDNA sequence for P30 of SEQ. P34 of SEQ ID NO: 48 is the fixed cDNA sequence. P36 SEQ ID NO: 49 is the fixed cDNA sequence. 50 is the fixed cDNA sequence for P38 SEQ. P39 SEQ ID NO: 51 is the fixed cDNA sequence. ID NO: 52 is the fixed cDNA sequence for P42 SEQ. P47 of SEQ ID NO: 53 is the fixed cDNA sequence. P49 of SEQ ID NO: 54 is the fixed cDNA sequence. 55 is the fixed cDNA sequence for P50 SEQ. SEQ ID NO: 56 is the fixed cDNA sequence for P53 SEQ. P55 SEQ ID NO: 57 is the fixed cDNA sequence. ID NO: 58 is the fixed cDNA sequence for P60 SEQ. P64 of SEQ ID NO: 59 is the fixed cDNA sequence. P65 SEQ ID NO: 60 is the fixed cDNA sequence. P73 is the fixed cDNA sequence of SEQ. SEQ ID NO: 62 is the fixed cDNA sequence for P75 SEQ. P76 is the fixed cDNA sequence of SEQ. P79 of SEQ ID NO: 64 is the fixed cDNA sequence. P84 SEQ ID NO: 65 is the fixed cDNA sequence. SEQ ID NO: 66 is the fixed cDNA sequence for P68 of SEQ. SEQ ID NO: 67 is the fixed cDNA sequence for P80 SEQ. P82 of SEQ ID NO: 68 is the fixed cDNA sequence. SEQ ID NO: 69 is the fixed cDNA sequence for SEQ. ID NO: 70 is the fixed cDNA sequence for SEQ U1-3065. SEQ ID NO: 71 is the determined cDNA sequence for V1-3692. ID NO: 72 is the determined cDNA sequence for SEQ 1A-3905. SEQ ID NO: 73 is the established cDNA sequence for V1-3686. 74 is the fixed cDNA sequence for R1-2330 of SEQ. ID NO: 75 is the fixed cDNA sequence for SEQ ID NO: 1B-3976. SEQ ID NO: 76 is the determined cDNA sequence for V1-3679. ID NO: 77 is the determined cDNA sequence for SEQ ID NO: 4736. SEQ ID NO: 78 is the determined cDNA sequence for SEQ ID NO: 4738. SEQ ID NO: 79 is the determined cDNA sequence for SEQ ID NO: 4741. ID NO: 80 is the fixed cDNA sequence for SEQ ID NO: 4744. ID NO: 81 is the determined cDNA sequence for 1G-4734 of SEQ. ID NO: 82 is the determined cDNA sequence for 1H-4774 SEQ. ID NO: 83 is the established cDNA sequence for 1H-4781

PL 200 772 B1

KNOT. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. ID NO.

as P504S)

KNOT. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. SEQ ID NO. ID NO .:

is the fixed sequence 1H-4785 cDNA is the fixed sequence 1H-4787 cDNA is the fixed sequence 1H-4796 cDNA is the fixed sequence 11-4807 cDNA is the fixed sequence 11-4810 cDNA is the fixed 11-4811 cDNA sequence cDNA sequence for 1J-4876 is cDNA fixed sequence 1K-4884 is cDNA fixed sequence 1K-4896 is cDNA fixed sequence 1G-4761 is cDNA fixed sequence 1G-4762 is cDNA fixed sequence 1H-4766 is cDNA fixed sequence for 1H-4770 is cDNA fixed sequence for 1H-4771 is cDNA fixed sequence for 1H-4772 is cDNA fixed sequence for 1D-4297

100 is the fixed cDNA sequence for 1D-4309

101 is the fixed cDNA sequence for 1D1-4278

102 is the fixed cDNA sequence for 1D-4288

103 is the fixed cDNA sequence for 1D-4283

104 is the fixed cDNA sequence for 1D-4304

105 is the fixed cDNA sequence for 1D-4296

106 is the fixed cDNA sequence for 1D-4280

107 is the fixed full length cDNA sequence for F1-12 (also referred to as

108 is the predicted amino acid sequence for F1-12

109 is the fixed full length cDNA sequence for J1-17

110 is the fixed full length cDNA sequence for L1-12

111 is the fixed full length cDNA sequence for N1-1862

112 is the predicted amino acid sequence for J1-17

113 is the predicted amino acid sequence for L1-12

114 is the predicted amino acid sequence for N1-1862

115 is the fixed cDNA sequence for P89

116 is the fixed cDNA sequence for P90

117 is the fixed cDNA sequence for P92

118 is the fixed cDNA sequence for P95

119 is the fixed cDNA sequence for P98

120 is the fixed cDNA sequence for P102

121 is the fixed cDNA sequence for P110

122 is the fixed cDNA sequence for P111

123 is the fixed cDNA sequence for P114

124 is the fixed cDNA sequence for P115

125 is the fixed cDNA sequence for P116

126 is the fixed cDNA sequence for P124

127 is the fixed cDNA sequence for P126

128 is the fixed cDNA sequence for P130

129 is the fixed cDNA sequence for P133

130 is the fixed cDNA sequence for P138

131 is the fixed cDNA sequence for P143

132 is the fixed cDNA sequence for P151

133 is a specific cDNA sequence for P156

134 is the fixed cDNA sequence for P157

135 is the fixed cDNA sequence for P166

136 is the fixed cDNA sequence for P176

137 is the fixed cDNA sequence for P178

138 is the fixed cDNA sequence for P179

PL 200 772 B1

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

KNOT.

ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO., ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO. ID NO.

139 is a constant sequence of cDNA for P 185

140 is the constant equation of cDDNd Ia 0 182

141 is equal to DDN for 0201

142 is equal to DDN for 0204

143 is equal to DDN for 0200

144 is equal to DDN for 211

145 is equal to DDN for 211

146 is equal to DDN for 211

147 is the constant equation DDN for about 203

145 is the constant equation DDN for about 203

149 is the constant equation DDN for 208

150 is a constant sequence DDNd la o201

151 is a constant sequence DDNd la o205

150 is a constant sequence DDNd la o206

153 is a constant sequence DDNd la o205

154 is a constant sequence DDNd la o206

155 is a constant sequence DDNd la o206

156 is a constant sequence DDNd la P204

157 is the fixed cDDN sequence for P206

155 is the fixedDDN sequence for o207

159 is the fixed DDN sequence for P202

160 is the fixedDDN sequence for o207

161 is a fixed sequence DDNd Ia PW0

160 is the fixed DDN sequence for PW7

163 is a fixed sequence DDNd Ia P233

164 is the fixedDDN sequence for o ^

165 is the fixedDDN sequence for o ^

166 is the fixed sequence of ^ lDDNA for owe

167 is a fixedDDN sequence for o200

165 is the fixed DDN sequence for o204

169 is the fixed DDN sequence for o203

170 is the fixed DDN sequence for 0228

171 is a fixed DNN sequence for P270P-DD1

170 is the airing sequence of the sminone acid Cla 0270P-DN1

173 is a constant sequence DDN for o2733-0 ^

174 is the fixed cDDN sequence for ^ 733-0 ^

175 it is the fixed cDDN sequence for 0273P-DN18

176 is the airflow sequence of Cla P270P-DN18

177 is the fixed cDDN sequence for 0273P-DN14

175 is the ventilated cmino sequence for P270P-DN14 179 is fixed Longer cDDN sequence for o G-4476

150 is a permanent longer cCDN equivalent for 1-4473

151 is a constant cCDN for o 1-4441 150 is a plotted longer cCDN sequence for o G-4784

153 is a constant equivalent of cCDN for 1-4474

154 is a constant equivalent of cCDN for 1-4471

155 is the constant C Ozszas the equator of cCDN for 1-4785

156 is a fixed longer cCDN sequence for o 1-4787

157 is constant The longer cCDN equivalent for 1-4796 155 is the defined CCDN equivalent for o

159 is the constant C 'cCDN for 1-4718

190 jtaf with the 3 'cDNA sequence aio 11-4511

191 cDNA aio 11-4576 190 jtaf cDNA aio sequence 1K-4554

193 cDNA aio 1K-4596

194 cDNA aio 1G-4761 cDNA sequence

PL 200 772 B1

KNOT. SEQ ID NO: 195 is the fixed longer cDNA sequence for SEQ ID NO: 4762. 196 is the fixed longer cDNA sequence for SEQ 1H-4766. 197 is the fixed 3 'cDNA sequence for 1H-4770 of SEQ. 198 is the 3 'fixed cDNA sequence for 1H-4771 of SEQ. ID NO: 199 is the fixed longer cDNA sequence for SEQ 1H-4772. ID NO: 200 is the fixed longer cDNA sequence for SEQ ID NO: 4309. 201 is the fixed longer cDNA sequence for 1D.1-4278 SEQ. 202 is the fixed longer cDNA sequence for SEQ ID NO: 4288. ID NO: 203 is the fixed longer cDNA sequence for SEQ ID NO: 4283. ID NO: 204 is the fixed longer cDNA sequence for SEQ ID NO: 4304. 205 is the fixed longer cDNA sequence for SEQ ID NO: 4296. ID NO: 206 is the fixed longer cDNA sequence for SEQ ID NO: 4280. ID NO: 207 is the fixed cDNA sequence for 10-d8fwd of SEQ. SEQ ID NO: 208 is the determined cDNA sequence for SEQ. ID NO: 209 is the determined cDNA sequence for 11-C8rev SEQ. ID NO: 210 is the determined cDNA sequence for 7g6fwd of SEQ. ID NO: 211 is the determined cDNA sequence for SEQ ID NO: 7g6rev. ID NO: 212 is the determined cDNA sequence for 8-b5fwd of SEQ. ID NO: 213 is the determined cDNA sequence for 8-b5rev SEQ. ID NO: 214 is the determined cDNA sequence for 8-b6fwd of SEQ. ID NO: 215 is the determined cDNA sequence for 8-b6rev SEQ. ID NO: 216 is the determined cDNA sequence for 8-d4fwd of SEQ. ID NO: 217 is the determined cDNA sequence for 8-d9rev SEQ. ID NO: 218 is the determined cDNA sequence for 8-g3fwd of SEQ. ID NO: 219 is the determined cDNA sequence for 8-g3rev SEQ. ID NO: 220 is the determined cDNA sequence for 8-h11rev SEQ. SEQ ID NO: 221 is the determined cDNA sequence for g-f12fwd. SEQ ID NO: 222 is the determined cDNA sequence for g-f3rev. SEQ ID NO: 223 is the fixed cDNA sequence for P509S. ID NO: 224 is the fixed cDNA sequence for P510S of SEQ. ID NO: 225 is the established cDNA sequence for P703DE5 of SEQ. ID NO: 226 is the determined cDNA sequence for 9-AII of SEQ. ID NO: 227 is the determined cDNA sequence for 8-C6 of SEQ. ID NO: 228 is the determined cDNA sequence for 8-H7 of SEQ. NO: 229 is the determined cDNA sequence for JPTPN13 SEQ. SEQ ID NO: 230 is the determined cDNA sequence for JPTPN14. ID NO: 231 is the determined cDNA sequence for JPTPN23 SEQ. SEQ ID NO: 232 is the fixed cDNA sequence for JPTPN24 SEQ. SEQ ID NO: 233 is the established cDNA sequence for JPTPN25. SEQ ID NO: 234 is the determined cDNA sequence for SEQ. SEQ ID NO: 235 is the determined cDNA sequence for JPTPN34. ID NO: 236 is the determined cDNA sequence for JPTPN35 SEQ. SEQ ID NO: 237 is the established cDNA sequence for JPTPN36. SEQ ID NO: 238 is the established cDNA sequence for JPTPN38. SEQ ID NO: 239 is the determined cDNA sequence for JPTPN39. ID NO: 240 is the fixed cDNA sequence for JPTPN40 SEQ. ID NO: 241 is the determined cDNA sequence for JPTPN41 SEQ. ID NO: 242 is the determined cDNA sequence for JPTPN42 SEQ. ID NO: 243 is the established cDNA sequence for JPTPN45 SEQ. ID NO: 244 is the determined cDNA sequence for JPTPN46 SEQ. SEQ ID NO: 245 is the established cDNA sequence for JPTPN51. ID NO: 246 is the determined cDNA sequence for JPTPN56 SEQ. ID NO: 247 is the determined cDNA sequence for JPTPN64 SEQ. SEQ ID NO: 248 is the determined cDNA sequence for JPTPN65 SEQ. ID NO: 249 is the determined cDNA sequence for JPTPN67 of SEQ. ID NO: 250 is the fixed cDNA sequence for JPTPN76

PL 200 772 B1

KNOT. SEQ ID NO: 251 is the established cDNA sequence for JPTPN84 SEQ. SEQ ID NO: 252 is the determined cDNA sequence for JPTPN85 SEQ. SEQ ID NO: 253 is the determined cDNA sequence for JPTPN86 SEQ. SEQ ID NO: 254 is the determined cDNA sequence for JPTPN87 SEQ. SEQ ID NO: 255 is the fixed cDNA sequence for JPTPN88 SEQ. SEQ ID NO: 256 is the fixed cDNA sequence for JPIF1. SEQ ID NO: 257 is the determined cDNA sequence for JPIF2. ID NO: 258 is the determined cDNA sequence for JP1C2 SEQ. SEQ ID NO: 259 is the established cDNA sequence for JP1B1. ID NO: 260 is the fixed cDNA sequence for JP1B2 SEQ. ID NO: 261 is the fixed cDNA sequence for JP1D3 SEQ. SEQ ID NO: 262 is the established cDNA sequence for JP1A4. SEQ ID NO: 263 is the determined cDNA sequence for SEQ. ID NO: 264 is the fixed cDNA sequence for JP1E6 SEQ. ID NO: 265 is the determined cDNA sequence for JP1D6 SEQ. ID NO: 266 is the determined cDNA sequence for JP1B5 SEQ. ID NO: 267 is the determined cDNA sequence for JP1A6 SEQ. ID NO: 268 is the established cDNA sequence for JP1E8 SEQ. ID NO: 269 is the determined cDNA sequence for JP1D7 SEQ. ID NO: 270 is the fixed cDNA sequence for JP1D9 SEQ. ID NO: 271 is the determined cDNA sequence for JP1C10 SEQ. SEQ ID NO: 272 is the established JPIA9 cDNA sequence. SEQ ID NO: 273 is the fixed cDNA sequence for JPIF12. ID NO: 274 is the determined cDNA sequence for JP1E12 SEQ. SEQ ID NO: 275 is the determined cDNA sequence for SEQ. ID NO: 276 is the determined cDNA sequence for JP1C11 SEQ. ID NO: 277 is the determined cDNA sequence for JP1C12 SEQ. SEQ ID NO: 278 is the determined cDNA sequence for JPIB12. ID NO: 279 is the determined cDNA sequence for JP1A12 SEQ. ID NO: 280 is the determined cDNA sequence for JP8G2 SEQ. SEQ ID NO: 281 is the fixed cDNA sequence for SEQ. SEQ ID NO: 282 is the determined cDNA sequence for SEQ. 283 is the fixed cDNA sequence for JP8A3 SEQ. SEQ ID NO: 284 is the determined cDNA sequence for SEQ. ID NO: 285 is the determined cDNA sequence for JP8C3 SEQ. ID NO: 286 is the determined cDNA sequence for JP8G4 SEQ. SEQ ID NO: 287 is the determined cDNA sequence for SEQ. SEQ ID NO: 288 is the determined cDNA sequence for SEQ. ID NO: 289 is the fixed cDNA sequence for JP8FS SEQ. SEQ ID NO: 290 is the fixed cDNA sequence for SEQ. SEQ ID NO: 291 is the determined cDNA sequence for SEQ. SEQ ID NO: 292 is the determined cDNA sequence for SEQ. SEQ ID NO: 293 is the determined cDNA sequence for jP8D8. ID NO: 294 is the determined cDNA sequence for JP8E7 of SEQ. SEQ ID NO: 295 is the determined cDNA sequence for SEQ. ID NO: 296 is the determined cDNA sequence for JP8G8 SEQ. ID NO: 297 is the determined cDNA sequence for JP8B10 SEQ. ID NO: 298 is the determined cDNA sequence for JP8C10 SEQ. ID NO: 299 is the determined cDNA sequence for JP8E9 of SEQ. ID NO: 300 is the fixed cDNA sequence for JP8E10 SEQ. SEQ ID NO: 301 is the determined cDNA sequence for SEQ. SEQ ID NO: 302 is the determined cDNA sequence for SEQ. SEQ ID NO: 303 is the determined cDNA sequence for SEQ. ID NO: 304 is the fixed cDNA sequence for JP8E11 SEQ. ID NO: 305 is the determined cDNA sequence for JP8E12 SEQ. ID NO: 306 is the amino acid sequence for PS2 # 12 peptide

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KNOT. SEQ ID NO: 307 is the determined cDNA sequence for SEQ. ID NO: 308 is the fixed cDNA sequence for P712P SEQ. ID NO: 309 is the fixed cDNA sequence for CLONE23 SEQ. ID NO: 310 is the fixed cDNA sequence for P774P SEQ. ID NO: 311 is the determined cDNA sequence for P775P SEQ. SEQ ID NO: 312 is the fixed cDNA sequence for P715P. SEQ ID NO: 313 is the fixed cDNA sequence for P710P. ID NO: 314 is the determined cDNA sequence for P767P SEQ. ID NO: 315 is the fixed cDNA sequence for P768P

KNOT. NOS. 316-325 are the established cDNA sequences of previously isolated genes

KNOT. ID NO: 326 is the fixed cDNA sequence for P703PDE5

KNOT. ID NO: 327 is the predicted amino acid sequence for P703PDE5

KNOT. ID NO: 328 is the fixed cDNA sequence for P703P6.26

KNOT. ID NO: 329 is the predicted amino acid sequence for P703P6.26

KNOT. ID NO: 330 is the fixed cDNA sequence for Ρ703ΡΧ-23

KNOT. ID NO: 331 is the predicted amino acid sequence for Ρ703ΡΧ-23

KNOT. ID NO: 332 is the fixed full length cDNA sequence for P509S

KNOT. ID NO: 333 is the fixed longer cDNA sequence for P707P (also referred to as 11-C9)

KNOT. ID NO: 334 is the fixed cDNA sequence for P714P

KNOT. ID NO: 335 is the fixed cDNA sequence for P70SP (also referred to as 9-F3)

KNOT. ID NO: 336 is the predicted amino acid sequence for P705P of SEQ. ID NO: 337 is the amino acid sequence of the PJEST # 10 peptide of SEQ. ID NO: 338 is the amino acid sequence of p5 peptide

KNOT. ID NO: 339 is the predicted amino acid sequence P509S of SEQ. SEQ ID NO: 340 is the fixed cDNA sequence for P778P. SEQ ID NO: 341 is the fixed cDNA sequence for P786P. ID NO: 342 is the fixed cDNA sequence for P789P

KNOT. ID NO: 343 is the established cDNA sequence for a clone with Homo sapiens MM46 mRNA homology

KNOT. ID NO: 344 is the fixed cDNA sequence of a clone with homology to mRNA for TNF-alpha stimulated ABC (ABC50) protein from Homo sapiens

KNOT. ID NO: 345 is the established cDNA sequence for a clone with homology to Homo sapiens E-cadherin mRNA

KNOT. ID NO: 346 is the established cDNA sequence for a clone with homology to the human nucleus-encoded mitochondrial serine hydroxymethyltransferase (SHMT)

KNOT. ID NO: 347 is the established cDNA sequence for a clone with homology to the Natural Immunity Related Macrophage 2 protein (NRAMP2) from Homo sapiens

KNOT. ID NO: 348 is the cDNA fixed sequence for a clone having homology to a phosphoglucomutase related protein (PGMRP) from Homo sapiens

KNOT. ID NO: 349 is the established cDNA sequence for a clone with homology to the mRNA of the human proteosome p40 subunit

KNOT. ID NO: 350 is the fixed cDNA sequence for P777P

KNOT. ID NO: 351 is the established cDNA sequence for P779P

KNOT. ID NO: 352 is the fixed cDNA sequence for P790P

KNOT. ID NO: 353 is the fixed cDNA sequence for P784P

KNOT. ID NO: 354 is the fixed cDNA sequence for P776P

KNOT. ID NO: 355 is the fixed cDNA sequence for P780P

KNOT. ID NO: 356 is the fixed cDNA sequence for P544S

KNOT. ID NO: 357 is the fixed cDNA sequence for P745S

KNOT. ID NO: 358 is the fixed cDNA sequence for P782P

KNOT. ID NO: 359 is the fixed cDNA sequence for P783P

KNOT. ID NO: 360 is the fixed cDNA sequence for the unknown 17984

KNOT. ID NO: 361 is the fixed cDNA sequence for P787P

KNOT. ID NO: 362 is the fixed cDNA sequence for P788P

KNOT. ID NO: 363 is the fixed cDNA sequence for unknown 17994

KNOT. ID NO: 364 is the fixed cDNA sequence for P781P

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KNOT. ID NO: 365 is the fixed cDNA sequence for P785P

KNOT. NOS. 366-375 are the fixed cDNA sequences for the splice variant B305D.

KNOT. ID NO: 376 is the predicted amino acid sequence encoded by the sequence

KNOT. ID NO .: 366.

KNOT. ID NO: 377 is the predicted amino acid sequence encoded by the sequence SEQ. ID NO .: 372.

KNOT. ID NO: 378 is the predicted amino acid sequence encoded by the sequence SEQ. ID NO .: 373.

KNOT. ID NO: 379 is the predicted amino acid sequence encoded by the sequence SEQ. ID NO .: 374.

KNOT. ID NO: 380 is the predicted amino acid sequence encoded by the sequence SEQ. ID NO .: 375.

KNOT. ID NO: 381 is the fixed cDNA sequence for B716P.

KNOT. ID NO: 382 is the fixed full length cDNA sequence for P711P.

KNOT. ID NO: 383 is the predicted amino acid sequence for P711P.

KNOT. ID NO: 384 is the cDNA sequence for P1000C.

KNOT. ID NO: 385 is the cDNA sequence for CGI-82.

KNOT. ID NO: 386 is the cDNA sequence for 23320.

KNOT. ID NO: 387 is the cDNA sequence for CGI-69.

KNOT. ID NO: 388 is the cDNA sequence for 2-L-iditol dehydrogenase.

KNOT. ID NO: 389 is the cDNA sequence for 23379.

KNOT. ID NO: 390 is the cDNA sequence for 23381.

KNOT. ID NO: 391 is the cDNA sequence for KIAA0122.

KNOT. ID NO: 392 is the cDNA sequence for 23399.

KNOT. ID NO: 393 is the cDNA sequence for the previously identified gene. KNOT. ID NO: 394 is the cDNA sequence for HCLBP.

KNOT. ID NO: 395 is the cDNA sequence for transglutaminase.

KNOT. ID NO: 396 is the cDNA sequence for the previously identified gene. KNOT. ID NO: 397 is the cDNA sequence for PAP.

KNOT. ID NO: 398 is the cDNA sequence for the Ets PDEF transcription factor. KNOT. ID NO: 399 is the cDNA sequence for hTGR.

KNOT. ID NO: 400 is the cDNA sequence for KIAA0295.

KNOT. ID NO: 401 is the cDNA sequence for 22545.

KNOT. ID NO: 402 is the cDNA sequence for 22547.

KNOT. ID NO: 403 is the cDNA sequence for 22548.

KNOT. ID NO: 404 is the cDNA sequence for 22550.

KNOT. ID NO: 405 is the cDNA sequence for 22551.

KNOT. ID NO: 406 is the cDNA sequence for 22552.

KNOT. ID NO: 407 is the cDNA sequence for 22553.

KNOT. ID NO: 408 is the cDNA sequence for 22558.

KNOT. ID NO: 409 is the cDNA sequence for 22562.

KNOT. ID NO: 410 is the cDNA sequence for 22565.

KNOT. ID NO: 411 is the cDNA sequence for 22567.

KNOT. ID NO: 412 is the cDNA sequence for 22568.

KNOT. ID NO: 413 is the cDNA sequence for 22570.

KNOT. ID NO: 414 is the cDNA sequence for 22571.

KNOT. ID NO: 415 is the cDNA sequence for 22572.

KNOT. ID NO: 416 is the cDNA sequence for 22573.

KNOT. ID NO: 417 is the cDNA sequence for 22573.

KNOT. ID NO: 418 is the cDNA sequence for 22575.

KNOT. ID NO: 419 is the cDNA sequence for 22580.

KNOT. ID NO: 420 is the cDNA sequence for 22581.

KNOT. ID NO: 421 is the cDNA sequence for 22582.

KNOT. ID NO: 422 is the cDNA sequence for 22583.

KNOT. ID NO: 423 is the cDNA sequence for 22584.

KNOT. ID NO: 424 is the cDNA sequence for 22585.

PL 200 772 B1

KNOT. ID NO: 425 is the cDNA sequence for 22586.

KNOT. ID NO: 426 is the cDNA sequence for 22587.

KNOT. ID NO: 427 is the cDNA sequence for 22588.

KNOT. ID NO: 428 is the cDNA sequence for 22589.

KNOT. ID NO: 429 is the cDNA sequence for 22590.

KNOT. ID NO: 430 is the cDNA sequence for 22591.

KNOT. ID NO: 431 is the cDNA sequence for 22592.

KNOT. ID NO: 432 is the cDNA sequence for 22593.

KNOT. ID NO: 433 is the cDNA sequence for 22594.

KNOT. ID NO: 434 is the cDNA sequence for 22595.

KNOT. ID NO: 435 is the cDNA sequence for 22596.

KNOT. ID NO: 436 is the cDNA sequence for 22847.

KNOT. ID NO: 437 is the cDNA sequence for 22848.

KNOT. ID NO: 438 is the cDNA sequence for 22849.

KNOT. ID NO: 439 is the cDNA sequence for 22851.

KNOT. ID NO: 440 is the cDNA sequence for 22852.

KNOT. ID NO: 441 is the cDNA sequence for 22853.

KNOT. ID NO: 442 is the cDNA sequence for 22854.

KNOT. ID NO: 443 is the cDNA sequence for 22855.

KNOT. ID NO: 444 is the cDNA sequence for 22856.

KNOT. ID NO: 445 is the cDNA sequence for 22857.

KNOT. ID NO: 446 is the cDNA sequence for 23601.

KNOT. ID NO: 447 is the cDNA sequence for 23602.

KNOT. ID NO: 448 is the cDNA sequence for 23605.

KNOT. ID NO: 449 is the cDN A sequence for 23606.

KNOT. ID NO: 450 is the cDNA sequence for 23612.

KNOT. ID NO: 451 is the cDNA sequence for 23614.

KNOT. ID NO: 452 is the cDNA sequence for 23618.

KNOT. ID NO: 453 is the cDNA sequence for 23622.

KNOT. ID NO: 454 is the cDNA sequence for folate hydrolase.

KNOT. ID NO: 455 is the cDNA sequence for the LIM protein.

SEQ ID NO: 456 is a cDNA sequence for a known gene.

SEQ ID NO: 457 is the cDNA sequence for a known gene.

KNOT. ID NO: 458 is the cDNA sequence for the previously identified gene.

KNOT. ID NO: 459 is the cDNA sequence for 23045.

KNOT. ID NO: 460 is the cDNA sequence for 23032.

KNOT. ID NO: 461 is the cDNA sequence for 23054.

KNOT. NOS. 462-467 are cDNA sequences for known genes.

KNOT. ID NOs: 468-471 are the cDNA sequences for P710P.

KNOT. ID NO: 472 is the cDN A sequence for P1001C.

Detailed Description of the Invention

As noted above, the present invention relates generally to compositions and methods for the treatment and diagnosis of cancer, such as prostate cancer. Compositions described herein may include prostate cancer polypeptides, polynucleotides encoding such polypeptides, binding agents such as antibodies, antigen presenting cells (APCs), and / or immune system cells (e.g., T cells). The polypeptides of the present invention generally contain at least a portion (such as an immunogenic portion) of a prostate cancer protein or variant thereof. A "prostate tumor protein" is a protein that is expressed in prostate tumor cells at a high level that is at least twice, preferably at least five times, the level of normal tissue expression as determined using a representative assay presented herein. Certain prostate cancer proteins are cancer proteins that react detectably (in an immunoassay such as ELISA or Western blot) with the immune serum of a patient afflicted with prostate cancer. The polynucleotides of the invention generally contain DNA or RNA sequences that encode all or part of such a polypeptide or are complementary to such a sequence. Antibodies are generally proteins of the immune system, or antigen-binding fragments thereof, and are capable of binding a polypeptide as described above. Cells

Antigen-presenting cells include dendritic cells, macrophages, monocytes, fibroblasts, and B cells that express a polypeptide as described above. T cells that can be used in such compositions are generally T cells that are specific for the polypeptide described above.

The present invention is based on the discovery of human prostate cancer proteins. Polynucleotide sequences encoding certain tumor proteins, or portions thereof, are set forth in SEQ. ID NO .: 1-111, 115-171, 173-175, 177, 179-305, 307-315, 326, 328, 330, 332-335, 340-375, 381.382 or 384-472. Polypeptide sequences containing at least a portion of the tumor protein are set forth in SEQ. ID NO .: 112-114, 172, 176, 178, 327, 329, 331, 336-339, 376-380, and 383.

Polynucleotides for prostate cancer protein

Any polynucleotide that encodes a prostate tumor protein, or a portion or other variant thereof, as described herein is included in the present invention. It is preferred that nucleotides contain at least 15 contiguous nucleotides, preferably at least 30 contiguous nucleotides, and more preferably at least 45 contiguous nucleotides, which code for a portion of a prostate tumor protein. Polynucleotides complementary to any such sequence are also included in the present invention. Polynucleotides can be single-stranded (encoding or antisense) or double-stranded, and can be DNA (genomic, cDNA, or synthetic) or RNA molecules. RNA molecules include hnRNA molecules that contain introns and correspond to the DNA molecule one-to-one, and mRNA molecules that do not contain introns. Additional coding or non-coding sequences may or may not be present within the polynucleotide of the present invention, and the polynucleotide may or may not be linked to other molecules and / or adjunct materials.

The polynucleotides may contain the native sequence (ie, the endogenous sequence that codes for a prostate cancer protein, or a portion thereof), or may contain a variant of such sequence. Polynucleotide variants may contain one or more substitutions, additions, deletions and insertions such that the immunogenicity of the encoded protein is not reduced relative to the native tumor protein. The effect on the immunogenicity of the encoded polypeptide can generally be tested as described herein. Preferably, the variants exhibit at least 70% identity, preferably at least about 80% identity, and most preferably at least about 90% identity, with the polynucleotide sequence that encodes the native prostate cancer protein or a portion thereof.

Two polypeptides or sequences are said to be "identical" if the nucleotide or amino acid sequence of the two sequences is the same when aligned so as to be maximally correspondent, as described below. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. The term "comparison window" as used herein means a segment of about 20 consecutive positions, typically 30 to about 75, 40 to about 50, in which a sequence can be compared to a reference sequence with the same number of consecutive positions after the two sequences have been optimally aligned.

Optimal sequence alignment for comparison can be performed using the Mega 1 ign program from the Lasergene software suite (DNAST AR, Inc., Madjeston, WI), using standard parameters. This program uses several comparison schemes described in the following references: Dayhoff, MO (1978) A model of evolutionary change in proteins - Matrices for detecting distant relationships. In Dayhoff, MO (ed.) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington DC Vol. 5, Suppl. 3, pp. 345-358; Hein J. (1990) Unified Approachto Alignment and Phylogenes pp. 626-645 Methods in Enzymology vol. 183, Academic Press, Inc., San Diego, C. A; Higgins, DG and Sharp, PM (1989) CABIOS 5: 151-153; Myers, EW and Muller W. (1988) CABIOS 4: 11-17; Robinson, ED (1971) Comb. Theor 11: 105; Santou, N. Nes, M. (1987) Mol. Biol. Evol. 4: 406-425; Sneath, PHA and Sokal, RR (1973) Numerical Taxonomy - the Principles and Practice of Numerical Taxonomy, Freeman Press, San Francisco, C. A; Wilbur, WJ and Lipman, DJ (1983) Proc. Nad. Acad, Sci. USA 80: 726730.

Preferably, the "percent sequence identity" is determined by comparing two optimally aligned sequences in a comparison window of at least 20 positions, wherein a portion of the polynucleotide or polypeptide sequence in the comparison window may contain insertions or deletions (i.e. gaps) of 20 percent or less, typically 5 to 15 percent, 10 to 12 percent, compared to reference sequences (which contain no insertions or deletions) for an optimal alignment of the two sequences. The percentage is calculated by finding the number of positions where identical nucleic acid bases or amino acid residues exist in both sequences to obtain the number of matching positions by dividing the number of matching positions by the total number of positions in the reference sequence (i.e., window size) and multiplying the result by 100 to obtain the percent sequence identity.

Variants may also or alternatively be substantially homologous to a native gene or a portion or sequence complement thereof. Such polynucleotide variants are capable of hybridizing under moderately stringent conditions to a naturally occurring DNA sequence encoding a native prostate tumor protein (or a complementary sequence). Suitable moderately stringent conditions include a pre-rinse with 5X SSC, 0.5% SDS, 1.0mM EDTA (pH 8.0); hybridization overnight at 50 ° C-65 ° C. 5 X SSC; followed by washing twice at 65 ° C for 20 minutes with each of 2X, 0.5X and 0.2X SSC containing 0.1% SDS.

It will be appreciated by those skilled in the art that as a result of the degeneracy of the genetic code there may be multiple nucleotide sequences that encode a polypeptide described herein. Some of these polynucleotides share minimal homology with the nucleotide sequence of any native gene. Moreover, polynucleotides that exhibit differences due to differences in codon usage are particularly contemplated in the present invention. In addition, alleles of the genes containing the polynucleotide sequences provided herein are within the scope of the present invention. Alleles are endogenous genes that are altered as a result of one or more mutations, such as nucleotide deletions, insertions, and / or substitutions. The resulting mRNA and protein may or may not have altered structure or function. Alleles can be identified using standard techniques (such as hybridization, amplification and / or sequence database comparison).

Polynucleotides can be produced using a variety of techniques. For example, a polynucleotide can be identified as described in more detail below by screening cDNA microplates for tumor associated expression (i.e., an expression that is at least five times greater in a prostate tumor than in normal tissue as determined using a representative assay provided herein). ). Such searches can be performed using Synetani microplates (Palo Alto, CA) according to the manufacturer's instructions (and essentially as described by Schen et al., Proc. Natl. Acad Sci USA 93: 10614-10619, 1996 and Heller et al. , Proc. Natl. Acad Sci. USA 94: 2150-2155,1997). Alternatively, the polypeptides can be amplified from cDNA prepared from cells expressing the proteins described herein, such as prostate tumor cells. Such polynucleotides can be amplified by the polymerase chain reaction (PCR). In this approach, sequence-specific primers can be designed based on the sequences provided, and can be purchased or synthesized.

The amplified portion can be used to isolate a full-length gene from an appropriate library (e.g., a prostate tumor cDNA library) using well-known techniques. Among these techniques, the library (cDNA or genomic) is screened using one or more polynucleotide probes or primers suitable for amplification. The library is preferably sized to include larger molecules. Libraries subjected to random DNA synthesis may also be beneficial for identifying the 5 'and upstream regions of genes. Genomic libraries are preferred for obtaining introns and sequences extending to the 5 'side.

For hybridization techniques, partial sequences can be labeled (e.g., by nick-translation or end-labeling). ³²P) using well-known techniques. Bacterial or bacteriophage libraries are then screened by hybridizing filters containing denatured bacterial colonies (or a patch containing phage plaques) with a labeled probe (see Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratories, Cold Spring Harbor, NY, 1989) ). Hybridizing colonies or plaques are selected and expanded, and DNA is isolated for further analysis. CDNA clones can be analyzed to determine numerous additional sequences by, for example, PCR using a primer from a partial sequence and a primer from a vector. Restriction maps and partial sequences can be generated to identify one or more overlapping clones. The complete sequence can then be determined using standard techniques, which may include the generation of a series of deletion clones. The resulting overlapping sequences can then be assembled into one contiguous sequence. The full-length cDNA molecule can then be made by ligating the appropriate fragments using well-known techniques.

Alternatively, numerous amplification techniques exist to obtain a full-length coding sequence from a partial cDNA sequence. Among such techniques, amplification is performed with gene16

PL 200 772 B1 by PCR. Any of a wide variety of commercial kits can be used to perform the amplification step. Primers can be designed using, for example, software known in the art. Primers are preferably 22-30 nucleotides in length, have a GC content of at least 65%, and anneal to the target sequence at a temperature of about 68 ° C to 72 ° C. The duplicated region can be sequenced as described above and overlapping sequences assembled into a contiguous sequence.

One such amplification technique is reverse PCR (see Triglia et al., Nuc. Acids Res. 16: 8186, 1988), which uses restriction enzymes to generate a fragment in a known region of the gene. This fragment is then rounded over by intracellular ligation and used as a template for PCR with various primers derived from a known region. In a similar approach, sequences adjacent to a partial sequence can be obtained by primer amplification against a linker and primer sequence specific for a known region. The amplified sequences are usually subjected to a second round of amplification with the same linker primer and a second primer specific to the known region. Variants of these procedures which use two primers which initiate extension in opposite directions from the known sequence are described in WO 96/38591. Another such technique is known as "rapid amplification of the cDNA or RACE ends. The technique involves the use of an inner primer and an outer primer that hybridize to the poly A region or vector sequence to identify sequences that are 5 'and 3' of a known sequence. Additional techniques include catch PCR (Lagerstrom et al., PCR Methods Applic. 1: 111-19, 1991) and rolling PCR (Parker et al., Nucl. Acids. Res. 19: 3055-60, 1991). Other amplification methods can also be used to obtain full-length cDNA sequences.

In some cases, it is possible to obtain full-length cDNA sequences by analyzing the sequences provided in an expressed sequence tag (EST) database, such as that available from GenBank. Overlapping EST searches can generally be performed using well-known programs (e.g., NCBI BLAST searches), and such EST sequences can be used to generate full-length contiguous sequences.

Certain nucleotide sequences of cDNA molecules encoding at least a portion of a prostate cancer protein are set forth in SEQ. ID NO .: 1-111, 115-171, 173-175, 177, 179, 305, 307-315, 326, 328, 330, 332-335, 340-375, 381, 382 or 384-472. The isolation of these polynucleotides is shown below. Each of these prostate cancer proteins was overproduced in prostate cancer tissues.

Polynucleotide variants can generally be made by any of the methods known in the art, including chemical synthesis, for example solid phase phosphoramidite chemical synthesis. Modifications to the polynucleotide sequence can also be made using standard mutagenesis techniques, such as site-specific polynucleotide-directed metagenesis (see Adelman et al, DNA 2: 183, 1983). Alternatively, RNA molecules can be produced by in vivo or in vitro transcription of DNA sequences encoding a prostate cancer protein or portion thereof, provided that the DNA is incorporated into the vector with an appropriate RNA polymerase promoter (such as T7 or SP6). Certain parts can be used to generate an encoded peptide as described herein. Additionally, or alternatively, a portion may be administered to a patient such that the encoded polypeptide is produced in vivo (e.g. by transfecting antigen presenting cells such as dendritic cells with a cDNA construct encoding a prostate tumor polypeptide and administering the transfected cells to the patient).

A portion of the sequence complementary to the coding sequence (i.e., antisense polynucleotide) may also be used as a probe or to modulate gene expression. CDNA constructs that can be transcribed into antisense RNA can also be introduced into tissue cells to facilitate the production of antisense RNA. Antisense polynucleotides can be used as described herein to inhibit tumor protein expression. Antisense technology can be used to control gene expression by creating a triple helix structure, which increases the ability of the double-stranded helix to finally open to binding polymerases, transcription factors, or regulatory molecules (see Gee et al., In Huber and Carr, Molecular and Immunologie Approaches, Futura Publishing Co. (Mt. Kisco, NY; 1994). Alternatively, the antisense molecule may be designed to hybridize to a control region (e.g., a promoter, enhancer, or transcription initiation site) and block the gene or block translation by inhibiting the binding of the transcript to the ribosomes.

PL 200 772 B1

Part of the coding sequence or the complementary sequence may also be designed as a probe or primer to detect gene expression. Probes may be labeled with a variety of reporter groups such as radioisotopes or enzymes and are at least 10 nucleotides in length, preferably at least 20 nucleotides in length, even more preferably at least 30 nucleotides in length. As noted above, the primers are preferably 22-30 nucleotides in length.

Any polynucleotide may further be modified to increase in vivo stability. Possible modifications include, but are not limited to, adding flanking sequences to the 5 'and 3' ends; the use of phosphorothioate or 2'O-methyl instead of phosphodiesterase linkages in the carbon skeleton; and / or the inclusion of atypical bases such as inosine, keosin and bututosin as well as -acetyl, -methyl, -thio and other modified forms of adenine, cytidine, guanine, thymine and uridine.

The nucleotide sequences described herein can be joined to a variety of other nucleotide sequences using established recombinant DNA techniques. For example, a polynucleotide can be cloned into a variety of cloning vectors, including plasmids, phagemids, lambda phage derivatives, and cosmids. Vectors of particular interest include expression vectors, replication vectors, probe production vectors, and sequencing vectors. In general, vectors will contain an origin of replication functional in at least one organism, a convenient restriction enzyme recognition site, and one or more sequence markers. Other elements will depend on the desired application and will not be apparent to those skilled in the art.

In some embodiments, the polynucleotides can be designed to allow entry into and expression within a mammalian cell. One skilled in the art will appreciate that there are many ways to obtain expression of a polynucleotide in a target cell, and any suitable method may be used. For example, the polynucleotide may be inserted into a viral vector such as, but not limited to, adenovirus, adeno-associated virus, retrovirus, vaccinia virus, or other poxviruses (e.g., avian pox). Techniques for inserting DNA into such vectors are well known to those of skill in the art. Retroviral vectors may additionally carry or insert a gene for a secretory marker (to assist in the identification or selection of transduced cells) and / or a targeting molecule such as a gene that encodes a ligand for a receptor on a specific target cell to make the vector target specific. Targeting can also be achieved using an antibody by methods known to those skilled in the art.

Other compositions for pharmaceutical purposes include colloidal dispersion systems, such as macromolecular complexes, nanocapsules, microspheres, spheres, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. A preferred colloidal system for use as a transport molecule in vitro and in vivo is a liposome (ie an artificial membrane vesicle). The preparation and use of such systems is well known in the art.

Prostate cancer polypeptides

In the context of the present invention, the polypeptides may comprise at least the immunogenic portion of a prostate cancer protein or a variant thereof as described herein. As noted above, a "prostate tumor protein" is a protein that is expressed by prostate tumor cells. Proteins that are prostate cancer proteins also react detectably in immunoassays (such as ELISAs) with the immune sera from prostate cancer patients. Polypeptides as described herein may be of any length. Additional sequences derived from native protein and / or heterologous sequences may be present and such sequences may or may not have additional immunogenic or antigenic properties.

The term "immunogenic" portion as used herein is that portion of a protein that is recognized (i.e. bound specifically) by the surface antigen receptor of B cells and / or T cells. Such immunogenic portions generally contain at least 5 amino acid residues, more preferably at least 10, even more preferably at least 20 amino acid residues in a prostate cancer protein or variant thereof. Certain preferred immunogenic fragments include peptides in which the N-terminal leader sequence and the transmembrane domain have been removed. Other preferred immunogenic fragments may contain small N- and C-terminal deletions (e.g. 1-30 amino acids, preferably 5-15 amino acids) relative to the mature protein.

Immunogenic fragments can generally be identified using well-known techniques, such as those listed in Paul, Fundamental Immunology, 3rd ed., 243-247 (Raven Press, 1993) and references cited therein. Such techniques include screening polypeptides for the ability to react with antigen-specific antibodies, sera

Antisera or antibodies are "antigen-specific" if they bind specifically to an antigen (i.e., react with a protein in an ELISA or other immunoassay and do not react with a protein in an ELISA or other immunoassay) as used herein. react detectably with unrelated proteins). Such antisera and antibodies can be produced as described herein using well known techniques. An immunogenic fragment of a native prostate cancer protein is a fragment that reacts with such antiserum and or T cells at a level that is not significantly less than the reactivity of a full-length polypeptide. Such searches may be performed using methods well known to those skilled in the art such as those described in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988. For example, the polypeptide may be immobilized on such a medium and brought into contact with the patient's serum to allow serum antibodies to bind to the immobilized polypeptide. Unbound serum can then be removed and bound antibodies detected using, for example, labeled protein A¹²⁵AND.

As noted above, the composition may include a native prostate tumor protein variant. The term "variant" of a polypeptide as used herein means a polypeptide that differs from the native prostate cancer protein in one or more substitutions, deletions and additions and / or insertions such that the immunogenicity of the polypeptide is not substantially reduced. In other words, the ability of the variant to react with the antigen-specific antiserum may be enhanced or unchanged relative to the native protein, or it may be reduced by less than 50%, preferably less than 20%, relative to the native protein. Such variants can generally be identified by modifying one of the above polypeptide sequences and determining the reactivity of the modified polypeptide with the antigen-specific antibodies or antisera described herein.

Preferred variants include those in which the N-terminal leader sequence and the transmembrane domain have been removed. Other preferred variants include variants in which small stretches (e.g. 1-30 amino acids, preferably 5-15 amino acids have been removed from the mature protein, from the N- and / or C-terminus). Preferably, the polypeptide variants share about 70%, more preferably at least about 90%, and most preferably at least about 95% identity (as defined above) to the identified polypeptides.

Preferably, the variant contains conservative substitutions. A "conservative substitution" is one in which one amino acid is substituted with another amino acid which has similar properties such that one skilled in the art of peptide chemistry would expect the secondary structure and hydropathic nature of the polypeptide to remain substantially unchanged. Amino acid substitutions can generally be made on the basis of the similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and / or the amphipathic nature of the residues. For example, negatively charged amino acids include aspartic acid and glutamic acid, positively charged amino acids include lysine and arginine, and amino acids with uncharged polar head groups with similar hydrophilicity include leucine, isoleucine and valine, glycine and alanine, asparagine, and glutamine, serine, phenylalanine and tyrosine. Other groups of amino acids that may represent conservative changes include: (1) ala, pro, gly, glu, asp, gin, asn, ser, thr; (2) cys, cheese, tyr, thr; (3) val, ile, leu, met, ala, phe; (4) lys, arg, his; and (5) phe, tyr, trp, his. A variant may also or alternatively contain non-conservative changes. In a typical embodiment, the variant polypeptides differ from the native sequence by a substitution, deletion, or addition of five or fewer amino acids. Variants may also (or alternatively) be modified, for example by removing or adding amino acids that have minimal effect on the immunogenicity, secondary structure, and hydropathic nature of the polypeptide. As noted above, the polypeptides may contain a signal (or leader) sequence at the N-terminus of the protein that cotranslatively or post-translational direct transport of the protein. The polypeptide may also be linked to a linker or other sequence to facilitate synthesis, purification, and identification of the polypeptide (e.g., poly-His), or to enhance binding of the polypeptide to a solid support. For example, a polypeptide can be fused to the Fc region of an immunoglobulin.

Polypeptides can be produced using any of the well-known techniques. Recombinant polypeptides encoded by DNA sequences as described above can be readily prepared from DNA sequences using any of a variety of expression vectors known to those skilled in the art. Expression can be achieved in any suitable host cell that has been transformed or transferred with an expression vector containing a DNA molecule that encodes a recombinant polypeptide. Suitable host cells include prokaryotes, yeast, and eukaryotic cells. Preferably the host cells used are E. coli, yeast or mammalian cell lines such as COS and CHO. The supernatant from suitable host / vector systems that secrete the recombinant protein or polypeptide into the culture medium may first be concentrated using commercially available filters. After concentration, the concentrate can be applied to a suitable purification matrix, such as an affinity matrix or ion exchange resins. Finally, one or more reversed-phase HPLC steps may be used to further purify the recombinant polypeptide.

Portions and other variants of less than about 2,100 amino acids and generally less than about 50 amino acids can also be made synthetically using techniques well known to those skilled in the art, for example, such polypeptides can be synthesized using any of the commercially available solid phase techniques, such as a synthetic method. in a Merrifield solid phase, where amino acids are added sequentially to the growing amino acid chain. See Merrifield, J. Am. Chem. Soc. 85: 2149-2146, 1963. Automatic polypeptide synthesis devices are commercially available from vendors such as Perkin Elmer / Applied BioSystems Divsion (Foster City, CA) and may be operated according to the manufacturers' instructions.

In some embodiments, the polypeptide can be a fusion protein that includes a plurality of polypeptides described herein, or that includes at least one polypeptide as described herein and an unrelated sequence, such as a known cancer protein. For example, the fusion partner may participate in the delivery of T helper epitopes (immunological fusion partner), preferably T helper epitopes recognized in humans, or may participate in the expression of the protein (expression enhancer) at levels higher than the native recombinant protein. Other fusion partners may be chosen to increase the solubility of the protein or to allow the protein to reach appropriate intracellular compartments. Still other fusion partners include affinity tags that facilitate protein purification.

Protein fusions can generally be made using standard techniques, including chemical linkage. Preferably, the fusion protein is expressed as a recombinant protein, allowing the production of increased levels relative to the non-fused protein in the expression system. Briefly, DNA sequences encoding polypeptide components can be assembled separately and ligated into an appropriate expression vector. The 3 'end of the DNA sequence encoding one of the polypeptide components is ligated with or without a polypeptide linker to the 5' end of the DNA sequence encoding the second polypeptide component such that the reading frames of the sequence are in phase. This allows translation into a single fusion protein that retains the biological activity of both constituent polypeptides.

The peptide linker sequence may be used to separate the first and second polypeptide components by a distance sufficient to ensure that each polypeptide folds into its secondary and tertiary structure. Such a peptide linker sequence is inserted into the fusion protein using standard techniques well known in the art. Suitable linker peptide sequences can be selected taking into account the following factors: (1) their ability to adopt a flexible extended conformation; (2) their inability to adopt a secondary structure that would interact with functional epitopes of the first and second polypeptides; and (3) no hydrophobic or charged residues that would react with the polypeptide functional epitopes. Preferred polypeptide linker sequences include Gly, Asn, and Ser residues. Other nearly neutral amino acids such as Thr and Ala can also be used in the linker sequence. Amino acid sequences that can typically be used as linkers include those disclosed in Maratea et al, Gene 40: 39-46, 1985; Murphy et al, Proc. Natl. Acad. Sci USA 83: 8258-8262,186; U.S. Patent No. 4,935,233 and U.S. Patent No. 4,751,180. The linker sequence can typically be from 1 to about 50 amino acids in length. Linker sequences are not required when the first and second polypeptides have the necessary N-terminal amino acid regions that can be used to separate the functional domains and prevent steric hindrance.

The ligated DNA sequences are operably linked to appropriate and transcriptional or translational regulatory elements. Regulatory elements responsible for expression of DNA are located only 5 'of the DNA sequence encoding the first polypeptides. Likewise, stop codons required to complete translation and transcription termination signals are only present at the 3 'end of the DNA sequence encoding the second polypeptide.

PL 200 772 B1

Protein fusions are also provided that contain a polypeptide of the present invention together with an unrelated immunogenic protein. Preferably, the immunogenic protein is capable of eliciting a boost response. Examples of such proteins include tetanus, tuberculosis and hepatitis proteins (see, e.g., Stoute et al. New Engl. J. Med., 336: 8691,1997).

In preferred embodiments, the immune fusion partner is derived from protein D, a gram-negative surface protein of Haemophilus influenza B (WO 91/18926). Preferably, the protein D derivative comprises the initial one-third of the protein (e.g., the initial N-terminal 100-110 amino acids) and the protein D derivative may be lipid-attached. In some preferred embodiments, the first 109 residues of the fusion partner lipoprotein D are attached to the N terminus to provide the polypeptide with an additional exogenous T-cell epitope and to increase the level of expression in E. coli (thus acting as an expression enhancer). The lipid tail ensures optimal antigen presentation to the antigen presenting cells. Other fusion partners include the non-structural protein from the influenza virus, NS1 (haemagglutinin). Typically 81 N-terminal amino acids are used, although various fragments which contain the T helper epitopes may be used.

In another embodiment, the immune fusion partner is the protein known as LYTA or a portion thereof (preferably a C-terminal portion). LYTA is derived from Streptococcus pneumoniae, which synthesizes the N-acetyl-L-alanine amidase known as LYTA amidase (encoded by the LyłA gene; Gene 43: 265-292, 1986). LYTA is an autolysin that specifically breaks down certain bonds in the peptidoglycan backbone. The C-terminal domain of the LYTA protein is responsible for the affinity for choline and for some choline analogs such as DEAE. This ability was used to develop E. coli C-LYTA expressing plasmids useful for the expression of fusion proteins. Purification of hybrid proteins containing the amino-terminal LYTA-C fragment has been described (see Biotechnology 10: 795-798, 1992). In a preferred embodiment, the repeat portion may be inserted into the fusion protein. A repeat portion is located in the C-terminal region starting at residue 178. A particularly preferred repeat portion is comprised of residues 188-305.

Generally, the polypeptides (including fusion proteins) and polynucleotides described herein are isolated. An "isolated" polypeptide or polynucleotide is one that is transferred from its normal environment. For example, a naturally occurring protein is isolated if it is separated from some or all of its coexisting material in the natural system. It is preferred that such polypeptides are about 90% pure, more preferably at least 95% pure, and most preferably at least 99% pure. A polynucleotide is considered to be isolated if, for example, it is cloned in a vector that is not part of its natural surroundings.

Binding factors

The present invention further provides agents, such as antibodies, and antigen-binding fragments thereof, that specifically bind to a prostate tumor protein. As used herein, an antibody or antigen-binding fragment thereof is said to "specifically bind" to a prostate cancer protein if it reacts at a detectable level (e.g., in an ELISA assay) with the prostate cancer protein and does not detectably react with unrelated proteins in the like. conditions. The term "bond" as used herein means a non-covalent link between two distinct molecules such that a complex is formed. The ability to bind can be assessed, for example, by determining a binding constant for complex formation. The binding constant is the value obtained when the concentration of the complex is divided by the product of the component concentrations. It is generally said in the context of the present invention that two components are linked when the binding constant for complex formation exceeds about 10³ l / mol. The binding constant can be determined using methods known in the art.

Binding agents may furthermore be capable of distinguishing between cancer-free and cancer-like patients with prostate cancer using the representative assays provided herein. In other words, antibodies or other binding agents that bind to a prostate tumor protein will produce a signal indicative of cancer in at least 20% of patients with the disease and will give a negative signal indicative of no disease in at least 90% of tumor-free subjects. To determine if a binding agent meets these requirements, biological samples (e.g., blood, serum, urine, and / or tumor biopsies) from patients with and without tumor (as determined by standard clinical tests) may be tested as described herein for the presence of polypeptides that bind to the binding agent. It will be clear that a statistically significant number of samples with and without disease should be tested. Each binding agent should meet the above criteria,

However, those skilled in the art will appreciate that binding agents can be used in combination to increase sensitivity.

Any factor that meets these requirements can be the binding factor. For example, the binding agent can be a ribosome, with or without a peptide component, an RNA molecule, or a polypeptide. In a preferred embodiment, the binding agent is an antibody or an antigen-binding fragment thereof. Antibodies can be prepared by any of a variety of techniques known to those of skill in the art. See, e.g., Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988. Generally, the antibodies can be produced by a cell culture technique, including the production of monoclonal antibodies as described herein, or by the transfection of the antibody genes into appropriate bacterial or mammalian host cells to allow the production of recombinant antibodies. In one technique, an immunogen-containing polypeptide is initially injected into any of a wide variety of mammals (e.g., mice, rats, rabbits, sheep, or goats). In this step, the polypeptides of the invention can serve as an immunogen without modification. Alternatively, especially for relatively short polypeptides, a greater immune response may be elicited if the polypeptide is linked to a carrier protein such as bovine serum albumin or keyhole limpet hemocyanin. Immunogen is injected into the host, preferably according to a predetermined schedule that includes one or more booster immunizations, and the animals are periodically bled. Polyclonal antibodies specific for the polypeptide can then be purified from the serum by, for example, affinity chromatography using the polypeptide attached to a solid support.

Monoclonal antibodies specific for an antigenic polypeptide of interest can be prepared, for example, using the technique of Kohler and Milstein, Eur. J. Immunol. 6: 511-519, 1976, and its improvements. Briefly, this method involves generating immortalized cell lines capable of producing antibodies having the desired specificity (ie, reactivity with the polypeptide of interest). Such cell lines can be generated, for example, from spleen cells obtained from an immunized animal as described above. The spleen cells are then immortalized, for example, by fusion with a myeloma cell fusion partner, preferably one that is syngeneic with the immunized animal. A variety of fusion techniques can be used. For example, spleen cells and myeloma cells can be mixed with a non-ionic detergent for several minutes and then plated at low density onto a selection medium that supports the growth of hybrid cells but not myeloma cells. A preferred selection technique uses HAT (hypoxantbine, aminopterin, thymidine) selection. After a sufficient period of time, usually around 1 to 2 weeks, the hybrid cells are observed. Single colonies are sequenced and their culture supernatants tested for binding activity against the polypeptide. Hybridomas having high reactivity and specificity are preferred.

Monoclonal antibodies can be isolated from the supernatants of growing hybridoma colonies. In addition, various techniques can be used to increase productivity, such as injecting the hybridoma cell line into the peritoneal cavity of a suitable vertebrate host, such as a mouse. The monoclonal antibodies can then be harvested from the ascites fluid or blood. Contaminants can be removed from the antibodies using conventional techniques, such as chromatography, gel filtration, precipitation, and extraction. The polypeptides of the invention can be used in a purification process, for example an affinity chromatography step.

In some embodiments, it may be advantageous to use antigen-binding antibody fragments. Such fragments include Fab fragments that can be produced using standard techniques. Briefly, immunoglobulins can be purified from rabbit serum by affinity chromatography on a protein A column (Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988) and digested with papain to obtain Fab and Fc fragments. Fab and Fc fragments can be separated by affinity chromatography on a protein A matrix.

The monoclonal antibodies of the present invention can be combined with one or more therapeutic agents. Suitable factors in this regard include radioactive isotopes, differential inducers, drugs, toxins, and derivatives thereof. Preferred radioactive isotopes include^{ą 123}AND, ¹²⁵AND,¹³¹AND, ¹⁸⁶Re, ¹⁸⁸Re, ²¹¹Μ ^{and 212}Bl · ^K.orz^yst^btake it^and methotrexate, anate^gi pyrimidines and purines. Preferred differential inducers include phorbolic esters and butyric acid. Preferred toxins include ricin, abrin, cholera diphtheria toxin, gelonin, Pseudomonas exotoxin, Shigella toxin, and pokeweed antiviral protein.

PL 200 772 B1

The therapeutic agent may be linked (e.g., covalently linked) to a suitable monoclonal antibody either directly or indirectly (e.g., via a linker group). A direct reaction between the agent and the antibody is possible if each has a substituent capable of reacting with each other. For example, a nucleophilic group such as an amino or sulfhydryl group on one of them may be capable of reacting with a carbonyl-containing group, such as an anhydride or acid halide, or with an alkyl group having a good leaving group (e.g., halide) on the other.

Alternatively, it may be desirable to link the therapeutic agent and the antibody via a linker group. A linker group may function as a spacer to spatially separate the antibody from an agent to avoid immersing binding capacity. A linker group can also serve to increase the chemical reactivity of a substituent on an agent or an antibody and thus increase the linkage efficiency. Increasing the chemical reactivity may facilitate the use of the agent or functional groups of the factors, which would not otherwise be possible.

It will be apparent to one skilled in the art that a variety of bifunctional or polyfunctional reagents, both homo- and hetero-functional, can be used as linking groups. (such as described in the Pierce Chemical Co., Rockdlad, IL catalog). Linking can be performed, for example, through amino, carboxyl, silphhydryl groups, or oxidized carbohydrate moieties. There are a number of publications describing such a methodology, e.g., US Patent No. 4,671,958 to Rodwell et al.

Where the therapeutic agent is more potent than the antigenic portion of the immunoconjugates of the present invention, it may be desirable to use a linker group that is cleaved with time or after entry into the cell. A variety of cleavable linking groups have been described. Mechanisms of intracellular release of an agent from these linking groups include cleavage by reduction of disulfide bridges (e.g. U.S. Patent No. 4,489,710 to Spitler), exposure of photolabile bonds (e.g., U.S. Patent No. 4,625,014 to Senter et al.), by hydrolysis of derivatives in amino acid side chains (e.g., U.S. Patent No. 4,638,045 to Kohn et al.) by hydrolysis mediated by complement from serum, e.g., US Patent No. 4,671,958 to Rodwell et al.) and acid catalyzed hydrolysis, e.g., US Patent No. 4,569,789 to Blattler et al.).

It may be desirable to combine more than one agent with the antibody. In one embodiment, multiple molecules of the agent can be linked to a single antibody molecule. In another embodiment, more than one type of agent may be linked to a single antibody. Regardless of the particular embodiment, immunoconjugates with more than one agent can be prepared in a variety of ways. For example, more than one agent can be bound to the antibody molecule, or linkers that provide multiple sites for attachment can be used. Alternatively, a carrier can be used.

The carrier can carry the agents in a number of ways, including covalent bond formation either directly or through a linking group. Suitable carriers include proteins such as albumin (e.g., US Patent No. 4,507,234 to Kato et al.), Peptides, and polysaccharides such as aminodextran (e.g., US Patent No. 4,699,784 to Shih et al.). The carrier may also carry the agent via a non-covalent bond or encapsulated as in the case of lipid vesicles (e.g., US Patent Nos. 4,429,008 and 4,873,088. Carriers specific to radionuclide-containing agents include radiohalogenated small molecules and chelating compounds. For example, US Patent No. 4,735. , 792 discloses representative radiohalogenated small molecules and their synthesis. Radionuclide chelates can be formed from chelating compounds, which include those containing nitrogen and sulfur atoms as donor atoms for binding the metal or metal oxide to the radionuclide. For example, U.S. Patent No. 4,673,562 to Davison et al. discloses representative chelating compounds and their synthesis.

A variety of routes for administering antibodies and immunoconjugates can be used. Typically, administration will be intravenous, intramuscular, subcutaneous or at the site of an excised tumor. It will be appreciated that the precise dose of the antibody / immunoconjugate will vary depending on the antibody used, the antigen density in the tumor, and the rate at which the antibodies disappear.

T cells

The immunotherapeutic compositions may also or alternatively contain prostate tumor protein specific T cells. Such cells can generally be produced in vitro or ex vivo using standard procedures. For example, T cells can be isolated from the bone marrow, peripheral blood, or a bone marrow or peripheral blood fraction of a patient using a commercially available separation system, such as the CEPRA TETM System, available from CellPL 200 772 B1.

Pro Inc., Bothell WA (see also US Patent No. 5,240,856; US Patent No. 5,215,926; WO 89/06280; WO 91/16116 and WO 92/07243). Alternatively, the T cells may be derived from related or unrelated humans, non-human mammals, lineages, or tissue cultures.

T cells can be stimulated with a prostate cancer polypeptide, a polynucleotide encoding a prostate cancer polypeptide, and / or an antigen presenting cell (APC) that expresses such a polypeptide. Such stimulations are performed under conditions, and for a sufficient time, to allow the production of T cells which are specific for the polypeptide. Preferably, the prostate cancer polypeptide or polynucleotide is present within a delivery vehicle such as microspheres to generate specific T cells.

T cells are considered to be specific for prostate cancer polypeptides if the T cells kill target cells coated with the polypeptide or expressing a gene encoding the polypeptide. T cell specificity can be assessed using a variety of standard techniques. For example, in a chromium release assay or a proliferation assay, the stimulation index for more than a twofold increase in lysis and / or proliferation compared to the negative controls indicates the specificity of T cells. Such assays can be performed, for example, as described in Chen et al, Cancer Res. 54: 1065-1070, 1994. Alternatively, detection of T cell proliferation can be performed using a variety of known techniques. For example, T cell proliferation can be detected by measuring an increase in the rate of DNA synthesis (e.g., by plus labeling a T culture with tritiated thymidine and measuring the amount of tritiated thymidine incorporated into DNA). Contact with a prostate tumor polypeptide (100ng / ml - 100gg / ml, preferably 200ng / ml - 25gg / ml) for 3-7 days should lead to at least a twofold increase in T cell proliferation. Contact as described above for 2-7 days. 3 hours should result in T cell activation as measured by a standard cytokine assay in which a two-fold increase in cytokine release (e.g. TNF or IFN-γ) is indicative of T cell activation (see Coligan et al. Current Protocols in Immunology. vol. 1. Wiley Interscience (Greene 1998)). T cells that have been activated in response to a prostate cancer polypeptide. polynucleots^{dy l}at^b in^yra^withay^andce ^pabout^Jule^{APC peptide} mo^{they can be} CD⁴+ ^ uId cont⁸+. Komórld^T. s^pec^yphic voice^bThe ec of the prostate cancer fracture can be propagated using standard techniques. In a preferred embodiment. T cells either derived from the patient. or of a related or unrelated donor are administered to the patient after stimulation and amplification.

For medicinal purposes. CD4 + or CD8 + T cells. which proliferate in response to a prostate tumor polypeptide. a polynucleotide or APC can be grown both in vitro and in vivo. The in vitro proliferation of such T cells can be achieved in a variety of ways. For example. T cells can be re-exposed to a prostate tumor polypeptide or a short peptide corresponding to the immunogenic portion of such a polypeptide with or without the addition of T cell growth factors. such as interleukin 2 and / or stimulator cells. that synthesize a prostate tumor polypeptide. Alternatively. one or more T cells that proliferate in the presence of a prostate tumor protein can be expanded by cloning. Methods for cloning cells are well known in the art and include limited dilution.

Pharmaceutical compositions and vaccines

In some aspects, the polypeptides disclosed herein. polynucleotides. T cells and / or binding agents may be included in pharmaceutical compositions or immunogenic compositions (i.e., vaccines). The pharmaceutical compositions can include one or more of these compounds and a non-specific immune response enhancer. Any substance can be a non-specific immune response enhancer. which increases the immune response to an exogenous antigen. Examples of enhancers of the nonspecific immune response include adjuvants. biodegradable microspheres (e.g., polylactic galactide) and liposomes (into which a compound may be incorporated; see, e.g., Fullerton. US Patent No. 4,235,877). The preparation of a vaccine is generally described in, e.g., MF Powell and MJ Newman. ed., "Vaccine Design (the subunit and adjuvant approach)" Plenum Press (NY. 1995). Other compounds may also be included in the pharmaceutical compositions and vaccines within the scope of the present invention. which may be biologically active or inactive. For example. One or more immunogenic fragments of other tumor antigens may be present in the composition or vaccine. or included in a fusion protein. be as a separate union.

A pharmaceutical composition or vaccine may contain DNA encoding one or more of the polypeptides described above. such as in situ generated polypeptide.

PL 200 772 B1

As noted above, DNA can be present in any of a variety of delivery systems known to those of skill in the art, including nucleic acid expression systems, bacteria, and viral expression systems. Numerous gene delivery techniques are known in the art, such as those described by Rolland, Crit. Rev. Therap. Drug Carrier Systems 15: 143-198, 1998, and references cited therein. Suitable nucleic acid expression systems contain DNA sequences appropriate for expression in the patient (such as an appropriate promoter and termination signal). The bacterial delivery system involves administering a bacterium, such as Bacillus-Calmette-Guerrin), that expresses an immunogenic portion of the polypeptide on its surface or secretes such an epitope. In a preferred embodiment, the DNA can be introduced using a viral delivery system (e.g. vaccinia virus or other pox virus, retrovirus or adenovirus), which may involve the use of non-pathogenic (defective) replication competent viruses. Suitable systems are disclosed in, for example, Fisher-Hoch et al., Proc. Natl. Acad Sci USA 86: 317-321,1989; Flexner et al., Ann. NY: Acad Sci. 569: 86-103,1989; Flexner et al., Vaccine 8: 17-21,1990; U.S. Patent Nos. 4,603,112, 4,769,330, and 5,017,487; WO 89/01973; US Patent No. 4,777,127; GB 2,200,651; BP 0.345.242; WO 91/02805; Berkner, Biotechniques 6: 616-627, 1988; Rosenfeld et al., Science 252: 431-434,1991; Kolls et al., Proc. Natl. Acad Sci USA 91: 215-219,1994; Kass-Eisler et al. Proc. Natl. Acad Sci USA 90: 11498-11502,1993; Guzman et al., Circulation 88: 2838-2848, 1993 and Guzman et al., Cir. Res. 73: 1202-1207, 1993. Techniques for incorporating DNA into such expression systems are well known to those of skill in the art. DNA can also be "naked" as described in, for example, Ulmer et al., Science 259: 1745-1749, 1993 and Cohen Review, Science 259: 1691-1692, 1993. Naked DNA uptake can be enhanced by coating the DNA on biodegradable beads. which are efficiently transported into the cells.

While any carrier known to those skilled in the art can be used in the pharmaceutical compositions of this invention, the type of carrier will vary depending on the mode of administration. The compositions of the present invention may be formulated for any suitable mode of administration, including, for example, topical, oral, intranasal, intravenous, intracranial, intraperitoneal, subcutaneous or intramuscular administration. For parenteral administration, such as subcutaneous injection, the carrier preferably comprises water, saline, alcohol, fat, wax and buffer. For oral administration, any of the above carriers or a solid carrier such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, and magnesium carbonate can be used. Biodegradable microspheres (e.g. polylactate polyglycolate). Suitable biodegradable spheres are disclosed in, for example, US Patents 4,897,268 and 5,075,109.

Such compositions may also contain buffers (e.g., neutral buffered saline or phosphate buffered saline), carbohydrates (e.g., glucose, sucrose and dextrans), mannitol, proteins, polypeptides or amino acids such as glycine, antioxidants, chelating compounds such as EDTA or glutathione, adjuvants (e.g., aluminum hydroxide) and / or preservatives. Alternatively, the compositions of the present invention may be formulated as a lyophilisate. The compounds can also be encapsulated in liposomes using well known technology.

Any of the non-specific enhancers of the immune response may be used in the vaccines of the invention. For example, adjuvants can be included there. Most adjutants contain a substance designed to protect the antigen from rapid metabolism, such as aluminum hydroxide or mineral oil, and immune stimulants such as lipid A, proteins derived from Bortadella pertussis, or Mycobacterium tuberculosis. Suitable adjuvants are commercially available, such as, for example, Incomplete Freund's Adjuvant and Complete Freund's Adjuvant (Difco Laboratories, Detroit, MI); Merck Adjuvant 65 (Merck and Company, Inc., Rahway, NJ); aluminum salts such as aluminum hydroxide gel (alum) or aluminum phosphate; calcium, iron or zinc salts, acylated tyrosine insoluble suspension, acylated sugars, cationic or anionic polysaccharide derivatives, polyphosphazenes; biodegradable microspheres; monophosphoryl lipid A and quail A. Cytokines such as GM-CSF or interleukin -2, -7, or -12 may also be used as adjuvants.

In the vaccines provided herein, a preferred adjuvant composition is designed to induce an immune response predominantly of the Th1 type. High levels of Th1-type cytokines (e.g., IFN-γ, IL-2 and IL-12) favor the induction of a cellular immune response to the administered antigen. In contrast, high levels of Th2-type cytokines (e.g., IL-4, IL-5, IL-6, IL-10, and TNF-β) favor the induction of a humoral immune response. After the administration provided here

Following vaccination, the patient will develop an immune response that will include Th1 and Th2 responses. In a preferred embodiment, where the Th1-type response is predominant, the level of Th1-type cytokines will increase to a level greater than that of Th2-type cytokines. The levels of these cytokines can be readily measured using standard assays. For a review of cytokines see Mosmann and Coffman, Ann. Rev. Immunol. 7: 145-173.1989.

Preferred adjuvants for use in inducing a predominantly Th1-type response include, for example, combinations of monophosphoryl lipid A, preferably 3-de-O-acylated monophosphoryl lipid A (3D-MPL), including an aluminum salt. Adjuvants are available from Ribi ImmunoChem Research Inc. (Hamilton, MT; see US Patent Nos. 4,436,727; 4,877,611; 4,866,034 and 4,912,094). CpG-containing oligonucleotides (in which the CpG dinucleotide is unmethylated) also induce a predominantly Th1 response. Such oligonucleotides are well known and are described, for example, in WO 96/02555. Another preferred adjuvant is a saponin, preferably QS21, which may be used alone or in combination with other adjuvants. For example, the enhanced system includes combinations of monophosphoryl lipid A and saponin derivatives such as the combination of QS21 and 3DMPL as described in WO 94/00153, or a less reactive combination where QS21 is quenched with cholesterol as described in WO 96/33739. Other preferred compositions include an oil-in-water emulsion and tocopherol. A particularly potent blend of adjuvants including QS21, 3D-MPL and tocopherol in an oil in water emulsion is described in WO 95/17210. Any vaccine presented herein can be prepared using well known methods that result in a combination of an antigen, an immune response enhancer and a suitable carrier or excipient.

The compositions described herein can be administered as part of a sustained release formulation (ie, a formulation such as a capsule or wipe that provides a sustained release of the ingredient after administration). Such preparations in general can be prepared using well known technology and administered, e.g., by oral, rectal or subcutaneous implantation, or by implantation at a desired site. Sustained-release preparations may contain a polypeptide, polynucleotide or antibody suspended in a carrier material and / or contained in a reservoir surrounded by a rate-controlling membrane. The carriers to be used for such formulas are biologically acceptable and may also be biodegradable; preferably the formulations allow a relatively constant release of the active ingredient. The amount of active ingredient contained in the sustained release formulation depends on the site of implantation, the level and expected release time, and the nature of the condition to be treated or prevented.

Any of a variety of delivery vehicles can be used in pharmaceutical compositions and vaccines to facilitate the production of an antigen-specific immune response against tumor cells. Delivery vehicles include antigen presenting cells (APCs) such as dendritic cells, macrophages, B cells, monocytes, and other cells that can be altered to be efficient APC cells. Such cells may or may not be genetically modified to increase antigen presentation capacity, to improve activation and / or maintenance of T cell responses, to have anti-tumor activity per se, and / or to be immunologically compatible with the donor (ie, have a matching HLA haplotype). APC cells can generally be isolated from one of a variety of biological fluids and organs including tumor and peritumor tissues, and can be autologous, allogeneic, syngeneic, or xenogeneic cells.

Certain preferred uses of the present invention utilize dendritic cells or their precursors as antigen presenting cells. Dendritic cells are highly efficient APC cells (Bancherau and Steinman, Nature 392: 245-251, 1998) and have been shown to be effective physiological adjuvants for eliciting a prophylactic or therapeutic immune response against cancer (see Timmerman and Levy, Ann. Rev. Med. 50). : 507-529,1999). In general, dendritic cells can be identified by their typical shape (in situ stellate with marked in vitro cytoplasmic extensions (dendrites)) and by the absence of B-cell differentiation markers (CD19 and CD20), T-cells (CD3), monocytes ( CD14) and natural killer cells (CD56) as determined using standard assays. Of course, dendritic cells can be altered to express specific cell surface receptors or ligands not commonly found on dendritic cells in vivo or ex vivo, and such modified dendritic cells are contemplated in the present invention. As an alternative to dendritic cells in the vaccine, secreted vesicles of antigen-charged dendritic cells (called exosome) can be used (see Zitvogel et al., Nature Med. 4: 594-600, 1998).

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Dendritic cells and precursors can be obtained from peripheral blood, bone marrow, tumor-penetrating cells, cells penetrating into peritumor tissues, lymph nodes, spleen, skin, umbilical cord blood, or any other available tissue or fluid. For example, dendritic cells can be dedifferentiated ex vivo by adding combinations of cytokines such as GM-CSF, IL-4, IL-13 and / or TNF? To the culture of monocytes harvested from peripheral blood. Alternatively, CD35 positive cells harvested from peripheral blood, umbilical cord blood, or bone marrow can be differentiated into dendritic cells by adding a combination of GM-CSF, IL-3, TNF?, CD40 ligand, LPS, ft13 ligand and / or another component to the culture medium ( s) inducing maturation and multiplication of dendritic cells.

Dendritic cells are conveniently subdivided into "immature" and "mature" which allows a simple distinction between two well-characterized phenotypes. However, this nomenclature should not be considered as excluding the existence of all intermediate stages of differentiation. Immature dendritic cells are characterized as APC with high antigen uptake and processing capacity, which correlates with high expression of the Fcy receptor, the mannose receptor and the DEC-205 marker. The mature phenotype is typically characterized by low expression of these markers but high expression of T cell activation molecules such as MHC class I and II, adhesion molecules (e.g. CD54 and CD11) and costimulatory molecules (e.g. CD40, CD80 and CD86) ).

APC cells generally can be transfected with a polynucleotide encoding a prostate tumor protein (or a portion or other variant thereof) such that the prostate tumor polypeptide or immunogenic portion thereof is expressed on the cell surface. Such transfection may take place ex vivo, and a composition or vaccine containing such transfected cells may then be used for therapeutic purposes as described herein. Alternatively, the patient may be administered a gene delivery vehicle that ends up in dendritic cells or other antigen presenting cells, leading to in vivo transfection. In vivo and ex vivo transfection of dendritic cells can generally be performed using methods known in the art such as those described in WO 97/24447 or the gene gun approach described by Mahvi et al., Immunology and Cell Biology 75: 456-460,1997. . Antigen loading of dendritic cells can be obtained by incubating dendritic cells or precursor cells with a prostate tumor polypeptide, DNA (naked or on a plasmid vector), or RNA; or with a recombinant bacterium or virus expressing an antigen (e.g., vaccinia, fowlpox, adenoviral or lentiviral vectors). Prior to loading, the polypeptide may be covalently coupled to an immune partner that supports T cells (e.g., a carrier molecule). Alternatively, the cell may be pulsed with an unconjugated immune partner, either alone or in the presence of the polypeptide.

Cancer therapy

In further aspects of the invention, the compositions described herein can be used for immunotherapy of cancers, such as prostate cancer. Within such methods, pharmaceutical compositions and vaccines are typically administered to a patient. The term "patient" as used herein refers to any warm-blooded animal, preferably a human. The patient may or may not be affected by the cancer. Thus, the above pharmaceutical compositions and vaccines can be used to prevent tumor growth or to treat a patient afflicted with cancer. A tumor can be diagnosed using criteria generally accepted in the art, including the presence of a malignant tumor. The pharmaceutical compositions and vaccines may be administered before or after surgical removal of the primary tumor and / or treatment such as radiation therapy or administration of conventional chemotherapeutic drugs.

In certain embodiments, the immunotherapy can be an active immunotherapy where the treatment involves stimulating in vivo the host's endogenous immune system to respond against tumors by administering immune response modifying agents (such as the polypeptides and polynucleotides disclosed herein).

In other embodiments, the immunotherapy may be passive immunotherapy, wherein the treatment involves the delivery of agents with established immune activity against the tumor (such as effector cells or antibodies) that may directly or indirectly mediate anti-tumor activity and do not necessarily depend on the intact immune system of the host. Examples of effector cells include T cells, as discussed above, T cells (such as cytotoxic CD8 + lymphocytes and tumor-infiltrating T lymphocytes), killer cells (such as Natural Killers and killer cells), B cells, and cells. presenting an antigen (such as dendritic cells and macrophages) expressing herein

The delivered CD4 polypeptide⁺). T cell receptors and antibody receptors specific for the polypeptides specified herein can be cloned, expressed, and transferred to other vectors or effector cells for adoptive immunotherapy. The polypeptides provided herein can also be used to generate anti-idiotype antibodies or antibodies (as described above and in US Patent No. 4,918,164) for passive immunotherapy.

Effector cells can generally be obtained in amounts sufficient for adaptive immunotherapy by growth in vitro as described herein. The culture conditions for expanding single antigen-specific effector cells to a number of several billion while maintaining antigen recognition in vivo are well known in the art. Such in vitro culture conditions typically utilize intermittent antigen stimulation, often in the presence of cytokines (such as IL-2) and non-dividing feeder cells. As noted above, the immunoreactive peptides presented herein can be used to rapidly expand antigen-specific T cells in culture to create a sufficient number of cells for immunotherapy. In particular, antigen presenting cells such as dendritic cells, macrophages, monocytes, fibroblasts, or B cells can be pulsed with immunoreactive peptides or transfected with one or more polynucleotides using standard techniques well known in the art. For example, antigen presenting cells can be transfected with a polynucleotide having a promoter suitable for enhancing expression in a recombinant virus or other expression system. Cultured effector cells to be used in therapy must be capable of being broadly grown and multiplied extensively and long-term survival in vivo. Studies have shown that cultured effector cells can be induced to grow in vivo and survive long in significant numbers by repeated stimulation with IL-1 supplemented antigen (see, for example, Cheever et al, Immunological Reviews 157: 177, 1997).

Alternatively, a vector expressing a polypeptide as set forth herein can be introduced into antigen presenting cells removed from a patient and cloned ex vivo for transplantation back into the same patient. The transfected cells can be reintroduced into the patient by any method known in the art, preferably in sterile form by intravenous, intra-intravenous, intraperitoneal or intratumoral administration.

The route and frequency of administration of the therapeutic compositions disclosed herein, as well as the dosages, will vary from person to person and can be readily ascertained using standard techniques. Generally, the pharmaceutical compositions and vaccines can be administered by injection (e.g., intradermal, intramuscular, intravenous, or subcutaneous), intranasally (e.g., by aspiration), or orally. Preferably, between 1 and 10 doses may be administered over a 52 week period. Preferably, 6 doses are given at intervals of 1 month and booster vaccinations may be given periodically thereafter. Varying protocols may be appropriate for individual patients. A suitable dose is the amount of a component when, when administered as described above, it is capable of enhancing the immune response against a tumor and is at least 10-50% above baseline (i.e. inactive). Such a response can be observed by measuring anti-tumor antibodies in a patient or by vaccine-dependent generation of cytolytic effector cells capable of killing the patient's tumor cells in vitro. Such vaccines should also be capable of eliciting an immune response leading to an improvement in the clinical outcome (e.g. more frequent remissions, complete or partial or longer disease-free survival) in vaccinated patients compared to unvaccinated patients. Generally, for single or multiple polypeptide pharmaceutical compositions and vaccines, the amount of each peptide present in a dose ranges from about 100 µg to 5 mg per kilogram of host body weight. Suitable dose sizes will vary with patient size but typically will be in the range from about 0.1 ml to about 5 ml.

In general, an appropriate regimen of dosing and operation will provide the active ingredient (s) in an amount sufficient to cause a therapeutic and / or prophylactic benefit. Such a response can be monitored by establishing an improvement in the clinical outcome (e.g., more frequent remissions, complete or partial, or longer disease-free survival) in treated patients compared to untreated patients. Increased pre-existing immune responses to prostate cancer generally correlate with improved clinical outcomes. Such immune responses can generally be assessed using standard proliferation, cytotoxicity, or cytokine assays, which can be performed using samples obtained from patients before and after treatment.

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Cancer detection methods

Generally, a tumor can be detected in a patient based on the presence of one or more proteins and / or polynucleotides encoding prostate tumor proteins in a biological sample (e.g., blood, serum, urine, and / or tumor biopsy) obtained from the patient. In other words, such proteins can be used as markers to indicate the presence or absence of a cancer such as prostate cancer. Additionally, such proteins may be useful in detecting other cancers. The binding agents provided herein generally detect the level of antigen that binds to the agent in a biological sample. Polynucleotide primers and probes can be used to detect the level of mRNA coding for tumor proteins, which also indicates the presence or absence of a tumor. In general, the prostate tumor sequence should be present at a level at least three times higher in tumor tissue than in normal tissue.

There are a variety of assay methods known to those skilled in the art using the binding agent to detect polypeptide markers in a sample. See, e.g., Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988. In general, the presence or absence of a tumor in a patient can be determined by a) contacting a biological sample obtained from the patient with a binding agent; b) detecting the level of the binding agent binding polypeptide in the sample; and c) comparing the level of the polypeptide to a predetermined cutoff.

In preferred embodiments, the assay comprises using a binding agent immobilized on a solid support to bind to and remove the polypeptide from the remainder of the sample. The bound polypeptide can then be detected using a detection reagent that contains a reporter group and binds specifically to the binding agent and polypeptide complex. Such detection reagents may include, for example, an agent that specifically binds to a polypeptide or an antibody, or another agent that specifically binds to a binding agent, such as anti-immunoglobin, protein G, protein A, or a lectin. Alternatively, a competitive assay may be used in which the polypeptide is labeled with a reporter group and allowed to bind to the immobilized binding agent after incubating the binding agent with the sample. The degree to which components of the sample inhibit the binding of the labeled polypeptide to the binding agent is indicative of the reactivity of the sample with the immobilized binding agent. Suitable polypeptides for use in such an assay include full-length prostate cancer proteins and portions thereof to which a binding agent binds, as described above.

The solid support can be any material known to those skilled in the art to which tumor proteins can be attached. For example, the solid support may be a well in a microtiter plate or nitrocellulose or other suitable membrane. Alternatively, the substrate may be a ball or disk such as glass, glass wool, latex, or a plastic material such as polystyrene or polyvinyl chloride. The substrate may also be a magnetic particle or a sensor optical fiber, such as disclosed e.g. in U.S. Patent No. 5,359,681. The binding agent can be immobilized on a solid support using a number of techniques known to those skilled in the art and extensively described in the patent and scientific literature. In the context of the present invention, the term "immobilization" refers to both types of adhesion: non-covalent association, such as adsorption, and covalent bonding (which may be a direct link between the agent and functional groups on a substrate, or linked by a cross-linking agent). Immobilization by adsorption to a well on a microtiter plate or to a membrane is preferred. In such cases, adsorption can be achieved by contacting the binding agent, in a suitable buffer, with the solid support for an appropriate amount of time. Contact time varies with temperature but is typically between about 1 hour and about 1 day. Generally, contacting a well of a microtiter plate (such as polystyrene or polyvinyl chloride) with an amount of binding agent ranging from about 10 ng to about 10 gg, and preferably about 100 ng to about 1 gg, is sufficient to immobilize the appropriate amount of the binding agent.

Covalent association of the binding agent with a solid support may generally be achieved by first reacting with a bifunctional reagent which is reactive with both the support and with a functional group, such as the hydroxyl or amino group of the binding agent. For example, the binding agent can be covalently linked to substrates having an appropriate polymer coating using benzoquinone or by condensation of the aldehyde group on the substrate with an amine and the binding partner's anti-hydrogen (see, e.g., Pierce Immunotechnology Catalog and Handbook, 1991, in A12-A13).

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In some embodiments, the test is a dual antibody sandwich test. This assay can be performed by first contacting an antibody immobilized on a solid support, usually a well of a microtiter plate, with the sample such that the polypeptides of the sample are allowed to bind to the immobilized antibody. The unbound sample is then removed from the immobilized polypeptide-antibody complex and a detection reagent (preferably a second antibody capable of binding to another site on the polypeptide) containing a reporter group is added. The amount of detection reagent remaining bound to the solid support is determined using a method appropriate to the specific indicator group.

More specifically, when an antibody is immobilized on a support as described above, the remaining protein binding sites on the support are typically blocked. Any blocking agent known to those skilled in the art can be used, such as bovine serum albumin or Tween 20 ™ (Sigma Chemical Co., St. Louis, MO). The immobilized antibody is then incubated with the sample and the polypeptide is allowed to bind to the antibody. The sample may be diluted with a suitable diluent such as phosphate buffer (PBS) prior to incubation. In general, a suitable contact time (ie, incubation time) is a period of time that is sufficient to detect the presence of the polypeptide in a sample obtained from an individual with prostate cancer. Preferably, a contact time is sufficient to achieve a binding level of at least 95% that is achieved at an equilibrium between the bound and unbound polypeptide. It will be appreciated by those skilled in the art that the time required to achieve equilibrium can be readily determined by determining the level of binding achieved over a period of time. At room temperature, an incubation time of about 30 minutes is generally sufficient.

Unbound sample can then be removed by washing the solid support with an appropriate buffer, such as PBS containing 0.1% Tween 20 ™. The second antibody containing the reporter group can then be added to the solid support. Preferred indicator groups include the aforementioned groups.

The detection agent is then incubated with the immobilized antibody-polypeptide complex for a time sufficient to detect the bound polypeptide. The time required can generally be determined by determining the level of binding achieved over a period of time. Unbound detection reagent is then removed, and bound detection reagent is detected using the reporter group. The method used to detect the indicator group depends on the nature of the indicator group. For radioactive groups, scintillation counting or autoradiographic methods are generally appropriate. Spectroscopic methods can be used to detect dyes, luminescent and fluorescent groups. Biotin can be detected using avidin bound to another pointing group (commonly a radioactive or fluorescent group, or an enzyme). Enzyme pointer groups can generally be detected by adding substrate (generally for a specific period of time) followed by spectroscopic or other analysis of the reaction products.

To determine the presence or absence of a tumor, such as prostate cancer, the signal detected from the indicator group bound to the solid support is usually compared to a signal corresponding to a predetermined cutoff. In one preferred embodiment, the cutoff value for tumor detection is the average of the signal obtained when the immobilized antibody is incubated with tumor-free patient samples. In general, samples giving a signal greater than three standard deviations above the predetermined cut-off are considered tumor positive. In another preferred embodiment, the cutoff value is established using the Receiver Operator Curve according to the method of Sackett et al, Clinical Epidemiology: A Basic Science for Clinical Medicine, Little Brown and Co., 1985, pp. 106-7. Briefly, in this embodiment, the cutoff value can be established from a pair of true positive (ie, sensitivity) and false positive (100% specificity) pairs which correspond to each possible cutoff for a diagnostic test result. The cutoff value in the chart closest to the top left corner (i.e. value covering the largest area) is the most accurate limit and a sample giving a signal higher than the limit value determined by this method can be considered positive. Alternatively, the cutoff value can be shifted to the left along the plot to minimize the level of false negatives. In general, a sample giving a signal higher than the cut-off value established by this method is considered positive for tumor.

In related uses, the assay is performed in flow or tape format, where the binding agent is immobilized on a membrane, such as nitrocellulose. In the flow-through test, polypeptides from the sample bind to the immobilized binding agent as the sample passes through the membrane. The second, labeled binding agent binds to the factor complex

Binding-polypeptide when a solution containing the second binding agent passes through a membrane. Detection of the bound second binding agent can then be performed as described above. In the case of the tape test, one end of the membrane to which the binding agent is bound is immersed in the solution containing the sample. The sample migrates along the membrane through the region containing the second binding agent and into the region of the immobilized binding agent. The concentration of the second binding agent in the region of the immobilized antibody indicates the presence of a tumor. Typically, the concentration of the second binding agent at this location produces a pattern such as a line that can be read visually. The presence of such a pattern indicates a negative result. In general, the amount of the binding agent immobilized on the membrane is selected to be sufficient to produce a visually discernible pattern when the biological sample contains sufficient levels of polypeptide to produce a positive signal in the two-antibody sandwich assay in the format described above. Preferred binding agents for use in such assays are antibodies and antigen-binding fragments thereof. Preferably, the amount of the antibody immobilized on the membrane ranges from 25 ng to about 1 µg, and more preferably from about 50 ng to about 500 ng. Such tests can typically be performed with a very small amount of biological sample.

Of course, there are numerous other assay protocols suitable for use with the tumor proteins or binding agents of the invention. The above descriptions are only examples. For example, it will be apparent to those skilled in the art that the above protocols can be readily modified to use prostate cancer polypeptides to detect antibodies binding those polypeptides in a biological sample. The detection of such antibodies specific for prostate tumor proteins may correlate with the presence of a tumor.

The tumor may also or alternatively be detected based on the presence of T cells specifically reactive with prostate tumor proteins in the biological sample. In certain methods, a biological sample containing CD4 + and / or CD8 + T cells isolated from a patient is incubated with a prostate cancer polypeptide, a polynucleotide encoding such polypeptide, and / or APC cells expressing at least an immunogenic dose of such polypeptide, and the presence or absence of specific T cell activation is detected. Suitable biological samples include, but are not limited to, isolated T cells. For example, T cells can be isolated from a patient by routine techniques (such as peripheral blood lymphocyte centrifugation on a Ficoll / Hypaque density gradient). T cells can be incubated in vitro for 2-9 days (typically 4 days) at 37 ° C with a prostate tumor polypeptide (e.g., 5-25 µg / ml). It may be desirable to incubate the next volume of a T cell sample in the absence of a prostate tumor polypeptide as a control. For CD4 + T cells, activation is preferably detected by assessing proliferation of the T cells. For CD8 + T cells, activation is preferably detected by assessing cytolytic activity. A level of proliferation at least twice as high and / or a level of cytolytic activity at least 20% greater than in non-diseased patients indicates the presence of a tumor in the patient.

As noted above, a tumor may also or alternatively be detected based on the level of mRNA encoding a prostate tumor protein in a biological sample. For example, one can use at least two oligonucleotide primers in a polymerase chain reaction (PCR) based assay to amplify an aliquot of prostate cancer cDNA derived from a biological sample, wherein at least one oligonucleotide primer is specific (i.e. hybridizes with a) polynucleotide encoding a prostate tumor protein. The amplified cDNA is separated and detected using techniques well known in the art such as electrophoresis. Similarly, oligonucleotide probes that specifically hybridize to a polynucleotide encoding a prostate tumor protein can be used in a hybridization assay to detect the presence of a polynucleotide encoding a tumor protein in a biological sample.

To allow hybridization under the conditions of the assay, the oligonucleotide primer and probe should contain at least about 60%, preferably at least about 75%, and more preferably at least about 90% identical oligonucleotide sequence to a portion of the polynucleotide encoding a prostate cancer protein at least 10 nucleotides in length, and preferably at least 20 nucleotides. Preferably, oligonucleotide primers and / or probes will hybridize to a polynucleotide encoding a polypeptide disclosed herein under moderately stringent conditions as defined above. Oligonucleotide primers and / or probes that may be useful for use in the diagnostic methods described herein are preferably at least 10-40 nucleotides in length. In a preferred embodiment, the oligonucleotide primers include at least 10 contiguous nucleotides, more preferably at least 15 contiguous nucleotides in a DNA molecule having the sequence shown in Id. KNOT. No. 1-111, 115-171, 173-175, 177, 179-305, 307-315, 326, 328, 330, 332-335,

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340-375 and 381. Techniques for both PCR-based and hybridization assays are well known in the art (see, for example, Mullis et al, Cold Spring Harbor Symp. Quant. Biol., 51: 263, 1987; Erlich ed., PCR Technology, Stockton Press, NY, 1989).

One preferred assay uses RT-PCR, in which PCR is used in conjunction with reverse transcription. Typically RNA is isolated from a biological sample, such as biopsy tissue, and reverse transcribed to obtain cDNA molecules. Amplification by PCR using at least one specific primer produces a cDNA molecule that can be separated and visualized using, for example, gel electrophoresis. Reproduction can be performed on a biological sample taken from the test patient and from an individual who is not cancerous. The propagation reaction can be performed on different cDNA dilutions differing by two orders of magnitude. A two-fold or greater increase in expression at several dilutions of the test patient sample as compared to the same dilutions of the non-cancerous sample is typically considered positive.

In another embodiment, the disclosed compositions can be used as markers for tumor growth. In this application, assays, as described above for cancer diagnosis, can be performed at intervals and assess the change in the level of reactive peptide (s) and polynucleotides. For example, tests may be performed every 24-72 hours for a period of 6 months to 1 year and then as needed. In general, cancer progresses in those patients where the level of polypeptide or polynucleotide detectable increases over time. Conversely, cancer does not progress when the level of reactive polypeptide or polynucleotide either remains constant or declines over time.

Certain in vivo diagnostic assays can be performed directly on the tumor. One such assay involves bringing the tumor cells into contact with a binding agent. Bound binding agent can then be detected directly or indirectly via the reporter group. Such binding agents can also be used in histological applications. Alternatively, polynucleotide probes may be used in such applications.

As noted above, numerous prostate tumor proteins can be determined in a given tissue to improve sensitivity. It will be appreciated that binding agents specific to the various proteins provided herein can be combined in a single assay. In addition, multiple primers or probes can be used in parallel. The selection of tumor marker proteins can be based on routine experimentation to determine combinations that result in optimal sensitivity. Additionally or alternatively, assays for the cancer proteins provided herein may be combined with assays for other known cancer antigens.

Diagnostic kits

The present invention further provides kits for use in any of the above diagnostic methods. Such kits typically include two or more components necessary to perform a diagnostic assay. The ingredients can be ingredients, reagents, containers and / or accessories. For example, one kit container may contain a monoclonal antibody or fragment thereof that specifically binds to prostate cancer proteins. Such antibodies or fragments thereof may be provided attached to a support as described above. One or more containers may contain elements such as reagents or buffers for use in the assay. Such a kit may also or alternatively contain a detection reagent as described above which comprises a reporter group suitable for the direct or indirect detection of antibody binding.

Alternatively, the kit can be designed to detect the level of mRNA encoding a prostate tumor protein in the biological sample. Such kits generally comprise at least one oligonucleotide probe or primer as described above that hybridizes to a polynucleotide encoding a prostate tumor protein. Such an oligonucleotide can be used for, for example, a PCR reaction or a hybridization assay. Additional components that may be included in such a kit include a second oligonucleotide and / or a diagnostic reagent or container to facilitate detection of a polynucleotide encoding a prostate tumor protein.

The following examples are provided for the purpose of illustration and not limitation.

Examples

Example 1

Isolation and characterization of prostate cancer polypeptides

This example describes the isolation of certain prostate cancer polypeptides from a prostate cancer cDNA library.

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A human prostate tumor cDNA expression library was constructed from prostate tumor poly A + RNA using the Superscript Plasmid System DNA synthesis and cloning kit for cDNA Synthesis and Plasmid Cloning (BRL Life Technologies, Gaithersburg, MD 20897) according to the manufacturer's protocol. Specifically, prostate tumor tissue was homogenized with a polytrone (Kinematica, Switzerland) and total RNA was extracted using the Trizol reagent (BRL Life Technologies) as recommended by the manufacturer. The poly A + RNA was then purified using a Qiagen oligotex spin mRNA purification column kit (Qiagen, Santa Clarita, CA 91355) according to the manufacturer's protocol. First strand cDNA was synthesized using a NotI / Oligo-dT 18 primer. Double-stranded DNA was synthesized, ligated with EcoRI / BAXI adapters (Invitrogen, San Diego, CA) and digested with NotI. After size fractionation using Chroma Spin-1000 columns (Clontech, Palo Alto, CA), the cDNA was ligated into the EcoRI / NotI site of pCDNA3.1 (Invitrogen) and transformed into ElectroMax E. coli DH1OB cells (BRL Life Technologies) by electroporation.

Using the same procedure, a human pancreas cDNA expression library was prepared from a pool of six tissue samples (Clontech). The cDNA libraries were characterized by determining the number of independent colonies, the percentage of clones carrying an insert, the average insert size, and sequence analysis. The human prostate tumor library contained 1.64 x 10⁷ independent colonies, with 70% of the clones having an insert and an average insert size of 1745 bp. The normal pancreas cDNA library contained 3.3 x 10⁶ independent colonies, with 69% of the clones having an insert with an average insert size of 1120 bp. For both libraries, sequence analysis showed that most of the clones had full-length cDNA sequence and were synthesized from mRNA with minimal rRNA and mitochondrial DNA contamination.

The cDNA library elimination was performed using the above prostate cancer and normal pancreas cDNA libraries as described by Hara et al. (Blood, 8-1: 189-199,1994) with some modifications. Specifically, an elimination-narrowed prostate tumor cDNA library was prepared as follows. A normal pancreatic cDNA library (70 pg) was digested with EcoRI, NotI and Sful, followed by a tail-filling reaction using the Klenow fragment of DNA polymerase. After phenol-chloroform extraction and ethanol precipitation, the DNA was dissolved in 100 µl H₂0, thermally denatured and mixed with 100 µl (100 µg) of Photoprobe biotin (Vector Laboratories, Burlingame, CA) as recommended by the manufacturer, the resulting mixture was irradiated with a 270 W quartz lamp on ice for 20 minutes. Additional Photoprobe biotin (50 µl) was added and the biotinylation reaction was repeated. After extraction with butanol five times, the DNA was precipitated with ethanol and dissolved in 23 µl H₂O to make a DNA for elimination (driver).

To generate a tracer DNA, 10 µg of a prostate tumor cDNA library was digested with BamHI and XhoI, extracted with phenol-chloroform and passed over Chroma spin-400 columns (Clontech). After ethanol precipitation, the tapered DNA was dissolved in 5 µl H₂O. The concentrated DNA was mixed with 15 µl of eliminating DNA and 20 µl of 2 x hybridization buffer (1.5 M Na-Cl / 10 mM EDTA / 50 mM HEPES pH 7.5 / 0.2% sodium dodecyl sulfate), oiled mineral and completely thermally denatured. The sample was immediately transferred to a 68 ° C water bath and incubated for 20 hours (long hybridization [LH]). The reaction mixture was then treated with streptavidin followed by phenol / chloroform extraction. This process was repeated three more times. Elimination DNA was precipitated and dissolved in 12 µl H₂0, mixed with 8 µl of elimination DNA and 20 µl of 2 × hybridization buffer and hybridized at 68 ° for hours (short hybridization [SH]). After removal of the biotinylated double-stranded DNA, the elimination cDNA was ligated into the BamHI / XhoI site of chloramphenicol resistant pBCSK + (Stratagene, La Jolla. CA 92037) and transformed into ElectroMax E. coli DH1OB by electroporation to generate a prostate tumor-specific elimination-narrowed cDNA library (referred to as prostate constriction 1).

For the analysis of the narrowed cDNA library, plasmid DNA was obtained from 100 independent clones selected randomly from the narrowed prostate tumor specific library and grouped by insert size. Representative cDNA clones were further characterized by DNA sequencing using a Perkin Elmer / Applied Biosystems Division Automated Sequencer Model 373 A sequencer (Foster City, CA). Six cDNA clones were shown to be the most abundant in the prostate tumor-specific cDNA library, hereinafter designated F1-13, F1-12, F1-16, H1-1, H1-9 and H1-4. The 3 'and 5' fixed sequences for F1-12 are provided in SEQ. ID NO .:

PL 200 772 B1 and 3, respectively, and the 3 'cDNA sequences for F1-13, F1-16, H1-1, H1-9 and H1-4 are provided in SEQ. ID NO .: 1 and 4-7, respectively.

The cDNA sequences for the isolated clones were compared to known sequences in a gene bank using the EMBL and GenBank databases (version 96). Four of the prostate cancer cDNA clones, F1-13, F1-16, H1-1 and H1-4, were found to encode the following previously identified proteins: prostate specific antigen (PSA), human glandular kallikrein, mitochondrial cytochrome C oxidase II subunit . H1-9 was found to be identical to the previously identified human autonomously replicating sequence. No significant homology was found to the cDNA sequence for F1-12.

Further research resulted in the isolation of the full-length cDNA sequence for F1-12. This sequence is shown in SEQ. ID NO: 107, with the corresponding predicted amino acid sequence set forth in SEQ. ID NO .: 108.

In order to clone the less abundant prostate tumor specific genes, a narrowing of the cDNA library was made by eliminating the normal pancreatic cDNA library from the prostate tumor cDNA library described above and the three most abundant genes from the earlier prostate tumor cDNA library: human glandular kallikrein, PSA and cytochrome C mitochondrial oxidase II subunit II. Specifically, 1 gg of human glandular kallikrein cDNA, prostate specific antigen (PSA) and cytochrome C mitochondrial oxidase II subunit II in pCDNA3.1 were added to the eliminating DNA and refined as above to provide a second narrowed by elimination cDNA library, hereinafter referred to as "Additionally narrowed prostate specific cDNA library".

Twenty-two cDNA clones were isolated from an additional narrowed prostate-specific cDNA library. Fixed 3 'and 5' cDNA sequences of clones designated J1-17, L1-12, N1-1862, J1-13, J1-19, J1-25, J1-24, K1-58, K1-63, L1-4 and L1-14 are provided in SEQ. ID NO .: 8-9, 10-11, 12-13, 14-15, 16-17, 18-19, 20-21, 22-23, 24-25, 26-27 and 28-29, respectively. Fixed 3 'cDNA sequences for clones J1-12, J1-16, J1-21, K1-48, K1-55, L1-2, L1-6, N1-1858, N1-1860, N1-1861, N1 -1864 are presented in SEC. ID NO .: 30-40 respectively. Comparison of these sequences with the sequences in the database as described above showed no significant homology for three of the five most abundant DNA classes (J1-17, L1-12 and N1-1862; SEQ ID NOs: 89, 10-11 and 12- 13, respectively). Of the remaining most abundant classes, one (J1-12; SEQ ID NO: 30) was found to be identical to the previously identified human lung surface protein, and another (K1-48; SEQ ID NO: 33) was found to be identical to the previously identified human lung surface protein. homology with mRNA for R. norvegicus 2-arylpropionyl-CoA epimerase. Of the 17 least abundant cDNA clones isolated from an additionally narrowed prostate-specific cDNA library, four (J16, K1-55, L1-6, and N1-1864; SEQ. ID NOs: 31, 34, 36 and 40 respectively) were found to be identical to the previously identified sequences, two (J1-21 and N1-1860; SEQ ID NOs: 32 and 38, respectively) showed some homology with the sequences non-human, and two (L1-2 and N1-1861; SEQ ID NOS: 35 and 39, respectively) showed homology to known human sequences. No significant homology was found for the J1-13, J1-19, J1-24, J1-25, K1-58, K1-63, L1-4, L1-14 polypeptides (SEQ. ID NO .: 14-15, 16-17, 20-21, 18-19, 22-23, 24-25, 26-27, 28-29, respectively).

Subsequent studies resulted in the isolation of the full-length cDNA sequences for J1-17, L1-12 and N1-1862 (SEQ ID NOs: 109-111, respectively). The corresponding predicted amino acid sequences are set out in SEQ. ID NO .: 112-114. L1-12 is also referred to as P501S.

In further experiments, four additional clones were identified by eliminating from the prostate tumor cDNA library the normal prostate cDNA prepared from a pool of three poly A⁺RNA from normal prostate (referred to as prostate narrowing 2). The determined cDNA sequences for these clones, hereinafter referred to as U1-3064, U1-3065, V1-3692 and 1A-3905, are provided in SEQ. ID NO .: 69-72, respectively. Comparison of the established sequences with those in the database showed no significant homology for U1-3065.

A second additional constriction (referred to as additional prostate 2 constriction) was performed by eliminating from the additionally narrowed cDNA library for tumor and prostate library for normal pancreas cDNA and further exclusion of PSA, J1-17, lung surface protein, mitochondrial DNA, subunit II of cytochrome C mitochondrial oxidase. , N1-1862, an autonomously replicating sequence, L1-12, and a tumor expression enhancing gene. Four additional clones were isolated, hereinafter referred to as V1-3686, R1-2330, 1B-3976, and V1-3679. The determined cDNA sequence for these clones is shown in SEQ. ID NO .: 73-76, respectively.

PL 200 772 B1

Comparison of the established sequences with those in the database showed no significant homology for V1-3686 and R1-2330.

Further analysis of the three prostate constrictions described above (prostate constriction 2, additional narrowed prostate tumor specific cDNA library, and additional constriction 2) led to the identification of sixteen additional clones designated 1G-4736,1G-4738, 1G4741, 1G-4744, 1G -4734, 1H-4774, 1H-4781, 1H-4785, 1H-4787, 1H-4796, 1I-4810, 1I-4811, 1J-4876, 1K-4884, and 1K-4896. The determined cDNA sequence for these clones is shown in SEQ. ID NO .: 77-92, respectively. Comparison of the established sequences with those in the database showed no significant homology of 1G-4741, 1G-4734, 1I-4807, 1J-4876 and 1K-4896 (SEQ ID NO: 79, 81, 87, 90 and 92, respectively) . Further analysis of the isolated clones led to the establishment of longer cDNA sequences for 1G-4736, 1G-4738, 1G-4741, 1G-4744, 1H-4774, 1H-4781,1H-4785, 1H-4787, 1H-4796, 1I-4807 , 1J-4876, 1K-4884 and 1K-4896, set forth in SEQ. NO: 179-188 and 191-193, respectively, and the determination of additional partial cDNA sequences for 11-4810 and 11-4811, provided in SEQ. ID NO .: 189 and 190, respectively.

Further studies with the additional narrowed prostate library 2 resulted in the isolation of three more clones. Their sequence was determined as described above and compared to the most recent version of GenBank. Homology was found for all three clones with known genes, which are the cysteine-rich proteins KIAA0242 and KIAA0280 (SEQ ID NO: 317, 319 and 320, respectively). Further analysis of these clones using Synteni microplates (Synteni, Palo Alto, CA) showed that all three clones were overexpressed in most prostate and BPH tumors as well as in most normal prostate tissues tested, but low in all other normal tissues.

Additional constriction was performed by eliminating normal pancreatic cDNA from the library (designated as "prostate constriction 3"). This led to the identification of six additional clones designated 1G-4761, 1G-4762, 1H-4766, 1H4770, 1H-4771, and 1H-4772 (SEQ ID NOs: 93-98). Comparison of the established sequences with those in the database showed no significant homology for 1G-4761 and 1H-4771 (SEQ ID NOS: 93 and 97, respectively). Further analysis of the isolated clones revealed longer cDNA sequences for 1G-4761, 1G-4762, 1H-4766 and 1H-4772 shown in SEQ. ID NOs: 194-196 and 199, respectively, and the determination of additional partial cDNA sequences for 1H-4770 and 1H-4771, provided in SEQ. ID NO .: 197 and 198, respectively.

Narrowing of a prostate cancer cDNA library prepared from a pool of poly A + RNA from three prostate cancer patients using a normal pancreatic cDNA library (prostate narrowing 4) led to the identification of eight clones, designated 1D-4297, 1D-4309, 1D-4278 , 1D4288, 1D-4283,1D-4304,1D-4296 and 1D-4280 (SEQ ID NO: 99-107). These sequences were compared to those in the gene bank database as noted above. No significant homology was found for 1D-4283 and 1D-4304 (SEQ. ID NOs: 103 and 104, respectively). Further analysis of the isolated clones resulted in the determination of longer cDNA sequences for 1D-4309, 1D-1-4278, 1D-4288,1D-4283, 1D-4304, 1D-4296, and 1D-4280, shown in SEQ. ID NO .: 200-206, respectively.

The cDNA clones isolated from the narrowed prostate 1 library and narrowed prostate 2 library described above were amplified by colony PCR and mRNA levels were determined in prostate tumor, normal prostate and various other normal tissues using microplate technology (Synteni, Palo Alto, CA). Briefly, PCR amplification products were spotted onto slides in an orderly fashion, each occupying the appropriate position on the plate. mRNA was extracted from the tissue sample to be tested, reverse transcribed, and fluorescently labeled cDNA probes were produced. Microplates were incubated with labeled cDNA probes, slides were scanned and the intensity of fluorescence was measured. This intensity correlates with the intensity of hybridization. Two clones (designated P509S and P510S) were found to be overexpressed in prostate cancer and normal prostate and low in all other normal tissues tested (liver, pancreas, skin, bone marrow, brain, breast, adrenal gland, bladder, testes, salivary gland, colon, kidney, ovary, lung, spinal cord, skeletal muscle, and colon). The determined cDNA sequences for P509S and P510S are provided in SEQ. ID NO .: 223 and 224, respectively. Comparison of these sequences with those in the gene bank as noted above showed some homology with the previously identified EST sequences. Further studies led to the isolation of the full length cDNA sequence for P509S. The sequence is

PL 200 772 B1 disclosed in SEQ. ID NO: 332, with the corresponding predicted amino acid sequence set forth in SEQ. ID NO .: 339.

Example 2

Determination of the tissue specificity of prostate cancer polypeptides

Using specific primers, mRNA expression levels for representative prostate cancer polypeptides F1-16, H1-1, J1-17 (also referred to as P502S), L1-22 (also referred to as P501S), F1-12 (also referred to as P504S) were examined. and N1-1862 (also referred to as P503S) in a variety of normal and neoplastic tissues using RT-PCR.

Briefly, total RNA was isolated from a variety of normal and neoplastic tissues using the Trizol reagent as described above. First strand synthesis was performed using 1-2 µg total RNA and SuperScript II reverse transcriptase (BRL Life Technologies) at 42 ° C for one hour. cDNA was amplified by PCR using gene specific primers. To ensure a semi-quantitative RT-PCR run, β-actin was used as an internal control for each tissue tested. First, a series of first-strand cDNA dilutions were prepared and RT-PCR tests were performed using β-actin specific primers. Dilutions were then selected which provided a linear range for amplification of the β-actin matrix and which were sensitive enough to reflect the difference in the starting copy number. Using these conditions, β-actin levels were determined for each reverse transcription reaction from each tissue. DNA contamination was minimized by DNase treatment and by making it negative when using first strand cDNA that had been prepared without adding reverse transcriptase.

MRNA expression levels were studied in four different types of cancer tissue (prostate cancer from two patients, breast cancer from three patients, colon cancer and lung cancer) and sixteen different normal tissues including prostate, colon, kidney, liver, lung, ovary, pancreas. , skeletal muscle, skin, stomach, testes, bone marrow and the brain. F1-16 was found to be expressed at high levels in prostate tumor tissue, colon tumor, normal prostate, and at a lower level in normal liver, skin and testes with undetectable expression in other tissues tested. H1-1 was found to be highly expressed in tissue from prostate cancer, lung cancer, breast cancer, normal prostate, normal colon, normal brain, to a much lower level in normal lung, pancreas, skeletal muscle, skin, small intestine, marrow bone and was not detectable in other tissues tested. 11-17 (P502S) and L1-12 (P501S) have been shown to be specifically overproduced in the prostate, with both genes highly expressed in prostate cancer and normal prostate, but low to undetectable levels in all other tissues tested. N1-1862 (P503S) was found to be overexpressed in 60% of prostate tumors and was detectable in normal colon and kidney. The RT-PCR results therefore indicate that F1-16, H1-1, J1-17 (P502S), N1-1862 (P503S) and L1-12 (P501S) are either prostate specific or expressed at increased levels in the prostate.

Further RT-PCR studies showed that F1-12 (P504S) is overexpressed in 60% of prostate tumors, was detectable in normal kidney, but not detectable in other tissues tested. Similarly, R1-2330 was shown to be overexpressed in 40% of prostate tumors, was detectable in normal kidney and liver, but was not detectable in other tissues tested. It was found that U1-3064 was overexpressed in 60% of prostate cancers, it was also expressed in breast and colon tumors, but was not detectable in other tissues examined.

Study of R1-2330, U1-3064 and 1D-4279 by RT-PCR showed that these three antigens are overproduced in prostate and / or prostate tumors.

Northern blot analysis for four prostate tumors, two normal prostate samples, two BPH prostate samples, and normal colon, kidney, liver, lung, pancreas, skeletal muscle, brain, stomach, testes, small intestine, and bone marrow showed that L1-12 (P501S ) is overproduced in prostate and normal prostate cancer, and is undetectable in other tissues tested. 11-17 (P502S) was found to be overexpressed in two prostate tumors but not in the other tissues examined. F1-12 (P504S) was found to be highly expressed in two prostate tumors and undetectable in all other tissues tested.

The microplate technology described above was used to determine expression levels of representative antigens described herein in prostate cancer, breast cancer and the following normal tissues: prostate, liver, pancreas, skin, bone marrow, brain, breast, adrenal gland, bladder, testes, salivary gland, intestine. thick, kidney, ovary, lung, core

The spinal cord, skeletal muscle and colon. L1-12 (P501S) was found to be overexpressed in normal prostate and prostate cancer with some expression level detectable in normal skeletal muscle. Both J1-12 and F1-12 (P504S) were found to be overexpressed in the prostate tumor, with expression being lower or undetectable in all other tissues examined. N1-1862 (P503S) was found to be expressed at high levels in prostate cancer and normal prostate, at much lower levels in normal large intestine and normal colon, with undetectable expression in all other tissues examined. R1-2330 was found to be expressed at high levels in prostate tumor and normal prostate, and at lower levels in all other tissues examined. It was found that 1D-4279 was expressed at high levels in prostate cancer and normal prostate, and at lower levels in the spinal cord, and was undetectable in all other tissues tested.

Further microplate analysis to investigate the extent of P501S (SEQ ID NO: 110) expression in the breast tumor showed moderate overexpression not only in the breast tumor but also in metastatic breast tumor (2/31) with barely visible to low expression in normal tissues . These data suggest that P501S may be overexpressed in a variety of breast tumors as well as prostate tumors.

Expression levels 32 ESTs (expressed sequence tags) described by Vasmatzis et al. (Proc. Natl. Acad Sci. USA 95: 300-304,1998) in a variety of neoplastic and normal tissues were examined by the use of microplate technology as described above. Two of these clones (designated P1000C and P1001C) were found to be overexpressed in prostate cancer and normal prostate and expressed at lower to undetectable levels in all other tissues examined (normal aorta, thymus, resting and activated PBMCs, endothelial cells, spinal cord, adrenal gland, fetal tissue, skin, salivary gland, large intestine, bone marrow, liver, lung, dendritic cells, stomach, lymph nodes, brain, heart, small intestine, skeletal muscle, colon, and kidney. The determined cDNA sequences for P1000C and P1001C are provided in SEQ. ID NO .: 384 and 472, respectively. P1001C was found to have some homology to previously isolated human mRNA for the JM27 protein. No significant homology was found with the P1000C sequence.

Expression of the polypeptide encoded by the full length cDNA sequence for F1-12 (also referred to as P504S; SEQ ID NO: 108) was examined by histochemical analysis. Rabbit anti-P504S polyclonal antibodies against full-length P504S protein were generated using standard techniques. The isolation and characterization of the polyclonal antibodies were then performed by techniques well known in the art. Histochemical analysis showed that the P504S polypeptide was expressed in 100% of the tested samples (n = 5) of the prostate cancer.

The rabbit anti-P504S polyclonal antibody does not appear to label benign prostatic hyperplasia cells with only granular cytoplasmic staining, but rather light nuclear staining. Normal tissue analysis has shown that the encoded polypeptide is expressed in some, but not all, normal human tissues. Positive cytoplasmic staining with rabbit polyclonal anti-P504S antibody was found in normal human kidney, liver, brain, colon, and lung-associated macrophages, while the heart and bone marrow were negative.

These data indicate that the P504S polypeptide is present in prostate cancer tissues and that there are qualitative and quantitative differences in staining between benign prostatic hyperplasia tissues and prostate cancer tissues, suggesting that the polypeptide can be selectively detected in prostate tumors and therefore be useful in diagnosing prostate cancer.

Example 3

Isolation and characterization of prostate cancer polypeptides by PCR-based narrowing

A narrowed cDNA library containing cDNA from normal tissue eliminated CDBA from ten other normal tissues (brain, heart, kidney, liver, lung, ovary, placenta, skeletal muscle, spleen, and thymus) and then subjected to the first round of PCR amplification was obtained from Clontech. This library was subjected to a second round of PCR amplification according to the manufacturer's protocol. The obtained cDNA fragments were subcloned into the pT7 Blue T-vector (Novagen, Madison, WI) and transformed into E. coli XL-1 Blue MRF '(Stratagene). DNA was isolated from independent clones and sequenced using a Perkin Elmer / Applied Biosystems Division Automated Sequencer Model 373A.

PL 200 772 B1

Fifty-nine positive clones were sequenced. Comparison of the DNA sequences of these clones with those of the gene bank as described above showed no significant homology to 25 of these clones, hereinafter referred to as P5, P8, P9, P18, P20, P30, P34, P36, P38, P39, P42, P49, P50, P53, P55, P60, P64, P65, P73, P75, P76, P79 and P84. The determined cDNA sequences for these clones are provided in SEQ. ID NO .: 41-45, 47-52, and 54-65, respectively. P29, P47, P68, P80 and P82 (SEQ. Nos. 46, 53 and 66-68 respectively) show some degree of homology with previously identified DNA sequences. To the knowledge of the inventors, none of these sequences has previously been shown to be present in the prostate.

Further studies using the PCR-based methodology described above resulted in the isolation of more than 180 additional clones, 23 of which were not found to show significant homology with known sequences. The determined cDNA sequences for these clones are provided in SEQ. ID NO .: 115-123, 127, 131, 137, 145, 147-151, 153, 156-158, and 160. For twenty-three clones (SEQ. ID NO: 124-126, 128-130, 132-136, 138-144, 146, 152, 154, 155 and 159) were found to share some homology with previously identified EST sequences. For an additional ten clones (SEQ ID NOs: 161-170) they show some degree of homology with known genes. The larger cDNA colons containing the P20 sequence represent the splicing variants designated P703P. The determined DNA sequence for the variants designated DE1, DE13 and DE14 is shown in SEQ. ID NOs: 171, 175, and 177, respectively, with the corresponding predicted amino acid sequence are set forth in SEQ. ID NO .: 172, 176 and 178, respectively. The determined cDNA sequence for the longer spliced ​​forms of P703 is shown in SEQ. ID NO: 225. The DNA sequences for the splice variants designated DE2 and DE6 are provided in SEQ. ID NO .: 173 and 174 respectively.

MRNA expression levels for representative clones in neoplastic tissues (prostate (n-5), breast (n = 2), colon and lung), normal tissues (prostate (n = 5), colon, kidney, liver, lung (n = 2) ), skeletal muscle, skin, stomach, small intestine and brain) and the activated and non-activated PBMCs were determined by TR-PCR as described above. Expression was tested in one sample from each tissue type unless otherwise stated.

For P9, a high level of expression was found in normal prostate and prostate tumor compared to all normal tissues except the normal colon, which showed comparable expression. For P20, part of the P703P gene, a high level of expression was found in normal prostate and prostate cancer compared to all twelve normal tissues tested. A slight increase in P20 expression in breast cancer (n = 2), colon cancer and lung cancer was seen compared to all other normal tissues except lung (1 of 2). Increased expression of P18 was found in normal prostate, prostate cancer and breast cancer as compared to all normal tissues except lung and stomach. A slight increase in P5 expression was observed in the normal prostate compared to most other normal tissues. However, some increase in expression was seen in normal lung and PBMC. Increased P5 expression was also observed in prostate cancer (2 out of 5), breast cancer and one lung cancer sample. For P30, a similar level of expression was seen in normal prostate and prostate carcinoma, compared to six of the twelve normal tissues tested. Increased expression was seen in breast tumor, one lung tumor sample and one colon tumor sample, as well as normal PBMC. P29 was found to be overexpressed in prostate cancer (5 out of 5) and in normal prostate (5 out of 5) compared to most normal tissues. However, significant expression of P29 was observed in the normal colon and normal lung (2 out of 2). P80 was found to be overexpressed in prostate cancer (5 out of 5) and normal prostate (5 out of 5) compared to all other normal tissues tested with increased expression also seen in colon cancer.

Further research led to the isolation of twelve additional clones, hereinafter referred to as 10-d8, 10-h10, 11-c8, 7-g6, 8-b5, 8-b6, 8-d4, 8-d9, 8-g3, 8- h11,9-f12 and 9-f1. The determined DNA sequences for 10-d8, 10-h10, 11-c8, 8-d4, 8-d9, 8-h11, 9-f12 and 9-f1 are provided in SEQ. ID NO .: 207, 208, 209, 216, 217, 220, 221 and 222, respectively. The determined sequences and their complementary sequences for 7-g6, 8-b5, 8-b6 and 8-g3 are provided in SEQ. ID NO: 210 and 211; 212 and 213; 214 and 215; and 218 and 219, respectively. Comparison of these sequences with those in a database showed no significant homology to the 9-f3 sequence. Clones 10-d8, 11-c8 and 8-h11 were found to share some homology with previously identified EST sequences, while clones 10-h10, 8-b5, 8-b6, 8-d4, 8-d9, 8- g3 and 9-f12 share some homology with previously identified genes.

PL 200 772 B1

Further characterization of 7-G6 and 8-G3 showed identity with the known PAP and PSA genes, respectively.

The mRNA expression levels for these clones were established using the microplate technology described above. Clones 7-G6, 8-G3, 8-B5, 8-B6, 8-D4, 8-D9, 9-F3, 9F12, 9-H3, 10-A2, 10-A4, 11-C9 and 11 were overexpressed -F2 in prostate cancer and normal prostate, and expression in other tissues tested was low or undetectable. Increased expression of 8-F11 was observed in prostate cancer and normal prostate, bladder, skeletal muscle and colon. Increased expression of 10-H10 has been observed in prostate cancer and normal prostate, bladder, lung, colon, brain and large intestine. Increased expression of 9-B1 was seen in prostate cancer, breast cancer and normal prostate, salivary gland, large intestine and skin, with increased expression of 11-C8 seen in prostate cancer and normal prostate and large intestine.

The additional PCR-based and normal prostate-based narrowing DNA fragment described above has been found to be prostate specific in both microplate and RT-PCR technology. The determined cDNA sequence for this clone (referred to as 9A11) is shown in SEQ. ID NO: 226. Comparison of this sequence with those in public databases revealed 99% identity with the known HOXB13 gene.

Further research led to the isolation of clones 8-C6 and 8-H7. The determined cDNA sequences for these clones are provided in SEQ. ID NO .: 227 and 228, respectively. These sequences were found to share some homology with previously identified EST sequences.

PCR-based and hybridization methodologies were used to obtain longer DNA sequences for the P20 clone (also referred to as P703P), yielding three additional DNA fragments extending further and further towards the 5 'of the gene. The fragments referred to as P703PDE5, P703P6.26, and P703PX-23 (SEQ ID NOs: 326, 328 and 330, with the predicted corresponding amino acid sequence provided in SEQ ID NO: 327, 329 and 331, respectively) contain an additional sequence 5 '. P703PDE5 was obtained by screening a cDNA library (# 141-26) with P703P as a probe. P703P6.26 was obtained from a mixture of three prostate tumor DNA, and P703PX-23 was obtained from a cDNA library (# 438-48). Collectively, the additional sequences include all three putative mature serine proteases along with part of the putative signal sequence. Further studies using a narrowed library based on PCR obtained from prostate cancer pools with pools of normal tissue eliminated (referred to as narrowing JP: PCR) resulted in the isolation of thirteen additional clones, seven of which did not show any significant homology with known sequences in GenBank. The determined cDNA sequences for these seven clones (P711P, P712P, novel 23, P774P, P775P, P710P and P768P) are shown in SEQ. ID NOs: 307-311, 313 and 315, respectively. The remaining six clones (SEQ ID NOs: 316 and 321-325) were found to share some homology with known genes. By analysis of microplates, all thirteen clones were shown to be three times or more overexpressed in prostate tissues, including prostate cancer, BPH and normal prostate as compared to normal non-prostate tissues. Clones P711P, P712P, novel 23, and P768P were overexpressed in most prostate and BPH tissues tested (n = 29) and in most normal prostate tissues (n = 4), but at the background level to low expression in all normal tissues. Clones P774P, P775P and P710P showed relatively low expression and expression in fewer prostate cancer and BPH samples, with no to low expression in normal prostate.

Full-length cDNA for P711P was obtained by using the partial sequence SEQ. ID NO: 307 to search a cDNA library. Specifically, a directly cloned prostate DNA library was prepared using standard techniques. One million colonies from this library were plated on LB / Amp plates. Nylon filters were used to transfer these colonies, and the cDNA that adhered to the filters was denatured and bound to the filters using UV light. P711P DNA fragment from SEQ. ID NO: 307 was radiolabeled and dihybridized with these filters. Positive clones were selected and cDNA was isolated and sequenced using a Perkin Elmer Applied Biosystems automated sequencer. The determined full-length P711P sequence is shown in SEQ. ID NO: 382, ​​with the corresponding predicted amino acid sequence set forth in SEQ. ID NO .: 383.

Using PCR-based and hybridization methodologies, additional sequence information was obtained for the two clones described above, 11-C9 and 9-F3, hereinafter referred to as P707P and P714P, respectively (SEQ ID NO: 333 and 334). Compared to the most recent GeneBank,

P707P was found to be a splicing variant of the known HoxB13 gene. In contrast, no significant homology with P714P was found.

Clones 8-B3, P89, P98, P130, and P201 (disclosed in US Patent Application No. 09 / 020,956, filed February 9, 1998) were found to be contained in one contiguous sequence, designated P705P (SEQ ID NO: 335, with the predicted amino acid sequence provided in SEQ ID NO: 336) which was found to be a splice variant of the known NKX 3.1 gene.

Example 4

Synthesis of polypeptides

Polypeptides can be synthesized on a peptide synthesizer

Perkin Elmer / Applied Biosystems 430A using FMOC chemistry with HPTU activation (O-Benzotriazole-N, N, N ', N'-tetramethyluronion hexafluorophosphate). Gly-Cys-Gly sequences can be fused to the amino terminus of the peptide to provide a method for conjugating, binding to the immobilized surface, or labeling the peptide. Cleavage of the peptide from the solid support can be performed using the following cleavage mixture: trifluoroacetic acid: ethanedithiol: thioanisole: water: phenol (40: 1: 2: 2: 3). After cleavage for 2 hours, the peptides can be precipitated in cold methyl t-butyl ether. The peptide precipitates can then be dissolved in water containing 0.1% trifluoroacetic acid (TFA) and lyophilized prior to purification by C18 reverse phase HPLC. A gradient of 0% -60% acetonitrile (containing 0.1% TFA) in water (containing 0.1% TFA) can be used to elute the peptides. After lyophilization of the pure fractions, the peptides may be characterized by electrospray or other type of mass spectrometry and by amino acid analysis.

Example 5

Further isolation and characterization of prostate cancer polypeptides by PCR-based narrowing

A DNA library prepared from primary prostate cancer tumor mRNA as described above was narrowed using DNA from normal prostate. The constriction was performed using a PCR based protocol (Clontech) which was no longer modified to produce larger fragments. In this protocol, constricted and eliminated DNA was digested separately with five restriction enzymes that recognize six-nucleotide restriction sites (MluI, MscI, PvuII, SalI, and StuI). This digestion led to the formation of fragments of an average size of 600 bp instead of an average size of 300 bp as a result of Rsal digestion according to the Clontech protocol. This modification has no effect on the elimination performance. Two test populations with different adapters were then created, while the library being eliminated was left without adapters.

The tested and eliminated libraries were then hybridized with an excess of eliminated DNA. In the first step of hybridization, the eliminated DNA was hybridized with each of the two tested DNA populations. The result was a population of (a) non-hybridized test DNA, (b) test DNA hybridized with other test DNA, (c) test cDNA hybridized with eliminated DNA, and (d) non-hybridized eliminated DNA. Two separate hybridization reactions were combined together and rehybridized in the presence of additional denatured eliminated DNA. After this second hybridization, in addition to the population from (a) to (d), a fifth population (e) was formed in which the tested DNA with one adapter hybridized with the test DNA with the other adapter. Thus, the result of the second hybridization step was the enrichment of the differentially expressed sequences that could serve as templates for amplification with adapter-specific primers.

The ends were then filled in and PCR reactions were performed using adapter specific primers. Only the population (s) that contained test DNA that did not hybridize with the eliminated DNA were amplified exponentially. A second amplification step was then performed to reduce background and further enrich the differentially expressed sequences.

This PCR-based elimination technique normalizes the differentially expressed DNA, allowing the recovery of rare transcripts that are overproduced in such prostate tissue. Such transcripts would be difficult to isolate by traditional elimination methods.

In addition to genes known to be overexpressed in prostate cancer, seven further clones have been identified. The sequences of these partial DNA sequences are provided in SEQ. ID NOs: 29 to 305. Most of these clones did not have significant homology with the sequences in the databases. The exceptions were JPTPN23 (SEQ ID NO: 23); similarity to porcine valosine containing protein), JPTPN30 (SEQ ID NO: 234; similarity to rat mRNA for the proteasome subunit), JPTPN45 (SEQ. ID NO .: 243; resemblance to cytosolic rat norvegicus

PL 200 772 B1

NADP-dependent isocitate dehydrogenase), JPTPN46 (SEQ ID NO: 244; similarity to the human DNA sequence of H8 subclone 4 d4), JP1D6 (SEQ ID NO: 265; similarity to the A dynein light chain from G. gallus), JP8D6 (SEQ ID NO: 288; similarity to the human BAC clone RG016J04), JP8F5 (SEQ ID NO: 289; similarity to the human DNA sequence of H8 subclone 3b5) and JP8E9 (SEQ ID NO: 299; similarity to the human Alu sequence).

Additional studies with a PCR-based narrowed library consisting of a pool for prostate tumor elimination using a pool for normal prostate (referred to as PT-PN PCR narrowing) resulted in three additional clones. Comparison of the DNA sequences of these clones with the most recent version of GenBank showed no significant homology for the two clones designated P71SP and P767P (SEQ ID NO: 312 and 314). Homologies to the new KIAA00S6 gene (SEQ ID NO: 318) were found for the remaining clones. Using microplate analysis to measure mRNA expression levels in various tissues, all three clones were found to be overexpressed in prostate tumors and BPH tissues. Specifically, clone P715P was overexpressed in most prostate tumor tissues and BPH tissues, on the order of 3 times or more, with increased expression seen in most samples of right ^ - ^ <^ '^^ j prostate and fetal tissue, but no low expression in all other normal tissues. Clone P767P was overexpressed in several tissues of prostate cancer and BPH, with little expression seen in half of the normal prostate specimens and background expression to low in all other normal tissues tested.

Subsequent microplate analysis as described above of the narrowed PT-PN PCR library and the narrowed DNA library containing prostate cancer DNA with eliminated DNA from normal tissues resulted in the isolation of 27 additional clones (SEQ ID NOs: 340-365 and 381) which were shown to be overexpression in prostate cancer. Clones from SEK. ID NO: 341, 342, 345, 347, 348, 349, 351, 355-359, 361, 362, and 364 are also expressed in normal prostate). Expression of all 26 clones in a variety of normal tissues was found to be low or undetectable, with the exception of P544S (SEQ ID NO: 356) which was found to be overexpressed in the small intestine. Of the 26 clones, 10 (SEQ ID NOs: 340-349) showed some homology to the early identified sequences. No significant homology was found for the clones from the SEK. ID NO .: 350-365.

Example 6

Peptide treatment of mice and generation of CTL lines

6. 1. This example illustrates the generation of CTL lines specific for cells expressing the P502S gene.

Mice expressing the human HLA A2.1 transgene (supplied by Dr. L. Sherman, The Scripps Research Institute, La Jolla, CA) were immunized with P2S # 12 peptide (VLGWVAEL; SEQ ID NO: 306), which is derived from the P502S gene ( also referred to herein as J1-17, SEQ ID NO: 8) as described by Theobald et al., Proc. Natl. Acad Sci. USA 92: 11993-11997,1995 with the following modifications. Mice were immunized with 100 µg P2S # 12 and 120 µg 1-A binding peptide^b hepatitis B virus protein as an emulsion in incomplete Freund's adjuvant. Three weeks later, these mice were sacrificed and single cell suspensions were prepared using a nylon mesh. Cells were then resuspended at a concentration of 6 x 10⁶ cells / ml in complete medium (RPMI-I640; Gibco BRL, Gaithersburg, MD) containing 10% FCS, 2 mM glutamine (Gibco BRL), pyro^gron^andan sodium (^Gibwhat B^RL) Ne Nez^willne amnosacids (^Gibwhat B^RL) ² x W.^{5 M 2}-mayor^kand^Frioe^volanoh ⁵⁰units / ml penicillin and streptomycin and cultured in the presence of pulsed P2S # 12 (5 mg / ml P2S # 12 and 10 mg / ml 02-microglobulin) irradiated (3000 rad) LPS blastocytes (A2 transgenic spleen cells were cultured in the presence of 7 ng / ml dextran sulfate and 25 µg / ml LPS ^pslaughter ^volnoun^y dN). ^S.that^life drn ^lateNej tomórld (⁵ x ^105/m^l) stimulated ^pawesome ^2,5 x peptide pulsed irradiated (20,000 rad) EL4A2Kb cells (Sherman et al, Science 258: 815-818 (1992) and 3 x 106 / ml spleen A2 transgenic feeder cells. Cells were cultured in the presence of 20 U / ml IL-2. Cell restimulation was continued weekly as described in preparation of the cloning line.

The P2S # 12 line was cloned by limiting dilution analysis using peptide pulsed A2Kb EL4 tumor cells (1 x 10⁴ cells / well) as stimulator and A2 transgenic feeder cells (5 x 105 cells / well) as feeder cells in the presence of 30 U / ml IL-2. On day 14, cells were restimulated as before. On day 21, clones that had grown were isolated and maintained in culture. Several of these clones showed

Significantly higher reactivity (lysis) towards P502S transduced human fibroblasts (expressing HLA A2.1) as compared to control fibroblasts. An example is shown in Fig. 1.

These data indicate that P2S # 12 represents the naturally processed epitope of the P502S protein expressed in the context of the human HLA A2.1 molecule.

6.2. This example illustrates the preparation of murine CTL lines and CTL clones specific for cells expressing the S P501 gene.

These series of experiments were performed similar to those described above. Mice were immunized with P1S # 10 peptide (SEQ ID NO: 337) which is derived from the P501S gene (also referred to herein as L1-12, SEQ ID NO: 110). The P1S # 10 peptide was derived from analysis of the predicted P501S polypeptide sequence for potential HLA-A2 binding sequences determined from published HLA-A2 binding motifs (Parker, KC, el al., J: Immunol., 152: 163, 1994). The P1S # 10 peptide was synthesized as described in Example 4 and tested experimentally for the ability to bind HLA-A2 using a T-cell competition assay. Predicted A2 binding peptides were tested for their ability to compete with HLA-A2 specific display. antigen against an HLA-A2 restricted CTL clone (D150M58) which is specific for the HLA-A2 binding fluM58 peptide from influenza virus matrices. CTL D150M58 secrete TNF in response to self-presentation of the fluM58 peptide. In the competition assay, labeled test peptides were added at a concentration of 100-200 ng / ml to the culture of CTL D150M58 to bind HLA-A2 to the CTL. Thirty minutes later, CTLs cultured with test peptides or control peptides were tested for their antigen dose response to the fluM58 peptide in a standard TNF assay. As shown in Fig. 3, P1S # 10 peptide competes with HLA-A2 restricted presentation of fluMS8, showing that P1S # 10 peptide binds HLA-A2.

Mice expressing the human HLA A2.1 transgene were immunized as described by Theobald et al. (Proc. Natl. Acad Sci. USA 92: 11993-11997, 1995) with the following modifications. Mice were immunized with 62.5 ng P1S # 10 and 120 ng 1-A binding peptide^bhepatitis B virus protein as an emulsion in incomplete Freund's adjuvant. Three weeks later, these mice were sacrificed and single cell suspensions were prepared using a nylon mesh. The cells were then resuspended at a concentration of 6 x 10⁶ cells / ml in complete medium (as described above) and cultured in the presence of pulsed P1S # 10 (2 ng / ml P1S # 10 and 10 mg / ml 32-microglobulin) irradiated (3000 rad) LPS blasts (A2 transgenic spleen cells cultured in the presence of 7 ng / ml dextran sulfate and 25 ng / ml LPS for 3 days). Six days later, cells (5 x 10⁵/ ml) was re-stimulated with 2.5 x 106 / ml pulsed with the peptide irradiated (²⁰⁰⁰⁰ ra^downin) ^kom <óre^{k E}L.⁴A2^K.b, i^k about^pisano ^pthat^yżhey ^{and 3} x ^volrans^gen^andczn^yc^h Itomcirkelt spleen nutrient A2. Cells were grown in the presence of 20 U / ml IL-2. Cell restimulation was continued weekly as described in preparation of the cloning line. After three rounds of in vitro stimulation, one line was generated that recognized the pulsed P1S # 10 target Jurkat A2Kb cells and the P501S transduced Jurkat target cells as shown in Figure 4.

The P1S # 10 specific CTL line was cloned by limiting dilution analysis using peptide pulsed A2Kb EL4 tumor cells (1 x 10⁴cells / well) as stimulator and A2 transgenic spleen feeder cells (5 x 10⁵cells / well) as feeder cells in the presence of 30 U / ml IL-2. On day 14, cells were restimulated as before. On day 21, live clones were isolated and maintained in culture. As shown in Figure 5, five of these clones showed specific cytolytic reactivity against the P501S transduced Jurkat A2Kb target cells. These data indicate that P1S # 10 represents the naturally processed epitope of the P501S protein expressed in the context of the human HLA-A2.1 molecule.

Example 7

The ability of human T cells to recognize prostate cancer polypeptides

This example illustrates the ability of prostate tumor polypeptide-specific T cells to recognize human tumor.

Human CD8 + T cells were plated with m vrtro ^peptyd ^P2S-¹² (^KNOT. ^NO ID.: ³⁰⁶) ^poclio^dwith^andcym with P502S (also referred to as J1-17) using dendritic cells according to the protocol of Van Tsai et al. (Critical Reviews in Immunology 18: 65-75,1998). The resulting micro-cultures of CD8 + T cells were tested for their ability to recognize the P2S-12 peptide presented by autologous fibroblasts or fibroblasts that had been transduced to express the P502S gene in the ELIESTPOT interferon γ assay (see Lalvani et al., J. Exp. Med

PL 200 772 B1

186: 859-865,1997). Briefly, the titrated number of T cells was tested in duplicate out of 10⁴ fibroblasts in the presence of 1 µg / ml human microglobulin and 1 µg / ml P2S-12 peptide or E75 control peptide. In addition, T cells were tested simultaneously on autologous fibroblasts that were transduced with the P502S gene or HER-2 / neu transduced fibroblasts as a control. Prior to the test, fibroblasts were treated with 10 µg / ml interferon γ for 48 hours to raise the level of MHC class I expression. One microculture (# 5) strongly recognized both fibroblasts pulsed with polypeptide and transduced fibroblasts in the ELIESTPOT test for interferon γ. Figure 2 shows that there is a strong increase in the number of γ interferon spots with increasing number of T cells on fibroblasts pulsed with P2S-12 peptide (solid bars) but not with the control E75 peptide (open bars). This demonstrates the ability of these T cells to specifically recognize the P2S-12 peptide. As shown in Fig. 2B, this microculture also showed an increase in the number of γ interferon spots with increasing number of T cells on the fibroblasts transduced to express the P502S gene but not the HER-2 / neu gene. These results provide additional confirmation that the P2S-12 peptide is a naturally processed epitope of the P502S protein. Furthermore, it also shows that there are high affinity T cells among human T cells that are capable of recognizing this epitope. T cells should also be capable of recognizing human tumors that express the P502S gene.

Example 8

In vivo CTL induction against prostate antigen using naked DNA immunization

Prostate tumor antigen L1-12, described herein above, is also referred to as P501S. HLA A2Kb Tg mice (provided by Dr. L. Sherman, The Scripps Research Institute, La Jolla, CA) were immunized with 100 pg VR10132-P501S either intramuscularly or intradermally. Mice were immunized three times at two-week intervals between each immunization. Two weeks after the last immunization, spleen cells of immunized mice were cultured with Jurkat stimulating cells transduced with A2Kb-P501S. CTL lines were stimulated weekly. After two weeks of in vitro stimulation, the CTL activity was determined against P501S transduced cells. Two of the eight mice developed a strong CTL conditioned anti-P501S response. These results show that P501S contains at least one naturally processed A2-restricted CTL epitope.

Example 9

Generation of human CTL with prostate tumor antigen in vitro using whole gene excitation and stimulation techniques

Using in vitro whole gene excitation with naturally occurring (autologous) fibroblasts transduced with P501S using retoviruses (cf. for example Yee et al., The Jurnal of Immunology, 157 (9): 4079-86, 1996), human CTL cell lines were derived , specifically recognizing autologous P501S transduced fibroblasts (also known as L1-12) as confirmed by ELISPLOT analysis for interferon-γ as described above. Using a set of P501S transduced HLA-mismatched fibroblast lines, the derived CTL lines were shown to be restricted to the HLA-A2 class I allele. Specifically, dendritic cells (DCs) were differentiated from monocyte cultures derived from PBMCs of normal (tumorigenic) human donor cells by five-day growth in RPMI medium containing 10% human serum, 50 ng / ml human GM-CSF and 30 ng / ml ml of human IL-4. After culturing under the conditions described, dendritic cells were infected overnight with P501S recombinant vaccinia virus under multiplicity of infection (MV) conditions. multiplicity of infection (MOI) of five, then allowed to mature overnight by adding 3 pg / ml CD40 ligand. The virus was inactivated by irradiation with ultraviolet light. CD8 + T cells were removed using a magnetic bead system and then seed cultures were established using standard techniques used in tissue culture. Cultures were restimulated every seven to ten days using autologous, primary P501S transduced fibroblasts by a retroviral system. After four stimulation cycles, CD8 + T cell lines were detected to produce interferon-γ upon stimulation with autologous P501S transduced fibroblasts. P501S dependent activity can be confirmed by further stimulation of the cultures with P501S transduced fibroblasts in the presence of IL-15. A set of fibroblast lines with altered P501S transduced histocompatibility antigens was created to define to which allele the response is limited. By measuring interferon-γ by ELISPLOT assay, the specific response was shown to be limited to HLA-A2. The reported results show that a CD8 + CTL response against P501S can be induced.

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Example 10

Identification of a naturally processed CTL epitope contained in a prostate tumor antigen

The nine-amino acid p5 peptide (SEQ ID NO: 338) was derived from the P703P antigen (also referred to as P20). The p5 peptide is immunogenic to human HLA-A2 donor cells while being a naturally recognized epitope. Antigen-specific CD8 + T cells can be raised after repeated in vitro stimulation with monocytes pulsed with p5 peptide. Such CTLs specifically recognize p5-pulsed target cells in both the ELISPLOT assay described above and the chromium release assay. In addition, immunization of HLA-A2 transgenic mice with p5 peptide results in the generation of CTL cell lines which recognize P703P transduced target cells that express HLA-A2Kb or HLA-A2. Specifically, HLA-A2 transgenic mice were immunized subcutaneously in a footpad with 100 µg p5 peptide together with 140 µg hepatitis B core peptide (Th peptide) in incomplete Freund's adjuvant. Three weeks after immunization, spleen cells from immunized mice were stimulated in vitro with LPS pulsed blasts. CTL activity was measured using a chromium release assay five days after primary in vitro stimulation. Retroviral transduced cells expressing the control antigen P703P and HLA-A2Kb were used as target cells. CTL lines were identified that specifically recognized both cells pulsed with p5 peptide and those expressing the P703P antigen.

In vitro excitation experiments demonstrated the immunogenicity of the p5 peptide in humans. Dendritic cells (DCs) were differentiated from monocyte cultures derived from PBMCs of normal human donor cells by growing for five days in RPMI medium containing 10% human serum, 50 ng / ml human GM-CSF and 30 ng / ml human IL-4. After culturing, dendritic cells were pulsed with p5 peptide and cultured in the presence of GM-CSF and IL-4 together with CD8 + T cells, enriching the PBMC cultures. CTL lines were restimulated weekly with p5 pulsed monocytes. Five to six weeks after initiating the CTL culture, recognition of p5-pulsed target cells was demonstrated.

Example 11

Prostate tumor derived antigen expression

The isolation of the B305D antigen from a tumor by differential dispaly (PCR) is described in US Patent Application No. 08 / 700,014 filed August 20, 1996. Several forms have been isolated as a result of alternative splicing of exons. The cDNA sequences for each form are available as SEQ. ID NO .: 366-375, simultaneously the sequences of the encoded proteins corresponding to the sequences of SEQ. ID NOs: 292, 298 and 301-303 are available as SEQs, respectively. ID NO .: 299-306.

B305D expression levels in various neoplastic and normal (non-neoplastic) tissues were investigated using real time PCR and Northern blot analysis. The results indicate that B305D is highly expressed in cancers of the breast, prostate, normal prostate and normal testicular tissue. In contrast, low or undetectable levels were observed in the remaining tissues tested (colorectal cancer, lung cancer, ovarian cancer, and normal bone marrow, colon, kidney, liver, ovary, skin, small intestine and stomach).

Example 12

Induction of a prostate tumor antigen specific CTL response in human blood

The example describes the ability to elicit a specific CTL response by a prostate tumor antigen in human blood.

Autologous dendritic cells (DCs) were differentiated from monocyte cultures derived from PBMCs of normal human donor cells by growing for five days in RPMI medium containing 10% human serum, 50 ng / ml human GM-CSF and 30 ng / ml human IL-4. After culturing under the conditions described, dendritic cells were infected overnight with P501S recombinant vaccinia virus under an MOI of five, then allowed to mature overnight by adding 2 µg / ml CD40 ligand. The virus was inactivated by irradiation with ultraviolet light. CD8 + T cells were isolated by positive selection using a magnetic bead system, then starting cultures were plated in 24-well plates. Then, after five stimulation cycles, CD8 + cell lines were detected to produce interferon-y when stimulated with autologous P501S transduced fibroblasts. P501S specific cell activity

The 3A-1 cell line was maintained after additional stimulation cycles on P501S transduced autologous B-LCL cells. It was demonstrated using a cytotoxicity test (release⁵¹Cr) and markings ^pro^dsuppression^and mterferon ^gamma flnterferon ^gamma E.^L.AND^S.P.^L.OT^,see above and Lalvani et al, J Exp. Med. 186: 859-865,1997) that the 3A-1 cell line specifically recognized autologous B-LCL cells transduced to express P501S while not recognizing autologous EGFP transduced B-LCL cells. The results of the described experiments are shown in Figures 6A and 6B.

Example 13

Identification of prostate tumor antigens using microplate analysis

The example describes a method of isolating certain prostate cancer polypeptides from a prostate cancer cDNA library.

The human prostate cancer cDNA expression library as described previously was analyzed by microplates to identify clones showing at least three times the expression level in prostate cancer and / or non-cancerous prostate tissue relative to other non-cancerous tissues (not including the testes). 372 clones were identified, 319 of which were sequenced. Table 1 summarizes the identified clones, which are shown as SEQ. ID NO .: 385-400. Sequences about SEK. ID NO: 386, 389, 390 and 392 correspond to the new genes, while the sequences in SEQ. ID NOs: 393 and 396 correspond to previously identified sequences. The others (SEQ ID NOs: 385, 387, 388, 391, 394, 395 and 397-400) correspond to known sequences as shown in Table I.

Table I.

Summary of prostate cancer antigens

<td>Known genes</td><td>Previously identified genes</td><td>New Genes</td>

<td>T cell gamma chain</td><td>P504S</td><td>23379 (SEQ ID NO: 389)</td>

<td>Kallikrein</td><td>P1000C</td><td>23399 (SEQ ID NO: 392)</td>

<td>Vector</td><td>P501S</td><td>23320 (SEQ ID NO: 386)</td>

<td>CGI-82 MRNA (23319; SEQ ID NO: 385)</td><td>P503S</td><td>23381 (SEQ ID NO: 390)</td>

<td>PSA</td><td>P510S</td><td></td>

<td>Aldehyde dehydrogenase</td><td>P784P</td><td></td>

<td>L-iditol dehydrogenase (23376; SEQ ID NO: 3 88)</td><td>P502S</td><td></td>

<td>Transcription factor PDEF (22672; SEQ ID NO: 398)</td><td>P706P</td><td></td>

<td>hTGR (22678; SEQ ID NO: 399)</td><td>191 42.2 bangur.seq (22621; SEQ ID NO: 396)</td><td></td>

<td>KIAA0295 (22685; SEQ ID NO: 400)</td><td>5566.1 Wang (23404; SEQ ID NO: 393)</td><td></td>

<td>Prostate acid phosphatase (22655; SEQ ID NO: 397)</td><td>P712P</td><td></td>

<td>Transglutaminase (2261L; SEQ ID NO: 395)</td><td>P778P</td><td></td>

<td>HDLBP (23508; SEQ ID NO: 394)</td><td></td><td></td>

<td>CGI-69 protein (23367; SEQ ID NO: 387)</td><td></td><td></td>

<td>KIAA0122 (23383; SEQ ID NO: 391)</td><td></td><td></td>

<td>TEEG</td><td></td><td></td>

Clone CGI-82 showed 4.06 times higher expression in prostate tissues compared to other normal tissues. The described clone was overexpressed in 43% in prostate tumors, 25% in normal prostate tissue and was not detected in other tissues. L-iditol dehydrogenase

PL 200 772 B1 showed 4.94 times higher expression in prostate tissues as compared to other normal tissues. It was overexpressed 90% in prostate tumors, 100% in normal prostate tissue, and was not detected in other tissues. The transcription factor PDEF showed 5.55 times higher expression in prostate tissues as compared to other, normal tissues. It was overexpressed 47% in prostate tumors, 25% in normal prostate tissue, and was not detected in other tissues. hTGR1 showed 9.11 times higher expression in prostate tissues as compared to other normal tissues. It was overexpressed in 63% in prostate tumors and was not detected in other normal tissues including the prostate. KIAA0295 showed 5.59 times higher expression in prostate tissues as compared to other normal tissues. It was overexpressed 47% in prostate tumors and was detected at very low or no levels in other normal tissues including the prostate. Prostate acid phosphatase showed 9.14 times higher expression in prostate tissues as compared to other normal tissues. It was overexpressed 67% in prostate tumors, 50% in normal prostate tissue, and was not detected in other tissues. Transglutaminase was 14.84 times more expressed in prostate tissues than in other normal tissues. It was overexpressed in 30% in prostate tumors, 50% in normal prostate tissue, and was not detected in other tissues.

HDL binding protein (HDLBP) was 28.06 times more expressed in prostate tissues than in other normal tissues. It was overexpressed 97% in prostate tumors, 75% in normal prostate tissue, and was not detected in other tissues. Clone CGI-69 showed 3.56 times higher expression in prostate tissues as compared to other normal tissues. This clone was low-expressed and detected in more than 90% of prostate tumors and in 75% of normal prostate tissue. Expression of this gene in normal non-prostate tissues has been very low. KIAA0122 showed 4.24 times higher expression in prostate tissues as compared to other normal tissues. It was overexpressed in 57% in prostate tumors and was not detected in other normal tissues including the prostate. 19142.2 bangaroo was 23.25 times more expressed in prostate tissues than other normal tissues, it was overexpressed 97% in prostate tumors, 100% in normal prostate tissue, and was not detected in other tissues. 5,566.1 Wang showed 3.31 times higher expression in prostate tissues as compared to other normal tissues. It was overexpressed 97% in prostate tumors, 75% in normal prostate tissue, and it was also overexpressed in bone marrow, pancreas and activated PBMCs. The newly identified clone 23379 showed 4.86 times higher expression in prostate tissues compared to other normal tissues. It was overexpressed 97% in prostate tumors, 75% in normal prostate tissue, and was not detected in other tissues. The newly identified clone 23399 showed 4.09 times higher expression in prostate tissues compared to other normal tissues. It was overexpressed in 27% in prostate tumors and was not detected in other non-neoplastic tissues including the prostate. The newly identified clone 23320 showed 3.15 times higher expression in prostate tissues compared to other normal tissues. It was overexpressed in all prostate tumors, 75% in normal prostate tissue, and it was also expressed in the colon and thyroid gland. Other normal tissues did not express the gene described.

Example 14

Identification of prostate cancer antigens using the technique of electronic narrowing

Potential genes specifically expressed in the prostate and at the same time stored in the GenBank database of human EST sequences were identified using the electronic narrowing method (described by Vesmatizis et al., Proc. Natl. Acad. Sci. USA 95: 300-304, 1998). Human EST clone sequences (43,482) derived from various prostate libraries were obtained from the human EST sequence database of the public GenBank database. Each prostate EST sequence served as a query in the BLASTN program (available from the National Biotechnology Information Center NCBI) of the entire database of human EST sequences. All sequences found to be identical (i.e., fragment length matching&gt; 100 bp and percent identity 70%) were grouped into sets. Sets containing more than 200 EST sequences were removed because they most likely represented repetitive elements or genes with very high expression levels (e.g., genes encoding ribosomal proteins). If two or more sets shared EST sequences, they were grouped into "supersets", resulting in a collection of 4,345 prostate-specific "supersets".

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All records of the 479 cDNA libraries collected at GenBank were imported to create a database of all cDNA sequence records. 479 cDNA libraries are divided into three groups: Plus (libraries from normal and neoplastic prostate tissue and breast cell lines whose expression was required), Minus (libraries from other normal tissues where expression was not required) and Rest (libraries of fetal tissues, infant tissues, tissues specific only for women, non-prostate neoplastic tissues, and libraries of non-prostate cell lines, whose expression was found not to be directly related to the topic). The grouping is summarized in Table II.

Table II

Prostate cDNA libraries and EST sequences

<td>Group</td><td>Number of libraries</td><td>Number of EST sequences</td>

<td>Plus</td><td> 25</td><td> 43482</td>

<td>Normal</td><td> 11</td><td> 18875</td>

<td>Cancerous</td><td> 11</td><td> 21769</td>

<td>Cell lines</td><td> 3</td><td> 2838</td>

<td>Minus</td><td> 166</td><td></td>

<td>Rest</td><td> 287</td><td></td>

Each superset was analyzed for its EST sequences. The source of each EST sequence was recorded and used for the classification of supersets. 4 groups were created: type 1 EST sequences found only in the Plus libraries group, while not detecting expression in the Minus and Rest groups; type 2 - EST sequences found only in the Plus and Rest groups, while not detecting expression in the Minus group; type 3 - EST sequences found in the groups of Plus, Minus and Remnant libraries, but with the proviso that their expression in the Plus group is higher in relation to both the Minus group and the Remainder group; and type 4 - EST sequences found in the Plus, Minus and Rest groups, but with the proviso that their expression in the Plus group is higher than in the Minus group. This analysis found 4345 suitable sets (shown in Table III). From these kits, 3,172 EST sequences were ordered from Research Genetics, Inc. which were shipped in glycerol on 96-well plates.

Table III

Prostate-specific EST sets

<td>^T.yp</td><td>Number of supersets</td><td>Number of ESTs ordered</td>

<td> 1</td><td> 688</td><td> 677</td>

<td> 2</td><td> 2899</td><td> 2484</td>

<td> 3</td><td> 85</td><td> 11</td>

<td> 4</td><td> 673</td><td> 0</td>

<td>Sum</td><td> 4345</td><td> 3172</td>

The appropriate inserts were amplified using PCR and primers suitable for further analysis using Synteni microplates. In case more than one PCR product was obtained from an appropriate clone, such product was further analyzed in terms of expression. A total of 2528 clones obtained by the electronic narrowing down method were subjected to microplate analysis to identify clones having high levels of tumor specific to normal mRNA. This search was performed using the Synteni system (Palo Alto, CA) following the manufacturer's instructions (as described in Schena et al., Proc. Natl. Acad. Sci. USA 93: 10614-10619, 1996 and in Heller et al., Proc. Natl. Acad. Sci. USA 94: 21502155,1997). During the description of the analysis, the clones were placed in an orderly manner on the plate, which was then tested with fluorescent probes obtained from prostate cDNA from neoplastic and normal tissue as well as various other normal tissues. Finally, the plates were scanned to measure the fluorescence intensity.

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Clones with an expression ratio of neoplastic tissue versus normal tissue equal to 3 (i.e. where the level of cDNA in the prostate tumor was at least three times higher compared to the non-neoplastic tissue) were treated as prostate tumor specific (Table IV). The sequences of the described clones are available as SEQs. ID NOs: 401-453, of which the completely new sequences are SEQ. ID NO .: 407, 413, 416-419, 422, 426, 427 and 450.

Table IV

<td>KNOT. ID NO.</td><td>Sequence designation</td><td>Comment</td>

<td> 1</td><td> 2</td><td> 3</td>

<td> 401</td><td> 22545</td><td>previously identified as P1000C</td>

<td> 402</td><td> 22547</td><td>previously identified as P704P</td>

<td> 403</td><td> 22548</td><td>Known</td>

<td> 404</td><td> 22550</td><td>Known</td>

<td> 405</td><td> 22551</td><td>PSA</td>

<td> 406</td><td> 22552</td><td>Prostate secretion protein 94</td>

<td> 407</td><td> 22553</td><td>New</td>

<td> 408</td><td> 22558</td><td>previously identified as P509S</td>

<td> 409</td><td> 22562</td><td>glandular kallikrein</td>

<td> 410</td><td> 22565</td><td>previously identified as P1000C</td>

<td> 411</td><td> 22567</td><td>PAP</td>

<td> 412</td><td> 22568</td><td>B1006C (breast cancer antigen)</td>

<td> 413</td><td> 22570</td><td>New</td>

<td> 414</td><td> 22571</td><td>PSA</td>

<td> 415</td><td> 22572</td><td>previously identified as P706P</td>

<td> 416</td><td> 22573</td><td>New</td>

<td> 417</td><td> 22574</td><td>New</td>

<td> 418</td><td> 22575</td><td>New</td>

<td> 419</td><td> 22580</td><td>New</td>

<td> 420</td><td> 22581</td><td>PAP</td>

<td> 421</td><td> 22582</td><td>Prostate secretion protein 94</td>

<td> 422</td><td> 22583</td><td>New</td>

<td> 423</td><td> 22584</td><td>Prostate secretion protein 94</td>

<td> 424</td><td> 22585</td><td>Prostate secretion protein 94</td>

<td> 425</td><td> 22586</td><td>Known</td>

<td> 426</td><td> 22587</td><td>New</td>

<td> 427</td><td> 22588</td><td>New</td>

<td> 428</td><td> 22589</td><td>PAP</td>

<td> 429</td><td> 22590</td><td>Known</td>

<td> 430</td><td> 22591</td><td>PSA</td>

<td> 431</td><td> 22592</td><td>Known</td>

<td> 432</td><td> 22593</td><td>previously identified as P777P</td>

<td> 433</td><td> 22594</td><td>T cell receptor gamma chain</td>

PL 200 772 B1 cont. table IV

<td> 1</td><td> 2</td><td> 3</td>

<td> 434</td><td> 22595</td><td>previously identified as P705P</td>

<td> 435</td><td> 22596</td><td>previously identified as P707P</td>

<td> 436</td><td> 22847</td><td>PAP</td>

<td> 437</td><td> 22848</td><td>Known</td>

<td> 438</td><td> 22849</td><td>Prostate secretion protein 57</td>

<td> 439</td><td> 22851</td><td>PAP</td>

<td> 440</td><td> 22852</td><td>PAP</td>

<td> 441</td><td> 22853</td><td>PAP</td>

<td> 442</td><td> 22854</td><td>previously identified as P509S</td>

<td> 443</td><td> 22855</td><td>previously identified as P705P</td>

<td> 444</td><td> 22856</td><td>previously identified as P774P</td>

<td> 445</td><td> 22857</td><td>PSA</td>

<td> 446</td><td> 23601</td><td>previously identified as P777P</td>

<td> 447</td><td> 23602</td><td>PSA</td>

<td> 448</td><td> 23605</td><td>PSA</td>

<td> 449</td><td> 23606</td><td>PSA</td>

<td> 450</td><td> 23612</td><td>Known</td>

<td> 451</td><td> 23614</td><td>PSA</td>

<td> 452</td><td> 23618</td><td>previously identified as P1000C</td>

<td> 453</td><td> 23622</td><td>previously identified as P705P</td>

Example 15

Further identification of prostate cancer antigens using microplates

The example describes the isolation of further prostate tumor specific polypeptides from a prostate tumor cDNA library.

The human prostate cancer cDNA expression library, as described previously, was analyzed by microplates to identify clones showing at least three times the expression level in prostate cancer and / or non-cancerous prostate tissue relative to other non-cancerous tissues (not including the testes). 142 clones were identified and sequenced. Clones are shown as SEK. ID NO .: 454-467. Sequences about SEK. NOS. 459-461 correspond to the new genes, while the sequences in SEQ. NOS. 454-458 and 461-467 correspond to known sequences.

Example 16

Further characterization of the P710P prostate tumor antigen

The example shows the cloning of the full-length P710P coding sequence.

The prostate cDNA library as described previously was screened with the P710P fragment, also described previously. After plating one million colonies in L-medium and ampicillin plates, they were transferred to a nylon filter, then the cDNA on the filter was denatured and bound to the filter under UV light. Hybridization was performed with the radiolabeled P710P fragment. After hybridization, positive clones were recovered and their cDNAs were sequenced in an ABI automated sequencing apparatus. The four sequences identified were given SEQ. ID NO .: 468-471.

It will be appreciated from the foregoing that, while specific embodiments of the invention have been described herein by way of illustration, various modifications may be made without departing from the spirit and scope of the invention. Thus, the present invention is to be limited only by the appended claims.

PL 200 772 Β1

SEQUENCE LISTING &lt;11O&gt; Corixa Corporation &lt;12 o&gt; Compositions and methods of treatment and diagnosis of prostate cancer &lt;130&gt; 210121.42701PC &lt;140&gt; PCT &lt;141&gt; 1999-07-08 &lt;160&gt; 472 &lt;170&gt; FastSEQ for Windows Version 3.0 &lt;210 &gt; 1 &lt;211&gt; 814 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (814} &lt;223&gt; n = A, T, C or G &lt;400&gt; 1

CttCtttttt tttttcacag tataacagct ctttatttct gtgagttcta ctaggaaatc atcaaatctg agggttgtct ggaggacttc aatacacctc cccccatagt gaatcagctt ccagggggtc cagtccctct ccttacttca tccccatccc atgccaaagg aagaccctcc ctccttggct cacagccctc tctaggcttc ccagtgcctc caggacagag tgggttatgt tttcagctcc atccttgctg tgagtgtctg gcgcgttgtg cctccagctt ctgctcagtg cttcatggac agtgtccagc acatgtcact ctccactctc tcagtgtgga tccactagtt ctagagcggc cgccaccgcg gtggagctcc agcttttgtt ccctttagtg agggttaatc gcgcgcttgg cgtaatcaCg gtcataactg tttcctgtgt gaaattgtta tccgctcaca attccacaca acatacgagc cggaagcata aagtgtaaag cctggggtgc ctaatgagtg anctaactca cattaattgc gttgcgctca ctgnccgctt tccagtcngg aaaactgtcg tgccagctgc attaatgaat cggccaacgc ncggggaaaa gcggtttgcg ttttgggggc tcttccgctt ctcgctcact nantcctgcg ctcggtcnct cggctgcggg gaacggtatc actcctcaaa ggnggtatta cggttatccn naaatcnggg gatacccngg aaaaaanttt aacaaaaggg cancaaaggg cngaaacgta aaaa &lt;210&gt; 2 &lt;211&gt; 816 &lt;212&gt; DNA &lt; 213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (816) &lt;223&gt; n = A, T, C (ubG &lt;400&gt; 2 acagaaatgt tggatggtgg agcacctttc tatacgactt acaggacagc agatggggaa ttcatggctg ttggagcaat agaaccccag ttctacgagc tactrgatcaa

GB 200 772 Β1 ctaaagtctg atgaacttcc caatcagatg agcatggatg attggccaga aatgaagaag 180 aagttcgcag atgtatttgc aaagaagacg aaggcagagt ggtgtcaaat ctttgacggc 240 acagacgcct gtgtgactcc ggttctgact tttgaggagg ttgttcatca tgatcacaac 300 aaggaacggg gctcgtttat caccagtgag gagcaggacg tgagcccccg ccctgcacct 360 ctgctgttaa acaccccagc catcccctct ttcaaaaggg atccactagt tctagaagcg 420 gccgccaccg cggtggagct ccagcttttg ttccctttag tgagggttaa ttgcgcgctt 480 ggcgtaatca tggtcatagc tgtttcctgt gtgaaattgt tatccgctca caattccccc 540 aacatacgag ccggaacata aagtgttaag cctggggtgc ctaacgantg agctaactcn 600 cattaattgc gttgcgctca ctgcccgctt tccagtcggg aaaactgtcg tgccactgcn 660 ttantgaatc ngccaccccc cgggaaaagg cggttgcntt ttgggcctct tccgctttcc 720 tcgctcattg atcctngcnc ccggtcttcg gctgcggnga acggttcact cctcaaaggc 780 ggtntnccgg ttacccccaa acnggggata cccnga 816 &lt;210&gt; 3 &lt;211&gt; 773 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (773) &lt;223&gt; n = A, T, C Ułfe G &lt;400&gt; 3 cttttgaaag aagggatggc tggggtgttt aacagcagag gtgcagggcg ggggctcacg 60 tcctgctcct cactggtgat aaacgagccc cgttccttgt tgtgatcatg atgaacaacc 120 tcctcaaaag tcagaaccgg agtcacacag gcatctgtgc cgtcaaagat ttgacaccac 180 tctgccctcg tcttctttgc aaatacatct gcaaacttct tcttcatttc tggccaatca 240 tccatgctca tctgattggg aagctcatca gactttagtc canntccttt gatcagcagc 300 tcgtagaact ggggttctat tgccccaaca gccatgaatt ccccatctgc tgtcctgtaa 360 gtcgtataga aaggtgctcc accatccaac atgttctgtc ctcgaggggg ggcccggtac 420 ccaattcgcc ctatantgag tcgtattacg cgcgctcact ggccgtcgtt ttacaacgtc 480 gtgactggga aaaccctggg cgttaccaac Ctaatcgcct tgcagcacat ccccctttcg 540 ccagctgggc gtaatancga aaaggcccgc accgatcgcc cttccaacag ttgcgcacct 600 gaacgggnaa atgggacccc cctgttaccg cgcattnaac ccccgcnggg tttngttgtt 660 acccccacnt nnaccgctta cactttgcca gcgccttanc gcccgctccc tttcnccttt 720 cttcccttcc tttcncnccn ctttcccccg gggtttcccc cntcaaaccc cna 773 &lt;210&gt; 4 &lt;211&gt; 828 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misć_feature &lt;222&gt; (1) ... (828) &lt;223&gt; n = A, T, C or G &lt;400&gt; 4 cctcctgagt cctactgacc tgtgctttct ggtgtggagt ccagggctgc taggaaaagg 60 aatggattcaga tttgctactcaga tttgccactcaga tttgcgcctgctgta tttgctactcaga tttgccactcaga cagcgaggac acacacaaag 180 acgtgggtga ccatgttgtt tgtggggtgc agagatggga ggggtggggc ccaccctgga 240 agagtggaca gtgacacaag gtggacactc tctacagatc actgaggata agctggagcc 300 acaatgcatg aggcacacac acagcaagga tgacnctg the aacatagccc acgctgtcct 360

GB 200 772 Β1 gngggcactg ggaagcctan atnaggccgt gagcanaaag aaggggagga tccactagtt 420 ccanagcggc cgccaccgcg gtgganctcc ancttttgtt ccctttagtg agggttaatt 480 gcgcgcttgg cntaaccatg gtcatanctn tctcctgtgt gaaattgtta tccgctcaca 540 attccacaca acatacganc cggaaacata aantgtaaac ctggggtgcc caatgantga 600 ctaactcaca ttaatcgcgt tgcgcccact gcccgctttc caatcnggaa acctgtcttg 660 ccncttgcat tnatgaatcn gccaaccccc ggggaaaagc gtttgcgttt tgggcgctct 720 tccgcttcct cnctcantta ntccctncnc tcggtcattc cggctgcngc aaaccggttc 780 accncctcca aagggggtat tccggtttcc ccnaatccgg gganancc 828 &lt;210&gt; 5 &lt;211&gt; 834 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (834) &lt;223&gt; n = A, T, C or G &lt;400&gt; 5 tttttttttt tttttactga tagatggaat ttattaagct tttcacatgt gatagcacat 60 agttttaatt gcatccaaag tactaacaattac tactaacaattac aacttgagcaattacgatgagcaattacgatgagcaattacgatgagcaattag aacttgagcaatta tttcataaga taatttatac 180 tgaagtaaat ctagccatgc ttttaaaaaa tgctttaggt cactccaagc ttggcagtta 240 acatttggca taaacaataa taaaacaatc acaatttaat aaataacaaa tacaacattg 300aaaaaa tagtagata tacaacattg 300aagataa taggaata tacaacattg 300aagataa cttggcctcc atgcaaatat gcctagacac Cttgattcac tcagccctga 420 cattcagttt tcaaagtagg agacaggttc tacagtatca ttttacagtt tccaacacat 480 tgaaaacaag tagaaaatga tgagttgatt cttattaatg cattacatcc ccaagagtta 540 tcaccaaccc ctcagttata aaaaattttc aagttatatt agtcatataa cttggtgtgc 600 ttattctaaa ttagtgctaa atggattaag tgaagacaac aatggtcccc taatgtgatt 660 gatattggtc atttttacca gcttctaaat ctnaactttc aggcttttga actggaacat 720 tgnatnacag tgttccanag ttncaaccta ctggaacatt acagtgtgct tgattcaaaa 780 tgttattttg ttaaaaatta aattttaacc tggtggaaaa ataatttgaa atna 834 &lt;210&gt; 6 &lt;211&gt; 818 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (818) &lt;223&gt; n = A, T, C or G &lt;400&gt; 6 tttttttttc tttttttttt aagaccctca tcaatagatg gagacataca gaaatagtca 60 aaccacatct acaaaatgcc agtatcaggc ggcggcttcg aagccaaagt gatgtttgga 120 tgtaaagtga aatattagtt ggcggatgaa gcagatagtg aggaaagttg agccaataat 180 gacgtgaagt ccgtggaagc ctgtggctac aaaaaatgtt gagccgtaga tgccgtcgga 240 aatggtgaag ggagactcga agtactctga ggcttgtagg agggtaaaat agagacccag 300 taaaattgta ataagcagtg cttgaattat ttggtttcgg ttgttttcta ttagactatg 360 gtgagctcag gtgattgata ctcctgatgc gagtaatacg gatgtgttta ggagtgggac 420 ttctagggga tttagcgggg tgatgcctgt tgggggccag tgccctccta gttggggggt 480 aggggctagg ctggagtggt aaaaggctca gaaaaatctacta 540 gaaagtacta

GB 200 772 Β1 ggtastaaat aggattatcc cgtatcgaag gcctttttgg acaggtggtg tgtggtggcc 600 ttggtatgtg ctttctcgtg ttacatcgcg ccatcattgg tatatggtta gtgtgttggg 660 ttantanggc ctantatgaa gaacttttgg antggaatta aatcaatngc ttggccggaa 720 gtcattanga nggctnaaaa ggccctgtta ngggtctggg ctnggtttta cccnacccat 780 ggaatncncc ccccggacna ntgnatccct attcttaa 818 &lt;210&gt; 7 &lt;211&gt; 817 &lt;212&gt; DNA &lt; 213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). .. (817) &lt;223&gt; n = A, T, C, G lob &lt;400&gt; 7 tttttttttt tttttttttt tggctctaga gggggtagag ggggtgctat agggtaaata 60 cgggccctat ttcaaagatc tttaggggaa ttaattctag gacgatgggt atgaaactgt 120 ggtttgctcc acagatttca gagcattgac cgcagtatac ccccggCcgt gtagcggtga 1B0 aagtggttcg gtttagacgt ccgggaattg catctgtttt taagcctaat gtggggacag 240 ctcatgagtg caagacgtct tgtgatgtaa ttattatacn aatgggggct tcaatcggga 300 gtactactcg attgtcaacg tcaaggagtc gcaggtcgcc tggttctagg aacaatgggg 360 gaagtatgta ggaattgaag attaatccgc cgtagtcggt gttctcctag gttcaatacc 420 attggtggcc aattgatttg atggtaaggg gagggatcgt tgaactcgtc tgttatgtaa 480 aggatnccct ngggatggga aggcnatnaa ggactangga tnaatggcgg gcangatatt 540 tcaaacngtc tctanttcct gaaacgtctg aaatgttaat aanaattaan tttngttatt 600 gaatnttnng gaaaagggct tacaggacta gaaaccaaat angaaaanta atnntaangg 660 cnttatcncn aaaggtnata accnctccta tnatcccacc caatngnatt ccccacncnn 720 acnattggat nccccanttc canaaanggc cnccccccgg tgnannccnc cttttgttcc 780 cttnantgan ggttattcnc ccctngcntt atcancc 817 &lt;210&gt; 8 &lt;211&gt; 799 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; miscfeature &lt;222&gt; (1) ... (799) &lt;223&gt; n = A, T, C lob G &lt;400&gt; 8 catttccggg tttactttct aaggaaagcc gagcggaagc tgctaacgtg ggaatcggtg 60 cataaggaga actttctgcta cataaggaga actttctgcta ggggagacagcga cataaggaga actttctgagct ggggagacagcga cataaggaga actttctgcta ggggagacagcga cataaggaga actttctgcta ggggagacagcga cataaggaga actttctgcta ggggagacagcga cataaggaga actttctgcta ggcgagacagcga gcctggagcga agctgggaca catccgcgag 180 tacgaacagc gcctgaaagt gctggagcgg gaggtccagc agtgtagccg cgtcctgggg 240 tgggtggccg angcctganc cgctctgcct tgctgccccc angtggcccacg ccctgccctg gcctgccctg gcacctcctg ccctgccctg 300 cctanantaa ggctcatctg ggcctcggcc cccccacctg gtcggccttg 420 tctttgangt gagccccatg tccatctggg ccactgtcng gaccaccttt ngggagtgtt 480 ctccttacaa ccacannatg cccggctcct cccggaaacc antcccancc tgngaaggat 540 caagncctgn atccactnnt nctanaaccg gccnccnccg cngcggaacc cnccttntgt 600 tccttttcnt tnagggttaa tnncgccttg gccttnccan ngccctncnc nttttccnnt 660 gttnaaattg ttangcnccc nccnntcccn cnncnncnan cccgacccnn annttnnann 720

PL 200 772 Β1 ncctgggggt nccnncngat tgacccnncc nccctntant tgcnttnggg nncnntgccc 780 ctttccctct nggganncg 799

<td> &lt;210&gt;</td><td> 9</td>

<td> &lt;211&gt;</td><td>eoi</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapiens</td>

<td colspan="2"> &lt;22 0&gt;</td>

<td> &lt;221&gt;</td><td>misc_feature</td>

<td> &lt;222&gt;</td><td> (1) ... (801)</td>

<td> &lt;223&gt;</td><td>n = A, T, C Io6</td>

<td> &lt;400&gt;</td><td> 9</td>

acgccttgat cctcccaggc tgggactggt tctgggagga gccgggcatg ctgtggtttg 60

Caangatgac actcccaaag gtggtcctga cagtggccca gatggacatg gggctcacct 120 caaggacaag gccaccaggt gcgggggccg aagcccacat gatccttact ctatgagcaa 180 aatcccctgt gggggcttct ccttgaagtc cgccancagg gctcagtctt tggacccang 240 caggtcatgg ggttgtngnc caactggggg ccncaacgca aaanggcnca gggcctcngn 300 cacccatccc angacgcggc tacactnctg gacctcccnc tccaccactt tcatgcgctg 360 ttcntacccg cgnatntgtc ccanctgttt cngtgccnac tccancttct nggacgtgcg 420 ctacatacgc ccggantcnc nctcccgctt tgtccctatc cacgtnccan caacaaattt 480 cnccntantg caccnattcc cacntttnnc agntttccnc nncgngcttc cttntaaaag 540 ggttganccc cggaaaatnc cccaaagggg gggggccngg tacccaactn ccccctnata 600 gctgaantcc ccatnaccnn gnctcnacgg anccntccnt tttaannacn ttctnaactt 660 gggaanancc ctcgnccntn cccccnttaa tcccnccttg cnangnncnt cccccnntcc 720 ncccnnntng gcntntnann cnaaaaaggc ccnnnancaa tctcctnncn cctcanttcg 780 ccanccctcg aaatcggccn c 801 &lt;210&gt; 10 &lt;211&gt; 789 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (789) &lt;223&gt; n = A, T, CLOB, G &lt;400&gt; 10 cagtctatnt ggccagtgtg gcagctttcc ctgtggctgc cggtgccaca tgcctgtccc 60 acagtgtggc cgtggtgaca gcttcagccg ccctcaccgg gctcaccttc tcagccctgc 120 agatcctgcc ctacacactg gcctccctct accaccggga gaagcaggtg ttcctgccca 180 aataccgagg ggacactgga ggtgctagca gtgaggacag cctgatgacc agcttcctgc 240 caggccctaa gcctggagct cccttcccta atggacacgt gggtgctgga ggcagtggcc 300 tgctcccacc tccacccgcg ctctgcgggg cctctgcctg tgatgtctcc gtacgtgtgg 360 tggtgggtga gcccaccgan gccagggtgg ttccgggccg gggcatctgc ctggacctcg 420 ccatcctgga tagtgcttcc tgctgtccca ngtggcccca tccctgttta tgggctccat 480 tgtccagctc agccagtctg tcactgccta tatggcgtct gccgcaggcc tgggtctggt 540 cccatttact ttgctacaca ggtantattt gacaagaacg anttggccaa atactcagcg 600 ttaaaaaatt ccagcaacat tgggggtgga aggcctgcct cactgggtcc aactccccgc 660 tcctgttaac cccatggggc tgccggcttg gccgccaatt tctgttgctg ccaaantnat 720 gtggctctct gctgccacct gttgctggct gaagtgcnta cngcncanct nggggggcng 780 ggngttccc 789

PL 200 772 Β1 &lt;210&gt; 11 &lt;211&gt; 772 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (772) &lt;223&gt; n = A, T, C UH G &lt;400&gt; 11 cccaccctac ccaaatatta gacaccaaca cagaaaagct agcaatggat tcccttctac 60 tttgttaaat aaataagtta aatattacgagagggat 120gcgctacggaggga 120gcgctacggagggat 120 gatcagcaaa aagacagtgc 180 tgtgggctga ggggacctgg ttcttgtgtg ttgcccctca ggactcttcc cctacaaata 240 actttcatat gttcaaatcc catggaggag tgtttcatcc tagaaactcc catgcaagatgag 300 ctgtagtaaggaaggtagtaaggag 300 ctgatagtagag ccaaaaaccc ttctctaggt gtgtctcaac taggaggcta gctgttaacc 420 ctgagcctgg gtaatccacc tgcagagtcc ccgcattcca gtgcatggaa cccttctggc 480 ctccctgtat aagtccagac tgaaaccccc ttggaaggnc tccagtcagg cagccctana 540 aactggggaa aaaagaaaag gacgccccan cccccagctg tgcanctacg cacctcaaca 600 gcacagggtg gcagcaaaaa aaccacttta ctttggcaca aacaaaaact ngggggggca 660 accccggcac cccnangggg gttaacagga ancngggnaa cntggaaccc aattnaggca 720 ggcccnccac cccnaatntt gctgggaaat ttttcctccc ctaaattntt tc 772 &lt;210 &gt; 12 &lt;211&gt; 751 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (751) &lt;223&gt; n = A, T, C or G &lt;400&gt; 12 gccccaattc cagctgccac accacccacg gtgactgcat tagttcggat gtcatacaaa 60 agctgattga agcaaccctc tactgtggg tcttgtgctaga tcttgtgctaga tcttgtgctaga tcttgtgctaga gaaaggcact gttctctttg 180 aagtanggtg agtcctcaaa atccgtatag ttggtgaagc cacagcactt gagccctttc 240 atggtggtgt tccacacttg agtgaagtct tcctgggaac cataatcttt cttgactgacagca 300 gcctgggaac cataatcttt cttgactgacagca 300 gcaatctt cttgactgacagca 300 gcaatctt cttgactgacagca gca acctcagcaa tgaagatgan gaggangatg aagaagaacg tcncgagggc 420 acacttgctc tcagtcttan caccatanca gcccntgaaa accaananca aagaccacna 480 cnccggctgc gatgaagaaa tnaccccncg ttgacaaact tgcatggcac tggganccac 540 agtggcccna aaaatcttca aaaaggatgc cccatcnatt gaccccccaa atgcccactg 600 ccaacagggg ctgccccacn cncnnaacga tganccnatt gnacaagatc tncntggtct 660 tnatnaacnt gaaccctgcn tngtggctcc tgttcaggnc cnnggcctga cttctnaann 720 aangaactcn gaagncccca cngganannc g 751 &lt;210&gt; 13 &lt;211&gt; 729 &lt;212&gt; DNA &lt;213&gt; Homo sapiens

PL 200 772 Β1 &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) .. . (729) &lt;223&gt; n = A, T, C or G &lt;400&gt; 13 gagccaggcg tccctctgcc tgcccactca gtggcaacac ccgggagctg ttttgtcctt 60 tgtggancct cagcagtncc ccctttcaga actcantgcc aaganccctg aacaggagcc 120 accatgcagt gcttcagctt cactaagacc atgatgatcc cccccaattt gctcatcttt 180 ctgcgtggcg cagccctgtt ggcagtgggc atctgggtgt caatcgatgg ggcatccttt 240 ctgaagatct tcgggccact gtcgtccagt gccatgcagt ttgtcaacgt gggctacttc 300 ctcatcgcag ccggcgttgt ggtcttagct ctaggtttcc tgggctgcta tggtgctaag 360 actgagagca agtgtgccct cgtgacgca ttcttcatcc tcctcctcat cttcattgct 420 gaggctgcaa tgccgtggtc gccttggtgt acaccacaat ggctgagcac ttcctgacgt 480 tgctggtaat gccCgccatc aanaaaagat tatgggttcc caggaanact tcactcaagt 540 gttggaacac caccatgaaa gggctcaagt gctgtggctt cnnccaacca tacggatttt 600 gaagantcac ctacttcaaa gaaaanagtg cctttccccc atttctgttg caactgacaa 660 acgtccccaa cacagccaat tgaaaacctg cacccaaccc aaangggtcc ccaaccanaa 720 attnaaggg 729 &lt;2L0&gt; 14 &lt;211&gt; 816 &lt; 212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (816) &lt;223&gt; n = A, T, C or G &lt;400&gt; 14 tgctcttcct caaagtCgtt cttgttgcca taacaaccac cataggtaaa gcgggcgcag 60 tgttcgctga aggggttgta gtaccagcgc gggatgctct ccttgcagag ccctgtgtct 120 ggcaggtcca cgcagtgccc tttgtcactg gggaaatgga cgcgctggag ctcgtcaaag 180 ccactcgtgt atttttcaca ggcagcctcg tccgacgcgt cggggcagtt gggggtgtct 240 tcacactcca ggaaactgtc natgcagcag ccattgctgc agcggaactg ggtgggctga 300 cangtgccag agcacactgg atggcgcctt tccatgnnan gggccctgng ggaaagtccc 360 tganccccan anctgcctct caaangcccc accttgcaca ccccgacagg ctagaatgga 420 atcttcttcc cgaaaggtag ttnttcttgt tgcccaancc anccccntaa acaaactctt 480 gcanatctgc tccgnggggg tcntantacc ancgtgggaa aagaacccca ggcngcgaac 540 caancttgtt tggatncgaa gcnataatct nctnttctgc ttggtggaca gcaccantna 600 ctgtnnanct ttagnccntg gtcctcntgg gttgnncttg aacctaatcn ccnntcaact 660 gggacaaggt aantngccnt cctttnaatt cccnancntn ccccctggtt tggggttttn 720 cncnctccta ccccagaaan nccgtgttcc cccccaacta ggggccnaaa ccnnttnttc 780 cacaaccctn ccccacccac gggttcngnt ggttng 816

<td> &lt;210&gt;</td><td> 15</td><td></td>

<td>&lt;2ll&gt;</td><td> 763</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td colspan="3"> &lt;220&gt;</td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> &lt;1)</td><td> ..(783)</td>

<td> &lt;223&gt;</td><td>π -.</td><td>A, T, C or</td>

GB 200 772 Β1 &lt;400&gt; 15 ccaaggcctg ggcaggcata nacttgaagg tacaacccca ggaacccctg gtgctgaagg 60 atgtggaaaa cacagattgg cgcctactgc ggggtgacac ggatgtcagg gtagagagga 120 aagacccaaa ccaggtggaa ctgtggggac tcaaggaang cacctacctg ttccagctga 180 cagtgactag ctcagaccac ccagaggaca cggccaacgt cacagtcact gtgctgtcca 240 ccaagcagac agaagactac tgcctcgcat ccaacaangt gggtcgctgc cggggctctt 300 tcccacgctg gtactatgac cccacggagc agatctgcaa gagtttcgtt tatggaggct 360 gcttgggcaa caagaacaac taccttcggg aagaagagtg cattctancc tgtcngggtg 420 tgcaaggtgg gcctttgana ngcanctctg gggctcangc gactttcccc cagggcccct 480 ccatggaaag gcgccatcca ntgttctctg gcacctgtca gcccacccag ttccgctgca 540 ncaatggctg ctgcatcnac antttcctng aattgtgaca acacccccca ntgcccccaa 600 ccctcccaac aaagcttccc tgttnaaaaa tacnccantt ggcttttnac aaacncccgg 660 cncctccntt ttccccnntn aacaaagggc nctngcnttt gaactgcccn aacccnggaa 720 tctnccnngg aaaaantncc ccccctggtt cctnnaancc cctccncnaa anctnccccc 780 ccc 783 &lt;210&gt; 16 &lt;211&gt; 801 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (801) &lt;223&gt; n = A, T, C Sub G &lt;400&gt; 16 gccccaattc cagctgccac accacccacg gtgactgcat tagttcggat gtcatacaaa 60 agctgattga agcaaccctc tactgtgggtcttgtgctaga tcttgtgctaga tcttgtgctaga tcttgtgctaga gaaaggcact gttctctttg 180 aagtagggtg agtcctcaaa atccgtatag ttggtgaagc cacagcactt gagccctttc 240 atggtggtgt tccacacttg agtgaagtct tcctgggaac cataatcttt cttgacgacgca gcagacgcagca gcagacgacgca 300 gccgacgacgca cctcagcaat gaagatgagg aggaggatga agaagaacgt cncgagggca 420 cacttgctct ccgtcttagc accacagcag cccangaaac caagagcaaa gaccacaacg 480 ccngctgcga atgaaagaaa ntacccacgt tgacaaactg catggccact ggacgacagt 540 tggcccgaan atcttcagaa aagggatgcc ccatcgattg aacacccana tgcccactgc 600 cnacagggct gcnccncncn gaaagaatga gccattgaag aaggatcntc ntggtcttaa 660 tgaactgaaa ccntgcatgg tggcccctgt tcagggctct tggcagtgaa ttctganaaa 720 aaggaacngc ntnagccccc ccaaangana aaacaccccc gggtgttgcc ctgaattggc 780 ggccaaggan ccctgccccn g 801

<td>&lt;2l0&gt;</td><td> 17</td>

<td> &lt;211&gt;</td><td> 740</td>

<td>&lt;2l2&gt;</td><td>GOUT</td>

<td>&lt;2l3&gt;</td><td>Homo sapiens</td>

<td> &lt;220&gt;</td><td></td>

<td> &lt;221&gt;</td><td>misc_feature</td>

<td> &lt;222&gt;</td><td>(1) ... Ϊ740)</td>

<td> &lt;223&gt;</td><td>n «A, T, C lob</td>

<td> &lt;400&gt;</td><td> 17</td>

gtgagagcca ggcgtccctc tgcctgccca ctcagtggca acacccggga gctgttttgt 60

GB 200 772 B1 cctttgtgga agccaccatg ctttctgtgt ctttctgaag cttcctcatc taagacggag tgctgaagct gacgttgctg aantntggaa gaattttgaa tgcaatgaaa caaaaaaant gcctcagcag cagtgcttca ggtgcagccc atcttcgggc gcagccggcg agcaagtgtg gcagctgctg gtantgcctg caccnccatg agantcnccc acntcccaan nnaagggttn ttccctcttt gcttcattaa ^^ ttggcagt cactgtcgtc ttgtggtctt ccctcgtgac tggtcgcctt ccatcaanaa aaaagggctc tacttccaaa acngccaatn cagagcttgt tantnttatg tgctcttggt gttcttcttc nntgtatact gnattgtgnn caatttctgn ggagaangnt aggacctgtc

<td>tgctagnagc</td><td>tttnag.tagg</td><td> 120</td>

<td>gtcttcttca</td><td>gεttgcttat</td><td> 180</td>

<td>gtgttagtcn</td><td>gtgggntatt</td><td> 240</td>

<td>cagtttnttg</td><td>acntgnncta</td><td> 300</td>

<td>ttcctggntt</td><td>gttatngtnc</td><td> 360</td>

<td>aŁc ^ cct ^</td><td>tcatcttcat</td><td> 420</td>

<td></td><td>agccattctt</td><td> 480</td>

<td>ttcccaggaa</td><td>agatttgctt</td><td> 540</td>

<td>tgntttctcc</td><td>ggctgtaccg</td><td> 600</td>

<td>tgcctttncc</td><td></td><td> 660</td>

<td>tnnncgagaa</td><td>ggnttπtagg</td><td> 720 740</td>

<td> &lt;210&gt;</td><td> 18</td><td></td>

<td> &lt;211&gt;</td><td> 802</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>rn.sc</td><td>Jżeature</td>

<td> &lt;222&gt;</td><td>(D. '</td><td> .. (802)</td>

<td> &lt;223&gt;</td><td colspan="2">n = A, T, C lab</td>

<td> &lt;400&gt;</td><td> 18</td><td></td>

ccgctggttg caaggtcttc ggatacactt gagcctctgt aagcaaacac cattgggcat ggatgagtgt ggttctgccc gctcaggatg gtcggctccc aancttcgtc aaccggncgc acccttnncg tnccanccnc cgctggtcca cagctgccgc tactttagca tagtggagga tgtgagcagc gtccagcagt ggccagcgct tgtcaccttc tccagagacg gccgantgng nggcccatgg caccgcnnnt ttaccttggt atangaagcc gnnnagcccc acaatacgca gccagnnnga a branch ^ ^ ^^ ccg cggnagnnag tctccgaaca gcccccttgg acttccgcac tggttccgcc ttcgtc ^ nc aattcaccnc ggaaatccac ng gaagcacgtc gggcaagagc caact.nagan cttcagctaa aggcaaagtc cgtggacgct ccgacttngt ttatcactgt ccctcnctta accggaactn tcctnttncc ttnt: nt: ntcn

<td>agcatacaca</td><td></td><td> 60</td>

<td>ctctagcaac</td><td>actgcatatg</td><td> 120</td>

<td>gtgttgganc</td><td>ttaittcttct</td><td> 180</td>

<td>gtagtcagcg</td><td>tatgtcccat</td><td> 240</td>

<td>actcttgncc</td><td>agntctctaa</td><td> 300</td>

<td>agr ^ g ^^ c</td><td>agntattgag</td><td> 360</td>

<td>taggagcaga</td><td>aaatgctcct</td><td> 420</td>

<td>actgagtgtg</td><td>gęgaga ^^</td><td> 480</td>

<td>atgacaccgn</td><td>CCannCaaCC</td><td> 540</td>

<td>gtctnctngc</td><td></td><td> 600</td>

<td>gWangatcca</td><td>ctnnttctat</td><td> 660</td>

<td>tttacttgag</td><td>ggttaan9tc</td><td> 720</td>

<td>anatnntnga</td><td>tcπnnncttg</td><td> 780 802</td>

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213 &gt;</td><td>19 731 GOUT Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc_</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (731)</td>

<td> &lt;223&gt;</td><td colspan="2">n = A, T, C lob</td>

<td> &lt;400&gt;</td><td> 19</td><td></td>

tngagctttc gagc ^ ac ^ cntngtttcg tagnggttgg gcncatccnt ggntngtnng tcgcgnggng gcttttcntc ggntggannc c ^ gCg ^^ gngnctttgt ncncantntg tggngtgtgtn tgngngngtgtc ntngcgngtgtc ntggngngtgtnn

<td>tgntgngatg</td><td>canttnntgn</td><td> 60</td>

<td>ggagccacat</td><td>ctttgngtnt</td><td> 120</td>

<td>ca ^ ac ^ a</td><td>ggt: nacgtnn</td><td> 180</td>

<td>nggggnncgn</td><td>ggctngctat</td><td> 240</td>

<td>tnttnggagg</td><td>gtnncntngg</td><td> 300</td>

GB 200 772 Β1 catgcccagn gttanataac nggcngagag tnantttgcc tctcccttcc ggctgcgcan 360 cgngtntgct tagnggacat aacctgacta cttaactgaa cccnngaatc tnccncccct 420 ccactaagct cagaacaaaa aacttcgaca ccactcantt gtcacctgnc tgctcaagta 480 aagtgtaccc catncccaat gtntgctnga ngctctgncc tgcnttangt tcggtcctgg 540 gaagacctat caattnaagc tatgtttctg actgcctctt gctccctgna acaancnacc 600 cnncnntcca agggggggnc ggcccccaac ccccccaacc ntnaattnan tttanccccn 660 cccccnggcc cggcctttta cnancntcnn nnacngggna aaaccnnngc tttncccaac 720 nnaatccncc t 731 &lt;210&gt; 20 &lt;211&gt; 754 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (754) &lt;223&gt; n = A, T, C and in-fo G &lt;400&gt; 20 tttttttttt tttttttttt taaaaacccc ctccattnaa tgnaaacttc cgaaattgtc 60 caaccccctc ntccaaatnn ccntttccgg gngggggttc caaacccaan ttanntttgg 120 annttaaatt aaatnttnnt tggnggnnna anccnaatgt nangaaagtt naacccanta 180 tnancttnaa tncctggaaa ccngtngntt ccaaaaatnt ttaaccctta antccctccg 240 aaatngttna nggaaaaccc aanttctcnt aaggttgttt gaaggntnaa tnaaaanccc 300 nnccaattgt ttttngccac gcctgaatta attggnttcc gntgttttcc nttaaaanaa 360 ggnnancccc ggttantnaa tccccccnnc cccaattata ccganttttt ttngaattgg 420 gancccncgg gaattaacgg ggnnnntccc tnttgggggg cnggnncccc ccccntcggg 480 ggttngggnc aggncnnaat tgtttaaggg tccgaaaaat ccctccnaga aaaaaanctc 540 ccaggntgag nntngggttt nccccccccc canggcccct ctcgnanagt tggggtttgg 600 ggggcctggg attttntttc ccctnttncc tccccccccc ccnggganag aggttngngt 660 tttgntcnnc ggccccnccn aaganctttn ccganttnan ttaaatccnt gcctnggcga 720 agtccnttgn agggntaaan ggccccctnn CGG G 754 &lt;210&gt; 21 &lt;211 &gt; 755 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;22l&gt; misc_feature &lt;222&gt; (1). . . (755) &lt;223&gt; n = A, T, C or G &lt;400&gt; 21 atcancccat gaccccnaac nngggaccnc tcanccggnc nnncnaccnc cggccnatca 60 nngtnagnnc actncnnttn natcacnccc cnccnactac gcccncnanc cnacgcncta 120 nncanatncc actganngcg cgangtngan ngagaaanct nataccanag ncaccanacn 180 ccagctgtcc nanaangcct nnnatacngg nnnatccaat ntgnancctc cnaagtattn 240 nncnncanat gattttcctn anccgattac ccntnccccc tancccctcc cccccaacna 300 cgaaggcnct ggnccnaagg nngcgncncc ccgctagntc cccnncaagt cncncnccta 360 aactcanccn nattacncgc ttcntgagta tcactccccg aatctcaccc tactcaactc 420 aaaaanatcn gatacaaaat aatncaagcc tgnttatnac actntgactg ggtctctatt 480 ttagnggtcc ntnaancntc ctaatacttc cagtctncct tcnccaattt ccnaanggctga 540 cttgncatttga gcatgncattttga gcatgccntcntga

PL 200 772 Β1 gggctcntct tttccttcgg ttancctggn ttcnnccgggc cagtcattat aaattcntnc cntttanttt tggcnttcna aacccccggc cttgaaaacg aaaaggttgt tttganaattattcttgtttttcccta gtttttcccta tttgtcccta

660

720

755

<td> &lt;210&gt;</td><td> 22</td><td></td>

<td> &lt;211&gt;</td><td> 849</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>mi sc.</td><td>_feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (849)</td>

<td> &lt;223&gt;</td><td>n = 4</td><td>A, T, C Lo</td>

<td> &lt;400&gt;</td><td> 22</td><td></td>

tttttttttt tttttangtg tngtcgtgca ggtagaggct tactacaant acgctnggan taangcgacc cganttctag ganncnccct aaaatcanac atcctgnnna cggaanggtc accggnngat nntgctaggg tgnccnctcc cataactcng nggccctgcc caccaccttc ggcggcccng ngnccgggcc gnnttaaccn cactnngcna ncggtttccn nccccnncng acccnggcga tctgtcttcc cctgnagncn anaaantggg ccncggnccc ctttacccct cngccntcta nccncngccc cccctccant nngggggact gccnanngct nnaccccnnn gggtncctcg gttgtcgant cnaccgnang ccanggattc tgcgttnttg gcccctaccc ttcgctncgg nncacccttc ccgacnanga cncnncgnng cctcncctcg caacacccgc nctcntcngt ncggnnnccc nccctcncnc ngncgnancn ctccnccncc gtctcannca ccaccccgcc ntcanccacn ggnngacnng nagcncnntc gcnccgcgcn gcgncnccct ctncntcngg ccantnncgc tcaanccnna cnaaacgccg ctgcgcggcc ncctccncga gtcctcccgn cttccnaccc angnnttccn cgaggacacn nncangcgg gtgaanacgt tgtgaagatn cannncnttn cgggtcattn tccggggtnc nnacaagcca ccgttnctng cnaaggaagg nccgctcccg ccccacccgc ccgccaggcc cgccncngaa cgnagcgncc nnaccccgcc

120

180

240

300

360

420

4B0

540

600

660

720

780

840

849

<td> &lt;210&gt;</td><td> 23</td>

<td> &lt;211&gt;</td><td> 872</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapien ^</td>

<td colspan="2"> &lt;220&gt;</td>

<td> &lt;221&gt;</td><td>misc_feature</td>

<td> &lt;222&gt;</td><td> (1)...(872)</td>

<td> &lt;223&gt;</td><td>n = A, T, C or</td>

<td> &lt;400&gt;</td><td> 23</td>

gcgcaaacta tacttcgctc gnactcgtgc gcctcgctnc tcttttcctc tctgacnanc ccgattnggc ngatatcnan aagntcganc agtccaaact cacacncnan aganaaatcc nctgccttcc anagtanacn attgaacnng nggcgaatcg taatnaggcg tgcgccgcca atntgtcncc gtttattntn ctnccnaccc tacntcttcn nagctgtcnn acccctngtn cgnacccccc tcgggtttnn nntgaccgng cnncccctcc ccccntccat nacganccnc nanngcncgc nccccgnnct cttcgccncc ctgtcctntn cccctgtngc accgcattga ccctcgccnn ctncnngaaa ncgnanacgt ccgggttgnn tgggnnngcg tctgcnccgc gttccttccn ncnncttcca ccatcttcnt ccncgccntc tcnnncacnc cctgggacgc tntcctntgc cccccttnac cgncgtgncc cgnccccacc ntcatttnca nacgntcttc acaannncct cnancngncn gtcanccnag ggaagggngg ggnnccnntg nttgacgttg cgaan ^ NCCC tcnccntcan cnctacccct cgggcgnnct ctcngttncc cgcaaccatg gantaacaca agaaccangc ccagcntcnc naggtcggga ccgcaccacc ctggcncngn annancgctg tacngggtct tccccccctt ggntnnctcc nggngangtc aacttancaa

120

180

240

300

360

420

480

540

600

660

720

780

PL 200 772 Β1 ntctcccccg ngngcncntc tcagcctcnc ccnccccnct ctctgcantg tnctctgctc 840 tnaccnntac gantnttcgn cnccctcttt cc 872 &lt;210&gt; 24 &lt;211&gt; 815 &lt;212&gt; DNA &lt;213&gt; &lt;Hom220&gt; 815 &lt;212&gt; DNA &lt;213&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (815) &lt;223&gt; n - A, T, C or G &lt;400&gt; 24 gcatgcaagc ttgagtattc tatagngtca cctaaatanc ttggcntaat catggtcnta 60 nctgncttcc tgtgtacactangatgtgantactangatgtgantactangatgtgantactangatntaatgantactangatntaatgantactnta 120 canattccca tnnattncgn 180 cgcattcncn 180 cgcattcncn gcncantatn taatngggaa ntcnnntnnn ncaccnncat ccatcntncc 240 gcnccctgac tggnagagat ggatnanttc tnntntgacc nacatgngtca tcttcgngtcagn 300 acttccgnngtagn 300 acttccgnngtagc 300 acttccgnngtagn 300 acttccgnngtagn aganncatca aacntgggaa acccgcnncc angtnnaagt ngnnncanan 420 gatcccgtcc aggnttnacc atcccttcnc agcgccccct ttngtgcctt anagngnagc 480 gtgtccnanc cnctcaacat ganacgcgcc agnccanccg caattnggca caatgtcgnc 540 gaacccccta gggggantna tncaaanccc caggattgtc cncncangaa atcccncanc 600 cccnccctac ccnnctttgg gacngtgacc aantcccgga gtnccagtcc ggccngnctc 660 ccccaccggt nnccntgggg gggtgaanct cngnntcanc cngncgaggn ntcgnaagga 720 accggncctn ggncgaanng ancnntcnga agngccncnt cgtataaccc cccctcncca 780 nccnacngnt agntcccccc cngggtncgg aangg 315 &lt;210&gt; 25 &lt;211&gt; 775 &lt;212&gt; DNA &lt;213&gt; Homo sapienS &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (775) &lt;223&gt; n = A, T, C or G &lt;400&gt; 25 ccgagatgtc tcgctccgtg gccttagctg tgctcgcgct actctctctt tctggcctgg 60 aggctatcca gcgtactcca aagattcagg tttactcacg tcatccagca gagaatggaa 120 agtcaaattt cctgaattgc tatgtgtctg ggtttcatcc atccgacatt gaanttgact 180 cactgaagaa tgganagaga atcgaaaaag tggagcattc agacttgtct ttcagcaagg 240 actggtcttt ctatctcntg tactacactg aattcacccc cactgaaaaa gatgagtatg 300 cctgccgtgt gaaccatgtg actttgtcac agcccaagat agttaagtgg gatcgagaca 360 tgtaagcagn cnncatggaa gtttgaagat gccgcatttg gattggatga attccaaatt 420 ctgcttgctt gcnttttaat antgatatgc ntatacaccc taccctttat gnccccaaat 480 tgtaggggtt acatnantgt tcncntngga catgatcttc ctttataant ccnccnttcg 540 aattgcccgt cncccngttn ngaatgtttc cnnaaccacg gttggctccc ccaggtcncc 600 tcttaoggaa gggcctgggc cnctttncaa ggttggggga accnaaaatt tcncttntgc 660 ccncccncca cnntcttgng nncncanttt ggaacccttc cnattcccct tggcctcnna 720 nccttnncta anaaaacttn aaancgtngc naaanntttn acttcccccc ttacc 775 &lt;210&gt; 26

PL 200 772 Β1 &lt;211&gt; 820 &lt;212&gt; DNA &lt;213&gt; Homo sapienS &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (820) &lt;223&gt; n = A, T, C or G &lt;400&gt; 26 anattantac agtgtaatct tttcccagag gtgtgtanag ggaacggggc ctagaggcat cccanagata ncttatanca acagtgcttt gaccaagagc tgctgggcac atttcctgca gaaaaggtgg cggtccccat cactcctcct ctcccatagc catcccagag gggtgagtag ccatcangcc ttcggtggga gggagtcang gaaacaacan accacagagc anacagacca ntgatgacca tgggcgggag cgagcctctt ccctgnaccg gggtggcana nganagccta nctgaggggt cacaccagncagnaccgtgaggggt cacaccagncana ccctgaggggt cacacncata ccctgccta gcngcctggg gacagcnctg ggancagcta acnnagcact cacctgcccc cccatggccg tncgcntccc tggtcctgnc aagggaagct ccctgttgga attncgggga naccaaggga nccccctcct ccanctgtga aggaaaaann gatggaattt tncccttccg gccnntcccc tcCtccttta cacgccccct nntactcntc tccctctntt ntcctgncnc acttttnacc ccnnnatttc ccttnattga tcggannctn ganattccac tnncgcctnc cntcnatcng naanacnaaa nactntctna cccnggggat gggnncctcg ntcatcctct ctttttcnct accnccnntt ctttgcctct ccttngatca

780tccaaccntc gntggccntn cccccccnnn tcctttnccc

820 &lt;210&gt; 27 &lt;211&gt; 818 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (818) &lt;223&gt; n - A, T, C (UB G &lt;400&gt; 27 tctgggtgat ggcctcttcc tcctcaggga cctctgactg ctctgggcca aagaatctct tgtttcttct ccgagcccca ggcagcggtg attcagccct gcccaacctg attctgatga ctgcggatgc tgtgacggac ccaaggggca aatagggtcc cagggtccag ggaggggcgc ctgctgagca cttccgcccc tcaccccgcc cagcccctgc catgagctct gggctgggtc tccgcctcca gggttctgct cttccangca ngccancaag tggcgctggg ccacactggc ttcttcctgc cccntccctg gctctgantc tctgtcttcc tgtcctgtgc angcnccttg gatctcagtt tccctcnctc anngaactct gtttctgann tcttcantta actntgantt tatnaccnan tggnctgtnc tgtcnnactt taatgggccn gaccggctaa tccctccctc nctcccttcc anttcnnnna accngcctnc cntcntctcc ccntancccg ccngggaanc ctcctttgcc ctnaccangg gccnnnaccg cccntnnctn ggggggcnng gtnnctncnc ctgntnnccc cnctcncnnt tncctcgtcc cnncnncgcn nngcannttc ncngtcccnn tnnctcttcn ngtntcgnaa ngntcncntn tnnnnngncn ngntnntncn tccctctcnc cnnntgnang tnnttnnnnc ncngnncccc nnnncnnnnn nggnnntnnn tctncncngc cccnnccccc ngnattaagg cctccnntct ccggccnc &lt;210&gt; 28 &lt;211&gt; 731 &lt;212&gt; DNA

PL 200 772 Β1 &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (731) &lt;223&gt; n = A, T, C or G &lt;400&gt; 28 aggaagggcg gagggatatt gcangggatt gagggatagg agnataangg gggaggtgtg 60 tcccaacatgattgttgnngt cnggtgatttgttcngggttttgttcngggttttgttcngggttttgttcngggttttgttcngggttttgttcngggttgnngt cngggttttgttcngggttannngt cngggtanngttac ttttcggctc ttatcagtat 180 ntanattcct gtnaatcgga aaatnatntt tcnncnggaa ttnttgctc ccatccgnaa 240 attnctcccg ggtagtgcat nttngggggn cngccagngnt tcccaggctg ctanaatcaggntt 300 ctagcaggctg ctanaatcaggntt tcccaggctg ctanaatcggntt 300 tcgccctntg actctgcnng agcccaatac ccnngngnat gtcncccngn 420 nnngcgncnc tgaaannnnc tcgnggctnn gancatcang gggtttcgca tcaaaagcnn 480 cgcttcncat naaggcactt tngcctcatc caaccnctng ccctcnncca tttngccgtc 540 nggttcncct acgctnntng cncctnnntn ganattttnc ccgcctnggg naancctcct 600 gnaatgggta gggncttntc ttttnaccnn gnggtntact aatcnnctnc acgcntnctt 660 tctcnacccc cccccttttt caatcccanc ggcnaatggg gtctccccnn cgangggggg c 731 720 nnncccannc

<td> &lt;210&gt;</td><td> 29</td><td></td>

<td> &lt;211&gt;</td><td> 822</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc_</td><td>feature</td>

<td> &lt;222&gt;</td><td> &lt;1&gt; /</td><td> (822)</td>

<td> &lt;223&gt;</td><td colspan="2">n = A, T, Clufa G.</td>

<td> &lt;400&gt;</td><td> 29</td><td></td>

actagtccag tgtggtggaa ttccattgtg ttggggncnc ttctatgant antnttagat 60 cgctcanacc tcacancctc ccnacnangc ctataangaa nannaataga nctgtncnnt 120 atntntacnc tcatanncct cnnnacccac tccctcttaa cccntactgt gcctatngcn 180 tnnctantct ntgccgcctn cnanccaccn gtgggccnac cncnngnatt ctcnatctcc 240 tcnccatntn gcctananta ngtncatacc ctatacctac nccaatgcta nnnctaancn 300 tccatnantt annntaacta ccactgacnt ngactttcnc atnanctcct aatttgaatc 360 tactctgact cccacngcct annnattagc ancntccccc nacnatntct caaccaaatc 420 ntcaacaacc tatctanctg ttcnccaacc nttncctccg atccccnnac aacccccctc 480 ccaaataccc nccacctgac ncctaacccn caccatcccg gcaagccnan ggncatttan 540 ccactggaat cacnatngga naaaaaaaac ccnaactctc tancncnnat ctccctaana 600 aatnctcctn naatttactn ncantnccat caancccacn tgaaacnnaa cccctgttCt 660 tanatccctt ctttcgaaaa ccnacccttt annncccaac ctttngggcc cccccnctnc 720 ccnaatgaag gncncccaat cnangaaacg nccntgaaaa ancnaggcna anannntccg 780 canatcctat cccttanttn ggggnccctt ncccngggcc cc 822 &lt;210&gt; 30 &lt;211&gt; 787 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature

PL 200 772 Β1 &lt;222&gt; (1). . . (787) &lt;223&gt; n = A, T, C or G &lt;400&gt; 30 cggccgcctg ctctggcaca tgcctcctga atggcatcaa aagtgatgga ctgcccattg 60 ctagagaaga ccttctctcc tactgtcatt atggagccct gcagactgag ggctcccctt 120 gtctgcagga tttgatgtct gaagtcgtgg agtgtggctt ggagctcctc atctacatna 180 gctggaagcc ctggagggcc tctctcgcca gcctccccct tctccccacg ctctccangg 240 acaccagggg ctccaggcag cccattattc ccagnangac atggtgtttc tccacgcgga 300 cccatggggc ctgnaaggcc agggtctcct ttgacaccat ctctcccgtc ctgcctggca 360 ggccgtggga tccactantt ctanaacggn cgccaccncg gtgggagctc cagcttttgt 420 tcccnttaat gaaggttaat tgcncgcttg gcgtaatcat nggtcanaac tntttcctgt 480 gtgaaattgt ttntcccctc ncnattccnc ncnacatacn aacccggaan cataaagtgt 540 taaagcctgg gggtngcctn nngaatnaac tnaactcaat taattgcgtt ggctcatggc 600 ccgctttccn ttcnggaaaa ctgtcntccc ctgcnttnnt gaatcggcca ccccccnggg 660 aaaagcggtt tgcnttttng ggggntcctt ccncttcccc cctcnctaan ccctncgcct 720 cggtcgttnc nggtngcggg gaangggnat nnnctcccnc naagggggng agnnngntat 780 ccccaaa 787 &lt;210 &gt; 31 &lt;211&gt; 799 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (799) &lt;223&gt; n = A, T, C lob G &lt;400&gt; 31 tttttttttt tttttttggc gatgctactg tttaattgca ggaggtgggg gtgtgtgtac 60 catgtaccag ggctgcaggcaggcta gccgcgcaggcta gcaggcacat ggggaggcct 180 cccgcagggt gggggccacc agtccagggg tgggagcact acanggggtg ggagtgggtg 240 gtggctggtn cnaatggcct gncacanatc cctacgattc ttgacacctg gatttcacca 300 ggggaccttc tgttctccca nggnaacttc ntnnatctcn aaagaacaca actgtttctt 360 cngcanttct ggctgttcat ggaaagcaca ggtgtccnat ttnggctggg acttggtaca 420 tatggttccg gcccacctct cccntcnaan aagtaattca cccccccccn ccntctnttg 480 cctgggccct taantaccca caccggaact canttantta ttcatcttng gntgggcttg 540 ntnatcnccn cctgaangcg ccaagttgaa aggccacgcc gtncccnctc cccatagnan 600 nttttnncnt canctaatgc ccccccnggc aacnatccaa tccccccccn tgggggcccc 660 agcccanggc ccccgnctcg ggnnnccngn cncgnantcc ccaggntctc ccantcngnc 720 ccnnngcncc cccgcacgca gaacanaagg ntngagccnc cgcannnnnn nggtnncnac 780 ctcgcccccc ccnncgnng 799 &lt;210&gt; 32 &lt;211&gt; 789 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (789) &lt;223&gt; n = A, T, C lob G

GB 200 772 Β1 &lt;400&gt; 32 tttttttttt tttttttttt tttttttttt tttttttttt tttttttttt tttttttttt 60 ttttnccnag ggcaggttta ttgacaacct cncgggacac aancaggctg gggacaggac 120 ggcaacaggc tccggcggcg gcggcggcgg ccctacctgc ggtaccaaat ntgcagcctc 180 cgctcccgct tgatnttcct ctgcagctgc aggatgccnt aaaacagggc ctcggccntn 240 ggtgggcacc ctgggatttn aatttccacg ggcacaatgc ggtcgcancc cctcaccacc 300 nattaggaat agtggtntta cccnccnccg ttggcncact ccccntggaa accacttntc 360 gcggctccgg catctggtct taaaccttgc aaacnctggg gccctctttt tggttantnt 420 nccngccaca atcatnactc agactggcnc gggctggccc caaaaaancn ccccaaaacc 480 ggnccatgtc ttnncggggt tgctgcnatn tncatcacct cccgggcnca ncaggncaac 540 ccaaaagttc ttgnggcccn caaaaaanct ccggggggnc ccagtttcaa caaagtcatc 600 ccccttggcc cccaaatcct ccccccgntt nctgggtttg ggaacccacg cctctnnctt 660 tggnnggcaa gntggntccc ccttcgggcc cccggtgggc ccnnctctaa ngaaaacncc 720 ntcctnnnca ccatcccccc nngnnacgnc tancaangna tccctttttt tanaaacggg 7B0 ccccccncg 789 &lt;210&gt; 33 &lt;211&gt; 793 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (793) &lt;223&gt; n = A, T, C liA G &lt;400&gt; 33 gacagaacat gttggatggt ggagcacctt tctatacgac ttacaggaca gcagatgggg 60 aattcatggc tgctgcaggaaggatgat 120gc agcgcagca atanaacgaaccgatgatgat 120actgaacca tgattggcca gaaatgaana 180 agaagtttgc agatgtattt gcaaagaaga cgaaggcaga gtggtgtcaa atctttgacg 240 gcacagatgc ctgtgtgact ccggttctga cttttgagga ggttgttcat catgatcaca 300gcagctcga ggttgttcat catgatcaca 300gcaangacga ggttgttcat catgatcaca 300gcaangacga ggttgttcatcagctgccgggcagctgcc aaacacccca gccatccctt ctttcaaaag ggatccacta cttctagagc 420 ggncgccacc gcggtggagc tccagctttt gttcccttta gtgagggtta attgcgcgct 480 tggcgtaatc atggtcatan ctgtttcctg tgtgaaattg ttatccgctc acaattccac 540 acaacatacg anccggaagc atnaaatttt aaagcctggn ggtngcćtaa tgantgaact 600 nactcacatt aattggcttt gcgctcactg cccgctttcc agtccggaaa acctgtcctt 660 gccagctgcc nttaatgaat cnggccaccc cccggggaaa aggcngtttg cttnttgggg 720 cgcncttccc gctttctcgc ttcctgaant ccttcccccc ggtctttcgg cttgcggcna 780 acggtatcna cct 793

<td> &lt;210&gt;</td><td> 34</td><td></td>

<td> &lt;211&gt;</td><td> 756</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td>&lt;2l3&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>_f eature</td>

<td> &lt;222&gt;</td><td> (1) -</td><td> . . (756)</td>

<td> &lt;223&gt;</td><td>n =.</td><td>A, T, Club G</td>

<td> &lt;400&gt;</td><td> 34</td><td></td>

gccgcgaccg gcatgtacga gcaactcaag ggcgagtgga accgtaaaag ccccaatctt 60 ancaagtgcg gggaanagct gggtcgactc aagctagttc ttctggagct caacttcttg 120

GB 200 772 Β1 ccaaccacag ggaccaagct gaccaaacag cagctaattc tggcccgtga catactggag 180 atcggggccc aatggagcat cctacgcaan gacatcccct ccttcgagcg ctacatggcc 240 cagctcaaat gctactactt tgattacaan gagcagctcc ccgagtcagc ctatatgcac 300 cagctcttgg gcctcaacct cctcttcctg ctgtcccaga accgggtggc tgantnccac 360 acgganttgg ancggctgcc tgcccaanga catacanacc aatgtctaca tcnaccacca 420 gtgtcctgga gcaatactga tgganggcag ctaccncaaa gtnttcctgg ccnagggtaa 480 catcccccgc cgagagctac accttcttca ttgacatcct gctcgacact atcagggatg 540 aaaatcgcng ggttgctcca gaaaggctnc aanaanatcc ttttcnctga aggcccccgg 600 atncnctagt nctagaatcg gcccgccatc gcggtgganc ctccaacctt tcgttnccct 660 ttactgaggg ttnattgccg cccttggcgt tatcatggtc acnccngttn cctgtgttga 720 aattnttaac cccccacaat tccacgccna catcng 755 &lt;210&gt; 35 &lt;211&gt; 834 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (834) &lt;223&gt; n = A, T, C lob G &lt;400&gt; 35 ggggatctct anatcnacct gnatgcatgg ttgtcggtgt ggtcgctgtc gatgaanatg 60 aacaggatct tgcccttgaa gctctcggct gctgtnttta agttgctcag tctgccgtca 120 tagtcagaca cnctcttggg caaaaaacan caggatntga gtcttgattt cacctccaat 180 aatcttcngg gctgtctgct cggtgaactc gatgacnang ggcagctggt tgtgtntgat 240 aaantccanc angttctcct tggtgacctc cccttcaaag ttgttccggc cttcatcaaa 300 cttctnnaan angannancc canctttgtc gagctggnat ttgganaaca cgtcactgtt 360 ggaaactgat cccaaatggt acgtcatcca tcgcctctgc tgcctgcaaa aaacttgctt 420 ggcncaaatc cgactccccn tccttgaaag aagccnatca cacccccctc cctggactcc 480 nncaangact ctnccgctnc cccntccnng cagggttggt ggcannccgg gcccntgcgc 540 ttcttcagcc agttcacnat nttcatcagc ccctctgcca gctgttntat tccttggggg 600 ggaanccgtc tctcccttcc tgaannaact ttgaccgtng gaatagccgc gcntcnccnt 660 acntnctggg ccgggttcaa antccctccn ttgncnntcn cctcgggcca ttctggattt 720 nccnaacttt ttccttcccc cnccccncgg ngtttggntt tttcatnggg ccccaactct 780 gctnttggcc antcccctgg gggcntntan cnccccctnt ggtcccntng ggcc 834 &lt;21O&gt; 36 &lt;211&gt; 814 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (814) &lt;223&gt; n = A, T, C or G &lt;400&gt; 36 cggncgcttt ccngccgcgc cccgtttcca tgacnaaggc tcccttcang ttaaatacnn 60 cctagnaaac attaatgggt cgctctacta atacatcata cnaaccagta agcctgccca 120 naacgccaac tcaggccatt cctaccaaag gaagaaaggc tggtctctcc accccctgta 180 ggaaaggcct gccttgtaag acaccacaat ncggctgaat ctnaagtctt gtgttttact 240 aatggaaaaa aaaaataaac aanaggtttt gttctcatgg ctgcccaccg cagcctggca 300 ctaaaacanc ccagcgctca cttctgcttg ganaaatatt ctttgctctt ttggacatca 360

GB 200 772 Β1 ggcttgatgg tatcactgcc acntttccac ccagctgggc ncccttcccc catntttgtc 420 antganctgg aaggcctgaa ncttagtctc caaaagtctc ngcccacaag accggccacc 480 aggggangtc ntttncagtg gatctgccaa anantacccn tatcatcnnt gaataaaaag 540 gcccctgaac ganatgcttc cancancctt taagacccat aatcctngaa ccatggtgcc 600 cttccggtct gatccnaaag gaatgttcct gggtcccant ccctcctttg ttncttacgt 660 tgtnttggac ccntgctngn atnacccaan tganatcccc ngaagcaccc tncccctggc 720 atttganttt cntaaattct ctgccctacn nctgaaagca cnattccctn ggcnccnaan 780 ggngaactca agaaggtctn ngaaaaacca cncn 814 &lt;210&gt; 37 &lt;211&gt; 760 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (760) &lt;223&gt; n = A, T, C or G &lt;400&gt; 37 gcatgctgct cttcctcaaa gttgttcttg ttgccataac aaccaccata ggtaaagcgg 60 gcgcagtgtt cgctgaaggg gttgtagtac cagcgcggga tgctctcctt gcagagtcct 120 gtgtctggca ggtccacgca atgccctttg tcactgggga aatggatgcg ctggagctcg 180 tcnaanccac tcgtgtattt ttcacangca gcctcctccg aagcntccgg gcagttgggg 240 gtgtcgtcac actccactaa actgtcgatn cancagctcg 180 tcnaanccac tcgtgtattt ttcacangca gcctcctccg aagcntccgg gcagttgggg 240 gtgtcgtcac actccactaa actgtcgatn cancagcta 360 tcnaanccac tcggctcccca ttgctgcagagc ggagctgccca ttggctgcagac 300 ggctgccagac ggagctggccca ttggctgcagagac ggagctggccca 300 caaactgcct ctcaaaggcc accttgcaca ccccgacagg ctagaaatgc 420 actcttcttc ccaaaggtag ttgttcttgt tgcccaagca ncctccanca aaccaaaanc 480 ttgcaaaatc tgctccgtgg gggtcatnnn taccanggtt ggggaaanaa acccggcngn 540 ganccncctt gtttgaatgc naaggnaata atcctcctgt cttgcttggg tggaanagca 600 caattgaact gttaacnttg ggccgngttc cnctngggtg gtctgaaact aatcaccgtc 660 actggaaaaa ggtangtgcc ttccttgaat tcccaaantt cccctngntt tgggtnnttt 720 ctcctctncc ctaaaaatcg tnttcccccc ccntanggcg 760 &lt;210&gt; 38 &lt;211&gt; 724 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;22l&gt; misc_feature &lt;222&gt; (1) ... (724) &lt;223&gt; n = A, T, C (ub G &lt;400&gt; 38 tttttttttt tttttttttt tttttttttt tttttaaaaa ccccctccat tgaatgaaaa 60 cttgccnaaat tgtccattccaga cttgccnaaat tgtccattccaga cttgccnaaat tgtccattccaga cttgccnaaat tgtccattccaga cttgccnaaat tgtccattccaga cttgccnaaat tgtccattccaga ctgccattccagaggngaaat tgtccattccagaggngnaaat tnattngggg aanaanccaa atgtnaagaa 180 aatttaaccc attatnaact taaatncctn gaaacccntg gnttccaaaa atttttaacc 240 cttaaatccc tccgaaattg ntaanggaaa accaaattcn cctaaggctn tctttaaggnac 300 ncctgntacnta cctnctn tctttaaggtc 300 ncctgnta cntnggtaac tcccgntaat gaannnccct aanccaatta aaccgaattt 420 tttttgaatt ggaaattccn ngggaattna ccggggtttt tcccntttgg gggccatncc 480 cccnctttcg gggtttgggn ntaggttgaa tttttnnang ncccaaaaaa ncccccaana 540 aaaaaactcc caagnnttaa ttngaatntc ccccttccca ggccttttgg gaaaggnggg 600

PL 200 772 Β1 tttntggggg ccngggantt cnttcccccn ttnccncccc ccccccnggt aaanggttat 660 ngnntttggt ttttgggccc cttnanggac cttccggatn gaaattaaat ccccgggn211 &lt;2010&gt; &lt;sub&gt; &lt;sub&gt; &lt;sub&gt; &lt;tb&gt; &lt;p&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (751) &lt;223&gt; n = A, T, C | ub G &lt;400&gt; 39 tttttttttt tttttctttg ctcacattta atttttattt tgattttttt taatgctgca 60 caacacaata tttatttcat ttgtttcttt tatttcattt tatttgtttg ctgctgccgt 120 tttatttatt tttactgaaa gtgagaggga acttttgtgg ccttttttcc tttttctgta 180 ggccgcctta agctttctaa atttggaaca tctaagcaag ctgaanggaa aagggggttt 240 cgcaaaatca ctcgggggaa nggaaaggtt gctttgttaa tcatgcccta tggtgggtga 300 ttaactgctt gtacaattac ntttcacttt taattaattg tgct.naangc tttaattana 360 cttgggggtt ccctccccan accaaccccn ctgacaaaaa gtgccngccc tcaaatnatg 420 tcccggcnnt cnttgaaaca cacngcngaa ngttctcatt ntccccncnc caggtnaaaa 480 tgaagggtta ccatntttaa cnccacctcc acntggcnnn gcctgaatcc tcnaaaancn 540 ccctcaancn aattnctnng ccccggtcnc gcntnngtcc cncccgggct ccgggaantn 600 cacccccnga anncnntnnc naacnaaatt ccgaaaatat tcccrmtcnc tcaattcccc 660 cnnagactnt cctcnncnan cncaattttc ttttnntcac gaacncgnnc cnnaaaatgn 720 nnnncncctc cnctngtccn naatcnccan c 751 &lt;21D&gt; 40 &lt;211 &gt; 753 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (753) &lt;223&gt; n = A, T, C or G &lt;400&gt; 40 gtggtatttt ctgtaagatc aggtgttcct ccctcgtagg tttagaggaa acaccctcat 60 agatgaaaaac ccccccgaga cagcagggagacaggggcagaca cagcaggcagaccaggggcagaccagggggaga cagcagggca 120 gatgtcaggc tcgatgtcaa 180 tggtctggaa gcggcggctg tacctgcgta ggggcacacc gtcagggccc accaggaact 240 tctcaaagtt ccaggcaacn tcgttgcgac acaccggaga ccaggtgatn agcttggggt 300 cggtcataan cgcggtggcg tcgtcgctgg gagctggcag ggcctcccgc aggaaggcna 360 ataaaaggtg cgcccccgca ccgttcanct cgcacttctc naanaccatg angttgggct 420 cnaacccacc accannccgg acttccttga nggaattccc aaatctcttc gntcttgggc 480 ttctnctgat gccctanctg gttgcccngn atgccaanca nccccaancc ccggggtcct 540 aaancacccn cctcctcntt tcatctgggt tnttntcccc ggaccntggt tcctctcaag 600 ggancccata tctcnaccan tactcaccnt ncccccccnt gnnacccanc cttctanngn 660 ttcccncccg ncctctggcc cntcaaanan gcttncacna cctgggtctg ccttcccccc 720 tnccctatct gnaccccncn tttgtctcan tnt 753 &lt;210&gt; 41

GB 200 772 Β1 &lt;211&gt; 341 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 41 actatatcca tcacaacaga catgcttcat cccatagact tcttgacata gcttcaaatg 60 agtgaaccca tccttgattt atatacatat atgttctcag tattttggga gcctttccac 120 ttctttaaac cttgttcatt atgaacactg aaaataggaa tttgtgaaga gttaaaaagt 180 tatagcctgt ttacgtagta agtttttgaa gtctacattc aatccagaca cttagttgag 240 tgttaaactg tgatttttaa aaaatatcat ttgagaatat tctttcagag gtattttcat 300 ttttactttt tgattaattg tgttttatat attagggtag t 341

<td>&lt;21O&gt;</td><td> 42</td>

<td> &lt;211&gt;</td><td> 101</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td>&lt;2l3&gt;</td><td>Homo sapien S.</td>

<td> &lt;400&gt;</td><td> 42</td>

acttactgaa tttagttctg tgctcttcct tatttagtgt tgtatcataa atactttgat 60 gtttcaaaca ttctaaataa ataattttca gtggcttcat and 101 &lt;210&gt; 43 &lt;211&gt; 305 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 43 acatctttgt tacagtctaa gatgtgttct taaatcacca ttccttcctg gtcctcaccc 60 tccagggtgg tctcacactg taattagagc tattgaggag tctCtacagc aaattaagat 120 tcagatgcct tgctaagtct agagttctag agttatgttt cagaaagtct aagaaaccca 180 cctcttgaga ggtcagtaaa gaggacttaa tatttcatat ctacaaaatg accacaggat 240 tggatacaga acgagagtta tcctggataa ctcagagctg agtacctgcc cgggggccgc 300 tcgaa 305 &lt;210&gt; 44 &lt;211&gt; 852 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (852) &lt;223&gt; n = A, T, C or G &lt;400&gt; 44 acataaatat cagagaaaag tagtctttga aatatttacg tccaggagtt ctttgtttct 60 gattattcgg tgtgtgattcat 120gtctcattagtcat 120gtccctcattcat 120 ggttcccattcattca tcttcgtcca tccacacgct 180 ccagaatttc tcttttgtag taatatctca tagctcggct gagcttttca taggtcatgc 240 tgctgttgtt cttcttttta ccccatagct gagccactgc ctgctgatttc aagaacctga 300 agttcgtgtcta 300 agttcgtgtctc agttcggtctta gatgaattcc cataagtgag tccctctcgg gttgtgcttt ttggtgtggc 420 acttggcagg ggggtcttgc tcctttttca tatcaggtga ctctgcaaca ggaaggtgac 480 tggtggttgt catggagatc tgagcccggc agaaagtttt gctgtccaac aaatctactg 540 tgctaccata gttggtgtca tataaatagt tctngtcttt ccaggtgttc atgatggaag 600

GB 200 772 Β1 gctcagtttg ttcagtcttg acaatgacat tgtgtgtgga ctggaacagg tcactactgc 660 actggccgtt ccacttcaga tgctgcaagt tgctgtagag gagntgcccc gccgtccctg 720 ccgcccgggt gaactcctgc aaactcatgc tgcaaaggtg ctcgccgttg atgtcgaact 780 cntggaaagg gatacaattg gcatccagct ggttggtgtc caggaggtga tggagccact 840 cccacacctg gt 852 &lt;210&gt; 45 &lt;211&gt; 234 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 45 acaacagacc cttgctcgct aacgacctca tgctcatcaa gttggacgaa tccgtgtccg 60 agtctgacac catccggagc atcagcattg cttcgcagtg ccctaccgcg gggaactctt 120 gcctcgtttc tggctggggt ctgctggcga acggcagaat gcctaccgtg ctgcagtgcg 180 tgaacgtgtc ggtggtgtct gaggaggtct gcagtaagct ctatgaccc4g ctgt 23

<td>&lt;21O&gt;</td><td> 46</td><td></td>

<td> &lt;211&gt;</td><td> 590</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td>&lt;2l3&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td>and 1&gt;</td><td>λ (590)</td>

<td> &lt;223&gt;</td><td colspan="2">η = A, T, C or</td>

<td> &lt;400&gt;</td><td> 46</td><td></td>

actttttatt taaatgttta taaggcagat ctatgagaat gatagaaaac atggtgtgta 60 atttgatagc aatattttgg agattacaga gttttagtaa ttaccaatta cacagttaaa 120 aagaagataa tatattccaa gcanatacaa aatatctaat gaaagatcaa ggcaggaaaa 180 tgantataac taattgacaa tggaaaatca attttaatgt gaattgcaca ttatccttta 240 aaagctttca aaanaaanaa ttattgcagt ctanttaatt caaacagtgt taaatggtat 300 caggataaan aactgaaggg canaaagaat taattttcac ttcatgtaac ncacccanat 360 ttacaatggc ttaaatgcan ggaaaaagca gtggaagtag ggaagtantc aaggtctttc 420 tggtctctaa tctgccttac tctttgggtg tggctttgat cctctggaga cagctgccag 480 ggctcctgtt atatccacaa tcccagcagc aagatgaagg gatgaaaaag gacacatgct 540 gccttccttt gaggagacct catctcactg gccaacgt 590

<td> &lt;210&gt;</td><td> 47</td><td></td>

<td> &lt;211&gt;</td><td> 774</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt; &lt;221&gt;</td><td>misc</td><td>_feature</td>

<td> &lt;222&gt;</td><td> (1) .</td><td> . . (774)</td>

<td> &lt;223&gt;</td><td>n -</td><td>A, T, C or</td>

<td> &lt;400&gt;</td><td>4Ί</td><td></td>

acaagggggc ataatgaagg agtggggana gattttaaag aaggaaaaaa aacgaggccc 60 tgaacagaat tttcctgnac aacggggctt caaaataatt ttcttgggga ggttcaagac 120 gcttcactgc ttgaaactta aatggatgtg ggacanaatt ttctgtaatg accctgaggg 180 cattacagac gggactctgg gaggaaggat aaacagaaag gggacaaagg ctaatcccaa 240 aacatcaaag aaaggaaggt ggcgtcatac ctcccagcct acacagttct ccagggctct 300

GB 200 772 Β1 cctcatccct ggaggacgac agtggaggaa caactgacca tgtccccagg ctcctgtgtg 360 ctggctcctg gtcttcagcc cccagctctg gaagcccacc ctctgctgat cctgcgtggc 420 ccacactcct tgaacacaca tccccaggtt atattcctgg acatggctga acctcctatt 480 cctacttccg agatgccttg ctccctgcag cctgtcaaaa tcccactcac cctccaaacc 540 acggcatggg aagcctttct gacttgcctg attactccag catcttggaa caatccctga 600 ttccccactc cttagaggca agatagggtg gttaagagta gggctggacc acttggagcc 660 aggctgctgg cttcaaattn tggctcattt acgagctatg ggaccttggg caagtnatct 720 tcacttctat gggcntcatt ttgttctacc tgcaaaatgg gggataataa tagt 774

<td> &lt;210&gt;</td><td> 48</td><td></td>

<td> &lt;211&gt;</td><td> 124</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>_feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> 7.(124)</td>

<td> &lt;223&gt;</td><td>n =.</td><td>A, T, C or</td>

<td> &lt;400&gt;</td><td> 48</td><td></td>

canaaattga aattttataa aaaggcattt ttctcttata tccataaaat gatataattt 60 ttgcaantat anaaatgtgt cataaattat aatgttcctt aattacagct caacgcaact 120 tggt 124 &lt;210&gt; 49 &lt;211&gt; 147 &lt;212&gt; DNA &lt;213&gt; &lt;220&gt; Homo &lt;213&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (147) &lt;223&gt; n = A, T, C, or G &lt;400&gt; 49 gccgatgcta ctattttatt gcaggaggtg ggggtgtttt tattattctc tcaacagctt 60 tgtggctaca ggtggtta tactgggttaactga gactgcata tcgata gacta &lt;210&gt; 50 &lt;211&gt; 107 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 50 acattaaatt aataaaagga ctgttggggt tctgctaaaa cacatggctt gatatattgc 60 atggtttgag gttaggagga gctaggcata tgttgggtga 107

<td colspan="2">&lt;210&gt; 51 &lt;211&gt; 204 &lt;212&gt; DNA &lt;2l3&gt; Homo sapiend</td>

<td> &lt;400&gt;</td><td> 51</td>

gtcctaggaa gtctagggga cacacgactc tggggccacg gggccgacac acttgcacgg 60

PL 200 772 Β1 cgggaaggaa aggcagagaa gtgacaccgt cagggggaaa tgacagaaag gaaaatcaag 120 gccttgcaag gtcagaaagg ggactcaggg cttccaccac agccctgccc cacttggcca 180 cctccctt210&gt; sggtggcca 180 52 cctcccttt210&gt; sggtggcca 180 52 cctccctttagien &lt;210&gt; &lt;sub&gt;

&lt;22l&gt; misc_feature &lt;222&gt; (1) ... (491) &lt;223&gt; n = A, T, C iol? G &lt;400&gt; 52 acaaagataa catttatctt ataacaaaaa tttgatagtt ttaaaggtta gtattgtgta 60 gggtattttc caaaagacta aagagataac tcaggtaaaa agttagaaat gtataaaaca 120 ccatcagaca ggtttttaaa aaacaacata ttacaaaatt agacaatcat ccttaaaaaa 180 aaaacttctt gtatcaattt cttttgttca aaatgactga cttaantatt cttaaatatt 240 tcanaaacac ttcctcaaaa attttcaana tggtagcttt canatgtncc ctcagtccca 300 atgttgctca gataaataaa tctcgtgaga acttaccacc caccacaagc tttctggggc 360 atgcaacagt gtcttttctt tnctttttct tttttttttt ttacaggcac agaaactcat 420 caattttatt tggataacaa agggtctcca aattatattg aaaaataaat ccaagttaat 480 atcactcttg t 491 &lt;210&gt; 53 &lt;211&gt; 484 &lt;212&gt; DNA &lt;213&gt; &lt;Hom220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (484) &lt;223&gt; n = A, T, C or G &lt;400&gt; 53 acataattta gcagggctaa ttaccataag atgctattta ttaanaggtn tatgatctga 60 gtattaacag ttgctgaagt ttgttacgattagtagta ttgttacgattagtagta ttgttacgattagtagta ttgttacgattagtagta gttcagaaac attagctgct 180 caatcaaatc tctacataac actatagtaa ttaaaacgtt aaaaaaaagt gttgaaatct 240 gcactagtat anaccgctcc tgtcaggata anactgcttt ggaacagaaa gggaaaaaanc 300 agctttgtagcta gggaaaaaanc 300 agctttgtagcta aggtcnggta aatnccaaaa catattccaa ctcaacactt cttttccncg 420 tancttgant ctgtgtattc caggancagg cggatggaat gggccagccc ncggatgttc 480 cant 484 &lt;210&gt; 54 &lt;211&gt; 151 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 54 actaaacctc gtgcttgtga actccataca gaaaacggtg ccatccctga acacggctgg 60 ccactgggta tactgctgac aaccgcaaca acaaaaacac aaatccttgg cactggctag 120 tctatgtcct ctcaagtgcc tttttgtttg t 151

PL 200 772 Β1

<td>&lt;21O&gt;</td><td> 55</td>

<td> &lt;211&gt;</td><td> 91</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapiens</td>

<td> &lt;400&gt;</td><td> 55</td>

acctggcttg tctccgggtg gttcccggcg ccccccacgg tccccagaac ggacactttc gccctccagt ggatactcga gccaaagtgg t

<td colspan="2">&lt;210&gt; 56 &lt;211&gt; 133 &lt;212&gt; DNA &lt;213&gt; Homo sapienS</td>

<td> &lt;400&gt;</td><td> 56</td>

ggcggatgtg cgttggttat atacaaatat gtcattttat gtaagggact tgagtatact tggatttttg gtatctgtgg gttgggggga cggtccagga accaataccc catggatacc aagggacaac tgt &lt;210&gt; &lt;210&gt; &lt;220&gt; &lt;sien&gt; s &lt;14713&gt; &lt;210&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (147) &lt;223&gt; n = A, T, C. Or G

120

133 &lt;400&gt; 57 actctggaga acctgagccg ctgctccgcc tctgggatga ggtgatgcan gcngtggcgc gactgggagc tgagccctcc cctttgcgcc tgcctcagag gattgttgcc gacntgcana tctcantggtg ctggatgtg

120

147

<td>&lt;2l0&gt;</td><td> 58</td><td></td>

<td> &lt;211&gt;</td><td> 198</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>_f eature</td>

<td> &lt;222&gt;</td><td>(l)</td><td> ..(198)</td>

<td> &lt;223&gt;</td><td>n =.</td><td>A, T, C or</td>

<td> &lt;400&gt;</td><td> 58</td><td></td>

acagggat aggtttnaag ttattgtnat tgtaaaatac attgaatttt ctgtatactc tgattacata catttatcct ttaaaaaaga tgtaaatctt aatttttatg ccatctatta atttaccaat gagttacctt gtaaatgaga agtttgata gcactgattgata gcactgattgata gcactga

120

180

198 &lt;210&gt; 59 &lt;211&gt; 330 &lt;212&gt; DNA &lt;213&gt; Homo sapiens

PL 200 772 Β1 &lt;400:

acaacaaatg ccattgaaaa cacctgtgct tacagtcaat cagaaggaat tttcgtcttt ggttgtgagg ttatcactaa agcttgctaa aaatgacaaa ctattttatc attggacttc aagtcttatc tgattttaaa aatgggagtt gccagggcct acatggatct tttgaagagt agcaaaaccg tgacaagtta aactctagag acaggtggtt ccgtctgtgc gtgatggcta tcaaaaactc caaacatagt tccagacttt tcaaaatacc ctgaaaagat acccaatttt atcttctgaa ccagacccag caatgatatt

120

180

240

300

330

<td> &lt;210&gt;</td><td> 60</td>

<td> &lt;211&gt;</td><td> 175</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapiens</td>

<td> &lt;400&gt;</td><td> 60</td>

accgtgggtg ccttctacat tcctgacggc tccttcacca acatctggtt ctacttcggc 60 gtcgtgggct ccttcctctt catcctcatc cagctggtgc tgctcatcga ctttgcgcac 120 tcctggaacagggggggcgcac 120 tcctggaacagggggggcgcac 120 tcctggaacaggggggcgcgcac 120 tcctggaacaggg

<td>&lt;21O&gt;</td><td> 61</td>

<td> &lt;211&gt;</td><td> 154</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapiens</td>

<td> &lt;400&gt;</td><td> 61</td>

accccacttt tcctcctgtg agcagtctgg acttctcact gctacatgat gagggtgagt 60 ggttgttgct cttcaacagt atcctcccct ttccggatct gctgagccgg acagcagtgc 120 tggactgcac agccccacgattggg ctgactgcac agccccacgattggg ctgactgcac agccccacgattggg ctgactgcac

<td> &lt;210&gt;</td><td> 62</td>

<td> &lt;211&gt;</td><td> 30</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapiens</td>

<td> &lt;400&gt;</td><td> 62</td>

cgctcgagcc ctatagtgag tcgtattaga &lt;210&gt; 63 &lt;211&gt; 89 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 63 acaagtcatt tcagcacccC ttgcttca aaactgacca tcttttatat ttaatgcttc 60 ctgtatgat 89

<td> &lt;210&gt;</td><td> 64</td>

<td> &lt;211&gt;</td><td> 97</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapiens</td>

<td> &lt;400&gt;</td><td> 64</td>

accggagtaa ctgagtcggg acgctgaatc tgaatccacc aataaataaa ggttctgcag aatcagtgca tccaggattg gtccttggat ctggggt

PL 200 772 Β1 &lt;210&gt; 65 &lt;211&gt; 377 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;22l&gt; misc_feature &lt;222&gt; (1). . . (377) &lt;223&gt; n = A, T, C or G &lt;400&gt; 65 acaacaanaa ntcccttctt taggccactg atggaaacct ggaaccccct tttgatggca 60 gcatggcgtc ctaggccttg acacagcggc tggggtttgg gctntcccaa accgcacacc 120 ccaaccctgg tctacccaca nttctggcta tgggctgtct ctgccactga acatcagggt 180 tcggtcataa natgaaatcc caanggggac agaggtcagt agaggaagct caatgagaaa 240 ggtgctgttt gctcagccag aaaacagctg cctggcattc gccgctgaac tatgaacccg 300 tgggggtgaa ctacccccan gaggaatcat gcctgggcga tgcaanggtg ccaacaggag 360 gggcgggagg agcatgt 377 &lt;210&gt; 66 &lt;211&gt; 305 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 66 acgcctttcc ctcagaattc agggaagaga ctgtcgcctg ccttcctccg ttgttgcgtg 60 agaacccgtg tgccccttcc caccatatcc accctcgctc catcttcgaa ctcaaacacg 120 aggaactaac tgcaccctgg tcctctcccc agtccccagt tcaccctcca tccctcacct 180 tcctccactc taagggatat caacactgcc cagcacaggg gccctgaatt tatgtggttt 240 ttatatattt tttaataaga tgcactttat gtcatttttt aataaagtct gaagaattac 300 tgttt 305 &lt;210&gt; 67 &lt;211&gt; 385 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 67 actacacaca ctccacttgc ccttgtgaga cactttgtcc cagcacttta ggaatgctga 60 ggtcggacca gccacatctc atgtgcaaga ttgcccagca gacatcaggt ctgagagttc 120 cccttttaaa aaaggggact tgcttaaaaa agaagtctag ccacgattgt gtagagcagc 180 tgtgctgtgc tggagattca cttttgagag agttctcctc tgagacctga tctttagagg 240 ctgggcagtc ttgcacatga gatggggctg gtctgatctc agcactcctt agtctgcttg 300 cctctcccag ggccccagcc tggccacacc tgcttacagg gcactctcag atgcccatac 360 catagtttct gtgctagtgg accgt 385

<td> &lt;210&gt;</td><td> 68</td>

<td> &lt;211&gt;</td><td> 73</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapiens</td>

<td> &lt;400&gt;</td><td> 68</td>

acttaaccag atatattttt accccagatg gggatattct ttgtaaaaaa tgaaaataaa 60 gtttttttaa tgg 73

PL 200 772 Β1

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td>69 536 GOUT Homo</td><td>sapienj</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1) - -</td><td> (536)</td>

<td> &lt;223&gt;</td><td>η = i</td><td>i, T, C lob</td>

<td> &lt;400&gt;</td><td> 69</td><td></td>

actagtccag tgtggtggaa ttccattgtg ttgggggctc tcaccctcct ctcctgcagc 60 tccagccttg tgctctgcct ctgaggagac catggcccag catctgagta ccctgctgct 120 cctgctggcc accctagctg tggccctggc ctggagcccc aaggaggagg ataggataat 180 cccgggtggc atctataacg cagacctcaa tgatgagtgg gtacagcgtg cccttcactt 240 cgccatcagc gagtataaca aggccaccaa agatgactac tacagacgtc cgctgcgggt 300 actaagagcc aggcaacaga ccgttggggg ggtgaattac ttcttcgacg tagaggtggg 360 ccgaaccata tgtaccaagt cccagcccaa cttggacacc tgtgccttcc atgaacagcc 420 agaactgcag aagaaacagt tgtgctcttt cgagatctac gaagttccct ggggagaaca 480 gaangtccct gggtgaaatc caggtgtcaa gaaatcctan ggatctgttg ccaggc 536 &lt;210&gt; 70 &lt;2il&gt; 477 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 70 atgaccccta acaggggccc tctcagccct cctaatgacc tccggcctag ccatgtgatt 60 tcacttccac tccataacgc tcctcatact aggcctacta accaacacac taaccatata 120 ccaatgatgg cgcgatgtaa cacgagaaag cacataccaa ggccaccaca caccacctgt 180 ccaaaaaggc cttcgatacg ggataatcct atttattacc tcagaagttt ttttcttcgc 240 agggattttt ctgagccttt taccactcca gcctagcccc taccccccaa ctaggagggc 300 actggccccc aacaggcatc accccgctaa atcccctaga agtcccactc ctaaacacat 360 ccgtattact cgcatcagga gtatcaatca cctgagctca ccatagtcta atagaaaaca 420 accgaaacca aattattcaa agcactgctt attacaattt tactgggtct ctatttt 477 &lt;210&gt; 71 &lt;211&gt; 533 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). .. (533) &lt;223&gt; n = A, T, C or G &lt;400&gt; 71 agagctatag gtacagtgtg atctcagctt tgcaaacaca ttttctacat agatagtact 60 aggtattaat agatatgtaa agaaagaaat cacaccatta ataatggtaa gattggttta 120 tgtgatttta gtggtatttt tggcaccctt atatatgttt tccaaacttt cagcagtgat 180 attatttcca taacttaaaa agtgagtttg aaaaagaaaa tctccagcaa gcatctcatt 240 taaataaagg tttgtcatct ttaaaaatac agcaatatgt gactttttaa aaaagctgtc 300 aaataggtgt gaccctacta ataattatta gaaatacatt taaaaacatc gagtacctca 360 agtcagtttg ccttgaaaaa tatcaaatat aactcttaga gaaatgtaca taaaagaatg 420 cttcgtaatt ttggagtang aggttccctc ctcaattttg tatttttaaa aagtacatgg 480 taaaaaaaaa aattcacaac agtatataag gctgtaaaat gaagaattct gcc 533

PL 200 772 Β1 &lt;210&gt; 72 &lt;211&gt; 511 &lt;212&gt; DNA &lt;213&gt; Homo sapien5 &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (511) &lt;223&gt; n = A, T, C or G &lt;400&gt; 72 tattacggaa aaacacacca cataattcaa ctancaaaga anactgcttc agggcgtgta 60 aaatgaaagg cttccaggca gttatctacga taaagctagga atgancctacga taaagctagga atgancctacga taaagctagga attaagctagga ttggctggag gagctgtgga 180 aaacatggan agattggcgc tgganatcgc cgtggctatt cctcattgtt attacanagt 240 gaggttctct gtgtgcccac tggtttgaaa accgttctnc aataatgata gaatagtagacag caggctacca 300 cacatagatcca ctagctacca 300 cacatagatcc acaataaccg atgaagaaaa gatggcctcc ttgtgccccc gtctgttatg 420 atttctctcc attgcagcna naaacccgtt cttctaagca aacncaggtg atgatggcna 480 aaatacaccc cctcttgaag naccnggagg a 511

<td> &lt;210&gt;</td><td> 73</td><td></td>

<td> &lt;211&gt;</td><td> 499</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>miso</td><td>_f eature</td>

<td> &lt;222&gt;</td><td> (1) .’</td><td> . . (499)</td>

<td> &lt;223&gt;</td><td>n = j</td><td>A, T, C or</td>

<td> &lt;400&gt;</td><td> 73</td><td></td>

cagtgccagc actggtgcca gtaccagtac caataacagt gccagtgcca gtgccagcac 60 cagtggtggc ttcagtgctg gtgccagcct gaccgccact ctcacatttg ggctcttcgc 120 tggccttggt ggagctggtg ccagcaccag tggcagctct ggtgcctgtg gtttctccta 180 caagtgagat tttagatatt gttaatcctg ccagtctttc tcttcaagcc agggtgcatc 240 ctcagaaacc tactcaacac agcactctag gcagccacta tcaatcaatt gaagttgaca 300 ctctgcatta aatctatttg ccatttctga aaaaaaaaaa aaaaaaaggg cggccgctcg 360 antctagagg gcccgtttaa acccgctgat cagcctcgac tgtgccttct anttgccagc 420 catctgttgt ttgcccctcc cccgntgcct tccttgaccc tggaaagtgc cactcccact 480 gtcctttcct aantaaaat 499

<td> &lt;210&gt;</td><td> 74</td><td></td>

<td> &lt;211&gt;</td><td> 537</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>_feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> ..(537)</td>

<td> &lt;223&gt;</td><td>n =,</td><td>A, T, C or</td>

<td> &lt;400&gt;</td><td> 74</td><td></td>

tttcatagga gaacacactg aggagatact tgaagaattt ggattcagcc gcgaagagat 60

GB 200 772 Β1 ttatcagctt aactcagata aaatcattga aagtaataag gtaaaagcta gtctctaact 120 tccaggccca cggctcaagt gaatttgaat actgcattta cagtgtagag taacacataa 180 cattgtatgc atggaaacat ggaggaacag tattacagtg tcctaccact ctaatcaaga 240 aaagaattac agactctgat tctacagtga tgattgaatt ctaaaaatgg taatcattag 300 ggcttttgat ttataanact ttgggtactt atactaaatt atggtagtta tactgccttc 360 cagtttgctt gatatatttg ttgatattaa gattcttgac ttatattttg aatgggttct 420 actgaaaaan gaatgatata ttcttgaaga catcgatata catttattta cactcttgat 480 tctacaatgt agaaaatgaa ggaaatgccc caaattgtat ggtgataaaa gtcccgt 537 &lt;210&gt; 75 &lt;211&gt; 467 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; {1) ... (467) &lt;223&gt; n = A, T, C l_aboutfc&gt; G &lt;400&gt; 75 caaanacaat tgttcaaaag atgcaaatga tacactactg ctgcagctca caaacacctc 60 tgcatattac acgtacctcc tcctgctcct caagtagtgt ggtctatttt gccatcatca 120 cctgctgtct gcttagaaga acggctttct gctgcaangg agagaaatca taacagacgg 180 tggcacaagg aggccatctt ttcctcatcg gttattgtcc ctagaagcgt cttctgagga 240 tctagttggg ctttctttct gggt.ttgggc catttcantt ctcatgtgtg tactattcta 300 tcattattgt ataacggttt tcaaaccngt gggcacncag agaacctcac tctgtaataa 360 caatgaggaa tagccacggt gatctccagc accaaatctc tccatgttnt tccagagctc 420 ctccagccaa cccaaatagc cgctgctatn gtgtagaaca tccctgn 467 &lt;210&gt; 76 &lt;211&gt; 400 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (400) &lt;223&gt; n = A, T, C | i * GG &lt;400&gt; 76 aagctgacag cattcgggcc gagatgtctc gctccgtggc cttagctgtg ctcgcgctac 60 tctcagatttc tgcgctacca gccagcgcagaccggcagcgcagatctgaccagcgcaga tcaaatttcc tgaattgcta tgtgtctggg tttcatccat 180 ccgacattga agttgactta ctgaagaatg gagagagaat tgaaaaagtg gagcattcag 240 acttgtcttt cagcaaggac tggtctttct atctcttgta ctacactgaa ttcaccccca 300 ctgaaaaaga tgagtatgcc tgccgtgtga accatgtgac tttgtcacag cccaagatng 360 ttnagtggga tcganacatg taagcagcan catgggaggt 400

<td colspan="2">&lt;21O&gt; 77 &lt;211&gt; 248 &lt;212&gt; DNA &lt;2L3&gt; Homo sapiens</td>

<td> &lt;400&gt;</td><td> 77</td>

ctggagtgcc ttggtgtttcaagcccctgc aggaagcaga atgcaccttc tgaggcacct 60

GB 200 772 Β1 ccagctgccc cggcggggga tgcgaggctc ggagcaccct tgcccggctg tgattgctgc 120 caggcactgt tcatctcagc ttttctgtcc ctttgctccc ggcaagcgct tctgctgaaa 180 gttcatatct ggagcctgat gtcttaacga ataaaggtcc catgctccac ccgaaaaaaa 240 aaaaaaaa 248 &lt;210&gt; 78 &lt;211&gt; 201 &lt;212&gt; DNA &lt;213&gt; Homo sapierte &lt;400&gt; 78 actagtccag tgtggtggaa ttccattgtg ttgggcccaa cacaatggct acctCtaaca 60 tcacccagac cccgccctgc ccgtgcccca cgctgctgct aacgacagta tgatgcttac 120 tctgctactc ggaaactatt tttatgtaat taatgtatgc tattaatgc atattaat 180 gatttaaaaa aaaaaaaaaa a 201

<td colspan="2"> &lt;210&gt; 79</td>

<td>&lt;2ll&gt;</td><td> 552</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapien S.</td>

&lt;220&gt;

&lt;221&gt; ntisc_feature &lt;222&gt; (1! ... (552) &lt;223&gt; n = A, T, C or G &lt;400&gt; 79 tccttttgtt aggtttttga gacaacccta gacctaaact gtgtcacaga cttctgaatg 60 tttaggcagt gcttcacaga cttctgaatg 60 tttaggcagt gctagtaatt tcatttcgtacta tttactttcgtactaat gttacttcgtactaat gttacttcgtacta ggataaatac aaaaaggtag 180 tgtgatagta taagtatcta agtgcagatg aaagtgtgtt atatatatcc attcaaaatt 240 atgcaagtta gtaattactc agggttaact aaattacttt aatatgctgt tgaacctact 300 ctttgttaattactaga gactgaacctact 300 ctttgttaattactaga gactata attaattaattaca tgttctaaaa gttgggctat acataaanta tnaagaaata tggaatttta 420 ttcccaggaa tatggggttc atttatgaat antacccggg anagaagttt tgantnaaac 480 cngttttggt taatacgtta atatgtccta aatnaaaaaa 540 gcnta aaactaaaa 540 gcnta

<td>&lt;2l0&gt;</td><td> 80</td><td></td>

<td> &lt;211&gt;</td><td> 476</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td>il).</td><td> ..(476)</td>

<td> &lt;223&gt;</td><td>n =,</td><td>A, T, C Feb.</td>

<td> &lt;400&gt;</td><td> 80</td><td></td>

acagggattt gagatgctaa ggccccagag atcgtttgat ccaaccctct tattttcaga 60 ggggaaaatg gggcctagaa gttacagagc atctagctgg tgcgctggca cccctggcct 120 cacacagact cccgagtagc tgggactaca ggcacacagt cactgaagca ggccctgttt 180 gcaattcacg ttgccacctc caacttaaac attcttcata tgtgatgtcc ttagtcacta 240 aggttaaact ttcccaccca gaaaaggcaa cttagataaa atcttagagt actttcatac 300 tcttctaagt cctcttccag cctcactttg agtcctcctt gggggttgat aggaantntc 360

PL 200 772 Β1 tcttggcttt ctcaataaaa tctctatcca tctcatgttt aatttggtac gcntaaaaat 420 gctgaaaaaa ttaaaatgtt ctggtttcnc tttaaaaaaa aaaaaaaaa2 &lt;aaaaaaa2aaaaaaa2 476112aaaaaaaaaaaaaaaaaaaaaa2

&lt;22l&gt; misc feature

<td> &lt;222&gt;</td><td> (1)</td><td> -.-(232)</td>

<td> &lt;223&gt;</td><td>n =</td><td>A, T, C LU</td>

<td> &lt;400&gt;</td><td> 81</td><td></td>

tttttttttg tatgccntcn ctgtggngtt attgttgctg ccaccctgga ggagcccagt 60 ttcttctgta tctttctttt ctgggggatc ttcctggctc tgcccctcca ttcccagcct 120 ctcatcccca tcttgcactt ttgctagggt tggaggcgct ttcctggtag cccctcagag 180 actcagtcag cgggaataag tcctaggggt ggggggtgtg gcaagccggc ct 232

<td> &lt;210&gt;</td><td> 82</td><td></td>

<td> &lt;211&gt;</td><td> 383</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapienS</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>.feature</td>

<td> &lt;222&gt;</td><td>(and)</td><td>Γ. (383)</td>

<td> &lt;223&gt;</td><td colspan="2">n - A, T, C IU,</td>

<td> &lt;400&gt;</td><td> 82</td><td></td>

aggcgggagc agaagctaaa gccaaagccc aagaagagtg gcagtgccag cactggtgcc 60 agtaccagta ccaataacat gccagtgcca gtgccagcac cagtggtggc ttcagtgctg 120 gtgccagcct gaccgccact ctcacatttg ggctcttcgc tggccttggt ggagctggtg 180 ccagcaccag tggcagctct ggtgcctgtg gtttctccta caagtgagat tttagatatt 240 gttaatcctg ccagtctttc tcttcaagcc agggtgcatc ctcagaaacc tactcaacac 300 agcactctng gcagccacta tcaatcaatt gaagttgaca ctctgcatta aatctatttg 360 ccatttcaaa aaaaaaaaaa aaa 383 &lt;210&gt; 83 &lt;211&gt; 494 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (494) &lt;223&gt; n = A, T, C lujo G &lt;400&gt; 83 accgaattgg gaccgctggc ttataagcga tcatgtcctc cagtattacc tcaacgagca 60 gggagatcga gtctatacgc tgaagaaatt tgacccgatg ggacaacaga cctgctcagc 120 ccaccetgct cggttctccc cagatgacaa atactctcga caccgaatca ccatcaagaa 180 acgcttcaag gtgctcatga cccagcaacc gcgccctgtc ctctgagggt ccttaaactg 240 atgtcttttc tgccacctgt tacccctcgg agactccgta accaaactct tcggactgtg 300 agccctgatg cctttttgcc agccatactc tttggcntcc agtctctcgt ggcgattgat 360

PL 200 772 Β1 tatgcttgtg tgaggcaatc atggtggcat cacccatnaa gggaacacat ttganttttt tttcncatat tttaaattac naccagaaca nttcagaata aatgaattga aaaactctta aaaaaasaaa aaaa

<td> &lt;210&gt;</td><td> 84</td><td></td>

<td> &lt;211&gt;</td><td> 380</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td>ΐl)</td><td> (380)</td>

<td> &lt;223 &gt;</td><td colspan="2">n = A, T, C Iiao</td>

<td> &lt;400&gt;</td><td> 84</td><td></td>

gctggtagcc tatggcgtgg ccacggangg gctcctgagg cacgggacag tgacttccca agtatcctgc gccgcgtctt ctaccgtccc tacctgcaga tcttcgggca gattccccag gaggacatgg acgtggccct catggagcac agcaactgct cgtcggagcc cggcttctgg gcacaccctc ctggggccca ggcgggcacc tgcgtctccc agtatgccaa ctggctggtg gtgctgctcc tcgtcatctt cctgcccgtg gccaacatcc tgctggtcac ttgctcattg ccatgttcag ttacacactc ggcaaagtac agggcaacag cnatctctac tgggaaggcc agcgttnccg cctcatccgg

<td>&lt;21O&gt;</td><td> 85</td><td></td>

<td> &lt;211&gt;</td><td> 481</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapienS</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1) . -</td><td> .(481)</td>

<td> &lt;223&gt;</td><td>n = i</td><td>i, T, C or</td>

<td> &lt;400&gt;</td><td> 85</td><td></td>

gagttagctc ctccacaacc ttgatgaggt cgtctgcagt ggcctctcgc ttcataccgc tnccatcgtc atactgtagg tttgccacca cctcctgcat cttggggcgg ctaatatcca ggaaactctc aatcaagtca ccgtcnatna aacctgtggc tggttctgtc ttccgctcgg tgtgaaagga tctccagaag gagtgctcga tcttccccac acttttgatg actttattga gtcgattctg catgtccagc aggaggttgt accagctctc tgacagtgag gtcaccagcc ctatcatgcc nttgaacgtg ccgaagaaca ccgagccttg tgtggggggt gnagtctcac ccagattctg cattaccaga nagccgtggc aaaaganatt gacaactcgc ccaggnngaa aaagaacacc tcctggaagt gctngccgct cctcgtccnt tggtggnngc gcntnccttt t

<td> &lt;210&gt;</td><td> 86</td>

<td> &lt;211&gt;</td><td> 472</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapiens</td>

&lt;400&gt; 86 &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (472) &lt;223&gt; n = A, T, C lido G

GB 200 772 Β1 aacatcttcc tgtataatgc tgtgtaatat cgatccgatn ttgtctgctg agaattcatt 60 acttggaaaa gcaacttnaa gcctggacac tggtattaaa attcacaata tgcaacactt 120 taaacagtgt gtcaatctgc tcccttactt tgtcatcacc agtctgggaa taagggtatg 180 ccctattcac acctgttaaa agggcgctaa gcatttttga ttcaacatct ttttttttga 240 cacaagtccg aaaaaagcaa aagtaaacag ttnttaattt gttagccaac tcactttctt 300 catgggacag agccatttga tttaaaaagc aaattgcata atattgagct ttgggagctg 360 atatntgagc ggaagantag cctttctact tcaccagaca caactccttt catattggga 420 tgttnacnaa agttatgect cttacagatg ggatgctttt gtggcaattc tg 472

<td>&lt;2l0&gt;</td><td> 87</td><td></td>

<td> &lt;211&gt;</td><td> 413</td><td></td>

<td> &lt;212 &gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapienS</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221 &gt;</td><td>misc_</td><td>feature</td>

<td> &lt;222&gt;</td><td>(1) T.</td><td> . (413)</td>

<td> &lt;223&gt;</td><td>π = i</td><td>OT.C (last</td>

<td> &lt;400&gt;</td><td> 87</td><td></td>

agaaaccagt atctctnaaa acaacctctc ataccttgtg gacctaattt tgtgtgcgtg 60 tgtgtgtgcg cgcatattat atagacaggc acatcttttt tacttttgta aaagcttatg 120 cctctttggt atctatatct gtgaaagttt taatgatctg ccaraatgtc ttggggacct 180 ttgtcttctg tgtaaatggt actagagaaa acacctatnt tatgagtcaa tctagttngt 240 tttattcgac atgaaggaaa tttccagatn acaacactna caaactctcc cttgactagg 300 ggggacaaag aaaagcanaa ctgaacatna gaaacaattn cctggtgaga aattncataa 360 acagaaattg ggtngtatat tgaaananng catcattnaa acgttttttt ttt 413 &lt; 210 »88 &lt;211» 448 &lt;212 »DNA &lt;213» Homo sapiens &lt;220 »&lt;221» misc_feature &lt;222&gt; (1) ... (448) &lt;223 »n = A, T, C lu-b G &lt;400» 88 cgcagcgggt cctctctatc tagctccagc ctctcgcctg ccccactccc cgcgtcccgc 60 gtcctagccn accatggccg ggcccctgcg cgccccgctg ctcctgctgg ccatcctggc 120 cgtggccctg gccgtgagcc ccgcggccgg ctccagtccc ggcaagccgc cgcgcctggr 180 gggaggccca tggaccccgc gtggaagaag aaggtgtgcg gcgtgcactg gactttgccg 240 tcggcnanta caacaaaccc gcaacnactt ttaccnagcn cgcgctgcag gttgtgccgc 300 cccaancaaa ttgttactng gggtaantaa ttcttggaag ttgaacctgg gccaaacnng 360 tttaccagaa ccnagccaat tngaacaatt ncccctecat aacagcccct tttaaaaagg 420 gaancantcc tgntcttttc caaatttt 448

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td>89 463 GOUT Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

PL 200 772 Β1 &lt;222&gt; (1) ... (463) &lt;223&gt; n = A, T, C / u (? G &lt;400&gt; 89 gaattttgtg cactggccac tgtgatggaa ccattgggcc aggatgcttt gagtttatca 60 gtagtgattc tgccaattagtagaagtagtgtca gagtagtgtca gagaattgtca gagtagtgtc gtctgcatat cagcagacag tttgtccgtg tattttgtag ccttgaagtt 180 ctcagtgaca agttnnttct gatgcgaagt tctnattcca gtgttttagt cctttgcatc 240 tttnatgttn agacttgcct ctntnaaatt gcttttgtnt tctgcaggta ctatctgtgg 300 tttaacaaaa tagaannact tctctgcttn gaanatttga atatcttaca tctnaaaatn 360 aattctctcc ccatannaaa acccangccc ttggganaat ttgaaaaang gntccttcnn 420 aattcnnana anttcagntn tcatacaaca naacngganc ccc 463 &lt;210&gt; 90 &lt;211&gt; 400 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_ £ eature &lt;222&gt; (1) ... (400) &lt;223&gt; n = A, T, C or G &lt;400&gt; 90 agggattgaa ggtctnttnt a ctgtcggac tgttcancca ccaactctac aagctgctgt 60 cttccactca ctgtctgtaaccttcagatantaa tcagata 120cta tcagata 120 tcacatcttc taggaccttt ttggattcag ttagtataag ctcttccact 180 tcctttgtta agacttcatc tggtaaagtc ttaagttttg tagaaaggaa tttaattgct 240 cgttctctaa caatgtcctc tccttgaagt atttggctga acaacccacc tnaagtccct 300 ttgtgcatcc attttaaata tacttaatag ggcattggtn cactaggtta aattctgcaa 360 gagtcatctg tctgcaaaag ttgcgttagt atatctgcca 400 &lt;210&gt; 91 &lt;211&gt; 480 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;22l&gt; misc_feature &lt;222&gt; (1) ... (480) &lt;223&gt; n = A, T, CG &lt;400&gt; 91 gagctcggat ccaataatct ttgtctgagg gcagcacaca tatncagtgc catggnaact 60 ggtctacccc acatgggagc agcatgccgt agntatataa ggtcattccc tgagtcagac 120 atgcctcttt gactaccgtg tgccagtgct ggtgattctc acacacctcc nnccgctctt 180 tgtggaaaaa ctggcacttg nctggaacta gcaagacatc acttacaaat tcacccacga 240 gacacttgaa aggtgtaaca aagcgactct tgcattgctt tttgtccctc cggcaccagt 300 tgtcaatact aacccgattgtc tca tcccggattgc tca gtactgaaga acttcttctt ttgtttcaaa agcaactctt ggtgcctgtt 420 ngatcaggtt cccatttccc agcccgaatg ttcacatggc atatnttact tcccacaaaa 480 &lt;210&gt; 92 &lt;211&gt; 477 &lt;212&gt; DNA

PL 200 772 Β1 &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_ £ eature &lt;222&gt; (1) ... (477) &lt;223&gt; n = A, T, C iuG G &lt;400&gt; 92 atacagccca natcccacca cgaagatgcg cttgttgact gagaacctga tgcggtcact 60 ggtcccgctg tagccccagctggcagcagctggcctgacagc tggcctgacagc tggcctgacagc tggcctgaccagc gccggtcaat gaactccact cgtggcttgg ggttgacggt 180 taantgcagg aagaggctga ccacctcgcg gtccaccagg acgcccgact gtgcgggacc 240 tgcagcgaaa ctcctcgatg gtcatgagcg ggaagcgaat gangcccagg gccttgccca 300 gaaccttccg cctgttctct ggcgtcacct gcagctgctg ccgctnacac tcggcctcgg 360 accagcggac aaacggcgtt gaacagccgc acctcacgga tgcccantgt gtcgcgctcc 420 aggaacggcn ccagcgtgtc caggtcaatg tcggtgaanc ctccgcgggt aatggcg 477 &lt;210&gt; 93 &lt;211&gt; 377 &lt;212&gt; DNA sapiens &lt;212&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (377) &lt;223&gt; n = A, T, C or G &lt;400&gt; 93 gaacggctgg accttgcctc gcattgtgct gctggcagga ataccttggc aagcagctcc 60 agtgtcagca gccccagacc gaggctcagcc gggctcctcc gggctcctcc gggctcctcc gggctcctcc gggctcagcacgggctcagcacgggctcagca agttaagagt gaacactgtn 180 tgattttact tgggaatttc ctctgttata tagcttttcc caatgctaat ttccaaacaa 240 caacaacaaa ataacatgtt tgcctgttna gttgtataaa agtangtgat tctgtatnta 300 aagattactacaatat tactgtatnta 300 aagattactacaatat tattaaa 377 &lt;210&gt; 94 &lt;211&gt; 495 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;22l&gt; misc_feature &lt;222&gt; (1) ... (495) &lt;223&gt; n = A, T, C or G &lt;400&gt; 94 ccctttgagg ggttagggtc cagttcccag tggaagaaac aggccaggag aantgcgtgc 60 cgagctgang cagattagtcccacggggctgcta cggggctgcta cggggctgcta cggggctgcta aggacctaga ggcaccaagg 180 gaaggcccca ttccggggct gttccccgag gaggaaggga aggggctctg tgtgcccccc 240 acgaggaana ggccctgant cctgggatca nacacccctt cacgtgtatc cccacacacaaa 300ca tgcagtagtc ccctccacacaaa 300ca tgcagtagtc ccctccacacaaa 300ca tgcagtagtccc agancancca cccgccatgg ggaatgtnct caaggaatcg cngggcaacg 420 tggactctng tcccnnaagg gggcagaatc tccaatagan gganngaacc cttgctnana 480

PL 200 772 Β1 aaaaaaaana aaaaa 495 &lt;210&gt; 95 &lt;211&gt; 472 &lt;212&gt; DNA &lt;213&gt; Homo sapien ^ &lt;220&gt;

&lt;22l&gt; misc_feature &lt;222&gt; (1Ϊ..... (472) &lt;223&gt; n = A, T, C lab G &lt;400&gt; 95 ggttacttgg tttcattgcc accacttagt ggatgtcatt tagaaccatt ttgtctgctc 60 cctctggaag ccttgcgcag agcggacttt gtaattgttg gagaataact gctgaatttt 120 tagctgtttt gagttgattc gcaccactgc accacaactc aatatgaaaa ctatttnact 180 tatttattat cttgcgaaaa gtatacaatg aaaattttgt tcatactgta tttatcaagt 240 atgatgaaaa gcaatagata tatattcttt tattatgttn aattatgatt gccattatta 300 atcggcaaaa tgtggagtgt atgttctttt cacagtaata tatgcctttt gtaacttcac 360 ttggttattt tattgtaaat gaattacaaa attcttaatt taagaaaatg gtangttata 420 tttanttcan taatttcttt ccttgtttac gttaattttg aaaagaatgc at 472 &lt;210&gt; 96 &lt;211&gt; 476 &lt;212&gt; DNA &lt;213&gt; Homo sapient &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; ¢ 1), .. (476) &lt;223&gt; n = A, T, C or G &lt;400&gt; 96 ctgaagcatt tcttcaaact tntctacttt tgtcattgat acctgtagta agttgacaat 60 ctttcatta tagtactcatta tagtactcatta tagtaacttactcattataga tatatagcct ctaagtcttt 180 attcttcaca gtagatgatg aaagagtcct ccagtgtctt gngcanaatg ttctagntat 240 agctggatac atacngtggg agttctataa actcatacct cagtgggact naaccaaactaat 300 tgtcactctcagtc tgcactcccctcagcta ctccagaaaa acngacaggg caggcttgca tgaaaaagtn acatctgcgt 420 tacaaagtct atcttcctca nangtctgtn aaggaacaat ttaatcttct agcttt 476

<td> &lt;210&gt;</td><td> 97</td><td></td>

<td> &lt;211&gt;</td><td> 479</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt; &lt;221&gt;</td><td>misc</td><td>_feature</td>

<td> &lt;222 &gt;</td><td>(l)</td><td> .. (479)</td>

<td> &lt;223&gt;</td><td>n =</td><td>A, T, C or</td>

<td>&lt;4O0&gt;</td><td> 97</td><td></td>

actctttcta atgctgatat gatcttgagt ataagaatgc atatgtcact agaatggata 60 aaataatgct gcaaacttaa tgttcttatg caaaatggaa cgctaatgaa acacagctta 120

GB 200 772 Β1 caatcgcaaa tcaaaactca caagtgctca tctgttgtag atttagtgta ataagactta 180 gattgtgctc cttcggatat gattgtttct canatcttgg gcaatnttcc ttagtcaaat 240 caggctacta gaattctgtt attggatatn tgagagcatg aaatttttaa naatacactt 300 gtgattatna aattaatcac aaatttcact tatacctgct atcagcagct agaaaaacat 360 ntnnttttta natcaaagta ttttgtgttt ggaantgtnn aaatgaaatc tgaatgtggg 420 ttcnatccta ttttttcccn gacnactant tnctttttta gggnctattc tganccatc 479 &lt;210&gt; 98 &lt;211&gt; 461 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 98 agtgacttgt cctccaacaa aaccccttga tcaagtttgt ggcactgaca atcagaccta 60 tgctagttcc tgtcatctat tcgctactaa atgcagactg gaggggacca aaaaggggca 120 tcaactccag ctggattatt ttggagcctg caaatctatt cctacttgta cggactttga 180 agtgattcag tttcctctac ggatgagaga ctggctcaag aatatcctca tgcagcttta 240 tgaagccact ctgaacacgc tggttatcta gatgagaaca gagaaataaa gtcagaaaat 300 ttacctggag aaaagaggcC ttggctgggg accatcccat tgaaccttct cttaaggact 360 ttaagaaaaa ctaccacatg ttgtgtatcc tggtgccggc cgtttatgaa ctgaccaccc 420 tttggaataa tcttgacgct cctgaacttg ctcctctgcg a 461 &lt;210&gt; 99 &lt;211&gt; 171 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 99 gtggccgcgc gcaggtgttt cctcgtaccg cagggccccc tcccttcccc aggcgtccct 60 cggcgcctct gcgggcccga ggaggagcgg ctggcgggtg gggggagtgt gacccaccct 120 cggtgagaaa agccttctct agcgatctga gaggcgtgcc ttgggggtac c 171 &lt;210&gt; 100 &lt;211&gt; 269 &lt;212&gt; DNA &lt;213&gt; Homo sapienS &lt;400&gt; 100 cggccgcaag tgcaactcca gctggggccg tgcggacgaa gattctgcca gcagttggtc 60 cgactgcgac gacggcggcg gcgacagtgcag gcaggcgcgacagtgcgg caggcgcgacagtgcgg 120 aaggctgagc tgacgccgca gaggtcgtgt cacgtcccac gaccttgacg ccgtcgggga 180 cagccggaac agagcccggt gaagcgggag gcctcgggga gcccctcggg aagggcggatgccaggggggcc 240 cgggtcc 240 cgggtcc

<td colspan="2">&lt;210&gt; 101 &lt;211&gt; 405 &lt;212&gt; DNA &lt;213&gt; Homo sapienS</td>

<td> &lt;400&gt;</td><td> 101</td>

tttttttttt ttttggaatc tactgcgagc acagcaggtc agcaacaagt ttattttgca 60 gctagcaagg taacagggta gggcatggtt acatgtCcag gtcaacttcc tttgtcgtgg 120 ttgattggtt tgtctttatg ggggcggggt ggggtagggg aaacgaagca aataacatgg 180 agtgggtgca ccctccctgt agaacctggt tacaaagctt ggggcagttc acctggtctg 240 tgaccgtcat tttcttgaca tcaatgttat tagaagtcag gatatctttt agagagtcca 300

GB 200 772 Β1 ctgttctgga gggagattag ggtttcttgc caaatccaac aaaatccact gaaaaagttg 360 gatgatcagt acgaataccg aggcatattc tcatatcggt ggcca 405 &lt;210&gt; 102 &lt;211&gt; 470 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 102 tttttttttt tttttttttt tttttttttt tttttttttt tttttttttt tttttttttt 60 ggcacttaat ccatttttat ttcaaaatgt ctacaaattt aatcccatta tacggtattt 120 tcaaaatcta aattattcaa attagccaaa tccttaccaa ataataccca aaaatcaaaa 180 atatacttct ttcagcaaac ttgttacata aattaaaaaa atatatacgg ctggtgtttt 240 caaagtacaa ttggtgtttt 240 caaagtacaa actgcaaaca ttttaaggaa ctaaaataaa aaaaaacact 300 ccgcaaaggt taaagggaac aacaaattct tttacaacac cattataaaa atcatatctc 360 aaatcttagg ggaatatata cttcacacgg gatcttaact tttactcact ttgtttattt 420 ttttaaacca ttgtttgggc ccaacacaat ggaatccccc ctggactagt 470 &lt;21o&gt; 103 &lt;211&gt; 581 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 103 tttttttttt ttttttttga cccccctctt ataaaaaaca agttaccatt ttattttact 60 tacacatatt tattttataa ttggtattag atattcaaaa ggcagctttt aaaatcaaac 120 taaatggaaa ctgccttaga tacataattc ttaggaatta gcttaaaatc tgcctaaagt 180 gaaaatcttc tctagctctt ttgactgtaa atttttgact cttgtaaaac atccaaattc 240 atttttcttg tctttaaaat tatctaatct ttccattttt tccctattcc aagtcaattt 300 gcttctctag cctcatttcc tagctcttat ctactattag taagtggctt ttttcctaaa 360 agggaaaaca ggaagagaaa tggcacacaa aacaaacatt ttatattcat atttctacct 420 acgttaataa aatagcattt tgtgaagcca gctcaaaaga aggcttagat ccttttatgt 480 ccattttagt cactaaacga tatcaaagtg ccagaatgca aaaggtttgt gaacatttat 540 tcaaaagcta atataagata tttcacatac tcatctttct g 581 &lt;210&gt; 104 &lt;211&gt; 578 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;400&gt; 104 tttttttttt tttttttttt tttttctctt cttttttttt gaaatgagga tcgagttttt 60 cactctctag atagggcatg aagaaaactc atctttccag ctttaaaata acaatcaaat 120 ctcttatgct atatcatatt ttaagttaaa ctaatgagtc actggcttat cttctcctga 180 aggaaatctg ttcattcttc tcattcatat agttatatca agtactacct tgcatattga 240 gaggtttttc ttctctattt acacatatat ttccatgtga atttgtatca aacctttatt 300 ttcatgcaaa ctagaaaata atgtttcttt tgcataagag aagagaacaa tatagcatta 360 caaaactgce caaattgttt gttaagttat ccattataat tagttggcag gagctaatac 420 aaatcacatt tacgacagca ataataaaac tgaagtacca gttaaatatc caaaataatt 480 aaaggaacat ttttagcctg ggtataatta gctaattcac tttacaagca tttattaca240g tgaattcac tttacaagca tttattagaa 540g tgaattcac tttacaagca tttattaca2 540g tgaattcac tttacaagca tttattaca240g tgaattcac tttacaagca

GB 200 772 Β1 &lt;213&gt; Homo sapien * &lt;400&gt; 105 tttttttttt tttttcagta ataatcagaa caatatttat ttttatattt aaaattcata 60 gaaaagtgcc ttacatttaa taaaagtttg tttctcaaag tgatcagagg aattagatat 120 gtcttgaaca ccaatattaa tttgaggaaa atacaccaaa atacattaag taaattattt 180 aagatcatag agcttgtaag tgaaaagata aaatttgacc tcagaaactc tgagcattaa 240 aaatccacta ttagcaaata aattactatg gacttcttgc tttaattttg tgatgaatat 300 ggggtgtcac tggtaaacca acacattctg aaggatacat tacttagtga tagattctta 360 tgtactttgc taatacgtgg atatgagttg acaagtttct ctttcttcaa tcttttaagg 420 ggcgagaaat gaggaagaaa agaaaaggat tacgcatact gttctttcta tggaaggatt 480 agatatgttt cctttgccaa tattaaaaaa ataataatgt ttactactag tgaaaccc 538 &lt;210&gt; 106 &lt;211&gt; 473 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 106 tttttttttt ttttttagtc aagtttctat ttttattata attaaagtct tggtcatttc 60 atttattagc tctgcaactt acatatttaa attaaagaaa cgttttagac aactgtacaa 120 tttataaatg taaggtgcca ttattgagta atatattcct ccaagagtgg atgtgtccct 180 tctcccacca actaatgaac agcaacatta gtttaatttt ateagtagat atacactgct 240 gcaaacgcta attctcttct ccatccccat gtgatattgt gtatatgtgt gagttggtag 300 aatgcatcac aatctacaat caacagcaag atgaagctag gctgggcttt cggtgaaaat 360 agactgtgtc tgtctgaatc aaatgatctg acctatcctc ggtggcaaga actcttcgaa 420 ccgcttcctc aaaggcgctg ccacatttgtggctctttgc acttgttcca aaa 473 &lt;210&gt; 107 &lt;211&gt; 1621 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 107 cgccatggca ctgcagggca tctcggtcat ggagctgtcc ggcctggccc cgggcccgtt 60 ctgtgctatg gtcctggctg acttcggggc gcgtgtggta cgcgtggacc ggcccggacctc 120 cgcccggacctg 120 gtgagccgct tgggccgggg caagcgctcg ctagtgctgg acctgaagca 180 gccgcgggga gccgccgtgc tgcggcgtct gtgcaagcgg tcggatgtgc tgctggagcc 240 cttccgccgc ggtgtcatgg agaaactcca gctgggccca gagattctgc agcgggaaaa 300 tccaaggctt atttatgcca ggctgagtgg atttggccag tcaggaagct tctgccggtt 360 agctggccac gatatcaact atttggcttt gtcaggtgtt ctctcaaaaa ttggcagaag 420 tggtgagaat ccgtatgccc cgctgaatct cctggctgac tttgctggtg gtggccttat 480 gtgtgcactg ggcattataa tggctctttt tgaccgcaca cgcactgaca agggtcaggt 540 cattgatgca aatatggtgg aaggaacagc atatttaagt tcttttctgt ggaaaactca 600 gaaatcgagt ctgtgggaag cacctcgagg acagaacatg ttggatggtg gagcaccttt 660 ctatacgact tacaggacag cagatgggga attcatggct gttggagcaa tagaacccca 720 gttctacgag ctgctgatca aaggacttgg actaaagtct gatgaacttc ccaatcagat 780 gagcatggat gattggccag aaatgaagaa gaagtttgca gatgtatttg caaagaagac 840 gaaggcagag tggtgtcaaa tctttgacgg cacagatgcc tgtgtgactc cggttctgac 900 ttttgaggag gttgttcatc atgatcacaa caaggaacgg ggctcgttta tcaccagtga 960 ggagcaggac gtgagccccc gccctgcacc tctgctgtta aacaccccag ccatcccttc 1020 tttcaaaagg gatcctttca taggagaaca cactgaggag atacttgaag aatttggatt 1080 cagccgcgaa gagatttatc agcttaactc agataaaatc attgaaagta ataaggtaaa 1140 agctagtctc taacttccag gcccacggct caagtgaatt tgaatactgc atttacagtg 1200 tagagtaaca cataacattg tatgcatgga aacatggagg aacagtatta cagtgtccta 1260

PL 200 772 Β1 ccactctaat aatggttatc agttattctg ttttgaatgg atttacactc aaaagtcacg a

caagaaaaga attagggctt ccttccagtt gttctagtga ttgattctac tgaaacaaaa attacagact ttgatttata tgcttgatat aaaaggaatg aatgtagaaa aaaaaaaaaa ctgattctac aaactttggg atttgttgat atatattctt atgaggaaat aaaaaaaaaa agtgatgatt tacttatact attaagattc gaagacatcg gccacaaatt aaaaaaaaaa gaattctaaa aaattatggt ttgacttata atatacattt gtatggtgat aaaaaaaaaa

1320

1380

1440

1500

1560

1620

1621 &lt;210&gt; 108 &lt;211&gt; 382 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 108

<td>Underworld</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Gly</td><td>How much</td><td>Cheese</td><td>Val</td><td>Underworld</td><td>Glu</td><td>Leu</td><td>Cheese</td><td>Gly</td><td>Leu</td><td>Ala</td><td>Pro</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td>Gly</td><td>Pro</td><td>Phe</td><td>Cys</td><td>Ala</td><td>Underworld</td><td>Val</td><td>Leu</td><td>Ala</td><td>Asp</td><td>Phe</td><td>Gly</td><td>Ala</td><td>Arg</td><td>Val</td><td>Val</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td>Arg</td><td>Val</td><td>Asp</td><td>Arg</td><td>Pro</td><td>Gly</td><td>Cheese</td><td>Arg</td><td>Tyr</td><td>Asp</td><td>Val</td><td>Cheese</td><td>Arg</td><td>Leu</td><td>Gly</td><td>Arg</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td>Gly</td><td>Lys</td><td>Arg</td><td>Cheese</td><td>Leu</td><td>Val</td><td>Leu</td><td>Asp</td><td>Leu</td><td>Lys</td><td>Gin</td><td>Pro</td><td>Arg</td><td>Gly</td><td>Ala</td><td>Ala</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td>Val</td><td>Leu</td><td>Arg</td><td>Arg</td><td>Leu</td><td>Cys</td><td>Lys</td><td>Arg</td><td>Cheese</td><td>Asp</td><td>Val</td><td>Leu</td><td>Leu</td><td>Glu</td><td>Pro</td><td>Phe</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td>Arg</td><td>Arg</td><td>Gly</td><td>Val</td><td>Underworld</td><td>Glu</td><td>Lys</td><td>Leu</td><td>Gin</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Glu</td><td>How much</td><td>Leu</td><td>Gin</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td>Arg</td><td>Glu</td><td>Asn</td><td>Prc</td><td>Arg</td><td>Leu</td><td>How much</td><td>Tyr</td><td>Ala</td><td>Arg</td><td>Leu</td><td>Cheese</td><td>Gly</td><td>Phe</td><td>Gly</td><td>Gin</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td>Cheese</td><td>Gly</td><td>Cheese</td><td>Phe</td><td>Cys</td><td>Arg</td><td>Leu</td><td>Ala</td><td>Gly</td><td>His</td><td>Asp</td><td>lle</td><td>Asn</td><td>Tyr</td><td>Leu</td><td>Ala</td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<td>Leu</td><td>Cheese</td><td>Gly</td><td>Val</td><td>Leu</td><td>Cheese</td><td>Lys</td><td>How much</td><td>Gly</td><td>Arg</td><td>Cheese</td><td>Gly</td><td>Glu</td><td>Asn</td><td>Pro</td><td>Tyr</td>

<td></td><td> 130</td><td></td><td></td><td></td><td></td><td> 135</td><td></td><td></td><td></td><td></td><td> 140</td><td></td><td></td><td></td><td></td>

<td>Ala</td><td>Pro</td><td>Leu</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Asp</td><td>Phe</td><td>Ala</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Leu</td><td>Underworld</td><td>Cys</td>

<td> 145</td><td></td><td></td><td></td><td></td><td> 150</td><td></td><td></td><td></td><td></td><td> 155</td><td></td><td></td><td></td><td></td><td> 160</td>

<td>Ala</td><td>Leu</td><td>Gly</td><td>How much</td><td>How much</td><td>Underworld</td><td>Ala</td><td>Leu</td><td>Phe</td><td>Asp</td><td>Arg</td><td>Thr</td><td>Arg</td><td>Thr</td><td>Asp</td><td>Lys</td>

<td></td><td></td><td></td><td></td><td> 165</td><td></td><td></td><td></td><td></td><td> 170</td><td></td><td></td><td></td><td></td><td> 175</td><td></td>

<td>Gly</td><td>Gin</td><td>Val</td><td>How much</td><td>Asp</td><td>Ala</td><td>Asn</td><td>Underworld</td><td>Val</td><td>Glu</td><td>Gly</td><td>Thr</td><td>Ala</td><td>Tyr</td><td>Leu</td><td>Cheese</td>

<td></td><td></td><td></td><td> 180</td><td></td><td></td><td></td><td></td><td> 185</td><td></td><td></td><td></td><td></td><td> 190</td><td></td><td></td>

<td>Cheese</td><td>Phe</td><td>Leu</td><td>Trp</td><td>Lys</td><td>Thr</td><td>Gin</td><td>Lys</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Trp</td><td>Glu</td><td>Ala</td><td>Pro</td><td>Arg</td>

<td></td><td></td><td> 195</td><td></td><td></td><td></td><td></td><td> 200</td><td></td><td></td><td></td><td></td><td> 205</td><td></td><td></td><td></td>

<td>Gly</td><td>Gin</td><td>Asn</td><td>Underworld</td><td>Leu</td><td>Asp</td><td>Gly</td><td>Gly</td><td>Ala</td><td>Pro</td><td>Phe</td><td>Tyr</td><td>Thr</td><td>Thr</td><td>Tyr</td><td>Arg</td>

<td></td><td> 210</td><td></td><td></td><td></td><td></td><td> 215</td><td></td><td></td><td></td><td></td><td> 220</td><td></td><td></td><td></td><td></td>

<td>Thr</td><td>Ala</td><td>Asp</td><td>Gly</td><td>Glu</td><td>Phe</td><td>Underworld</td><td>Ala</td><td>Val</td><td>Gly</td><td>Ala</td><td>How much</td><td>Glu</td><td>Pro</td><td>Gin</td><td>Phe</td>

<td> 225</td><td></td><td></td><td></td><td></td><td> 230</td><td></td><td></td><td></td><td></td><td> 235</td><td></td><td></td><td></td><td></td><td> 240</td>

<td>Tyr</td><td>Glu</td><td>Leu</td><td>Leu</td><td>How much</td><td>Lys</td><td>Gly</td><td>Leu</td><td>Gly</td><td>Leu</td><td>Lys</td><td>Cheese</td><td>Asp.</td><td>Glu</td><td>Leu</td><td>Pro</td>

<td></td><td></td><td></td><td></td><td> 245</td><td></td><td></td><td></td><td></td><td> 250</td><td></td><td></td><td></td><td></td><td> 255</td><td></td>

<td>Asn</td><td>Gin</td><td>Underworld</td><td>Cheese</td><td>Underworld</td><td>Asp</td><td>Asp</td><td>Trp</td><td>Pro</td><td>Glu</td><td>Underworld</td><td>Lys</td><td>Lys</td><td>Lys</td><td>Phe</td><td>Ala</td>

<td></td><td></td><td></td><td> 260</td><td></td><td></td><td></td><td></td><td> 265</td><td></td><td></td><td></td><td></td><td> 270</td><td></td><td></td>

<td>Asp</td><td>Val</td><td>Phe</td><td>Ala</td><td>Lys</td><td>Lys</td><td>Thr</td><td>Lys</td><td>Ala</td><td>Glu</td><td>Trp</td><td>Cys</td><td>Gin</td><td>How much</td><td>Phe</td><td>Asp</td>

<td></td><td></td><td> 275</td><td></td><td></td><td></td><td></td><td> 280</td><td></td><td></td><td></td><td></td><td> 285</td><td></td><td></td><td></td>

<td>Gly</td><td>Thr</td><td>Asp</td><td>Ala</td><td>Cys</td><td>Val</td><td>Thr</td><td>Pro</td><td>Val</td><td>Leu</td><td>Thr</td><td>Phe</td><td>Glu</td><td>Glu</td><td>Val</td><td>Val</td>

<td></td><td> 290</td><td></td><td></td><td></td><td></td><td> 295</td><td></td><td></td><td></td><td></td><td> 300</td><td></td><td></td><td></td><td></td>

<td>His</td><td>His</td><td>Asp</td><td>His</td><td>Asn</td><td>Lys</td><td>Glu</td><td>Arg</td><td>Gly</td><td>Cheese</td><td>Phe</td><td>How much</td><td>Thr</td><td>Cheese</td><td>Glu</td><td>Glu</td>

<td> 305</td><td></td><td></td><td></td><td></td><td> 310</td><td></td><td></td><td></td><td></td><td> 315</td><td></td><td></td><td></td><td></td><td> 320</td>

<td>Gin</td><td>Asp</td><td>Val</td><td>Cheese</td><td>Pro</td><td>Arg</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Leu</td><td>Asn</td><td>Thr</td><td>Pro</td><td>Ala</td>

PL 200 772 Β1

Ile Pro Ser Phe Lys Arg Asp Pro Phe Ile Gly Glu His Thr Glu Glu 340 345 350

Ile Leu Glu Glu Phe Gly Phe Ser Arg Glu Glu Ile Tyr Gln Leu Asn 355 360 365

Ser Asp Lys Ile Glu Ser Asn Lys Val Lys Ala Ser Leu 370 375 380 &lt;210&gt; 109 &lt;211&gt; 1524 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 109 ggcacgaggc tgcgccagggg cctgagcgga ggcgggggca gcctcggcagg cggccgccgcgcgcgcgccggcag 60 cagctggaae 120 cagtgcgacc tagtggctct cacctgcttc ctcctgggcg tgggctgccg gctgaccccg 180 ggtttgtacc acctgggccg cactgtcctc cgcatcgact tcatggtttt cacggtgcgg 240 ctgcttcaca tcttcacggt caacaaacag ctggggccca agatcgtcat cgtgagcaag 300 atgatgaagg acgtgttctt cttcctcttc ctcctcggcg tgtggctggt agcctatggc 360 gtggccacgg aggggctcct gaggccacgg gacagtgact tcccaagtat cctgcgccgc 420 gtcttctacc gtccctacct gcagatcttc gggcagattc cccaggagga catggacgtg 480 gccctcatgg agcacagcaa ctgctcgtcg gagcccggct tctgggcaca ccctcctggg 540 gcccaggcgg gcacctgcgt ctcccagtat gccaactggc tggtggtgct gctcctcgtc 600 atcttcctgc tcgtggccaa catcctgctg gtcaacttgc tcattgccat gttcagttac 660 acattcggca aagtacaggg caacagcgat ctctactgga aggcgcagcg ttaccgcctc 720 acccgggaat tccactctcg gcccgcgctg gccccgccct ttatcgtcat ctcccacttg 780 cgcctcctgc tcaggcaatt gtgcaggcga ccccggagcc cccagccgtc ctccccggcc 840 ctcgagcatt tccgggttta cctttctaag gaagccgagc ggaagctgct aacgtgggaa 900 tcggtgcata aggagaactt tctgctggca cgcgctaggg acaagcggga gagcgactcc 960 gagcgtctga agcgcacgtc ccagaaggtg gacttggcac tgaaacagct gggacacatc 1020 cgcgagtacg aacagcgcct gaaagtgctg gagcgggagg tccagcagtg tagccgcgtc 1080 ctggggtggg tggccgaggc cctgagccgc tctgccttgc tgcccccagg tgggccgcca 1140 ccccctgacc tgcctgggtc caaagactga gccctgctgg cggacttcaa ggagaagccc 1200 ccacagggga ttttgctcct agagtaaggc ccatctgggc ctcggccccc gcacctggtg 1260 gccttgtcct tgaggtgagc cccatgtcca tctgggccac tgtcaggacc acctttggga 1320 gtgtcatcct tacaaaccac agcatgcccg gctcctccca gaaccagtcc cagcctggga 1380 ggatcaaggc ctggatcccg ggccgttatc catctggagg ctgcagggtc cttggggtaa 1440 cagggaccac agacccctca ccactcacag attcctcaca ctggggaaat aaagccattt 1500 cagaggaaaa aaaaaaaaaa aaaa 1524 &lt;210&gt; 110 &lt;211 &gt; 3410 &lt;212&gt; DNA &lt;213&gt; Homo sapienS &lt;400&gt; 110 gggaaccagc ctgcacgcgc tggctccggg tgacagccgc gcgcctcggc caggatctga 60 gtgatgagac gtgtccccac tgaggtgccc cacagcagca ggtgttgagc atgggctgag 120 aagctggacc ggcaccaaag ggctggcaga aatgggcgcc tggctgattc ctaggcagtt 180 ggcggcagca aggaggagag gccgcagctt ctggagcaga gccgagacga agcagttctg 240 gagtgcctga acggccccct gagccctacc cgcctggccc actatggtcc agaggctgtg 390 ggtgagccgc ctgctgcggc accggaaagc ccagctcttg ctggtcaacc tgctaacctt 360 tggcctggag gtgtgtttgg ccgcaggcat cacctatgtg ccgcctctgc tgctggaagt 420 gggggtagag gagaagttca tgaccatggt gctgggcatt ggtccagtgc tgggcctggt 480

GB 200 772 Β1 ctgtgtcccg ctcctaggct cagccagtga ccactggcgt ggacgctatg gccgccgccg 540 gcccttcatc Cgggcactgt ccttgggcat cctgctgagc ctctttctca tcccaagggc 600 cggctggcta gcagggctgc tgtgcccgga tcccaggccc ctggagctgg cactgctcat 660 cctgggcgtg gggctgctgg acttctgtgg ccaggtgtgc ttcactccac tggaggccct 720 gctctctgac ctcttccggg acccggacca ctgtcgccag gcctactctg tctatgcctt 780 catgatcagt cttgggggct gcctgggcta cctcctgcct gccattgact gggacaccag 840 tgccctggcc ccctacctgg gcacccagga ggagtgcctc tttggcctgc tcaccctcat 900 cttcctcacc tgcgtagcag ccacactgct ggtggctgag gaggcagcgc tgggccccac 960 cgagccagca gaagggctgt cggccccctc cttgtcgccc cactgctgtc catgccgggc 1020 ccgcttggct ttccggaacc tgggcgccct gcttccccgg ctgcaccagc tgtgctgccg 1080 catgccccgc accctgcgcc ggctcttcgt ggctgagctg tgcagctgga tggcactcat 1140 gaccttcacg ctgttttaca cggatttcgt. gggcgagggg ctgtaccagg gcgtgcccag 1200 agctgagccg ggcaccgagg cccggagaca ćtatgatgaa ggcgtccgga tgggcagcct 1260 ggggctgttc ctgcagtgcg ccatctccct ggtcttctct ctggtcatgg accggctggt 1320 gcagcgattc ggcactcgag cagtctattt ggccagtgtg gcagctttcc ctgtggctgc 1380 cggtgccaca tgcctgtccc acagtgtggc cgtggtgaca gcttcagccg ccctcaccgg 1440 gttcaccttc tcagccctgc agatcctgcc ctacacactg gcctccctct accaccggga 1500 gaagcaggtg ttcctgccca aataccgagg ggacactgga ggtgctagca gtgaggacag 1560 cctgatgacc agcttcctgc caggccctaa gcctggagct cccttcccta atggacacgt 1620 gggtgctgga ggcagtggcc tgctcccacc tccacccgcg ctctgcgggg cctctgcctg 1680 tgatgtctcc gtacgtgtgg tggtgggtga gcccaccgag gccagggtgg ttccgggccg 1740 gggcatctgc ctggacctcg ccatcctgga tagtgccttc ctgctgtccc aggtggcccc 1800. atccctgttt atgggctcca ttgtccagct cagccagtct gtcactgcct atatggtgr.c 1860 tgccgcaggc ctgggtctgg tcgccattta ctttgctaca caggtagtat ttgacaagag 1920 cgacttggcc aaatactcag cgtagaaaac ttccagcaca ttggggtgga gggcctgcct 1980 cactgggtcc cagctccccg ctcctgttag ccccatgggg ctgccgggct ggccgccagt 2040 ttctgttgct gccaaagtaa tgtggctctc tgctgccacc ctgtgctgct gaggtgcgta 2100 gctgcacagc tgggggctgg ggcgtccctc tcctctctcc ccagtctcta gggctgcccg 2160 actggaggcc ttccaagggg gtttcagtct ggacttatac agcgaggcca gaagggctcc 2220 atgcactgga atgcggggac tctgcaggtg gattacccag gctcagggtt aacagctagc 2280 ctcctagttg agacacacct agagaagggt ttttgggagc tgaataaact cagtcacctg 2340 gtttcccatc tctaagcccc ttaacctgca gcttcgttta atgtagctct tgcatgggag 2400 tttctaggat gaaacactcc tccatgggat ttgaacatat gacttatttg taggggaaga 2460 gtcctgaggg gcaacacaca agaaccaggt cccctcagcc cacagcactg tctttttgct 2520 gatccacccc cctcttacct tttatcagga tgtggcctgt tggtccttct gttgccatca 2580 cagagacaca ggcatttaaa tatttaactt atttatttaa caaagtagaa gggaatccat 2640 tgctagcttt tctgtgttgg tgtctaatat ttgggtaggg tgggggatcc ccaacaatca 2700 ggtcccctga gatagctggt cattgggctg atcattgcca gaatcttctt ctcctggggt 2760 ctggcccccc aaaatgccta acccaggacc ttggaaattc tactcatccc aaatgataat 2820 tccaaatgct gttacccaag gttagggtgt tgaaggaagg tagagggtgg ggcttcaggt 2880 ctcaacggct tccctaacca cccctcttct cttggcccag cctggttccc cccacttcca 2940 ctcccctcta ctctctctag gactgggctg atgaaggcac tgcccaaaat ttcccctacc 3000 cccaactttc ccctaccccc aactttcccc accagctcca caaccctgtt tggagctact 3060 gcaggaccag aagcacaaag tgcggtttcc caagcctttg tccatctcag cccccagagt 3120 atatctgtgc ttggggaatc tcacacagaa actcaggagc accccctgcc tgagctaagg 3180 gaggtcttat ctctcagggg gggtttaagt gccgtttgca ataatgtcgt cttatttatt 3240 tagcggggtg aatattttat actgtaagtg agcaatcaga gtataatgtt tatggtgaca 3300 aaattaaagg ctttcttata tgtttaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 3360 aaaaaaaara aaaaaaaaaa aaaaaaaaaa aaaaaaataa aaaaaaaaaa 3410 &lt;2L0&gt; III &lt;211&gt; 1289 &lt; 212&gt; DNA &lt;213&gt; Homo sapiens

GB 200 772 Β1 &lt;400&gt; lll agccaggcgt ccctctgcct gcccactcag tggcaacacc cgggagctgt tttgtccttt 60 gtggagcctc agcagttccc tctttcagaa ctcactgcca agagccctga acaggagcca 120 ccatgcagtg cttcagcttc attaagacca tgatgatcct cttcaatttg ctcatctttc 180 tgtgtggtgc agccctgttg gcagtgggca tctgggtgtc aatcgatggg gcatcctttc 240 tgaagatctt cgggccactg tcgtccagtg ccatgcagtt cgecaacgtg ggctacttcc 300 tcatcgcagc cggcgttgtg gtctttgctc ttggtttcct gggctgctat ggtgctaaga 360 ctgagagcaa gtgtgccctc gtgacgttct tcttcatcct cctcctcatc ttcattgctg 420 aggttgcagc tgctgtggtc gccttggtgt acaccacaat ggctgagcac ttcctgacgt 480 tgctggtagt gcctgccatc aagaaagatt atggttccca ggaagacttc actcaagtgt 540 ggaacaccac catgaaaggg ctcaagtgce gCggcttcac caactatacg gattttgagg 600 actcacccta cttcaaagag aacagtgcct ttcccccatt ctgttgcaat gacaacgtca 660 ccaacacagc caatgaaacc tgcaccaagc aaaaggctca cgaccaaaaa gtagagggtt 720 gcttcaatca gcttttgtat gacatccgaa et. aatgcagt caccgtgggt ggtgtggcag 780 ctggaattgg gggcctcgag ctggctgcca tgattgtgtc catgtatctg tactgcaatc 840 tacaataagt ccacttctgc ctctgccact actgctgcca catgggaact gtgaagaggc 900 accctggcaa gcagcagtga ttgggggagg ggacaggatc taacaatgtc acttgggcca 960 gaatggacct gccctttctg ctccagactt ggggctagat agggaccact ccttttagcg 1020 atgcctgact ttccttccat tggtgggtgg atgggtgggg ggcattccag agcctctaag 1080 gtagccagtt ctgttgccca ttcccccagt ctattaaacc cttgatatgc cccctaggcc 1140 tagtggtgat cccagtgctc tactggggga tgagagaaag gcattttata gcctgggcat 1200 aagtgaaatc agcagagcct ctgggtggat gtgtagaagg cacttcaaaa tgcataaacc 1260 tgttacaatg ttaaaaaaaa aaaaaaaaa 1289 &lt;210&gt; PR21211&gt;

<td></td><td colspan="2"> &lt;400&gt;</td><td colspan="13"> 112</td>

<td>Underworld</td><td>val</td><td>Phe</td><td>Thr</td><td>Val</td><td>Arg</td><td>Le.u</td><td>Leu</td><td>Hi 3</td><td>How much</td><td>Phe.</td><td>Thr</td><td>Val</td><td>Asn</td><td>Lys</td><td>Main</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td>Leu</td><td>Gly</td><td>Pro</td><td>Lys</td><td>How much</td><td>Val</td><td>How much</td><td>Val</td><td>Cheese</td><td>Lys</td><td>Underworld</td><td>Underworld</td><td>Lys</td><td>Asp</td><td>Val</td><td>Phe</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td>Phe</td><td>Phe</td><td>Leu</td><td>Phe</td><td>Phe</td><td>Leu</td><td>Gly</td><td>Val</td><td>Trp</td><td>Leu</td><td>Val</td><td>Ala</td><td>Tyr</td><td>Gly</td><td>Val</td><td>Ala</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td>Thr</td><td>Glu</td><td>Gly</td><td>Leu</td><td>Leu</td><td>Arg</td><td>Pro</td><td>Arg</td><td>Asp</td><td>Cheese</td><td>Asp</td><td>Phe</td><td>Pro</td><td>Cheese</td><td>How much</td><td>Leu</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td>Arg</td><td>Arg</td><td>Val</td><td>Phe</td><td>Tyr</td><td>Arg</td><td>Pro</td><td>Tyr</td><td>Leu</td><td>Main</td><td>How much</td><td>Phe</td><td>Gly</td><td>Main</td><td>How much</td><td>Pro</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td>Main</td><td>Glu</td><td>Asp</td><td>Underworld</td><td>Asp</td><td>Val</td><td>Ala</td><td>Leu</td><td>Underworld</td><td>Glu</td><td>His</td><td>Cheese</td><td>Asn</td><td>Cys</td><td>Cheese</td><td>Cheese</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td>Glu</td><td>Pro</td><td>Gly</td><td>Phe</td><td>Trp</td><td>Ala</td><td>His</td><td>Pro</td><td>Pro</td><td>Gly</td><td>Ala</td><td>Gin</td><td>Ala</td><td>Gly</td><td>Thr</td><td>Cys</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td>Val</td><td>Cheese</td><td>Main</td><td>Tyr</td><td>Ala</td><td>Asn</td><td>Trp</td><td>Leu</td><td>Val</td><td>Val</td><td>Leu</td><td>Leu</td><td>Leu</td><td>Val</td><td>How much</td><td>Phe</td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<td>Leu</td><td>Leu</td><td>Val</td><td>Ala</td><td>Asn</td><td>How much</td><td>Leu</td><td>Leu</td><td>Val</td><td>Asn</td><td>Leu</td><td>Leu</td><td>How much</td><td>Ala</td><td>Underworld</td><td>Phe</td>

<td></td><td> 130</td><td></td><td></td><td></td><td></td><td> 135</td><td></td><td></td><td></td><td></td><td> 140</td><td></td><td></td><td></td><td></td>

<td>Cheese</td><td>Tyr</td><td>Thr</td><td>Phe</td><td>Gly</td><td>Lys</td><td>Val</td><td>Main</td><td>Gly</td><td>Asn</td><td>Cheese</td><td>Asp</td><td>Leu</td><td>Tyr</td><td>Trp</td><td>Lys</td>

<td> 145</td><td></td><td></td><td></td><td></td><td> 150</td><td></td><td></td><td></td><td></td><td> 155</td><td></td><td></td><td></td><td></td><td> 160</td>

<td>Ala</td><td>Main</td><td>Arg</td><td>Tyr</td><td>Arg</td><td>Leu</td><td>How much</td><td>Arg</td><td>Glu</td><td>Phe</td><td>His</td><td>Cheese</td><td>Arg</td><td>Pro</td><td>Ala</td><td>Leu</td>

<td></td><td></td><td></td><td></td><td> 165</td><td></td><td></td><td></td><td></td><td> 170</td><td></td><td></td><td></td><td></td><td> 175</td><td></td>

<td>Ala</td><td>Pro</td><td>Pro</td><td>Phe</td><td>How much</td><td>Val</td><td>How much</td><td>Cheese</td><td>His</td><td>Leu</td><td>Arg</td><td>Leu</td><td>Leu</td><td>Leu</td><td>Arg</td><td>Main</td>

<td></td><td></td><td></td><td> 180</td><td></td><td></td><td></td><td></td><td> 185</td><td></td><td></td><td></td><td></td><td> 190</td><td></td><td></td>

<td>Leu</td><td>Cys</td><td>Arg</td><td>Arg</td><td>Pro</td><td>Arg</td><td>Cheese</td><td>Pro</td><td>Main</td><td>Pro</td><td>Cheese</td><td>Cheese</td><td>Pro</td><td>Ala</td><td>Leu</td><td>Glu</td>

PL 200 772 Β1

<td></td><td> 195</td><td> 200</td><td> 205</td>

<td>His</td><td>Phe Arg Val Tyr Leu 210</td><td>Lys Glu Ala Glu cheese 215</td><td>Arg Lys Leu Leu Thr 220</td>

<td>Trp 225</td><td>Glu Ser Val His Lys 230</td><td>Glu Asn Phe Leu Leu 235</td><td>Ala 'Arg Ala Arg Asp 240</td>

<td>Lys</td><td>Arg Glu Cheese Asp Ser 245</td><td>Glu Arg Leu Lys Arg 250</td><td>Thr Ser Gin Lys Val 255</td>

<td>Asp</td><td>Leu Ala Leu Lys Gin 260</td><td>Leu Gly His Ile Arg 265</td><td>Glu Tyr Glu Gin Arg 270</td>

<td>Leu</td><td>Lys Val Leu Glu Arg 275</td><td>Glu Val Gin Gin Cys 280</td><td>Arg Val Leu Gly Cheese 285</td>

<td>Trp Pro 305</td><td colspan="2">Val Ala Glu Ala Leu Ser Arg Ser Ala Leu 290 295 Pro Pro Pro Asp Leu Pro Gly Ser Lys Asp 310 315 &lt;210&gt; 113 &lt;211&gt; 553 &lt;212&gt; PRT &lt;213&gt; Homo sapienS &lt;400&gt; 113</td><td>Leu Pro Pro Gly Gly 300</td>

<td>Underworld 1</td><td>Val Gin Arg Leu Trp 5</td><td>Val Ser Arg Leu Leu 10</td><td>Arg His Arg Lys Ala 15</td>

<td>Gin</td><td>Leu Leu Leu Val Asn twenty</td><td>Leu Leu Thr Phe Gly 25</td><td>Leu Glu Val Cys Leu 30</td>

<td>Ala</td><td>Ala Gly Ile Thr Tyr 35</td><td>Val Pro Pro Leu Leu 40</td><td>Leu Glu Val Gly Val 45</td>

<td>Glu</td><td>Glu Lys Phe Met Thr 50</td><td>Met Val Leu Gly Ile 55</td><td>Gly Pro Val Leu Gly 60</td>

<td>Leu 65</td><td>Val Cys Val Pro Leu 70</td><td>Leu Gly Ser Ala Ser 75</td><td>Asp His Trp Arg Gly 80</td>

<td>Arg</td><td>Tyr Gly Arg Arg Arg 85</td><td>Pro Phe Ile Trp Ala 90</td><td>Leu Cheese Leu Gly Ile 95</td>

<td>Leu</td><td>Leu Ser Leu Phe Leu 100</td><td>How much Pro Arg Ala Gly 105</td><td>Trp Leu Ala Gly Leu 110</td>

<td>Leu</td><td>Cys Pro Asp Pro Arg 115</td><td>Pro Leu Glu Leu Ala 120</td><td>Leu Leu Ile Leu Gly 125</td>

<td>Val</td><td>Gly Leu Leu Asp Phe 130</td><td>Cys Gly Gin Val Cys 135</td><td>Phe Thr Pro Leu Glu 140</td>

<td>Ala 145</td><td>Leu Leu Ser Asp Leu 150</td><td>Phe Arg Asp Pro Asp 155</td><td>His Cys Arg Gin Ala 160</td>

<td>Tyr</td><td>Val Tyr Ala Phe cheese 165</td><td>Met Ile Cheese Leu Gly 170</td><td>Gly Cys Leu Gly Tyr 175</td>

<td>Leu</td><td>Leu Pro Ala Ile Asp 180</td><td>Trp Asp Thr Ser Ala 185</td><td>Leu Ala Pro Tyr Leu 190</td>

<td>Gly</td><td>Thr Gin Glu Glu Cys 195</td><td>Leu Phe Gly Leu Leu 200</td><td>Thr Leu Ile Phe Leu 205</td>

<td>Thr</td><td>Cys Val Ala Ala Thr 210</td><td>Leu Leu Val Ala Glu 215</td><td>Glu Ala Ala Leu Gly 220</td>

<td>Pro 225</td><td>Thr Glu Pro Ala Glu 230</td><td>Gly Leu Ser Ala Pro 235</td><td>Leu Ser Pro His cheese 240</td>

<td>Cys</td><td>Cys Pro Cys Arg Ala 245</td><td>Arg Leu Ala Phe Arg 250</td><td>Asn Leu Gly Ala Leu 255</td>

<td>Leu</td><td>Pro Arg Leu His Gin</td><td>Leu Cys Cys Arg Met</td><td>Pro Arg Thr Leu Arg</td>

PL 200 772 B1

<td></td><td colspan="5"> 260</td><td colspan="5"> 265</td><td colspan="5"> 270</td>

<td>Arg</td><td>Leu</td><td>Phe</td><td>Val</td><td>Ala</td><td>Glu</td><td>Leu</td><td>Cys</td><td>Cheese</td><td>Trp</td><td>Underworld</td><td>Ala</td><td>Leu</td><td>Underworld</td><td>Thr</td><td>Phe</td>

<td></td><td></td><td> 275</td><td></td><td></td><td></td><td></td><td> 280</td><td></td><td></td><td></td><td></td><td> 285</td><td></td><td></td><td></td>

<td>Thr</td><td>Leu</td><td>Phe</td><td>Tyr</td><td>Thr</td><td>Asp</td><td>Phe</td><td>Val</td><td>Gly</td><td>Glu</td><td>Gly</td><td>Leu</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Val</td>

<td></td><td> 290</td><td></td><td></td><td></td><td></td><td> 295</td><td></td><td></td><td></td><td></td><td> 300</td><td></td><td></td><td></td><td></td>

<td>Pro</td><td>Arg</td><td>Ala</td><td>Glu</td><td>Pro</td><td>Gly</td><td>Thr</td><td>Glu</td><td>Ala</td><td>Arg</td><td>Arg</td><td>His</td><td>Tyr</td><td>Asp</td><td>Glu</td><td>Gly</td>

<td> 305</td><td></td><td></td><td></td><td></td><td> 310</td><td></td><td></td><td></td><td></td><td> 315</td><td></td><td></td><td></td><td></td><td> 320</td>

<td>Val</td><td>Arg</td><td>Underworld</td><td>Gly</td><td>Cheese</td><td>Leu</td><td>Gly</td><td>Leu</td><td>Phe</td><td>Leu</td><td>Main</td><td>Cys</td><td>Ala</td><td>How much</td><td>Cheese</td><td>Leu</td>

<td></td><td></td><td></td><td></td><td> 325</td><td></td><td></td><td></td><td></td><td> 330</td><td></td><td></td><td></td><td></td><td> 335</td><td></td>

<td>Val</td><td>Phe</td><td>Cheese</td><td>Leu</td><td>Val</td><td>Underworld</td><td>Asp</td><td>Arg</td><td>Leu</td><td>Val</td><td>GLn</td><td>Arg</td><td>Phe</td><td>Gly</td><td>Thr</td><td>Arg</td>

<td></td><td></td><td></td><td> 340</td><td></td><td></td><td></td><td></td><td> 345</td><td></td><td></td><td></td><td></td><td> 350</td><td></td><td></td>

<td>Ala</td><td>Val</td><td>Tyr</td><td>Leu</td><td>Ala</td><td>Cheese</td><td>Val</td><td>Ala</td><td>Ala</td><td>Phe</td><td>Pro</td><td>Val</td><td>Ala</td><td>Ala</td><td>Gly</td><td>Ala</td>

<td></td><td></td><td> 355</td><td></td><td></td><td></td><td></td><td> 360</td><td></td><td></td><td></td><td></td><td> 365</td><td></td><td></td><td></td>

<td>Thr</td><td>Cys</td><td>Leu</td><td>Cheese</td><td>His</td><td>Cheese</td><td>Val</td><td>Ala</td><td>Val</td><td>Val</td><td>Thr</td><td>Ala</td><td>Cheese</td><td>Ala</td><td>Ala</td><td>Leu</td>

<td></td><td> 370</td><td></td><td></td><td></td><td></td><td> 375</td><td></td><td></td><td></td><td></td><td> 380</td><td></td><td></td><td></td><td></td>

<td>Thr</td><td>Gly</td><td>Phe</td><td>Thr</td><td>Phe</td><td>Cheese</td><td>Ala</td><td>Leu</td><td>Main</td><td>How much</td><td>Leu</td><td>Pro</td><td>Tyr</td><td>Thr</td><td>Leu</td><td>Ala</td>

<td> 385</td><td></td><td></td><td></td><td></td><td> 390</td><td></td><td></td><td></td><td></td><td> 395</td><td></td><td></td><td></td><td></td><td> 400</td>

<td>Cheese</td><td>Leu</td><td>Tyr</td><td>His</td><td>Arg</td><td>Glu</td><td>Lys</td><td>Main</td><td>Val</td><td>Phe</td><td>Leu</td><td>Pro</td><td>Lys</td><td>Tyr</td><td>Arg</td><td>Gly</td>

<td></td><td></td><td></td><td></td><td> 405</td><td></td><td></td><td></td><td></td><td> 410</td><td></td><td></td><td></td><td></td><td> 415</td><td></td>

<td>Asp</td><td>Thr</td><td>Gly</td><td>Gly</td><td>Ala</td><td>Cheese</td><td>Cheese</td><td>Glu</td><td>Asp</td><td>Cheese</td><td>Leu</td><td>Underworld</td><td>Thr</td><td>Cheese</td><td>Phe</td><td>Leu</td>

<td></td><td></td><td></td><td> 420</td><td></td><td></td><td></td><td></td><td> 425</td><td></td><td></td><td></td><td></td><td> 430</td><td></td><td></td>

<td>Pro</td><td>Gly</td><td>Pro</td><td>Lys</td><td>Pro</td><td>Gly</td><td>Ala</td><td>Pro</td><td>Phe</td><td>Pro</td><td>Asn</td><td>Gly</td><td>His</td><td>Val</td><td>Gly</td><td>Ala</td>

<td></td><td></td><td> 435</td><td></td><td></td><td></td><td></td><td> 440</td><td></td><td></td><td></td><td></td><td> 445</td><td></td><td></td><td></td>

<td>Gly</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Leu</td><td>Leu</td><td>Pro</td><td>Pro</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Leu</td><td>Cys</td><td>Gly</td><td>Ala</td><td>Cheese</td>

<td></td><td> 450</td><td></td><td></td><td></td><td></td><td> 455</td><td></td><td></td><td></td><td></td><td> 460</td><td></td><td></td><td></td><td></td>

<td>Ala</td><td>Cys</td><td>Asp</td><td>Val</td><td>Cheese</td><td>Val</td><td>Arg</td><td>Val</td><td>Val</td><td>Val</td><td>Gly</td><td>Glu</td><td>Pro</td><td>Thr</td><td>Glu</td><td>Ala</td>

<td> 465</td><td></td><td></td><td></td><td></td><td> 470</td><td></td><td></td><td></td><td></td><td> 475</td><td></td><td></td><td></td><td></td><td> 480</td>

<td>Arg</td><td>Val</td><td>Vai</td><td>Pro</td><td>Gly</td><td>Arg</td><td>Gly</td><td>How much</td><td>Cys</td><td>Leu</td><td>Asp</td><td>Leu</td><td>Ala</td><td>How much</td><td>Leu</td><td>Asp</td>

<td></td><td></td><td></td><td></td><td> 485</td><td></td><td></td><td></td><td></td><td> 490</td><td></td><td></td><td></td><td></td><td> 495</td><td></td>

<td>Cheese</td><td>Ala</td><td>Phe</td><td>Leu</td><td>Leu</td><td>Cheese</td><td>Main</td><td>Val</td><td>Ala</td><td>Pro</td><td>Cheese</td><td>Leu</td><td>Phe</td><td>Underworld</td><td>Gly</td><td>Cheese</td>

<td></td><td></td><td></td><td> 500</td><td></td><td></td><td></td><td></td><td> 505</td><td></td><td></td><td></td><td></td><td> 510</td><td></td><td></td>

<td>He</td><td>Val</td><td>Main</td><td>Leu</td><td>Cheese</td><td>Main</td><td>Cheese</td><td>Val</td><td>Thr</td><td>Ala</td><td>Tyr</td><td>Underworld</td><td>Val</td><td>Cheese</td><td>Ala</td><td>Ala</td>

<td></td><td></td><td> 515</td><td></td><td></td><td></td><td></td><td> 520</td><td></td><td></td><td></td><td></td><td> 525</td><td></td><td></td><td></td>

<td>Gly</td><td>Leu</td><td>Gly</td><td>Leu</td><td>Val</td><td>Ala</td><td>How much</td><td>Tyr</td><td>Phe</td><td>Ala</td><td>Thr</td><td>Gin</td><td>Val</td><td>Val</td><td>Phe</td><td>Asp</td>

<td></td><td> 530</td><td></td><td></td><td></td><td></td><td> 535</td><td></td><td></td><td></td><td></td><td> 540</td><td></td><td></td><td></td><td></td>

<td>Lys</td><td>Cheese</td><td>Asp</td><td>Leu</td><td>Ala</td><td>Lys</td><td>Tyr</td><td>Cheese</td><td>Ala</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 54 5</td><td></td><td></td><td></td><td></td><td> 550</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 114 &lt;211&gt; 241 &lt;212&gt; PRT &lt;213&gt; Homo sapienS &lt;400&gt; 114

<td>Underworld</td><td>GLn</td><td>Cys</td><td>Phe</td><td>Cheese</td><td>Phe</td><td>How much</td><td>Lys</td><td>Thr</td><td>Underworld</td><td>Underworld</td><td>How much</td><td>Leu</td><td>Phe</td><td>Asn</td><td>Leu</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td>Leu</td><td>How much</td><td>Phe</td><td>Leu</td><td>Cys</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Val</td><td>Gly</td><td>How much</td><td>Trp</td><td>Val</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td>Cheese</td><td>How much</td><td>Asp</td><td>Gly</td><td>Ala</td><td>Cheese</td><td>Phe</td><td>Leu</td><td>Lys</td><td>How much</td><td>Phe</td><td>Gly</td><td>Pro</td><td>Leu</td><td>Cheese</td><td>Cheese</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td>Cheese</td><td>Ala</td><td>Underworld</td><td>GLn</td><td>Phe</td><td>Val</td><td>Asn</td><td>Val</td><td>Gly</td><td>Tyr</td><td>Phe</td><td>Leu</td><td>How much</td><td>Ala</td><td>Ala</td><td>Gly</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td>val</td><td>Val</td><td>Val</td><td>Phe</td><td>Ala</td><td>Leu</td><td>Gly</td><td>Phe</td><td>Leu</td><td>Gly</td><td>Cys'</td><td>Tyr</td><td>Gly</td><td>Ala</td><td>Lys</td><td>Thr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td>Glu</td><td>Cheese</td><td>Lys</td><td>Cys</td><td>Ala</td><td>Leu</td><td>Val</td><td>Thr</td><td>Phe</td><td>Phe</td><td>Phe</td><td>How much</td><td>Leu</td><td>Leu</td><td>Leu</td><td>How much</td>

PL 200 772 B1

<td colspan="3"></td><td colspan="6"> 85</td><td colspan="5"> 90</td><td colspan="2"> 95</td>

<td>Phe</td><td>How much</td><td>Ala</td><td>Glu</td><td>Val</td><td>Ala</td><td>Ala</td><td>Ala</td><td>Val</td><td>Val</td><td>Ala</td><td>Leu</td><td>Val</td><td>Tyr</td><td>Thr</td><td>Thr</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td>Underworld</td><td>Ala</td><td>Glu</td><td>His</td><td>Phe</td><td>Leu</td><td>Thr</td><td>Leu</td><td>Leu</td><td>Val</td><td>Val</td><td>Pro</td><td>Ala</td><td>He</td><td>Lys</td><td>Lys</td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<td>Asp</td><td>Tyr</td><td>Gly</td><td>Cheese</td><td>GLn</td><td>Glu</td><td>Asp</td><td>Phe</td><td>Thr</td><td>Main</td><td>Val</td><td>Trp</td><td>Asn</td><td>Thr</td><td>Thr</td><td>Underworld</td>

<td></td><td> 130</td><td></td><td></td><td></td><td></td><td> 135</td><td></td><td></td><td></td><td></td><td> 140</td><td></td><td></td><td></td><td></td>

<td>Lys</td><td>Gly</td><td>Leu</td><td>Lys</td><td>Cys</td><td>Cys</td><td>Gly</td><td>Phe</td><td>Thr</td><td>Asn</td><td>Tyr</td><td>Thr</td><td>Asp</td><td>Phe</td><td>Glu</td><td>Asp</td>

<td> 145</td><td></td><td></td><td></td><td></td><td> 150</td><td></td><td></td><td></td><td></td><td> 155</td><td></td><td></td><td></td><td></td><td> 160</td>

<td>Cheese</td><td>Pro</td><td>Tyr</td><td>Phe</td><td>Lys</td><td>GLu</td><td>Asn</td><td>Cheese</td><td>Ala</td><td>Phe</td><td>Pro</td><td>Pro</td><td>Phe</td><td>Cys</td><td>Cys</td><td>Asn</td>

<td></td><td></td><td></td><td></td><td> 165</td><td></td><td></td><td></td><td></td><td> 170</td><td></td><td></td><td></td><td></td><td> 175</td><td></td>

<td>Asp</td><td>Asn</td><td>Val</td><td>Thr</td><td>Asn</td><td>Thr</td><td>Ala</td><td>Asn</td><td>Glu</td><td>Thr</td><td>Cys</td><td>Thr</td><td>Lys</td><td>Main</td><td>Lys</td><td>Ala</td>

<td></td><td></td><td></td><td> 180</td><td></td><td></td><td></td><td></td><td> 185</td><td></td><td></td><td></td><td></td><td> 190</td><td></td><td></td>

<td>His</td><td>Asp</td><td>Main</td><td>Lys</td><td>Val</td><td>GLu</td><td>Gly</td><td>Cys</td><td>Phe</td><td>Asn</td><td>Main</td><td>Leu</td><td>Leu</td><td>Tyr</td><td>Asp</td><td>How much</td>

<td></td><td></td><td> 195</td><td></td><td></td><td></td><td></td><td> 200</td><td></td><td></td><td></td><td></td><td> 205</td><td></td><td></td><td></td>

<td>Arg</td><td>Thr</td><td>Asn</td><td>Ala</td><td>Val</td><td>Thr</td><td>Val</td><td>Gly</td><td>Gly</td><td>Val</td><td>Ala</td><td>Ala</td><td>Gly</td><td>How much</td><td>Gly</td><td>Gly</td>

<td></td><td> 210</td><td></td><td></td><td></td><td></td><td> 215</td><td></td><td></td><td></td><td></td><td> 220</td><td></td><td></td><td></td><td></td>

<td>Leu</td><td>Glu</td><td>Leu</td><td>Ala</td><td>Ala</td><td>Underworld</td><td>How much</td><td>Val</td><td>Cheese</td><td>Underworld</td><td>Tyr</td><td>Leu</td><td>Tyr</td><td>Cys</td><td>Asn</td><td>Leu</td>

<td> 225</td><td></td><td></td><td></td><td></td><td> 230</td><td></td><td></td><td></td><td></td><td> 235</td><td></td><td></td><td></td><td></td><td> 240</td>

<td>Main</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 115 &lt;211&gt; 366 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 115 gctctttctc tcccctcctc tgaatataat tctttcaact tgcaaattgc aaggaataca 60 gatttcactg tgatgtatat tgcgttgcca aaaaaaaaaa gtgtccttgt ttaaaattac 120 ttggtttgtg aatccatctt gctttttccc cattggaact agtcaataac ccatctctga 180 accggtagaa aaacatctga agagctcgtc tatcagcatc tgacaggtga attggatggt 240 tctcagaacc atttcaccca gacagcgcgt ttccatcctg tttaataaat tagtctgggt 300 cctctacatg cataacaaac cctggtccca tctgtcacat aaaaatcggt gacttgaagg 360 ttagtc 366 &lt;210&gt; 116 &lt;211&gt; 282 &lt;212&gt; DNA &lt;213&gt; Homo sapienS &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (282) &lt;223&gt; n = A, T, C, L b G &lt;400&gt; 116 acaaagatga accatttcct atattatagc aaaattaaaa ttctaatatt 60 gagaaatgag atnaaacaca atnttataaa gtccacttag agaagatcaa 120 agactttact attttcatat tttaagacac atgatttatc ctattttagt aacctggttc 180 atacgttaaa caaaggataa gtcgaacatc agagaggatt tg ^ ggcaga aaatctatgt 240 tcaatctnga actatcCana tcacagacat ttctattcct tt 282 &lt;210&gt; 117 &lt;211&gt; 305

PL 200 772 B1 acacatgtcg tatttatcct aataaggcaa tactgatccc gactgcccca tgggt

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapiens</td>

<td> &lt;220&gt;</td><td></td>

<td> &lt;221&gt;</td><td>misc feature</td>

<td> &lt;222&gt;</td><td> (1)...(305)</td>

<td> &lt;223&gt;</td><td>n = A, T, Club G</td>

<td> &lt;400&gt;</td><td> 117</td>

cttcactgcc ccctcctgaa aatatatgaa tgatcactgt gcttactgcc ttcttagatg acaattgcaa acaacaggtc cctaatgcag tgtagagagt cttctggtca aataanacaa tcgagatatt gatgtgggaa ttctangctg acatanagga aatatatgaa ggaaatcagt acagatgagg cagttcagac acagggacca acaattgcaa ctttgatggt tcacctctgt agggagaaat

120

180

240

300

305

<td> &lt;210&gt;</td><td> 118</td><td></td>

<td> &lt;211&gt;</td><td> 71</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapienS</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> ..(71)</td>

<td> &lt;223&gt;</td><td colspan="2">n = A, T, C Ut</td>

<td> &lt;400&gt;</td><td> 118</td><td></td>

accaaggtgt ntgaatctct gtcgtggggt tctctgattc ccgcacaatc tgagtggaaa ttntcctggg t

<td> &lt;210&gt;</td><td>11S</td><td></td>

<td> &lt;211&gt;</td><td> 212</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapienS</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> -.(212)</td>

<td> &lt;223&gt;</td><td>n = j</td><td>AT, C or</td>

<td> &lt;400&gt;</td><td> 119</td><td></td>

actccggttg gtgtcagcag cacgtggcat tgtacttngc aatgtggagc ccaaaccaca 60 gaaaatgggg tgaaattggc caactttcta tnaacttatg ttggcaantt tgccaccaac 120 αgtααgcttgat ccaggancatga ccaggtcta ccagtaacta 180 αgtααgcttcta

<td> &lt;210&gt;</td><td> 120</td><td></td>

<td> &lt;211&gt;</td><td> 90</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td>(l) -</td><td> . - (90)</td>

<td> &lt;223&gt;</td><td>n =.</td><td>A, T, C</td>

PL 200 772 Β1 &lt;400&gt; 120 actcgttgca natcaggggc cccccagagt caccgttgca ggagtccttc tggtcttgcc 60 ctccgccggc gcagaacatg ctgggtggt 90 &lt;210&gt; 121 &lt;211&gt; 218 &lt;212&gt; sap213&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (218) &lt;223&gt; n - A, T, C or G &lt;400&gt; 121 tgtancgtga anacgacaga nagggttgtc aaaaatggag aanccttgaa gtcattttga 60 gaacaagatt tgctaaaaga tttggggcta aaacatggtt attgggagac atttctgaag 120 atatncangt aaattangga atgaattcat ggttcttttg ggaattcctt tacgatngcc 180 agcatanact tcatgtgggg atancagcta cccttgta 218 &lt;210&gt; 122 &lt; 211&gt; 171 &lt;212&gt; DNA &lt;21'3&gt; Homo sapiens &lt;400&gt; 122 taggggtgta tgcaactgta aggacaaaaa ttgagactca actggcttaa ccaataaagg 60 catttgttag ctcatggaac aggaagtcgg atggtggggc 120 ccttcaggtgt 120 ccttcaggtg caccaccccg gcggggtcat ctgtgccaca ggtccctgtt gacagtgcgg t 171

<td> &lt;210&gt;</td><td> 123</td><td></td>

<td> &lt;211&gt;</td><td> 76</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapienS</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1) '</td><td> . (76)</td>

<td> &lt;223&gt;</td><td>n = fi.</td><td>i, T, C lob</td>

<td> &lt;400&gt;</td><td> 123</td><td></td>

tgtagcgtga agacnacaga atggtgtgtg ctgtgctacc caggaacaca tttattatca 60 ttatcaanta ttgtgt 76 &lt;210&gt; 124 &lt;211&gt; 131 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 124 acctttcccc aaggccaatg tcctgtgtgc taactggccg gctgcaggac agctgcaatt caatgtgctg ggtcatatgg aggggaggag actctaaaat agccaatttt attctcttgg ttaagatttg t

120

131

GB 200 772 Β1 &lt;210 »125 &lt;211» 432 &lt;212 »DNA &lt;213» Homo sapiens &lt;400 »125 actttatcta ctggctatga aatagatggt ggaaaattgc gttaccaact ataccactgg 60 cttgaaaaag aggtgatagc tcttcagagg acttgtgact cttgctcaga tgctgaagaa 120 ctacagtctg catttggcag aaatgaagac gaatttggat caaacgagga tgctgaagat 180 ttgccccacc aaacaaaagt gaaacaactg agagaaaatt Ctcaggaaaa aagacagcgg 240 ctcttgaagt aCcagCcact tttgagaatg ttccttagtt actgcatact tcatggatcc 300 catggtgggg gtcttgcatc tgtaagaatg gaattgattt tgcttttgca agaatctcag 360 caggaaacat cagaaccact attttctagc cctctgtcag agcaaacctc agtgcctctc 420 ctctttgctt gt 432

<td colspan="2">&lt;210&gt; 126 &lt;211&gt; 112 &lt;212&gt; DNA &lt;213&gt; Homo sapienS</td>

<td> &lt;400&gt;</td><td> 126</td>

acacaacttg aatagtaaaa tagaaactga gctgaaattt ctaacccact ttctaaccat 60 agtaagaatg atatttcccc ccagggatca ccaaatatct ataaaaattt gt 112 &lt;210 »127 &lt;211» 54 &lt;212 »DNA &lt;213» Homo sapieacgacagac &lt;210 cagaca »cagaca» 128 cagacaaacgaagaccagaccagacaaacgaagac &lt;210&gt; &lt;212 »DNA &lt;213» Homo sapiens &lt;400 »128 acctcattag taattgtttt gttgtttcat ttttttctaa tgtctcccct ctaccagctc 60 acctgagata acagaatgaa aatggaagga cagccagatt tctcctttgc tctctgctgagac 120 ttctctgctgagac ataggcaata aacacagttc 180 ccaaagcatt tggacagttt cttgttgtgt tttagaatgg ttttcctttt tcttagcctt 240 ttcctgcaaa aggctcactc agtcccttgc ttgctcagtg gactgggctc cccttagggcctt cccttagggcctg 300

<td> &lt;210&gt;</td><td> 129</td><td></td>

<td> &lt;211&gt;</td><td> 192</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td>&lt;22l&gt;</td><td>misc</td><td>_feature</td>

<td> &lt;222&gt;</td><td>(ll.</td><td> ..(192!</td>

<td> &lt;223&gt;</td><td>n =.</td><td>A, T, C | uL</td>

GB 200 772 Β1 &lt;400&gt; 129 acatacatgt gtgtatattt ttaaatatca cttttgtatc actctgactt tttagcatac 60 tgaaaacaca ctaacataat ttntgtgaac catgatcaga tacaacccaa atcattcatc 120 tagcacattc atctgtgata naaagatagg tgagtttcat ttccttcacg ttggccaatg 180 gataaacaaa gt 192 &lt;2L0&gt; 130 &lt;2LL&gt; 362 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt; 220&gt;

&lt;22l&gt; misc_feature &lt;222&gt; (1) ... (362) &lt;223&gt; n = A, T, CG &lt;400&gt; 130 cccttCttta tggaatgagt agactgtatg tttgaanate tanccacaac ctctttgaca 60 tataatgacg caacaaaaag gtgctgttta gtcctatggt tcagtttatg cccctgacaa 120 gtttccattg tgttttgccg atcttctggc taatcgtggt atcctccatg ttattagtaa 180 ttctgtattc cattttgtta acgcctggta gatgtaacct gctangaggc taactttata 240 cttatttaaa agctctcatt ttgtggtcat taaaatggca atttatgtgc agcactttat 300 tgcagcagga agcacgtgctttg a ggtaggctttg a ggtaggctttg a ggtaggctttg

<td> &lt;210&gt;</td><td> 131</td><td></td>

<td> &lt;211&gt;</td><td> 332</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>_feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> 7.(332)</td>

<td> &lt;223&gt;</td><td>n = j</td><td>4, T, C lot</td>

<td> &lt;400&gt;</td><td> 131</td><td></td>

ctttttgaaa gatcgtgtcc actcctgtgg acatcttgtt ttaatggagt ttcccatgca 60 gtangactgg tatggttgca gctgtccaga taaaaacatt tgaagagctc caaaatgaga 120 gttctcccag gttcgccctg ctgctccaag tctcagcagc agcctctttt aggaggcatc 180 ttctgaacta gattaaggca gcttgtaaat ctgatgtgat ttggtttatt atccaactaa 240 cttccatctg ttatcactgg agaaagccca gactccccan gacnggtacg gattgtgggc 300 atanaaggat tgggtgaagc gt tggcgttgtg 332

<td> &lt;210&gt;</td><td> 132</td>

<td> &lt;211&gt;</td><td> 322</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapien S.</td>

<td> &lt;220&gt;</td><td></td>

<td> &lt;221&gt;</td><td>misc_feature</td>

<td> &lt;222&gt;</td><td> (1) . . ,(322)</td>

<td> &lt;223&gt;</td><td>n = A, T, C Feb</td>

<td> &lt;400&gt;</td><td> 132</td>

acttttgcca ttttgtatat ataaacaatc ttgggacatt ctcctgaaaa ctaggtgtcc 60

EN 200 772 Β1 agtggctaag ctcaaattcc tttagcaagt ggatgcttct gtaacaatct agaactcgat caaacagggg taaaatgaan aaaaaaaact acaattggtc ttcaagcaat ctctgtggga atgacaggaa ttggtagaga ca tctgaaagga aaaatgaggg aggcttattt aaataggaat aaaccagcat aggacctttg atcaacaaag gctnaatcct gacacagaat tatctcgggt agaagagttg agggaagcct

120

180

240

300

322 acaagccttc cttgtttttc ctatttaaaa ctattcctgt cccacgaaac

<td> &lt;210&gt;</td><td> 133</td><td></td>

<td> &lt;211&gt;</td><td> 278</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1) . .</td><td> . (278)</td>

<td> &lt;223&gt;</td><td>n - i</td><td>i, T, C lufc</td>

<td> &lt;400&gt;</td><td> 133</td><td></td>

acaagtttaa tttccatctg aaaatcacaa tttgtcaaag actaataaaa ctaaattggg gctcctgggt atctttccct aaattatatt accacagaga attaatcttt tgacaatttg ttaagctatg ttgtccta ttgtgata acta ctgattaactac

120

180

240

278

<td> &lt;210&gt;</td><td> 134</td><td></td>

<td> &lt;211&gt;</td><td> 121</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapienj</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . .(121)</td>

<td> &lt;223&gt;</td><td colspan="2">n = A, T, C or</td>

<td> &lt;400&gt;</td><td> 134</td><td></td>

gtttanaaaa cttgtttagc tgattctctg aggttaaact t tccatagagg tggttttcaa aaagaatgtt atgttatttt aaactttgta tacttgtatt ttttaaaaca ttgcttttgg

120

121 acttanaacc atancaagtg aaacttgata gggtgccccc ccacctcaat ttcccaagga

<td> &lt;210&gt;</td><td> 135</td><td></td>

<td> &lt;211&gt;</td><td> 350</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapienS</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>_f eature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> ..(350)</td>

<td> &lt;223&gt;</td><td>n =.</td><td>A, T, C Feb.</td>

<td> &lt;400&gt;</td><td> 135</td><td></td>

atgcctagca gtgactggtt cttttgttct caactcctgc caagccctgg tgcaaagcct catcagaatc aagcgtgcga aagtaggaac agccgctcct gccatgctac ggtgctcaac cctcaaagaa caaaggtcag tagtatacag ctgtgccagn ctgcaattgg tcctggggcg catcagtata ctggcacatt tncctaggan ccctgnaagg ctgaacaaac tcaactcagt atcctatacc acttgtgtgc tggtactcca aactttcgct gtttgctgag

120

180

240

300

350

100

PL 200 772 Β1 &lt;210&gt; 13S &lt;211&gt; 399 &lt;212&gt; DNA &lt;213&gt; Homo sapienS &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (399) &lt;223&gt; n = A, T, C kit G &lt;400&gt; 136 tgtaccgtga agacgacaga agtcgcacgg cagggacagg gcagggccga ggccagggtt 60 gctgtgattg tatccgaata ntcctcgtga gaaaagataa tgagatgacg tgagcagcct 120 gcagacttgt gtctgccttc aanaagccag acaggaaggc cctgcctgcc ttggctctga 180 cctggcggcc agccagccag ccacaggtgg gcttcttcct cttgtggtga caacnccaag 240 aaaactgcag aggcccaggg tcaggtgtna gtgggtangt gaccataaaa caccaggtgc 300 tcccaggaac ccgggcaaag gccatcccca cctacagcca gcatgcccac tggcgtgatg 360 ggtgcagang gatgaagcag ccagntgttc tgctgtggt 399

<td> &lt;210&gt;</td><td> 137</td><td></td><td></td><td></td><td></td><td></td>

<td> &lt;211&gt;</td><td> 165</td><td></td><td></td><td></td><td></td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td><td></td><td></td><td></td><td></td>

<td> &lt;213&gt;</td><td colspan="2">Homo sapiens</td><td></td><td></td><td></td><td></td>

<td> &lt;220&gt;</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> &lt;221&gt;</td><td colspan="2">misc feature</td><td></td><td></td><td></td><td></td>

<td> &lt;222&gt;</td><td colspan="2"> (1)...(165)</td><td></td><td></td><td></td><td></td>

<td> &lt;223&gt;</td><td>n = A, T, C</td><td>kek G</td><td></td><td></td><td></td><td></td>

<td> &lt;400&gt;</td><td> 137</td><td></td><td></td><td></td><td></td><td></td>

<td>actggtgtgg</td><td>tngggggtga</td><td>tgctggtggt</td><td>anaagttgan</td><td>gtgacttcan</td><td>gatggtgtgt</td><td> 60</td>

<td>ggaggaagtg</td><td>tgtgaacgta</td><td>gggatgtaga</td><td>ngttttggcc</td><td>gtgctaaatg</td><td>agcttcggga</td><td> 120</td>

<td>ttggctggtc</td><td>ccactggtgg</td><td>tcactgtcat</td><td>tggtggggtt</td><td>cctgt</td><td></td><td> 165</td>

&lt;210&gt; 138 &lt;211&gt; 338 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (338) &lt;223&gt; n = A, T, C kk G &lt;400&gt; 138 actcactgga atgccacatt cacaacagaa tcagaggtct gtgaaaacat taatggctcc 60 ttaacttctc cagtaagaat cagggacttg aaatggaaac gttaacagcc acatgcccaa 120 tgctgggcag tctcccatgc cttccacagt gaaagggctt gagaaaaatc acatccaatg 180 tcatgtgttt ccagccacac caaaaggtgc tcggggtgga gggctggggg catananggt 240 cangcctcag gaagcctcaa gtcccatcca gctttgccac tgtacattcc ccatntttaa 300 aaaaactgat gccttttttt tttttttttg taaaattc 338 &lt;210&gt; 139 &lt;211&gt; 382

PL 200 772 Β1

101 &lt;212 »DNA &lt;213» Homo sapiens &lt;400 »139 gggaatcttg gtttttggca tctggtttgc ctatagccga ggccactttg acagaacaaa 60 gaaagggact tcgagtaaga aggtgattta cagccagcct agtgcccgaa gtgaaggaga 120 attcaaacag acctcgtcat ccctggtgtg agcctggtcg gctcaccgcc tatcatctgc 180 atttgcctta ctcaggtgct accggactct ggcccctgat gtctgtagtt tcacaggatg 240 ccttatttgt cttctacacc ccacagggcc ccctacttct tcggatgcgt ttttaataat 300 .gtcagctatg tgccccatcc tccttcatgc cctccctccc tttcctacca ctgctgagtg 360 gcctggaact tgtttaaagt gt 382 &lt;210 » 140 &lt;211 »200 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220» &lt;221 »misc_feature &lt;222» (1). . . (200) &lt;223 »n = A, T, C or G &lt;400» 140 accaaanctt ctttctgttg tgttngattt tactataggg gtttngcttn ttctaaanat 60 acttttcatt taacancttt tgttaagtgt caggctgcac tttgctccat anaattattg 120 ttttcacatt tcaacttgta tgtgtttgtc tcttanagca ttggtgaaat cacatatttt 180 atattcagca taaaggagaa 2C0 &lt;210 »141 &lt;211» 335 &lt;212 »DNA &lt;213» Homo sapiens &lt;220 »&lt;221» misc_feature &lt;222 »(1) ... (335) &lt;223» n = A, T, C or G &lt;400 »141 actttatttt caaaacactc atatgttgca aaaaacacat agaaaaataa agtttggtgg 60 gggtgctgac taaacttcaa gtcacagact tttatgtgac agattggagc agggtttgtt 120 atgcatgtag agaacccaaa ctaatttatt aaacaggata gaaacaggct gtctgggtga 180 aatggttctg agaaccatcc aattcacctg tcagatgctg atanactagc tcttcagatg 240 tttttctacc agttcagaga tnggttaatg actanttcca atggggaaaa agcaagatgg 300 attcacaaac caagtaattt taaacaaaga cactt 335

<td> &lt;210&gt;</td><td> 142</td><td></td>

<td> &lt;211&gt;</td><td> 459</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220^</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1) .</td><td> . . (459)</td>

<td> &lt;223&gt;</td><td>n =.</td><td>A, T, C Feb.</td>

102

GB 200 772 B1 &lt;400&gt; 142 accaggttaa tattgccaca tatatccttt ccaactgcgg gctaaacaga cgtgtattta 60 gggtcgttta aagacaaccc agcttaatat caagagaaat tgtgaccttt catggagtat 120 ctgatggaga aaacactgag ttttgacaaa tcttatttta ttcagatagc agtctgatca 180 cacatggtcc aacaacactc aaataataaa tcaaatatna tcagatgtta aagattggec 240 ttcaaacatc atagccaatg atgccccgct tgcctataat ctctccgaca taaaaccaca 300 tcaacacctc agtggccacc aaaccattca gcacagcttc cttaactgtg agccgtttga 360 agctaccagt ctgagcacta ttgactatnt tttccangct ctgaatagct ctagggatct 420 cagcangggt gggaggaacc agctcaacct tggcgtant 459

<td> &lt;210&gt;</td><td> 143</td>

<td> &lt;211&gt;</td><td> 140</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213 &gt;</td><td>Homo sapiens</td>

<td> &lt;400&gt;</td><td> 143</td>

acatttcctt ccaccaagtc aggactcctg gcttctgtgg gagttcttat cacctgaggg 60 aaatccaaac agtctctcct agaaaggaat agtgtcacca accccaccca tctccctgag 120 accatccgac ttccctgtgt2 &lt;14011&gt; 164&gt; &lt;144&gt; Homapiens &lt;144&gt;

&lt;221&gt; osC-teacure &lt;222? (1 | ... (164) &lt;223? N = A, T, C | p (, G &lt;400? 144 acttcagtaa caacatacaa taacaaacct aagtgtatat tgccatcttt gtcattttct 60 atctatacca ctcactctac tgaaaacaan aatcactanc caatcactta tacattaacttgata 164 tacattaacttga

<td> &lt;210?</td><td> 145</td>

<td> &lt;211?</td><td> 303</td>

<td> &lt;212?</td><td>GOUT</td>

<td> &lt;213?</td><td>Homo sapien S.</td>

&lt;220?

&lt;221? misc_feature &lt;222? (1) ... (303) &lt;223? n = A, T, CG &lt;400? 145 ^ a ^ tagac tccaacttat tattagttat ggcaaacatc ttgnatctaa ttcttatcaa 60 and GGA ^ ^^ aattataccc aatcatccca tacaataaca tgctcacttc ctcagggtat 120 gcatttcttc taccttattt atccagatac tactatttgt ataaacttca 180 gaagttttta cctattatga gacagttcta atcttttgag gatttggaac atttgcctag 240 aattaaatan atgcttatca gaaacagoca caaaagtatt tccgccttgg tgattaccat 300 303 caa &lt;210? 146

PL 200 772 Β1

103 actgcagctc actggcctgg ccaagtcagg cctgaacagg agacttgccc taggggtgag

<td>&lt;2ll&gt;</td><td> 327</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapien «</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc_</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1) . .</td><td> . (327)</td>

<td> &lt;223&gt;</td><td>n = f</td><td>i, T, C hatch</td>

<td> &lt;400&gt;</td><td> 146</td><td></td>

aattagaagt agtgactcat gctgggattt gagggtggga ctgggcctgt ctgtgtgact ggtctctgac tgctctggtt gtttcctttc ggagccagca cacacctact ctatggt tttcatcanc ttctctccctgac gcggctcctgac gacgctctcctgac gcgctctccctacagc ggctctcctgac gacgctctcctgac gcgctctccctacagc gggctctagacagc

<td>gctccatgac</td><td> 60</td>

<td>caacaggcct</td><td> 120</td>

<td>ctggccactt</td><td> 180</td>

<td>taaagtagcc</td><td> 240</td>

<td>ggatggaatg</td><td> 300 327</td>

<td>&lt;210&gt; &lt;2ll&gt; &lt;212&gt; &lt;213&gt;</td><td>147 173 GOUT Homo</td><td>sapienS</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> ..(173)</td>

<td> &lt;223&gt;</td><td colspan="2">n - A, T, C hatch</td>

<td> &lt;400&gt;</td><td> 147</td><td></td>

acattgtttt tttgagataa actggaacac atacccacat atattcaagc acatatgtta agcattgana ctttgttctg tatattattc gagctctcct taacgtgaca agggataatt ttctgataaa agttccatgt ttatagccta

<td>caacggaagg</td><td> 60</td>

<td>gtcttgctgt</td><td> 120</td>

<td>gtt</td><td> 173</td>

acaaccactt atgggatata gccctactac gtggtcctag nccancccac tagattatnt caccactggt ccaggcacag

<td> &lt;210&gt;</td><td> 148</td><td></td>

<td> &lt;211&gt;</td><td> 477</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>_f eature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (477)</td>

<td> &lt;223&gt;</td><td>n =.</td><td>A, T, C hatch</td>

<td> &lt;400&gt;</td><td> 148</td><td></td>

tatctcatcg ttatttgatg ctgctgcaat tggccatcag ctcaccgacc ccaaattcag aagccttctc gctacctcat aatttttaac ctccatttca aatcacattc tccangcctg ccatcctctt tcaattaagt cagccaacac cttcacaatc ccaaactcac tcactgtgcc tcacacatat atgaataata ccttcctgtc ctgaccctga caccttgagc ccttgagctc acacagctac ctccttgctc tactattaac actctacccg acacacacac acacncacac acccctttaa ttaccatgct

<td>tttctatcct</td><td> 60</td>

<td>cactcatact</td><td> 120</td>

<td>agccattggg</td><td> 180</td>

<td>cattgctcac</td><td> 240</td>

<td>tctaacccca</td><td> 300</td>

<td>acatgtccag</td><td> 360</td>

<td>acacacatat</td><td> 420</td>

<td>atggtgg</td><td> 477</td>

&lt;210&gt; 149 &lt;211&gt; 207 &lt;212&gt; DNA

104

GB 200 772 Β1 &lt;213&gt; Homo sapiens &lt;400&gt; 149 acagttgtat tataatatca agaaataaac ttgcaatgag agcatttaag agggaagaac 60 taacgtattt tagagagcca aggaaggtct ctgtggggag tgggatgtaa ggtggggcct 120 gatgataaat aagagtcagc caggtaagtg ggtggtgtgg tatgggcaca gtgaagaaca 180 tttcaggcag agggaacagc agtgaaa 207

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td>150 lll GOUT Homo</td><td>sapien&gt;</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1) '</td><td>.. (lll)</td>

<td> &lt;223&gt;</td><td>n =</td><td>A, T, C or</td>

<td>&lt;40U&gt;</td><td> 150</td><td></td>

accttgattt cattgctgct ctgatggaaa cccaactatc taatttagct aaaacatggg 60 cacttaaatg tggtcagtgt ttggacttgt taactantgg III catctttggg t &lt;210&gt; 151 &lt;211&gt; 196 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 151 agcgcggcag gtcatattga acattccaga tacctatcat tactcgatgc tgttgataac 60 agcaagatgg ctttgaactc agggtcacca ccagctat.tg gaccttacta tgaaaaccat 120 ggataccaac cggaaaaccc ctatcccgca cagcccactg tggtccccac tgtctacgag 180 gtgcatccgg ctcagt 196

<td colspan="2">&lt;210&gt; 152 &lt;211&gt; 132 &lt;212&gt; DNA &lt;213? Homo sapiens</td>

<td> &lt;400&gt;</td><td> 152</td>

acagcacttt cacatgtaag aagggagaaa ttcctaaatg taggagaaag ataacagaac 60 cttccccttt tcatctagtg gtggaaacct gatgctttat gttgacagga atagaaccag 120 gagggagttt gt 132

<td> &lt;210&gt;</td><td> 153</td><td></td>

<td> &lt;211&gt;</td><td> 285</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>_feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (285)</td>

<td> &lt;223&gt;</td><td>n =</td><td>A, T, C or</td>

<td> &lt;400&gt;</td><td> 153</td><td></td>

acaanaccca nganaggcca ctggccgtgg tgtcatggcc tccaaacatg aaagtgtcag 60

PL 200 772 Β1

105 cttccgctct tatgtcctca tctgacaact ctttaccatt tttatcctcg ctcagcagga 120 gcacatcaat aaagtccaaa gtcttggact Łggccttggc ttggaggaag ccatcaacac 180 cctggctagt gagggtgcgg cgccgctcct ggatgacggc atctgtgaag tcgtgcacca 240 gtctgcaggc cctgtggaag cgccgtccac acggagcnag gaatt 285 &lt;210? 154 &lt;211? 333 &lt;212? DNA &lt;213? Homo sapiens &lt;400? 154 accacagtcc tgttgggcca gggcttcatg accctttctg tgaaaagcca tattatcacc 60 accccaaatt tttccttaaa tatctttaac tgaaggggtc agcctctcga ctgcaaagac 120 cctaagccgg ttacacagct aactcccactgg ggccctgact tgtgaaattg ctgctgcctg 180 attggcacag gagtcgaagg tgttcagctc ccctcctccg tggaacgaga ctctgatttg 240 agtttcacaa atcctcgggc cacctcgtca ttgctcgatg cggctcgaaa cctg gtgctcctg 300 gtgctaaaa 155 &lt;211? 308 &lt;212? DNA &lt;213? Homo sapien ^ &lt;220?

&lt;221? misc_feature &lt;222? (1). .. (308) &lt;223? n = A, T, CG &lt;400? 155 actggaaata ataaaaccca catcacagtg tcgtgtcaaa gatcatcagg gcacggatgg 60 gaaagtgctt Cgggaactgt aaagtgccta acacatgatc gatgattttt gttataatat 120 ttgaatcacg gtgcatacaa actctcctgc ctgctcctcc tgggccccag ccccagcccc 180 atcacagctc actgctctgt tcatccaggc ccagcatgta gtggctgatt cttcttggct 240 gcttttagcc tccanaagtt tctctgaagc caaccaaacc tctangtgta aggcatgctg gccctggt 300 308 &lt;210? 156 &lt;211? 295 &lt;212? DNA &lt;213? Homo sapienc &lt;400? 156 accttgctcg gtgcttggaa catatcagga actcaaaata tgagatgata acagtgccta 60 ttattgatta ctgagagaac tgttagacat ttagttgaag attttctaca caggaactga 120 gaataggaga ttatgtttgg ccctcatatt cCctcctatc ctccttgcct cattctatgt 180 ccaatatatt ctcaatcaaa taaggttagc ataatcagga aatcgaccaa ataccaatat 240 aaaaccagat gtctatcctt aagattttca aatagaaaac aaattaacag actat 295

<td colspan="2">&lt;210? 157 &lt;211? 126 &lt;212&gt; DNA &lt;213? Homo sapiens</td>

<td> &lt;400?</td><td> 157</td>

acaagtttaa atagtgctgt cactgtgcat gtgctgaaat gtgaaatcca ccacatttct 60

106

PL 200 772 Β1 gaagagcaaa acaaattctg tcatgtaatc tctatcttgg gtcgtgggta tatctgtccc cttagt

120

126

<td>&lt;2l0&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td>158 442 GOUT Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> ..(442)</td>

<td> &lt;223&gt;</td><td colspan="2">n = a, t, C gap</td>

<td> &lt;400&gt;</td><td> 158</td><td></td>

acccactggt cttggaaaca cccatcctta atacgatgat ttttctgtcg tgtgaaaatg aanccagcag gctgccccta gccagtcctt ccttccagag aaaaagagat ttgagaaagt gcctgggtaa ttcaccatta atttcctccc ccaaactctc tgagtcttcc cttaatattt ctggtggttc tgaccaaagc aggtcaCggt ttgttgagca tttgggatcc cagtgaagta natgtttgta gccttgcata cttagccctt cccacgcaca aacggagtgg cagagtggtg ccaaccctgt tttcccagtc cacgtagaca gattcacagt gcggaattct ggaagctgga nacagacggg ctctttgcag agccgggact ctgagangga catgagggcc tctgcctctg tgttcattct gt ctgatgtcct

120

180

240

300

360

420

442

<td> &lt;210&gt;</td><td> 159</td>

<td> &lt;211&gt;</td><td> 498</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapiens</td>

<td colspan="2"> &lt;220&gt;</td>

<td> &lt;221&gt;</td><td>mi sc_feature</td>

<td> &lt;222&gt;</td><td> (1) . . . (498&gt;</td>

<td> &lt;223&gt;</td><td>n = A, T, C or</td>

<td> &lt;400&gt;</td><td> 159</td>

acttccaggt aacgttgttg tttccgttga gcctgaactg atgggtgacg ttgtaggttc tccaacaaga actgaggttg cagagcgggt agggaagagt gctgttccag ttgcacctgg gctgctgtgg actgttgttg attcctcact acggcccaag gttgtggaac tggcanaaag gtgtgttgtt gganttgagc tcgggcggct gtggtaggtt gtgggctctt caacaggggc tgctgtggtg ccgggangtg aangtgttgt gtcacttgag cttggccagc tctggaaagt antanattct tcctgaaggc cagcgcttgt ggagctggca ngggtcantg ttgtgtgtaa cgaaccagtg ctgctgtggg tgggtgtana tcctccacaa agcctgaagt tatggtgtcn tcaggtaana atgtggtttc agtgtccctg ggcngctgtg gaaggttgta nattgtcacc aagggaataa gctgtggt

120

180

240

300

360

420

480

498

<td> &lt;210&gt;</td><td> 160</td><td></td>

<td> &lt;211&gt;</td><td> 380</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> (380)</td>

<td> &lt;223&gt;</td><td colspan="2">n = A, T, C or</td>

&lt;400&gt; 160

PL 200 772 Β1

107 acctgcatcc agcttccctg ccaaactcac aaggagacat caacctctag acagggaaac 60 agcttcagga tacttccagg agacagagcc accagcagca aaacaaatat tcccatgcct 120 ggagcatggc atagaggaag ctganaaatg tggggtctga ggaagccatt tgagtctggc 180 cactagacat ctcatcagcc acttgtgtga agagatgccc catgacccca gatgcctctc 240 ccacccttac ctccatctca cacacttgag ctttccactc tgtataattc taacatcctg 300 gagaaaaatg gcagtttgac cgaacctgtt cacaacggta gaggctgatt tctaacgaaa 360 cttgtagaat gaagcctgga 380

<td colspan="2">&lt;210&gt; 161 &lt;211&gt; 114 &lt;212&gt; DNA &lt;213&gt; Homo sapien ^</td>

<td> &lt;400&gt;</td><td> 161</td>

actccacatc ccctctgagc aggcggttgt cgttcaaggt gtatttggcc ttgcctgtca 60 cactgtccac tggcccctta tccacttggt gcttaatccc tcgaaagagc atgt 114

<td colspan="2">&lt;210&gt; 162 &lt;211&gt; 177 &lt;212&gt; DNA &lt;213&gt; Homo sapien ^</td>

<td> &lt;400&gt;</td><td> 162</td>

actttctgaa tcgaatcaaa tgatacttag tgtagtttta atatcctcat atatatcaaa 60 gttttactac tctgataatt ttgtaaacca ggtaaccaga acatccagtc at.acagcttt 120 tggtgatata taacttggca ataacccagac ataacccagtacctgata 177

<td> &lt;210»</td><td> 163</td><td></td>

<td> &lt;211»</td><td> 137</td><td></td>

<td> &lt;212»</td><td>GOUT</td><td></td>

<td> &lt;213»</td><td>Homo</td><td>sapienS</td>

<td> &lt;220»</td><td></td><td></td>

<td> &lt;221»</td><td>misc</td><td>feature</td>

<td> &lt;222»</td><td> (1)</td><td>Γ. (137)</td>

<td> &lt;223»</td><td>n = j</td><td>4, T, C or</td>

<td> &lt;400»</td><td> 163</td><td></td>

catttataca gacaggcgtg aagacattca cgacaaaaac gcgaaattct atcccgtgac 60 canagaaggc agctacggct actcctacat cctggcgtgg gtggccttcg cctgcacctt 120 catcagcggc atgatgt &lt;211&gt; &lt;21013 &lt;Homap&gt; 164&gt; &lt;212&gt; &lt;21013 DNA&gt;

&lt;221 »misc_feature &lt;222» (1). . . (469) &lt;223&gt; n = A, T, CU »G &lt;400» 164 cttatcacaa tgaatgttct cctgggcagc gttgtgatct ttgccacctt cgtgacttta 60 tgcaatgcat catgctattt catacctaat gagggagttc caggagatta 120

108

GB 200 772 Β1 tgcatggatc tcaaaggaaa caaacaccca ataaactcgg agtggcagac tgacaactgt 180 gagacatgca cttgctacga aacagaaatt tcatgttgca cccttgtttc tacacctgtg 240 ggttatgaca aagacaactg ccaaagaatc ttcaagaagg aggactgcaa gtatatcgtg 300 gtggagaaga aggacccaaa aaagacctgt tctgtcagtg aatggataat ctaatgtgct 360 tctagtaggc acagggctcc caggccaggc ctcattctcc tctggcctct aatagtcaat 420 gattgtgtag ccatgcctat cagtaaaaag atntttgagc aaacacttt 469 &lt;210&gt; 165 &lt; 211? 195 &lt;212? DNA &lt;213? Homo puffers &lt;220&gt;

&lt;221&gt; misc_feature &lt;222? (1) ... (195) &lt;223&gt; n = A, T, C, G lab &lt;400&gt; 165 acagtttttt atanacatcg acattgccgg cacttgtgtt cagtttcata aagctggtgg 60 atccgctgtc atccactatt ccttggctag agtaaaaatt attcttatag cccatgtccc 120 tgcaggccgc ccgcccgtag ttctcgttcc agtcgtcttg gcacacaggg tgccaggact 180 tcctctgaga tgagt 195 &lt; 210? 166 &lt;211&gt; 383 &lt;212? DNA &lt;213&gt; Homo sapiens &lt;220?

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (383) &lt;223&gt; n = A, T, C or G &lt;400&gt; 166 acatcttagt agtgtggcac atcagggggc catcagggtc acagtcactc atagcctcgc 60 cgaggtcgga gtccacacca ccggtgtagg tgtgctcaat cttgggcttg gcgcccacct 120 ttggagaagg gatatgctgc acacacatgt ccacaaagcc tgtgaactcg ccaaagaatt 180 tttgcagacc agcctgagca aggggcggat gttcagcttc agctcctcct tcgtcaggtg 240 gatgccaacc tcgtctangg tccgtgggaa gctggtgtcc acntcaccta cccgggata agcta cagggata agcta cagggata agcta cagggata agcta 300 ttggtgaact ttc 383

<td> &lt;210&gt;</td><td> 167</td><td></td>

<td> &lt;211&gt;</td><td> 247</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213?</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td>(ll</td><td> ..(247)</td>

<td> &lt;223?</td><td>n =.</td><td>A, T, C or</td>

<td> &lt;400?</td><td> 167</td><td></td>

acagagccag accttggcca taaatgaanc agagattaag actaaacccc aagtcganat 60 tggagcagaa actggagcaa gaagtgggcc tggggctgaa gtagagacca aggccactgc 120

PL 200 772 Β1

109 tatanccata cacagagcca actctcaggc caaggcnatg gttggggcag anccagagac 180 tcaatctgan tccaaagtgg tggctggaac actggtcatg acanaggcag tgactctgac 240 tgangtc 247 &lt;210&gt; 168 &lt;211&gt; 273 &lt;132&gt; Homo &lt;211&gt; DNA &lt;132&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (273) &lt;223&gt; n = A, T, C / UB G &lt;400&gt; 168 actcctaagt tttctagaag tggaaggatt gtantcatcc tgaaaatggg tttacttcaa 60 aatccctcan ccttgttctt cacnactgtc tatactgana gtgtcatgtt tccacaaagg 120 gctgacacct gagcctgnat tttcactcat ccctgagaag ccctttccag tagggtgggc 180 aattcccaac ttccttgcca caagcttccc aggctttctc ccctggaaaa ctccagcttg 240 agtcccagat acactcatgg gctgccctgg gca 273 &lt;210&gt; 169 &lt;211&gt; 431 &lt;212&gt; DNA &lt;213&gt; Homo sapienS &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (431) &lt;223&gt; n = A, T, C or G &lt;400&gt; 169 acagccttgg cttccccaaa ctccacagtc tcagtgcaga aagatcatct tccagcagtc 60 agctcagacc agggtcaaagacggtcagaagacggtcagaagacggtcagaagacgtcagaaagacgtgctaagacggtcagaagacgtcagcatgacgtcagaaagacgtcagaaagacgtgcaga gtaagttttg cacaggtgag 180 ggcagcagaa agggggtant tactgatgga caccatcttc tctgtatact ccacactgac 240 cttgccatgg gcaaaggccc ctaccacaaa aacaatagga tcactgctgg gcaccacaacgacatca gcaccacaacgaca 300 actggctaacta gcaccacaacgacca 300 actgcacaacgaacta gatactggat tcttaattac cttcaaaagc ttctgggggc catcagctgc 420 tcgaacactg a 431

<td> &lt;210&gt;</td><td> 170</td><td></td><td></td><td></td><td></td>

<td> &lt;211&gt;</td><td> 266</td><td></td><td></td><td></td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td><td></td><td></td><td></td>

<td> &lt;213&gt;</td><td>Homo sapiens</td><td></td><td></td><td></td><td></td>

<td>c220&gt;</td><td></td><td></td><td></td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc_feature</td><td></td><td></td><td></td><td></td>

<td> &lt;222&gt;</td><td> (1)...(266)</td><td></td><td></td><td></td><td></td>

<td> &lt;223&gt;</td><td>n = A, T, C ΙΐΛ G</td><td></td><td></td><td></td><td></td>

<td> &lt;400&gt;</td><td> 170</td><td></td><td></td><td></td><td></td>

<td>acctgtgggc</td><td>tgggctgtta tgcctgtgcc</td><td>ggctgctgaa</td><td>agggagttca</td><td>gaggtggagc</td><td> 60</td>

<td>tcaaggagct</td><td>ctgcaggcat tttgccaanc</td><td>ctctccanag</td><td>canagggagc</td><td>aacctacact</td><td> 120</td>

<td>ccccgccaga</td><td>aagacaccag attggagtcc</td><td>cgggaggggg</td><td>agttggggtg</td><td>ggcatttgat</td><td> 180</td>

110

PL 200 772 Β1 gtatacttgt cacctgaatg aangagccag agaggaanga gacgaanatg anattggcct tcaaagctag gggtctggca ggtgga

<td> &lt;210?</td><td> 171</td>

<td> &lt;211?</td><td> 1248</td>

<td> &lt;212?</td><td>GOUT</td>

<td> &lt;213?</td><td>Homo gasps</td>

<td> &lt;220?</td><td></td>

<td> &lt;221?</td><td>misc feature</td>

<td> &lt;222?</td><td> (1) . . . (1248)</td>

<td> &lt;223?</td><td>n = A, T, C or</td>

<td> &lt;400?</td><td> 171</td>

ggcagccaaa tcataaacgg cgaggactgc agcccgcact cgcagccctg gcaggcggca ctggtcatgg aaaacgaatt gttctgctcg ggcgtcctgg tgcatccgca gtgggtgctg tcagccgcac actgtttcca gaagtgagtg cagagctcct acaccatcgg gctgggcctg cacagtcttg aggccgacca agagccaggg agccagatgg tggaggccag cctctccgta cggcacccag agtacaacag acccttgctc gctaacgacc tcatgctcat caagttggac gaatccgtgt ccgagtctga caccatccgg agcatcagca ttgcttcgca gtgccctacc gcggggaact cttgcctcgt ttctggctgg ggtctgctgg cgaacggcag aatgcctacc gtgctgcagt gcgtgaacgt gtcggtggtg tctgaggagg tctgcagtaa gctctatgac ccgccgtacc accccagcat gttctgcgcc ggcggagggc aagaccagaa ggactcctgc aacggtgact ctggggggcc cctgatctgc aacgggcact tgcagggcct tgtgtctttc ggaaaagccc cgtgtggcca agttggcgtg ccaggtgtct acaccaacct ctgcaaattc actgagtgga tagagaaaac cgtccaggcc agttaactct ggggactggg aacccatgaa attgaccccc aaatacatcc tgcggaagga attcaggaat atctgttccc agcccctcct ccctcaggcc caggagtcca ggcccccagc ccctcctccc tcaaaccaag ggtacagatc cccagcccct cctccctcag acccaggagt ccagaccccc cagcccctcc tccctcagac ccaggagtcc agcccctcct ccctcagacc caggagtcca gaccccccag cccctcctcc ctcagaccca ggggtccagg cccccaaccc ctcctccctc agactcagag gtccaagccc ccaacccntc attccccaga cccagaggtc caggtcccag cccctcntcc ctcagaccca gcggtccaat gccacctaga ctntccctgt acacagtgcc cccttgtggc acgttgaccc aaccttacca gttggttttt catttttngt ccctttcccc tagatccaga aataaagttt aagagaagng caaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaa &lt;210? 172 &lt;211&gt; 159 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;220?

&lt;221? VARIANT &lt;222&gt; (1) ... (159) &lt;223&gt; Xaa = any amino acid &lt;400&gt; 172

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<td>Underworld 1</td><td>Val</td><td>Glu</td><td>Ala</td><td>Cheese 5</td><td>Leu</td><td>Cheese</td><td>Val</td><td>Arg</td><td>His 10</td><td>Pro</td><td>Glu</td><td>Tyr</td><td>Asn</td><td>Arg 15</td><td>Pro</td>

<td>Leu</td><td>Leu</td><td>Ala</td><td>Asn</td><td>Asp</td><td>Leu</td><td>Underworld</td><td>Leu</td><td>How much</td><td>Lys</td><td>Leu</td><td>Asp</td><td>Glu</td><td>Cheese</td><td>Val</td><td>Cheese</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td>Glu</td><td>Cheese</td><td>Asp</td><td>Thr</td><td>How much</td><td>Arg</td><td>Cheese</td><td>How much</td><td>Cheese</td><td>How much</td><td>Ala</td><td>Cheese</td><td>Main</td><td>Cys</td><td>Pro</td><td>Thr</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td>Ala</td><td>Gly</td><td>Asn</td><td>Cheese</td><td>Cys</td><td>Leu</td><td>Val</td><td>Cheese</td><td>Gly</td><td>Trp</td><td>Gly</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Asn</td><td>Gly</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

PL 200 772 Β1

111

Arg Met Pro Thr Val Leu Gin Cys Val Asn Val Ser Val Val Ser Glu

70 75 80

Glu Val Cys Ser Lys Leu Tyr Asp Pro Leu Tyr His Pro Ser Met Phe

90 95

Cys Ala Gly Gly Gly Gin Xaa Gin Xaa Asp Ser Cys Asn Gly Asp Ser 100 105 110

Gly Gly Pro Leu Ile Cys Asn Gly Tyr Leu Gin Gly Leu Val Ser Phe 115 120 125

Gly Lys Ala Pro Cys Gly Gin Val Gly Val Pro Gly Val Tyr Thr Asn 130 135 140

Leu Cys Lys Phe Thr Glu Trp Ile Glu Lys Thr Val Gin Ala Ser

145 150 155 &lt;210&gt; 173 &lt;211&gt; 1265 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;22l&gt; misc_feature &lt;222&gt; (1). . . (1265) &lt;223&gt; n = A, T, C, the gaps G &lt;400&gt; 173 ggcagcccgc actcgcagcc ctggcaggcg gcactggtca tggaaaacga attgttctgc 60 tcgggcgtcc tggtgcatcc gcagtgggtg ctgtcagccg cacactgttt ccagaactcc 120 tacaccatcg ggctgggcct gcacagtctt gaggccgacc aagagccagg gagccagatg 180 gtggaggcca gcctctccgt acggcaccca gagtacaaca gacccttgct cgctaacgac 240 ctcatgctca tcaagttgga cgaatccgtg tccgagtctg acaccatccg gagcatcagc 300 attgcttcgc agtgccctac cgcggggaac tcttgcctcg cttctggctg gggtctgctg 360 gcgaacggtg agctcacggg tgtgtgtctg ccctcttcaa ggaggtcctc tgcccagtcg 420 ^c99999^ctga cccagagctc tgcgtcccag gcagaatgcc taccgtgctg cagtgcgtga 480 acgtgtcggt ggtgtctgag gaggtctgca gtaagctcta tgacccgctg taccacccca 540 gcatgttctg cgccggcgga gggcaagacc agaaggactc ctgcaacggt gactctgggg 600 ggcccctgat ctgcaacggg tacttgcagg gccttgtgtc tttcggaaaa gccccgtgtg 660 gccaagttgg cgtgccaggt gtctacacca acctctgcaa attcactgag tggatagaga 720 aaaccgtcca ggccagttaa ctctggggac tgggaaccca tgaaattgac ccccaaatac 780 atcctgcgga aggaattcag gaatatctgt tcccagcccc tcctccctca ggcccaggag 840 tccaggcccc cagcccctcc tccctcaaac caagggtaca gatccccagc ccctcctccc 900 tcagacccag gagtccagac cccccagccc ctcctccctc agacccagga gtccagcccc 960 tcctccntca gacccaggag tccagacccc ccagcccctc ctccctcaga cccaggggtt 1020 gaggccccca acccctcctc cttcagagtc agaggtccaa gcccccaacc cctcgttccc 1080 cagacccaga ggtnnaggtc ccagcccctc ttccntcaga cccagnggtc caatgccacc 1140 tagattttcc ctgnacacag tgcccccttg tggnangttg acccaacctt accagttggt 1200 ttttcatttt tngtcccttt cccctagatc cagaaataaa gtttaagaga ngngcaaaaa 1260 AAAAA 1265 &lt;210&gt; 174 &lt;211&gt; 1459 &lt;212&gt; DNA &lt;213&gt; Homo sapien $ &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (1459)

112

GB 200 772 Β1 &lt;223&gt; η = A, T, C | t "b G &lt;400&gt; 174 ggtcagccgc acactgtttc cagaagtgag tgcagagctc ctacaccatc gggctgggcc tgcacagtct tgaggccgac caagagccag ggagccagat ggtggaggcc agcctctccg tacggcaccc agagtacaac agacccttgc tcgctaacga cctcatgctc atcaagttgg acgaatccgt gtccgagtct gacaccatcc ggagcatcag cattgcttcg cagtgcccta ccgcggggaa ctcttgcctc gtttctggct ggggtctgct ggcgaacggt gagctcacgg gtgtgtgtct gccctcttca aggaggtcct ctgcccagtc gcgggggctg acccagagct ctgcgtccca ggcagaatgc ctaccgtgct gcagtgtgtgc agaccgtgtg tggtgtctga ngaggtctgc antaagctct atgacccgct gtaccacccc ancatgttct gcgccggcgg agggcaagac cagaaggact cctgcaacgt gagagagggg aaaggggagg gcaggcgact cagggaaggg tggagaaggg ggagacagag acacacaggg ccgcatggcg agatgcagag atggagagac acacagggag acagtgacaa ctagagagag aaactgagag aaacagagaa ataaacacag gaataaagag aagcaaagga agagagaaac agaaacagac atggggaggc agaaacacac acacatagaa atgcagttga ccttccaaca gcatggggcc tgagggcggt gacctccacc caatagaaaa tcctcttata acttttgact ccccaaaaac ctgactagaa atagcctact gttgacgggg agccttacca ataacataaa tagtcgattt atgcatacgt tttatgcatt catgatatac ctttgttgga attttttgat atttctaagc tacacagttc gtctgtgaat ttttttaaat cgttgcaact ctcctaaaat ttttctgatg tgtttattga aaaaatccaa gtataagtgg acttgtgcat tcaaaccagg gttgttcaag ggtcaactgt gtacccagag ggaaacagtg acacagattc atagaggtga aacacgaaga gaaacaggaa aaatcaagac tctacaaaga ggctgggcag ggtggctcat gcctgtaatc ccagcacttt gggaggcgag gcaggcagat cacttgaggt aaggagttca agaccagcct ggccaaaatg gtgaaatccc gtctgtacta aaaatacaaa agttagctgg atatggtggc aggcgcctgt aatcccagct acttgggagg ctgaggcagg agaattgctt gaacatggga ggcagaggtt gaagtgagtt gagatcacac cactatactc cagctggggc aacagagtaa gactctgtct caaaaaaaaa aaaa

<td> &lt;210&gt;</td><td> 175</td><td></td>

<td> &lt;211&gt;</td><td> 1167</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapien S</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>_feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> ..(1167)</td>

<td> &lt;223&gt;</td><td colspan="2">n = A, T, C</td>

<td> &lt;400&gt;</td><td> 175</td><td></td>

gcgcagccct ggcaggcggc actggtcatg gaaaacgaat tgttctgctc gggcgtcctg gtgcatccgc agtgggtgct gtcagccgca cactgtttcc agaactccta caccatcggg ctgggcctgc acagtcttga ggccgaccaa gagccaggga gccagatggt ggaggccagc ctctccgtac ggcacccaga gtacaacaga ctcttgctcg ctaacgacct catgctcatc aagttggacg aatccgtgtc cgagtctgac accatccgga gcatcagcat tgcttcgcag tgccctaccg cggggaactc ttgcctcgtn tctggctggg gtctgctggc gaacggcaga atgcctaccg tgctgcactg cgtgaacgtg tcggtggtgt ctgaggangt ctgcagtaag ctctatgacc cgctgtacca ccccagcatg ttctgcgccg gcggagggca agaccagaag gactcctgca acggtgactc tggggggccc ctgatctgca acgggtactt gcagggcctt gtgtctttcg gaaaagcccc gtgtggccaa cttggcgtgc caggtgtcta caccaacctc tgcaaattca ctgagtggat agagaaaacc gtccagncca gttaactctg gggactggga acccatgaaa ttgaccccca aatacatcct gcggaangaa ttcaggaata tctgttccca gcccctcctc cctcaggccc aggagtccag gcccccagcc cctcctccct caaaccaagg gtacagatcc ccagcccctc ctccctcaga cccaggagtc cagacccccc agcccctcnt ccntcagacc caggagtcca gcccctcctc cntcagacgc aggagtccag accccccagc

120

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1459

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840

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PL 200 772 Β1

113 ccntcntccg tcagacccag gggtgcaggc ccccaacccc tcntccntca gagtcagagg tccaagcccc caacccctcg ttccccagac ccagaggtnc aggtcccagc ccctcctccc tcagacccag cggtccaatg ccacctagan tntccctgta cacagtgccc ccttgtggca ngttgaccca accttaccag ttggtttttc attttttgtc cctttcccct agatccagaa ataaagtnta agagaagcgc aaaaaaa &lt;210&gt; 176 &lt;211&gt; 205 &lt;212&gt; PRT &lt;213&gt; Homo sapien5 &lt;220&gt;

&lt;221&gt; VARIANT &lt;222&gt; (1) ... (205) &lt;223&gt; Xaa = any amino acid &lt;400&gt; 176

<td>Underworld</td><td>Glu</td><td>Asn</td><td>Glu</td><td>Leu</td><td>Phe</td><td>Cys</td><td>Cheese</td><td>Gly</td><td>Val</td><td>Leu</td><td>Val</td><td>His</td><td>Pro</td><td>Main</td><td>Trp</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td>Val</td><td>Leu</td><td>Cheese</td><td>Ala</td><td>Ala</td><td>His</td><td>Cys</td><td>Phe</td><td>Main</td><td>Asn</td><td>Cheese</td><td>Tyr</td><td>Thr</td><td>How much</td><td>Gly</td><td>Leu</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td>Gly</td><td>Leu</td><td>His</td><td>Cheese</td><td>Leu</td><td>Glu</td><td>Ala</td><td>Asp</td><td>Main</td><td>Glu</td><td>Pro</td><td>Gly</td><td>Cheese</td><td>Main</td><td>Underworld</td><td>Val</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td>Glu</td><td>Ala</td><td>Cheese</td><td>Leu</td><td>Cheese</td><td>Val</td><td>Arg</td><td>His</td><td>Pro</td><td>Glu</td><td>Tyr</td><td>Asn</td><td>Arg</td><td>Leu</td><td>Leu</td><td>Leu</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td>Ala</td><td>Asn</td><td>Asp</td><td>Leu</td><td>Underworld</td><td>Leu</td><td>How much</td><td>Lys</td><td>Leu</td><td>Asp</td><td>Glu</td><td>Cheese</td><td>Val</td><td>Cheese</td><td>Glu</td><td>Cheese</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td>Asp</td><td>Thr</td><td>How much</td><td>Arg</td><td>Cheese</td><td>How much</td><td>Cheese</td><td>How much</td><td>Ala</td><td>Cheese</td><td>Main</td><td>Cys</td><td>Pro</td><td>Thr</td><td>Ala</td><td>Gly</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td>Asn</td><td>Cheese</td><td>Cys</td><td>Leu</td><td>Val</td><td>Cheese</td><td>Gly</td><td>Trp</td><td>Gly</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Asn</td><td>Gly</td><td>Arg</td><td>Underworld</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td>Pro</td><td>Thr</td><td>Val</td><td>Leu</td><td>His</td><td>Cys</td><td>Val</td><td>Asn</td><td>Val</td><td>Cheese</td><td>Val</td><td>Val</td><td>Cheese</td><td>Glu</td><td>Xaa</td><td>Val</td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<td>Cys</td><td>Cheese</td><td>Lys</td><td>Leu</td><td>Tyr</td><td>Asp</td><td>Pro</td><td>Leu</td><td>Tyr</td><td>His</td><td>Pro</td><td>Cheese</td><td>Underworld</td><td>Phe</td><td>Cys</td><td>Ala</td>

<td></td><td> 130</td><td></td><td></td><td></td><td></td><td> 135</td><td></td><td></td><td></td><td></td><td> 140</td><td></td><td></td><td></td><td></td>

<td>Gly</td><td>Gly</td><td>Gly</td><td>Main</td><td>Asp</td><td>Main</td><td>Lys</td><td>Asp</td><td>Cheese</td><td>Cys</td><td>Asn</td><td>Gly</td><td>Asp</td><td>Cheese</td><td>Gly</td><td>Gly</td>

<td> 145</td><td></td><td></td><td></td><td></td><td> 150</td><td></td><td></td><td></td><td></td><td> 155</td><td></td><td></td><td></td><td></td><td> 160</td>

<td>Pro</td><td>Leu</td><td>How much</td><td>Cys</td><td>Asn</td><td>Gly</td><td>Tyr</td><td>Leu</td><td>Main</td><td>Gly</td><td>Leu</td><td>Val</td><td>Cheese</td><td>Phe</td><td>Gly</td><td>Lys</td>

<td></td><td></td><td></td><td></td><td> 165</td><td></td><td></td><td></td><td></td><td> 170</td><td></td><td></td><td></td><td></td><td> 175</td><td></td>

<td>Ala</td><td>Pro</td><td>Cys</td><td>Gly</td><td>Main</td><td>Leu</td><td>Gly</td><td>Val</td><td>Pro</td><td>Gly</td><td>Val</td><td>Tyr</td><td>Thr</td><td>Asn</td><td>Leu</td><td>Cys</td>

<td></td><td></td><td></td><td>1B0</td><td></td><td></td><td></td><td></td><td> 185</td><td></td><td></td><td></td><td></td><td> 190</td><td></td><td></td>

<td>Lys</td><td>Phe</td><td>Thr</td><td>Glu</td><td>Trp</td><td>How much</td><td>Glu</td><td>Lys</td><td>Thr</td><td>Val</td><td>Main</td><td>Xaa</td><td>Cheese</td><td></td><td></td><td></td>

<td></td><td></td><td> 195</td><td></td><td></td><td></td><td></td><td> 200</td><td></td><td></td><td></td><td></td><td> 205</td><td></td><td></td><td></td>

&lt;210&gt; 177 &lt;211&gt; 1119 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 177 gcgcactcgc agccctggca ggcggcactg gtcatggaaa acgaattgtt ctgctcgggc gtcctggtgc atccgcagtg ggtgctgtca gccgcacact gtttccagaa ctcctacacc atcgggctgg gcctgcacag tcttgaggcc gaccaagagc cagggagcca gatggtggag gccagcctct ccgtacggca cccagagtac aacagaccct tgctcgctaa cgacctcatg ctcatcaagt tggacgaatc cgtgtccgag tctgacacca tccggagcat cagcattgct

960

1020

1080

1140

1167

120

180

240

300

114

GB 200 772 B1 tcgcagtgcc ctaccgcggg gaactcttgc ctcgtttctg gctggggtct gctggcgaac 360 gatgctgtga ttgccatcca gtcccagact gtgggaggct gggagtgtga gaagctttcc 420 caaccctggc agggttgtac catttcggca acttccagtg caaggacgtc ctgctgcatc 480 ctcactgggt gctcactact gctcactgca tcacccggaa cactgtgatc aactagccag 54 0 caccatagtt ctccgaagtc agactatcat gattactgtg ttgactgtgc tgtctattgt 600 actaaccatg ccgatgttta ggtgaaatta gcgtcacttg gcctcaacca tcttggtatc 660 cagttatcct cactgaattg agatttcctg cttcagtgtc agccattccc acataatttc 720 tgacctacag aggtgaggga tcatatagct cttcaaggat gctggtactc ccctcacaaa 780 ttcatttctc ctgttgtagt gaaaggtgcg ccctctggag cctcccaggg tgggtgtgca 840 ggtcacaatg atgaatgtat gatcgtgttc ccattaccca aagcctttaa atccctcatg 900 ctcagtacac cagggcaggt ctagcatttc ttcatttagt gtatgctgtc cattcatgca 960 accacctcag gactcctgga ttctctgcct agttgagctc ctgcatgctg cctccttggg 1020 gaggtgaggg agagggccca tggttcaatg ggatctgtgc agttgtaaca cattaggtgc 1080 ttaataaaca gaagctgtga tgttaaaaaa aaaaaaaaa 1119 &lt; 210&gt; 178 &lt;211&gt; 164 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; VARIANT &lt;222&gt; (1) ... 1664) &lt;223&gt; Xaa = any amino acid &lt;400&gt; 178

Met Glu Asn Glu Leu Phe Cys Ser Gly Val Leu Val His Pro Gin Trp 1 5 10 15

Val Leu Ser Ala Ala His Cys Phe Gin Asn Ser Tyr Thr Ile Gly Leu 20 25 30

Gly Leu His Ser Leu Glu Ala Asp Gin Glu Pro Gly Ser Gin Met Val 35 40 45

Glu Ala Ser Leu Ser Val Arg His Pro Glu Tyr Asn Arg Pro Leu Leu 50 55 60

Ala Asn Asp Leu Met Leu Ile Lys Leu Asp Glu Ser Val Ser Glu Ser

70 75 80

Asp Thr Ile Arg Ser Ile Ser Ile Ala Ser Gin Cys Pro Thr Ala Gly

90 95

Asn Ser Cys Leu Val Ser Gly Trp Gly Leu Leu Ala Asn Asp Ala Val 100 105 110

Ile Ala Ile Gin Cheese Xaa Thr Val Gly Gly Trp Glu Cys Glu Lys Leu 115 120 125

Ser Gin Pro Trp Gin Gly Cys Thr Ile Ser Ala Thr Ser Ser Ala Arg 130 135 140

Thr Ser Cys Cys Ile Leu Thr Gly Cys Ser Leu Leu Leu Thr Ala Ser

145 . 150 155 160

Pro Gly Thr Leu &lt;210&gt; 179 &lt;211&gt; 250 &lt;212&gt; DNA &lt;213&gt; Homo sapien £ &lt;400&gt; 179

PL 200 772 Β1

115 ctggagtgcc ttggtgtttc aagcccctgc aggaagcaga atgcaccttc tgaggcacct 60 ccagctgccc ccggccgggg gatgcgaggc tcggagcacc cttgcccggc tgtgattgct 120 gccaggcact gttcatctca gcttttctgt ccctttgctc ccggcaagcg cttctgctga 180 aagttcacat ctggagcctg atgtcttaac gaataaaggt cccatgctcc acccgaaaaa 240 aaaaaaaaaa 250

<td> &lt;210&gt;</td><td> 180</td>

<td> &lt;211&gt;</td><td> 202</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapien S.</td>

<td> &lt;400&gt;</td><td> 180</td>

actagtccag tgtggtggaa ttccatCgtg ttgggcccaa cacaatggct acctttaaca 60 tcacccagac cccgcccctg cccgtgcccc acgctgctgc taacgacagt atgatgcta 120 ctctgcta cttattaacta ttata 180 ctctgcta cttattgtaa

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td>181 558 GOUT Homo</td><td>sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc__</td><td>feature</td>

<td> &lt;222&gt;</td><td>and clay</td><td> (558)</td>

<td> &lt;223&gt;</td><td colspan="2">n = A, T, C or b</td>

<td> &lt;400&gt;</td><td> 181</td><td></td>

tccytttgkt naggtttkkg agacamccck agacctwaan ctgtgtcaca gacttcyngg. 60 aatgtttagg cagtgctagt aatttcytcg taatgattct gttattactt tcctnattct 120 ttattcctct ttcttctgaa gattaatgaa gttgaaaatt gaggtggata aatacaaaaa 180 ggtagtgtga tagtataagt atctaagtgc agatgaaagt gtgttatata tatccattca 240 aaattatgca agttagtaat tactcagggt taactaaatt actttaatat gctgttgaac 300 ctactctgtt ccttggctag aaaaaattat aaacaggact ttgttagttt gggaagccaa 360 attgataata ttctatgttc taaaagttgg gctatacata aattattaag aaatatggaw 420 ttttattccc aggaatatgg kgttcatttt atgaatatta cscrggatag awgtwtgagt 480 aaaaycagtt ttggtwaata ygtwaatatg tcmtaaataa acaakgcttt gacttatttc 540 caaaaaaaaa aaaaaaaa 558

<td> &lt;210&gt;</td><td> 182</td><td></td>

<td> &lt;211&gt;</td><td> 479</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapien S</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>_feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> 7.(479)</td>

<td> &lt;223&gt;</td><td>n -,</td><td>ATC hatch</td>

<td> &lt;400&gt;</td><td> 182</td><td></td>

acagggwttk grggatgcta agsccccrga rwtygtttga tccaaccctg gcttwttttc 60 agaggggaaa atggggccta gaagttacag mscatytagy tggtgcgmtg gcacccctgg 120 cstcacacag astcccgagt agctgggact acaggcacac agtcactgaa gcaggccctg 180 ttwgcaattc acgttgccac ctccaactta aacattcttc atatgtgatg tccttagtca 240 ctaaggttaa actttcccac ccagaaaagg caacttagat aaaatcttag agtactttca 300

116

PL 200 772 Β1 tactmttcta agtcctcttc cagcctcact kkgagtcctm cytgggggtt gataggaant 360 ntctcttggc tttctcaata aartctctat ycatctcatg tttaatttgg tacgcatara 420 awtgstgara aattattaataaaaaaaaaaaaaa9 183 &lt;211? 384 &lt;212? DNA &lt;213? Homo sapienc, &lt;400? 183 aggcgggagc agaagctaaa gccaaagccc aagaagagtg gcagtgccag cactggtgcc 60 agtaccagta ccaataacag tgccagtgcc agtgccagca ccagtggtgg cttcagtgct 120 ggtgccagcc tgaccgccac tctcacattt gggctcttcg ctggccttgg tggagctggt 180 gccagcacca gtggcagctc tggtgcctgt ggtttctcct acaagtgaga ttttagatat 240 tgttaatcct gccagtcttt ctcttcaagc cagggtgcat cctcagaaac ctactcaaca 300 cagcactcta ggcagccact atcaatcaat tgaagttgac actctgcatt aratctattt 360 gccatttcaa aaaaaaaaaa aaaa 384

<td>&lt;21O&gt;</td><td> 184</td><td></td>

<td> &lt;211&gt;</td><td> 496</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td>&lt;2ł3&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> ..(496)</td>

<td> &lt;223&gt;</td><td colspan="2">n = A, T, C or</td>

<td> &lt;400&gt;</td><td> 184</td><td></td>

accgaattgg gaccgctggc ttataagcga tcatgtyynt ccrgtatkac ctcaacgagc 60 agggagatcg agtctatacg ctgaagaaat ttgacccgat gggacaacag acctgctcag 120 cccatcctgc tcggttctcc ccagatgaca aatactctsg acaccgaatc accatcaaga 180 aacgcttcaa ggtgctcatg acccagcaac cgcgccctgt cctctgaggg tcccttaaac 240 tgatgtcttt tctgccacct gttacccctc ggagactccg taaccaaact cttcggactg 300 tgagccctga tgcctttttg ccagccatac tctttggcat ccagtctctc gtggcgattg 360 attatgcttg tgtgaggcaa tcatggtggc atcacccata aagggaacac atttgacttt 420 tttttctcat actttaaatt actacmagaw tattwmagaw waaatgawtt gaaaaactst 480 taaaaaaaaa aaaaaa 496 &lt;210? 185 &lt;211? 384 &lt;212? DNA &lt;213? Homo sapiens &lt;400? 185 gctggtagcc tatggcgkgg cccacggagg ggctcctgag gccacggrac agtgacttcc 60 caagtatcyt gcgcsgcgtc ttctaccgtc cctacctgca gatcttcggg cagattcccc 120 aggaggacat ggacgtggcc ctcatggagc acagcaactg ytcgtcggag cccggcttct 180 gggcacaccc tcctggggcc caggcgggca cctgcgtctc ccagtatgcc aactggctgg 240 tggtgctgct cctcgtcatc ttcctgctcg tggccaacat cctgctggtc aacttgctca 300 ttgccatgtt cagttacaca ttcggcaaag tacagggcaa cagcgatctc tactgggaag 360 gcgcagcgtt accgcctcat ccgg 384 &lt;210? 186 &lt;211? 577

PL 200 772 Β1

117 &lt;212? DNA &lt;213? Homo sapiens &lt;220?

&lt;221? misc_feature &lt;222? (1). . . (577) &lt;223? n = A, T, C, or G &lt;400? 136 gagttagctc ctccacaacc tcgatgaggt cgtctgcagt ggcctctcgc ttcataccgc 60 tnccatcgtc atactgtagg tttgccacca cytcctggca tcttggggcg gcntaatatt 120 ccaggaaact ctcaatcaag tcaccgtcga tgaaacctgt gggctggttc tgtcttccgc 180 tcggtgtgaa aggatctccc agaaggagtg ctcgatcttc cccacacttt tgatgacttt 240 attgagtcga ttctgcatgt ccagcaggag gttgtaccag ctctctgaca gtgaggtcac 300 cagccctatc atgccgttga mcgtgccgaa garcaccgag ccttgtgtgg gggkkgaagt 360 ctcacccaga ttctgcatta ccagagagcc gtggcaaaag acattgacaa actcgcccag 420 gtggaaaaag amcamctcct ggargtgctn gccgctcctc gtcmgttggt ggcagcgctw 480 tccttttgac acacaaacaa gttaaaggca ttttcagccc ccagaaanttaggatgctc 540? 187 &lt;211? 534 &lt;212? DNA &lt;213? Homo sapiens &lt;220?

&lt;221? misc_feature &lt;222? (1). . . (534) &lt;223 n = A, T, C. ^ G &lt;400 187 aacatcttcc tgtacaatgc tgtgtaatat cgatccgatn ttgtctgstg agaatycatw 60 actkggaaaa gmaacattaa agcctggaca ctggtattaa aattcacaat atgcaacact 120 ttaaacagtg tgtcaatctg ctcccyynac tttgtcatca ccagtctggg aakaagggta 180 tgccctattc acacctgtta aaagggcgct aagcattttt gattcaacat cttttttttt 240 gacacaagtc cgaaaaaagc aaaagtaaac agttatyaat ttgttagcca attcactttc 300 ttcatgggac agagccatyt gatttaaaaa gcaaattgca taatattgag cttygggagc 360 tgatatttga gcggaagagt agcctttcta cttcaccaga cacaactccc tttcatattg 420 ggatgctnac naaagtwatg tctctwacag atgggatgct tttgtggcaa ttctgttctg 480 aggatctccc agtttattta ccacttgcac aagaaggcgt tttcttcctc aggc 534 &lt;210? 188 &lt;211? 761 &lt;212? DNA &lt;213? Homo wheezing &lt;220?

&lt;221? misc_feature &lt;222? (1) ... (761) &lt;223&gt; n = A, T, CG &lt;400&gt; 188 agaaaccagt atctctnaaa acaacctctc ataccttgtg gacctaattt tgtgtgcgtg 60 tgtgtgtgcg cgtgtat 180tgtcaccttttgatgatgtgctcaccttttgatggacaggc acttatttga cgtgtgat atagacaggc acttatttga

118

GB 200 772 B1 ttgtcttctg tttattcgac ggggacaaag acagaaatwr gcaaaaaaca cttgcccttc ctgactcata atgcttaatt tttttccgtn gaaaataata tgtaaatcct atgaacgaaa aaaagcaaaa cgtagtatat tgtacncact attacatctt aagctctaca cacaaatcct ttcccagagc acattgaaga actagagaaa ttŁccagatn ctgamcataa tgaarnacac tcccgttgac tnaaagtggt aataagcagt aatttcatta tgagatntta aaaananaaa acacctatnt acaacactna raaacaatwa catcattaaa taatgccaag gtgctgggcc gtgcctaaca taaatgtttc cattttatct aaanaaaaaa tatgactcaa caaactctcc cctccęgaca rmgctwtktt ttcttttttt aaaatattga accaacacac ctaaaataca actatnaact a

tctacttnct ctkcaekarc arttgcataa wttctccctt tatnataaaa aatcatgcaa taatcttgac ctttgaacta caaaaantac

240

300

360

420

460

540

600

660

720

761 tttttttttt caccggggct aagccgcctg aaggcagggc tgataggcac ctcattgtgc aaatttgcct cttcggccca cc

<td>&lt;21O&gt;</td><td> 169</td><td></td>

<td> &lt;211&gt;</td><td> 482</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapienS</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1) . .</td><td> (482)</td>

<td> &lt;223&gt;</td><td>n = A</td><td>k, T, C t (* fe</td>

<td> &lt;400&gt;</td><td> 189</td><td></td>

tttgccgatn atnacfaacca ctcccttctc ccaccagtcc acc ^ a ^ cc cctccccacc ngtcatncaa cctccncgtc ctactatttt agaaggaagg tctctctctc aggggtggga gtacacaccc cacagcgtan nggccanttt caaaaantat attgntgnan agggagggca ctggttcagg a ^^ ccccc ctcggctcct atctccnnna tcnaanttgg taaccnnnct gcggccccgc canccccttg cacańgggga

Lgęg ^ ncgc gtaagctnga gtaantangc gctntctctg ccntantgct ntgcnccgca ctgngcnnca caccttcccc gcatnagaag ^^ gaccac tttccEtttc tc ^ ccncGO

120

180

240

300

360

420

480

482 &lt;2l0&gt; 190 &lt;211&gt; 471 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (471) &lt;223&gt; n = A, T, C LU G &lt;400&gt;

tgggtttttt nannctcgcc nntggcttgg cgcttttgac gangtactcn ggnnaaattg cgacntctnc

190 ttttaannca canccagtga caaangtnac tcacaaacaa cangtatgca cttgancang aantcaBcct gtttttnaca gancgacGnt aatggaacca caaaaaaaaa taagacacag aaccaaccaa gccaggaacn ccgtacngaa acnaaatgta acaccacagt ttcaatctta aggggggggg ttgntgtcca aaganttntn aantΓlttnnt ttagnagaat acagctngga cacatccacg gaccacatcg gtcnaaaatc tggtgatcat ancacncngc tatacactcc nctcgttgtg atctnctcca nnncnncanc ngtanaattg ganttctcga ncananatan

120

180

240

300

360

420

471 &lt;21O&gt; 191 &lt;211&gt; 402 &lt;212&gt; DNA

PL 200 772 B1

119 &lt;213&gt; Homo sapienS &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (402) &lt;223&gt; n = A, T, C or G &lt;400&gt; 191 gagggattga aggtctgttc tastgtcggm ctgttcagcc accaactcta acaagttgct 60 gtcttccact cactgtctgtac tactgtctgtac tactgtctgtac tactgtctgta tactgtctgtac tacgtgata actactactgata aaccta agttagtata agctcttcca 180 cttcctttgt taagacttca tctggtaaag tcttaagttt tgtagaaagg aattyaattg 240 ctcgttctct aacaatgtcc tctccttgaa gtatttggct gaacaaccca cctaaagtagcta cctaaagtagcta 300 ctttgtagtaga cctaaaagtaga tgtctgcaaa agttgcctta gtatatctgc ca 402 &lt;210&gt; 192 &lt;211&gt; 601 &lt;212&gt; DNA &lt;213&gt; Homo sapienS &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (601) &lt;223&gt; n = A, T, CUG &lt;400&gt; 192 gagcltccgat ccaataatct ttgtctgagg gcagcacaca tatncagtgc catggnaact 60 CC^tcCacccc acatcccagc agcatgccct agntatataa ggtcattccc tgagtcagac 120 atgeytyttt Ga ytaccgtg εcccaactgc tggtcattct yaacacacyt ccatcccgyt 180 ctt ^ lt ^^^^^ and aaaactggca cttktctgga actagcarga catcacttac aaattcaccc 240 acgagacact tgaaaggtgt aacaaagcga ytcttgcatt gctttttgtc cctccggcac 300 cagttgtcaa tactaacccg ctggtttgcc tccatcacat ttgtgatctg tagctctgga 360 tacatctcct cacagtactg ^^ aag c: tttct tcttctgttt caaaagcarc tctCggtgcc 420 tgttggatca ggttcccatt tcccagtcyg aatgttcaca tggcatattt wacttcccac 480 aaaacattgc gatttgaggc tcagcaacag caaatcctgt tccggcattg gctccaagac 540 cctcgatgta gccggccagc cccaaggcag c^ccccgtgag ccccaccagc agcagaagca 600 g 601 &lt;210&gt; 193 &lt;211&gt; 608 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (608) &lt;223&gt; n = A, T, C, MS G &lt;400&gt; 193 atacagccca natcccacca ccaacatgcg cttgttgact gagaacctga tgcgctcact 60 ggtcccgctc tagccccagc gactctccac ctgctggaag cggttgatgc tgcactcytt 120 cccaacgcac ccagmagccg csccgctcaa tgaactccay tcgtgccttc CCgtkgacgg 18 0 tkaagtgcag caagaggctc accacctcgc ggtccaccag gatgcccgac tgtgcgccac 240 ctgcagccaa actcctcgat gctcatgagc cccaagcgaa tgagccccag ggccttgccc 300

120

GB 200 772 Β1 agaaccttcc gcctgttctc tggcgtcacc tgcagctgct gccgctgaca ctcggcctcg 360 gaccagcgga caaacggcrt tgaacagccg cacctcacgg atgcccagtg tgtcgcgctc 420 caggammgsc accagcgtgt ccaggtcaat gtcggtgaag ccctccgcgg gtratggcgt 480 ctgcagtgtt tttgtcgatg ttctccaggc acaggctggc cagctgcggt tcatcgaaga 540 gtcgcgcctg cgtgagcagc atgaaggcgt tgtcggctcg cagttcttct tcaggaactc cacgcaat 600 608 &lt;210? 194 &lt;211? 392 &lt;212? DNA &lt;213? Homo puffers &lt;220?

&lt;221? misc_feature &lt;222? (1). . . (392) &lt;223? n = A, T, C lab G &lt;400? 194 gaacggctgg accttgcctc gcattgtgct tgctggcagg gaataccttg gcaagcagyt 60 ccagtccgag cagccccaga ccgctgccgc ccgaagctaa gcctgcctct ggccttcccc 120 tccgcctcaa tgcagaacca gtagtgggag cactgtgttt agagttaaga gtgaacactg 180 tttgatttta cttgggaatt tcctctgtta tatagctttt cccaatgcta atttccaaac 240 aacaacaaca aaataacatg tttgcctgtt aagttgtata aaagtaggtg attctgtatt 300 taaagaaaat attactgtta catatactgc ttgcaatttc tgtatttatt gktnctstgg 360 aaataaatat agttattaaa ggttgtcant 392 cc

<td> &lt;210&gt;</td><td> 195</td><td></td>

<td> &lt;211&gt;</td><td> 502</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> ..(502&gt;</td>

<td> &lt;223&gt;</td><td>n = j</td><td>k, T, C who</td>

<td> &lt;400&gt;</td><td> 195</td><td></td>

ccsttkgagg ggtkaggkyc cagttyccga gtggaagaaa caggccagga gaagtgcgtg 60 ccgagctgag gcagatgttc ccacagtgac ccccagagcc stgggstata gtytctgacc 120 cctcncaagg aaagaccacs ttctggggac atgggctgga gggcaggacc tagaggcacc 180 aagggaaggc cccattccgg ggstgttccc cgaggaggaa gggaaggggc tctgtgtgcc 240 ccccasgagg aagaggccct gagtcctggg atcagacacc ccttcacgtg tatccccaca 300 caaatgcaag ctcaccaagg tcccctctca gtccccttcc stacaccctg amcggccact 360 gscscacacc cacccagagc acgccacccg ccatggggar tgtgctcaag gartcgcngg 420 gcarcgtgga catctngtcc cagaaggggg cagaatctcc aatagangga ctgarcmstt 480 gctnanaaaa aaaaanaaaa aa 502

<td> &lt;210&gt;</td><td> 196</td><td></td>

<td> &lt;211&gt;</td><td> 665</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapien ^</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td>λ ¢ 665)</td>

PL 200 772 B1

121 &lt;²²³&gt; Π = A, T, C Kek G &lt;400&gt; 196 ggttacttgg tttcattgcc accacttagt ggatgtcatt tagaaccatt ttgtctgctc 60 cctctggaag ccttgcgcag agcgggactt gtaattgttg gagaataact gctgaatttt 120 waggtggttk gagttgatts gcaccactgc acccacaact tcaatatgaa aacyawttga 180 actwatttat tatctcgtga aaagtataac aatgaaaatt ttgttcatac tgtattkatc 240 aagtatgatg aaaagcaawa gatatatatt cttttattat gttaaattat gattgccatt 300 attaatcggc aaaatgtgga gtgtatgttc ttttaacagt aatatatgcc ttttgtaact 360 tcacttggtt attttattgt aaatgartta caaaattctt aatttaagar gattgεgtta 420 watatttatL tcattaattt ctttcctkgt ttacgtwaat ttggaaaaga wtgcatgatt 480 tctggacaga aatcgatctt gattctttgt aagtagtttg acccacatcc ctatgagttt 540 ttagacgagaata ttagacgagaata ttagacgagaata ttagacgagaata^cttaaatg tggcatgctn ttctaattcc aactttataa actagcaaan 660 aagtg 665 &lt;210&gt; 197 &lt;211&gt; 492 &lt;212&gt; DNA &lt;213&gt; Homo sapienS &lt;220&gt;

&lt;221&gt; miscfeature &lt;222&gt; (1). . . (492) &lt;223&gt; n = Me ATC G &lt;400&gt; 197 tcttnttttt ttttttttg ^ c aggtaggtet ccatttattg tggttgtttt ttcacaatat 60 atgtttattg gagcgatcca ttatcagtga aaaggatcaa ggggttataa natttttagg 120 aaggcagatt CaCl aat att-gctngtcngc ttgcaatttt aactcggana gganacagag 180 ggt.tgtatac nagccagtga acnnggtgtt tactatacga aagtttaaat ccaaactgaa 240 ttcttgggct. tactccatcc aaatatttga ataanagtca gcagggaaac 300 gtacacttca gasctteaga ttttctagaa agggatgtaa tagtgatcag gtggggtttt 360 agcggcntgg caBagttccc ttgctatggg aaatttgatc 420 catatcgctt tcgacgcggt gttcggtgca tctaggtgtt cttgcattct gttcatnctg gncntggcta 480 aa 492 &lt;21o&gt; 198 &lt;211&gt; 478 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;22l&gt; msc_feature &lt;222&gt; (1) ... (478) &lt;223&gt; n = ATC arc G &lt;400&gt; 198 «επ ^^ 9η gtannntgta gttagatang aaaatatnaa 60 tgtntccacn tcaaattgan ttacntnagg aagaggccacn tcaaattgan ttacntnagg aagaggccta ctacattgtgt 120aca ^agata ^ gtaga ctacattgtgt ca ^agata ^ gtag ca ^ gtanacncaa atatttttnc atancaccat 180 tgtacatggt ttgattgata ttaggtgtag canaaacŁga gtgagtttgtc agaaanaaat 240 natgagtgtt tattngatttt acagaaccta ttgt · gcatgn 300 gggta.gtgtt aatatgttta ctgaaaggca atgcagtttt ttgagcgggta gatggccgta 360 agcattctag atcttttgtt ccttggtaaa gnatcg ^^ cttatgttag catgtgantg 420

122

PL 200 772 Β1 gggtaagaat tgtgttaagt naanttatgg agaggtccan gagaaaaatt tgatncaa 478 &lt;210? 199 &lt;211? 482 &lt;212? DNA &lt;213? Homo sapienS &lt;220?

&lt;221? misc_feature &lt;222? (1) ... (482) &lt;223? n = A, T, C, or G &lt;400? 199 agtgacttgt cctccaacaa aaccccttga tcaagtttgt ggcactgaca atcagaccta 60 tgctagttcc tgtcatctat tcgctactaa atgcagactg gaggggacca aaaaggggca 120 tcaactccag ctggattatt ttggagcceg caaatctatt cctacttgta cggactttga 180 agtgattcag tttcctceac ggatgagaga ctggctcaag aatatcctca tgcagcttta 240 tgaagccnac tctgaacacg ctggttatct nagatgagaa ncagagaaat aaagtcnaga 300 aaatttacct ggangaaaag aggctttngg ctggggacca tcccattgaa ccttctctta 360 anggacttta agaanaaact accacatgtn tgtngtatcc tggtgccngg ccgtttantg 420 aacntngacn ncacccttnt ggaatanant cttgacngcn tcctgaactt gctcctctgc 480 ga 482

<td> &lt;210&gt;</td><td> 200</td><td></td>

<td> &lt;211&gt;</td><td> 270</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapienS</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>_feature</td>

<td> &lt;222&gt;</td><td>ii)</td><td> ..(270)</td>

<td> &lt;223&gt;</td><td>n =.</td><td>A, T, C (J?</td>

<td> &lt;400&gt;</td><td> 200</td><td></td>

cggccgcaag tgcaactcca gctggggccg tgcggacgaa gatcctgcca gcagttggtc 60 cgactgcgac gacggcggcg gcgacagtcg caggtgcagc gcgggcgcct ggggtcttgc 120 aaggctgagc tgacgccgca gaggtcgtgt cacgtcccac gaccttgacg ccgtcgggga 180 cagccggaac agagcccggt gaangcggga ggcctcgggg agcccctcgg gaagggcggc 240 ccgagagata cgcaggtgca ggtggccgcc 270

<td> &lt;210&gt;</td><td> 201</td><td></td>

<td> &lt;211&gt;</td><td> 419</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>_feature</td>

<td> &lt;222&gt;</td><td> (1!</td><td> ..(419)</td>

<td> &lt;223&gt;</td><td>n = j</td><td>8, T, C or</td>

<td> &lt;400&gt;</td><td> 201</td><td></td>

tttttttttt ttttggaatc tactgcgagc acagcaggtc agcaacaagt ttattttgca 60 gctagcaagg taacagggta gggcatggtt acatgttcag gtcaacttcc tttgtcgtgg 120 ttgattggtt tgtctttatg ggggcggggt ggggtagggg aaancgaagc anaantaaca 180 tggagtgggt gcaccctccc tgtagaacct ggttacnaaa gcttggggca gttcacctgg 240

PL 200 772 Β1

123 tctgtgaccg tcattttctt gacatcaatg ttattagaag tcaggatatc ttttagagag 300 tccactgcnt ctggagggag ateagggttt cttgccaana cccaancaaa acccacntga 360 aaaagctgga tgatncangt2S2G219HOMATCGGGATNCATCGGGGNGAACCG11

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (509) &lt;223&gt; n = A, T, C or G &lt;400&gt; 202 tttntttttC tttttttttc tctttttttt ttttttcctt tttcttcttt ttttttcttt 60 tggcacttaa tccattttca tcccaaaatg tctacaaant ttnaatncnc cattatacng 120 gtnatcttnc aaaatctaaa nntcatccaa atntnagcca aantccttac ncaaatnnaa 180 tacncncaaa aatcaaaaat atacntntct Ctcagcaaac ttngttacat aaatcaaaaa 240 aatatatacg gctggtgttt tcaaagtaca attatctcaa cactgcaaac atntctnnaa 300 ggaactaaaa taaaaaaaaa cactnccgca aaggttaaag ggaacaacaa attcntctca 360 caacancnnc nattataaaa atcatatctc aaatctcagg ggaatataca cctcacacng 420 ggaCctCaac ttctactnca ccttgtttat tttcttanaa ccactgcntt gggcccaaca 480 caatggnaat nccnccncnc tggactagt 509 &lt;210&gt; 203 &lt;211&gt; 583 &lt;213&gt; &lt;220&gt; DNA sapiens &lt;211&gt; 583 &lt;212&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (583) &lt;223&gt; n = A, T, C IgG g &lt;400&gt; 203 tttttttttt ttttttttga cccccctctt ataaaaaaca agttaccatt ttattttact 60 tacacatatt tattttataa ttggtacta 120tacatgatactaa 120gatgtcacta aagatgatta aagatgtcatta 120 gcttaaaatc tgcctaaagt 180 gaaaatcttc tctagctctt ttgactgtaa atttttgact cttgtaaaac atccaaattc 240 atttttcttg tctttaaaat tatctaatct ttccattttt tccctattccatt aagtcacta 300 gcttctccta ggaagagana atggcacaca aaacaaacat tttatattca tatttctacc 420 tacgttaata aaatagcatt ttgtgaagcc agctcaaaag aaggcttaga tccttttatg 480 tccattttag tcactaaacg atatcnaaag tgccagattatg tgccagattatg tgccagattatg tgccagattatg tgccagattatg tgccagattatg tgccagattatg caaaagtcata

<td> &lt;210&gt;</td><td> 204</td><td></td>

<td> &lt;211&gt;</td><td> 589</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapien ^</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc_</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td>. . i589)</td>

124

PL 200 772 Β1 &lt;223? η = A, T, C | or G &lt;400? 204 tttttttttt ttttttttnt ttttttnctc ttcttttttt ttganaatga ggatcgagtt 60 tttcactctc tagatagggc atgaagaaaa ctcatctttc cagctttaaa ataacaatca 120 aatctcttat gctatatcat attttaagtt aaactaatga gtcactggct tatcttctcc 180 tgaaggaaat ctgttcattc ttctcattca tatagttata tcaagtacta ccttgcatat 240 tgagaggttt ttcttctcta tttacacata tatttccatg tgaatttgta tcaaaccttt 300 attttcatgc aaactagaaa ataatgtntt cttttgcata agagaagaga acaatatnag 360 cattacaaaa ctgctcaaat tgtttgttaa gnttatccat tataattagt tnggcaggag 420 ctaatacaaa tcacatttac ngacnagcaa taataaaact gaagtaccag ttaaatatcc 480 aaaataatta aaggaacatt tttagcctgg gtataattag ctaattcact ttacaagcat 5409 ttacaattcacagcat 5409 ttacaattcacagcat? 205 &lt;211? 545 &lt;212? DNA &lt;213&gt; Homo sapienS &lt;220?

&lt;221? misc_feature &lt;222? (1). . . (545) &lt;223 n = A, T, CG &lt;400? 205 tttttntttt ttttttcagt aataatcaga acaatattta ttcttatatt taaaattcat 60 agaaaagtgc cttacattta ataaaagttt gtttctcaaa gtgatcagag gaattagata 120 tngtcttgaa caccaatatt aatttgagga aaatacacca aaatacatta agtaaattat 180 ttaagatcat agagcttgta agtgaaaaga taaaatttga cctcagaaac tctgagcatt 240 aaaaatccac tattagcaaa taaattacta tggacttctt gctttaattt tgtgatgaat 300 atggggtgtc actggtaaac caacacattc tgaaggatac attacttagt gatagattct 360 tatgtacttt gctanatnac gtggatatga gttgacaagt ttctctttct tcaatctttt 420 aaggggcnga ngaaatgagg aagaaaagaa aaggattacg catactgttc tttctatngg 480 aaggattaga tatgtttcct ttgccaatat taaaaaaata ataatgttta ctactagtga 540 aaccc 545 &lt;210? 206 &lt;211? 487 &lt;212? DNA &lt;213? Homo sapienj &lt;220?

&lt;221? misc_feature &lt;222? (1). . . (487) &lt;223 n = A, T, C Feb, G &lt;400? 206 tttttttttt ttttttagtc aagtttctna tttttattat aattaaagtc ttggtcattt 60 catttattag ctctgcaact tacatattta aattaaagaa acgttnttag acaactgtna 120 caatttataa atgtaaggtg ccattattga gtanatatat tcctccaaga gtggatgtgt 180 cccttctccc accaactaat gaancagcaa cattagttta attttattag tagatnatac 240 actgctgcaa acgctaattc tcttctccat ccccatgtng atattgtgta tatgtgtgag 300 ttggtnagaa tgcatcanca atctnacaat caacagcaag atgaagctag gcntgggctt 360 tcggtgaaaa tagactgtgt ctgtctgaat caaatgatct gacctatcct cggtggcaag 420 aactcttcga accgcttcct caaaggcngc tgccacattt gtggcntctn ttgcacttgt 480

PL 200 772 B1

125 ttcaaaa

487 &lt;210&gt; 207 &lt;211&gt; 332 &lt;212&gt; DNA &lt;213&gt; Homo sapien&gt;

tgaattggct tacatagcat gcatttatag atctttgcat gaaatgaagg aaaagaaggc &lt;220&gt;

&lt;221&gt; misc feature

<td> &lt;222&gt;</td><td> (1)</td><td> . . . (332)</td>

<td> &lt;223&gt;</td><td>η =</td><td>A, T, CG</td>

<td> &lt;400&gt;</td><td> 207</td><td></td>

aaaagactgc taaatcccaa gaccttctgg gcagaggagg ggccaggctt agcctaggcc atttttanaa atcctattta tggttctgct taaaaggtat actgagcttg ctggggagcc ctagcaactc aagacctgac gttacntttg tggattttca tccactggag ca ttatttcttt agcttgagaa aantctgaca cagtggtant ggctcatggg tctttaaaat ggtcactact atccttgana acacagcgca tgggacatgg

120

180

240

300

332 &lt;210&gt; 208 &lt;211&gt; 524 &lt;212&gt; DNA &lt;213&gt; Homo sapienS &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (i) ... (524) &lt;223&gt; n = A, T, C or G &lt;400&gt;

agggcgtggt gttgtgttcc tttaaaggac tcccgcgtga tttggcagaa gttattagaa atgagcccag tgtcatcaga aaaccactac

208 gcggagggcg ggccccatcc atggagc ^ ittg ttcacattta tacttnttga gtgggtcata acactgacat caggaggctg cŁgatccact ttactgtttt aaccacgaag tcacaatgtc gcaaccaaca aactcgcaga atatcaatta caaactaagc tcaccttgac tccggtaatg gtctcagtaa ttgatttctc acaatgtcac atagctcatg tgataactaa cctgttcaca ccacttagac caaattctca caccaccttg caataaaCac ttgtgtgcag agtgtgaagg agtccatact gttcctagtt tcagcttcca tctttatttc CCAG ^ AATC gtga aaaaagtctg agtgactgat gcatactcat tgcsaatact attccccaaa tttacaagtt cagtctgtct atctatccaa

120

180

240

300

360

420

480

524

<td> &lt;210&gt;</td><td> 209</td>

<td> &lt;211^</td><td> 159</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapien S.</td>

<td> &lt;400&gt;</td><td> 209</td>

gggtgaggaa atccagagtt gccatggaga tggccctctc ctacactctg gccagagata caaaggactc tcgacccaaa atgccccaga &lt;210&gt; 210 &lt;211&gt; 256 &lt;212&gt; DNA &lt;213&gt; Homo sapiens ttattcattgt ccacagtcctcaa cttgcctgt ccacagtcctcaa

120

159

126

PL 200 772 Β1

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1) -</td><td> ..&lt;256 &gt;</td>

<td> &lt;223&gt;</td><td>n =</td><td>A, T, C Feb;</td>

<td> &lt;400&gt;</td><td> 210</td><td></td>

actccctggc agacaaaggc agaggagaga gctctgttag ttctgtgttg ttgaactgcc 60 actgaatttc tttccacttg gactattaca tgccanttga gggactaatg gaaaaacgta 120 tggggagatt ttanccaatt tangtntgta aatggggaga ctggggcagg cgggagagat 180 ttgcagggtg naaatgggan ggctggtttg ttanatgaac agggacatag gaggtaggca 240 ccaggatgct aaatca 256 &lt;210&gt; 211 &lt;211&gt; 264 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220 &gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (264) &lt;223&gt; n = A, T, C andor G &lt;400&gt; 211 acattgtttt tttgagataa agcattgaga gagctctcct taacgtgaca caatggaagg 60 actggaacac atacccacat ctttgttctg agggataatt ttctgataaa gtcttgctgt 120 atattcaagc acatatgtta tatattattc agttccatgt tcatagccta gttaaggaga 180 ggggagatac attcngaaag aggactgaaa gaaatactca agtnggaaaa cagaaaaaga 240 aaaaaaggag caaatgagaa gcct 264 &lt;210&gt; 212 &lt;211&gt; 328 &lt;212&gt; DNA &lt;213&gt; Homo sapienS &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (328) &lt;223&gt; n = A, T, C iulo G &lt;400&gt; 212 acccaaaaat ccaatgctga atatttggct tcattattcc canattcttt gattgtcaaa 60 ggatttaatg ttgtctcagc ttgggcactt cagttaggac ctaaggatgc cagccggcag 120 gtttatatat gcagcaacaa tattcaagcg cgacaacagg ttattgaact tgcccgccag 180 ttnaatttca ttcccattga cttgggatcc ttatcatcag ccagagagat tgaaaattta 240 cccctacnac tctttactct ctgganaggg ccagtggtgg tagctataag cttggccaca 300 tttttttttc ctttattcct ttgtcaga 328 &lt;220&gt;

&lt;221&gt; misc feature &lt;210&gt; 213 &lt;211&gt; 250 &lt;212&gt; DNA &lt;213&gt; Homo sapienS

PL 200 772 Β1

127 &lt;222 »(1). . . (250) &lt;223 »n = A, T, C or G &lt;400» 213 acttatgagc agagcgacat atccnagtgt agactgaata aaactgaatt ctctccagtt 60 taaagcattg ctcactgaag ggatagaagt gactgccagg agggaaagta agccaaggct 120 cattatgcca aagganatat acatttcaat tctccaaact tcttcctcat tccaagagtt 180 ttcaatattt gcatgaacct gctgacaanc catgttaana aacaaatatc tctctnacct 240 tctcatcggt 250 &lt; 210 »214 &lt;211» 444 &lt;212 »DNA &lt;213» Homo sapienj &lt;220 »&lt;221» misc_feature &lt;222 »(1) ... (444) &lt;223&gt; n = A, T, C or G &lt;400» 214 acccagaatc caatgctgaa tatttggctt cattattccc agattctttg attgtcaaag 60 gatttaatgt tgtctcagct tgggcacttc agttaggacc taaggatgcc agccggcagg 120 tttatatatg cagcaacaat attcaagcgc gacaacaggt tattgaactt gcccgccagt 180 tgaatttcat tcccattgac ttgggatcct tatcatcagc canagagatt gaaaatttac 240 ccctacgact ctttactctc tggagagggc cagtggtggt agctataagc ttggccacat 300 ttttttttcc tttattcctt tgtcagagat gcgattcatc catatgctan aaaccaacag 360 agtgactttt acaaaattcc tataganatt gtgaataaaa ccttacctat agttgccatt 420 actttgctct ccctaatata cctc 444 &lt; 210 »215 &lt;211» 366 &lt;212 »DNA &lt;213&gt; Homo sapiens &lt;220» &lt;221 »misc_feature &lt;222» (1) ... (366) &lt;223 »n = A, T, C jut; G &lt;400 »215 acttatgagc agagcgacat atccaagtgt anactgaata aaactgaatt ctctccagtt 60 taaagcattg ctcactgaag ggatagaagt gactgccagg agggaaagta agccaaggct 120 cattatgcca aagganatat acatttcaat tctccaaact tcttcctcat tccaagagtt 180 ttcaatattt gcatgaacct gctgataagc catgttgaga aacaaatatc tctctgacct 240 tctcatcggt aagcagaggc tgtaggcaac atggaccata gcgaanaaaa aacttagtaa 300 tccaagctgt tttctacact gtaaccaggt ttccaaccaa ggtggaaatc tcctatactt 360 ggtgcc 366 &lt; 210&gt; 216 &lt;211&gt; 260 &lt;212&gt; DNA &lt;213&gt; Homo sapienS &lt;220&gt;

128

PL 200 772 Β1 &lt;221? misc_feature &lt;222? (1) ... (260) &lt;223? n = A, T, C lab G &lt;400? 216 ctgtataaac agaactccac tgcangaggg agggccgggc caggagaatc tccgcttgtc 60 caagacaggg gcctaaggag ggtctccaca ctgctnntaa gggctnttnc atttttttat 120 taataaaaag tnnaaaaggc ctcttctcaa cttttttccc ttnggctgga aaatttaaaa 180 atcaaaaatt tcctnaagtt ntcaagctat catatatact ntatcctgaa aaagcaacat 240 aattcttcct tccctccttt 260

<td> &lt;210?</td><td> 217</td><td></td>

<td> &lt;211?</td><td> 262</td><td></td>

<td> &lt;212?</td><td>GOUT</td><td></td>

<td> &lt;213?</td><td>Homo</td><td>sapien and</td>

<td> &lt;220?</td><td></td><td></td>

<td> &lt;221?</td><td>misc</td><td>feature</td>

<td> &lt;222?</td><td> (1) --</td><td> . (262)</td>

<td> &lt;223?</td><td>n = i</td><td>i, T, C 0G</td>

<td> &lt;400?</td><td> 217</td><td></td>

acctacgtgg gtaagtttan aaatgttata atttcaggaa naggaacgca tataattgta 60 tcttgcctat aattttctat tttaataagg aaatagcaaa ttggggtggg gggaatgtag 120 ggcattctac agtttgagca aaatgcaatt aaatgtggaa ggacagcact gaaaaatttt 180 atgaataatc tgtatgatta tatgtctcta gagtagattt ataattagcc acttacccta 240 atatccttca gt tgcttgtaaa 262

<td> &lt;210?</td><td> 218</td><td></td>

<td> &lt;211?</td><td> 205</td><td></td>

<td> &lt;212?</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapienS</td>

<td> &lt;220?</td><td></td><td></td>

<td> &lt;221?</td><td>misc</td><td>feature</td>

<td> &lt;222?</td><td>(1Ϊ /</td><td> 7. (205)</td>

<td> &lt;223?</td><td colspan="2">n = A, T, C gaps</td>

<td> &lt;400?</td><td> 218</td><td></td>

accaaggtgg tgcattaccg gaantggatc aangacacca tcgtggccaa cccctgagca 60 cccctatcaa ctcccttttg tagtaaactt ggaaccttgg aaatgaccag gccaagactc 120 aggcctccta agttctactg accttagntagta 180 aggcctccta agttctactg accttagntagta

<td colspan="2">&lt;210? 219 &lt;211? 114 &lt;212? GOUT &lt;213? Homo sapien S.</td>

<td> &lt;400?</td><td> 219</td>

tactgttttg tctcagtaac aataaataca aaaagactgg ttgtgttccg gccccatcca 60 accacgaagt tgatttctct tgtgtgcaga gtgactgatt ttaaaggaca tgga 114 &lt;210? 220 &lt;211? 93

PL 200 772 B1

129 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 220 actagccagc acaaaaggca gggtagcceg aattgctttc tgctctttac atttctttta 60 aaataagcat teagtgctca gtccctaceg agt 93

<td> &lt;210&gt;</td><td> 221</td><td></td>

<td> &lt;211&gt;</td><td> 167</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc_</td><td>-feature</td>

<td> &lt;222&gt;</td><td> (1 ..</td><td> .(167)</td>

<td> &lt;223&gt;</td><td colspan="2">n = A, T, C or</td>

<td> &lt;400&gt;</td><td> 221</td><td></td>

actangtgca ggtgcgcaca aatatttgtc ggtattccct tcatcttgga tcccatgagg 60 tctttggccc agcctgtggc tctactgtag taaatttctg ccgatgaggg ggccagntgg 120 tctccactac cttccctgac cttccctgac ac gcccc! 167

<td> &lt;210&gt;</td><td> 222</td>

<td> &lt;211&gt;</td><td> 351</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapiens</td>

<td> &lt;400&gt;</td><td> 222</td>

agggcgtggt gcggagggcg gtactgacct cattagtagg aggatgcatt C ggcacccc 60 gttcttcacc tgtcccccaa tccttaaaag gctatattgt ataaagtcaa ^ a ^ gat ^ 120 atgtttgctg aattaaagga tggatgaaaa aaattaataa tgaattcttg tataatttaa 180 ttttctcttt tatatttcta gaagaagttt ctttgagcct attagatccc gggaatctct 240 taggtgagca tgattagaga gcttgtaggt tgcttttaca tatatctggc atatttgagt 300 ctcgtatcaa aacaatagat tggtaaaggt ggtattattg Cattgataag t 351 aaaacaaaca tggtaattat ttaaaatgtc tgccaaagga taaaagactt ataggaccac atcattaagt

<td> &lt;210&gt;</td><td> 223</td><td></td>

<td> &lt;211&gt;</td><td> 383</td><td></td>

<td>&lt;2I2&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td></td><td> . . (383)</td>

<td> &lt;223&gt;</td><td>n =</td><td>A, T, C | in £</td>

<td> &lt;400&gt;</td><td> 223</td><td></td>

aacaaaaaaa ggtcaattta tgtgccaaaa agtctaagga tgattt ^ cctg agtcttcact tatatgttta acaattcttc atwrttttkt ttttgtattt attagtagtg gaaagacaat tctgatactt attcagaaaa ggggcctttc tatttggaga aaa taa eatatttt gtaaattaat attatcttag cttacattgt cttcttatca ttgtttggag cttcggtggg cttttattgc ggactgatat cttgacaaga tttgttttgt tgtgctattc ggaaanagtt acttgttttg

120

180

240

300

360

383 &lt;210&gt; 224

130

PL 200 772 Β1 &lt;211? 320 &lt;212&gt; DNA &lt;213? Homo sapiens &lt;400? 224 cccctgaagg cttcttgtta gaaaatagta cagttacaac caataggaac aacaaaaaga 60 aaaagtttgt gacattgtag tagggagtgt gtacccctta ctccccatca aaaaaaaaat 120 ggatacatgg ttaaaggata raagggcaat attttatcat atgttctaaa agagaaggaa 180 gagaaaatac tactttcccr aaacggaagc ccttaaaggt gctttgatac tgaaggacac 240 aaatgtggcc gtccatcctc ctttaragtt gcatgacttg gacacggtaa ctgttgcagt 300 tttaractcm gcattgtgac 320 &lt;210&gt; 225 &lt;211? 1214 &lt;212? DNA &lt;213&gt; Homo sapienj &lt;400? 225 gaggactgca gcccgcactc gcagccctgg caggcggcac tggtcatgga aaacgaattg 60 ttctgctcgg gcgtcctggt gcatccgcag tgggtgctgt cagccgcaca ctgtttccag 120 aactcctaca ccatcgggct gggcctgcac agtcttgagg ccgaccaaga gccagggagc 180 cagatggtgg aggccagcct ctccgtacgg cacccagagt acaacagacc cttgctcgct 240 aacgacctca tgctcatcaa gttggacgaa tccgtgtccg agtctgacac catccggagc 300 atcagcattg cttcgcagtg ccctaccgcg gggaactctt gcctcgtttc tggctggggt 360 ctgctggcga acggcagaat gcctaccgtg ctgcagtgcg tgaacgtgtc ggtggtgtct 420 gaggaggtct gcagtaagct ctatgacccg ctgtaccacc ccagcatgtt ctgcgccggc 480 ggagggcaag accagaagga ctcctgcaac ggtgactctg gggggcccct gatctgcaac 540 gggtacttgc agggccttgt gtctttcgga aaagccccgt gtggccaagt tggcgtgcca 600 ggtgtctaca ccaacctctg caaattcact gagtggatag agaaaaccgt ccaggccagt 660 taactctggg gactgggaac ccatgaaatt gacccccaaa tacatcctgc ggaaggaatt 720 caggaatatc tgttcccagc ccctcctccc tcaggcccag gagtccaggc ccccagcccc 780 tcctccctca aaccaagggt acagatcccc agcccctcct ccctcagacc caggagtcca 840 gaccccccag cccctcctcc ctcagaccca ggagtccagc ccctcctccc tcagacccag 900 gagtccagac cccccagccc ctcctccctc agacccaggg gtccaggccc ccaacccctc 960 ctccctcaga ctcagaggtc caagccccca acccctcctt ccccagaccc agaggtccag 1020 gtcccagccc ctcctccctc agacccagcg gtccaatgcc acctagactc tccctgtaca 1080 cagtgccccc ttgtggcacg ttgacccaac cttaccagtt ggtttttcat tttttgtccc 1140 tttcccctag atccagaaat aaagtctaag agaagcgcaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1200 1214 aaaa &lt;210? 226 &lt;211? 119 &lt;212? DNA &lt;213? Homo sapiens &lt;400? 226 acccagtatg tgcagggaga cggaacccca tgtgacagcc cactccacca gggttcccaa 60 agaacctggc ccagtcataa tcattcatcc tgacagtggc aataatcacg ataaccagt 119 &lt;210? 227 &lt;211? 818 &lt;212? DNA &lt;213? Homo puffers &lt;400? 227

PL 200 772 Β1

131 acaattcata gggacgacca atgaggacag ggaatgaacc cggctctccc ccagccctga 60 tttttgctac atatggggtc ccttttcatt ctttgcaaaa acactgggtt ttctgagaac 120 acggacggtt cttagcacaa tttgtgaaat ctgtgtaraa ccgggctttg caggggagat 180 aatcetcctc ctctggagga aaggtggtga ttgacaggca gggagacagt gacaaggcta 240 gagaaagcca cgctcggcct tctctgaacc aggatggaac ggcagacccc tgaaaacgaa 300 gcttgtcccc ttccaatcag ccacttctga gaacccccat ctaacttcct actggaaaag 360 agggcctcct caggagcagt ccaagagttt tcaaagataa cgtgacaact accatctaga 420 ggaaagggtg caccctcagc agagaagccg agagcttaac tctggtcgtt tccagagaca 480 acctgctggc tgtcttggga tgcgcccagc ctttgagagg ccactacccc atgaacttct 540 gccatccact ggacatgaag ctgaggacac tgggcttcaa cactgagttg tcatgagagg 600 gacaggctct gccctcaagc cggctgaggg cagcaaccac tctcctcccc tttctcacgc 660 aaagccattc ccacaaatcc agaccatacc atgaagcaac gagacccaaa cagtttggct 720 caagaggata tgaggactgt ctcagcctgg ctttgggctg acaccatgca cacacacaag 780 gtccacttct aggttttcag cctagatggg agtcgtgt 818 &lt;210&gt; 228 &lt;211&gt; 744 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 228 actggagaca ctgttgaact tgatcaagac ccagaccacc ccaggtctcc ttcgtgggat 60 gtcatgacgt ttgacatacc tttggaacga gcctcctcct tggaagatgg aagaccgtgt 120 tcgtggccga cctggcctct cctggcctgt ttcttaagat gcggagtcac atttcaatgg 180 taggaaaagt ggcttcgtaa aatagaagag cagtcactgt ggaactacca aatggcgaga 240 tgctcggtgc acattggggt gctttgggat aaaagattta tgagccaact attctctggc 300 accagattct aggccagttt gttccactga agcttttccc acagcagtcc acctctgcag 360 gctggcagct gaatggcttg ccggtggctc tgtggcaaga tcacactgag atcgatgggt 420 gagaaggcta ggatgcttgt ctagtgttct tagctgtcac gttggctcct tccaggttgg 480 ccagacggtg ttggccactc ccttctaaaa cacaggcgcc ctcctggtga cagtgacccg 540 ccgtggtatg ccttggccca ttccagcagt cccagttatg catttcaagt ttggggtttg 600 ttcttttcgt taatgttcct ctgtgttgtc agctgtcttc atttcctggg ctaagcagca 660 ttgggagatg tggaccagag atccactcct taagaaccag cggcgaaaga cactttcttt 720 cttcactctg aagtagctgg tggt 744 &lt;210&gt; 229 &lt;211&gt; 300 &lt;212&gt; DNA &lt;213&gt; Homo sapienS &lt;400&gt; 229 cgagtctggg ttttgtctat aaagtttgat ccctcctttt ctcatccaaa tcatgtgaac 60 cattacacat cgaaataaaa gaaaggtggc agacttgccc aacgccaggc tgacatgtgc 120 tgcagggttg ttgtttttta attattattg ttagaaacgt cacccacagt ccctgttaat 180 ttgtatgtga cagccaactc tgagaaggtc ctatttttcc acctgcagag gatccagtct 240 cactaggctc ctccttgccc tcacactgga gtctccgcca gtgtgggtgc ccactgacat 300

<td colspan="2">&lt;210&gt; 230 &lt;211&gt; 301 &lt;212&gt; DNA &lt;213&gt; Homo sapiens</td>

<td> &lt;400&gt;</td><td> 230</td>

cagcagaaca aatacaaata tgaagagtgc aaagatctca taaaatctat gctgaggaat 60 gagcgacagt tcaaggagga gaagcttgca gagcagctca agcaagctga ggagctcagg 120

132

GB 200 772 B1 caatataaag tcctggttca cactcaggaa cgagagctga cccagttaag ggagaagttg 180 cgggaaggga gagatgcctc cctctcattg aatgagcatc tccaggccct cctcactccg 240 gatgaaccgg acaagtccca ggggcaggac ctccaagaaa cagacctcgg ccgcgaccac 300 g 301 &lt;210&gt; 231 &lt;2LL&gt; 301 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 231 gcaagcacgc tggcaaatct ctgtccggtc aggtccagag aaagccatag tcattttagc 60 caggaacccc aagtccacat ccttggcaac tggggaattg cgcaagttag ccttgaggat 120 ggcaacacgg gacttctcat caggaagtgg ggtgtgagatg 180 gacgctgccagatg 180 gacgctgccagatg 180 ctacgattaa tgatgactgc cctCCtggCa Łgasc ^ c ^ 240 tttttt ^^ t ^ g cacat: cttat ccacttctgt ttgatgactc gggcagcagc 300 c 301 &lt;210&gt; 232 &lt;211&gt; 301 &lt;212&gt; dna &lt;213tgactagca213gctagca213gctagca &lt;213gacta 60 gctgatactc gggctctttg ataaccttgt ggaaattaac ag ^ ^ cG at 120 agaagacttt atttcttgtc aaggagagac agcgaaatct ggcctccgcc grc ^ e ^ ca 180 tgtcttctat taagtcttgg tgctagcctg ttacctgttc tcactgaaaa tctggctaat 240 attacttttc tcaatcaatc aaaggcccag agctatgaat 300 g 301 &lt;210&gt; 233 &lt;211&gt; 301 &lt;212&gt; DNA &lt;213&gt; Homo sapien ^ &lt;400&gt; 233 coccc ^ c ^ tcccaggaag ggggaagtag gaggccccac aggcCttcac 60 atcttaaggt ctttgagaat ggttgatcca accc ^^ at tttcagagcg gaaa ^ ^^ at tttcagagcg gaaa ^^ tagggggt 120 aactgggggg 120 aactcccccggas gactacaggc actctgacac tgaagtacgc cctgttac &lt;ta attctatgcg 240 tatcacttac ccagagatga gaagagactt tattgagaaa gcaagagaaa atcctattaa 300 c 301 &lt;210&gt; 234 &lt;211&gt; 301 &lt;212&gt; dna &lt;213ctcgatga &lt;213ctctata &lt;213ctctata 234ccttctatga ttaaaaatta caagcaccca 60 cattttattc cttctcatct tttcttttgg t tcttccttt cg ^^^ tc tttttctttt 120 ttactttcaa caacatactt t cagcattta aaatcttcac ggattgatct 180 cagcdattagttc aatttactgtttgc ^^ tgtttgc ^^ tca 240c aatttc ^ tgtttgc ^^^{tttactcat cataaaatct gatttaatgg ctttattcgt atagttcttc 300

PL 200 772 Β1

133 t 301 &lt;210&gt; 235 &lt;211 »283 &lt;212» DNA &lt;213 »Homo sapiens &lt;400» 235 tggggctgtg catcaggcgg gtttgagaaa tattcaattc tcagcagaag ccagaatttg 60 aattccctca tcctttaggg aatcatttac caggtttgga gaggactcag acagctcagg 120 tgctttcact aatgtctctg aacctctgtc cctctttgtt catggatagt ccaataaata 180 atgttatctt tgaactgatg ctcataggag agaatataag aactctgagt gatatcaaca 240 ttagggattc aaagaaatat tagatttaag ctcacactgg tca 283 &lt;210&gt; 236 &lt;211 »301 &lt;212» DNA &lt;213 »Homo sapiens &lt;400» 236 aggtcctcca ccaactgcct gaagcacggt taaaattggg aagaagtata gtgcagcata 60 aatactttta aatcgatcag atttccctaa cccacatgca atcttcttca ccagaagagg 120 tcggagcagc atcattaata ccaagcagaa tgcgtaatag ataaatacaa tggtatatag 180 tgggtagacg gcttcatgag tacagtgtac tgtggtatcg taatctggac ttgggttgta 240 aagcatcgtg taccagtcag aaagcatcaa tactcgacat gaacgaatat aaagaacacc 300 and 301 &lt;210&gt; 237 &lt;211 »301 &lt;212» DNA &lt;213 »Homo sapiens &lt;400 »237 cagtggtagt ggtggtggac gtggcgttgg tcgtggtgcc ttttttggtg cccgtcacaa 60 actcaatttt tgttcgctcc tttttggcct tttccaattt gtccatctca attttctggg 120 ccttggctaa tgcctcatag taggagtcct cagaccagcc atggggatca aacatatcct 180 ttgggtagtt ggtgccaagc tcgtcaatgg cacagaatgg atcagcttct cgtaaatcta 240 gggttccgaa attctttctt cctttggata atgtagttca tatccattcc ctcctttatc 300 t 301 &lt;210 »238 &lt;211» 301 &lt;212&gt; DNA &lt;213 »Homo sapiens &lt;400» 238 gggcaggttt tttttttttt ttttttgatg gtgcagaccc ttgctttatt tgtctgactt 60 gttcacagtt cagccccctg ctcagaaaac caacgggcca gctaaggaga ggaggaggca 120 ccttgagact tccggagtcg aggctctcca gggttcccca gcccatcaat cattttctgc 180 accccctgcc tgggaagcag ctccctgggg ggtgggaatg ggtgactaga agggatttca 240 gtgtgggacc cagggtctgt tcttcacagt aggaggtgga agggatgact aatttcttta 300 t 301 &lt;210 »239 &lt;211» 239

134

GB 200 772 Β1 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 239 ataagcagct agggaattct ttatttagta atgtcctaac ataaaagttc acataactgc 60 ttctgtcaaa ccatgatact gagctttgtg acaacccaga aataactaag agaaggcaaa 120 cataatacct tagagatcaa gaaacattta cacagttcaa ctgtttaaaa atagctcaac 180 attcagccag tgagtagagt gtgaatgcca gcatacacag tatacaggtc cttcaggga 239 &lt;210? 240 &lt;211&gt; 300 &lt;212&gt; DNA &lt;213&gt; Homo sapien?

&lt;400&gt; 240 ggtcctaatg aagcagcagc ttccacattt taacgcaggt ttacggtgat actgtccttt 60 gggatccgcc ctccagtgga accttttaag gaagaagtgg gcccaagcta agttccacat 120 gctgggtgag ccagatgact tctgttccct ggtcactttc ttcaatgggg cgaatggggg 180 ctgccaggtt tttaaaatca tgcttcatct tgaagcacac ggtcacttca cccccctcac 240 gctgtgggtg tactttgatg aaaataccca ctttgttggc ctttctgaag ctataatgtc 300 &lt;210&gt; 241 &lt;211? 301 &lt;2l2&gt; DNA &lt;213? Homo sapiens &lt;400? 241 gaggtctggt gctgaggtct ctgggctagg aagaggagtt ctgtggagct ggaagccaga 60 cctctttgga ggaaactcca gcagctatgt tggtgtctct gagggaatgc aacaaggctg 120 ctcctccatg tattggaaaa ctgcaaactg gactcaactg gaaggaagtg ctgctgccag 180 tgtgaagaac cagcctgagg tgacagaaac ggaagcaaac aggaacagcc agtcttttct 240 tcctcctcct gtcatacggt ctctctcaag catcctttgt tgtcaggggc ctaaaaggga 300 g 301 &lt;210&gt; 242 &lt;211? 301 &lt;212&gt; DNA &lt;213&gt; Homo sapien?

&lt;400&gt; 242 ccgaggtcct gggacgcaac caatcactct gttccacgtg acttttatca ccatacaatt 60 tgtggcattt cctcattttc tacattgtag aatcaagagt gtaaataaat gtatatcgat 120 gtcttcaaga atatatcatt cctttttcac tagaacccat tcaaaatata agtcaagaat 180 cttaatatca acaaatatat caagcaaact ggaaggcaga ataactacca taatttagta 240 taagtaccca aagttttata aaccaaaagc cctaatgata accattttta gaattcaatc 300 and 301

<td colspan="2">&lt;21O&gt; 243 &lt;211&gt; 301 &lt;212&gt; DNA &lt;213&gt; Homo sapiens</td>

<td> &lt;400&gt;</td><td> 243</td>

aggtaagtcc cagtttgaag ctcaaaagat ctggtatgag cataggctca tcgacgacat 60 ggtggcccaa gctatgaaat cagagggagg ccccatctgg gcctgtaaaa actatgatgg 120

PL 200 772 Β1

135 tgacgtgcag tcggactctg tggcccaagg gtatggctct ctcggcatga tgaccagcgt 180 gctggtttgt ccagatggca agacagtaga agcagaggct gcccacggga ctgtaacccg 240 tcactaccttacgcaggagttccga gccagtgagttcaga accagtgagttcaga accagtgagttcaga accagtggttcaga accagtgagttcaga 240 244 &lt;211? 300 &lt;212? DNA &lt;213? Homo sapiens &lt;400? 244 gctggtttgc aagaatgaaa tgaatgattc tacagctagg acttaacctt gaaatggaaa 60 gtcatgcaat cccatttgca ggatctgtct gtgcacatgc ctctgtagag agcagcattc 120 ccagggacct tggattactacgcagt tggggacct tggattactacgcagt tggggacct tggattactacgcagt tggcaccta atggtgaaaa cgtcttcctt ctttattgcc ccttcttatt tatgtgaaca 240 actgtttgtc ttttgtgtat cttttttaaa ctgtaaagtt caattgtgaa aatgaatatc 300 &lt;210? 245 &lt;211? 301 &lt;212? DNA &lt;213? Homo sapienS &lt;400? 245 gtccgagtat ttaaaatgtt attgaaatta tccccaacca atgttagaaa agagagaggt 60 tatatactta gataaaaaat gaggtgaatt actatccatt gaaatcatgc tcttagaatt 120 aaggccagga gatattgtca ttaatgtara cttcaggaca ctagagtata gcagccctat 180 gttttcaaag agcagagatg caattaaata ttgtttagca tcaaaaaggc cactcaatac 240 agctaataaa atgaaagacc taatttctaa agcaattctt tataatttac aaagttttaa 300 g 301 &lt;210? 246 &lt;211? 301 &lt;212? DNA &lt;213? Homo sapienS &lt;400? 246 ggtctgtcct acaatgcctg cttcttgaaa gaagtcggca ctttctagaa tagctaaata 60 acctgggctt attttaaaga actatttgta gctcagattg gttttcctat ggctaaaata 120 agtgcttctt gtgaaaatta aataaaacag ttaattcaaa gccttgatat atgttaccac 180 taacaatcat actaaatata ttttgaagta caaagtttga catgctctaa agtgacaacc 240 caaatgtgtc ttacaaaaca cgttcctaac aaggtatgct ttacactacc aatgcagaaa C 301 300 &lt;210? 247 &lt;211? 301 &lt;212? DNA &lt;213? Homo sapienS &lt;400? 247 aggtcctttg gcagggctca tggatcagag ctcaaaccgg agggaaaggc atttcgggta 60 gcctaagagg gcgactggcg gcagcacaac caaggaaggc aaggttgttt cccccacgct 120 gtgtcctgtg ttcaggtgcg acacacaatc ctcatgggaa caggatcaco catgcgctgc 180 ccttgatgat caaggttggg gcttaagtgg attaagggag gcaagttccg ggttccttgc 240 cttttcaaac catgaagtca ggctctgtat ccctcctttt cctaactgat attctaacta 300 and 301

136

PL 200 772 B1

<td>&lt;2l0&gt;</td><td> 248</td>

<td> &lt;211&gt;</td><td> 301</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapier &amp;</td>

<td> &lt;400&gt;</td><td> 248</td>

aggtccttgg agatgccatt tcagccgaag gactcttctw ttcggaagta caccctcact attaggaaga ttcttagggg taatttttct gaggaaggag aactagccaa cttaagaatt acaggaagaa agtggtttgg aagacagcca aagaaataaa agcagattaa attgtatcag gtacattcca gcctgttggc aactccataa aaacatttca gattttaatc ccgaatttag ctaatgagac tggatttttg ttttttatgt tgtgtgtcgc agagctaaaa actcagttcc c

120

180

240

300

301

<td> &lt;210&gt;</td><td> 249</td>

<td> &lt;211&gt;</td><td> 301</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapien S.</td>

<td> &lt;400&gt;</td><td> 249</td>

gtccagagga agcacctggt gctgaactag gcttgccctg ctgtgaactt gcacttggag ccctgacgct gctgttctcc ccgaaaaacc cgaccgacct ccgcgatctc cgtcccgccc ccagggagac acagcagtga ctcagagctg gtcgcacact gtgcctccct cctcaccgcc catcgtaatg aattattttg aaaattaatt ccaccatcct ttcagattct ggacggaaag actgaatctt tgactcagaa ttgcttgctg aaaagaatga r.gtgactttc and ttagtcactt

12 0 180 240

300

301

<td> &lt;210&gt;</td><td> 250</td>

<td> &lt;211&gt;</td><td> 301</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapiens</td>

<td> &lt;400&gt;</td><td> 250</td>

ggtctgtgac aaggacttgc aggctgtggg aggcaagtga cccttaacac tacacttctc cttatcttta ttggctcgat aaacataatt atttctaaca ctagcttatt tccagttgcc cataagcaca tcagtacttt tctctggctg gaatagtaaa ctaaagtatg gtacatctac ctaaaagact actatgtgga ataatacata ctaatgaagt attacatgae ttaaagacta caataaaacc aaacatgctt ataacattaa gaaaaacaat aaagatacat and gattgaaacc

120

160

240

300

301

<td> &lt;210&gt;</td><td> 251</td>

<td> &lt;211&gt;</td><td> 301</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapiens</td>

<td> &lt;400&gt;</td><td> 251</td>

gccgagaccc tacatttggc ccagtctccc ccTtgcaccct ctccagggcc cccgcctcac agacaacctc atagagcata ggagaactgg ttgccctggg ggcaggggga ctgtctggat ggcaggggtc ctcaaaaatg ccactgccac tgccaggaaa tgcttctgag cagtacacct cattgggatc aacgaaaagc ttcaagaaat cttcaggctc actctcttga aggcccggaa cctctggagg ggggcagtgg aaccccagct ccaggacgga ccctg ^ c ^ c gaa aagatatcct

120

180

240

300

301 &lt;210&gt; 252 &lt;211&gt; 301

PL 200 772 Β1

137 &lt;212 »DNA &lt;213» Homo sapiens &lt;400 »252 gcaaccaatc actctgtttc acgtgacttt tatcaccata caatttgtgg catttcctca 60 ttttctacat tgtagaatca agagtgtaaa taaatgtata tcgatgtctt caagaatata 120 tcattccttt ttcactagga acccattcaa aatataagtc aagaatctta atatcaacaa ISO atatatcaag caaactggaa ggcagaataa ctaccataat ttagtataag tacccaaagt 240 tttataaatc aaaagcccta atgataacca tttttagaat ccaatcatca ctgtagaatc 300 and 301 &lt;210 »253 &lt;211» 301 &lt;212 »DNA &lt;213&gt; Homo sapienS &lt;400» 253 ttccctaaga agatgttatt ttgttgggtt ttgttccccc tccatctcga ttctcgtacc 60 caactaaaaa aaaaaaataa agaaaaaatg tgctgcgttc tgaaaaataa ctccttagct 120 tggtctgatt gttttcagac cttaaaatat aaacttgttt cacaagcttt aatccatgtg 180 gatttttttt cttagagaac cacaaaacat aaaaggagca agtcggactg aatacctgtt 240 tccatagtgc ccacagggta ttcctcacat tttctccata ggaaaatgct ttttcccaag 300 g 301 &lt;210 »254 &lt;211&gt; 301 &lt;212&gt; DNA &lt;213&gt; Homo sapien} &lt;400 »254 cgctgcgcct ttcccttggg ggaggggcaa ggccagaggg ggtccaagtg cagcacgagg 60 aacttgacca attcccttga agcgggtggg ttaaaccctg taaatgggaa caaaatcccc 120 ccaaatctct tcatcttacc ctggtggact cctgactgta gaattttttg gttgaaacaa 180 gaaaaaaata aagctttgga cttttcaagg ttgcttaaca ggtactgaaa gactggcctc 240 acttaaactg agccaggaaa agctgcagat ttattaatgg gtgtgttagt gtgcagtgcc 300 t 301 &lt;210 »255 &lt;211» 302 &lt;212 »DNA &lt;213» Homo sapiens &lt;400 »255 agcttttttt tttttttttt tttttttttt ttcattaaaa aatagtgctc tttattataa 60 attactgaaa tgtttctttt ctgaatataa atataaatat gtgcaaagtt tgacttggat 120 tgggattttg ttgagttctt caagcatctc ctaataccct caagggcctg agtagggggg 180 aggaaaaagg actggaggtg gaatctttat aaaaaacaag agtgattgag gcagattgta 240 aacattatta aaaaacaaga aacaaacaaa a'aaatagaga aaaaaaccac cccaaco »DNA 300 aa 302 &lt;210» 256 &lt;212 &lt;212

138

PL 200 772 Β1 gttccagaaa aggaccctcc acccccaaaa aggcaaatag gtggcctctc t

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td colspan="2">misc feature</td>

<td> &lt;222&gt;</td><td> (1) .</td><td> . . (301)</td>

<td> &lt;223&gt;</td><td>n =</td><td>A, T, C Ιΐώ G</td>

<td> &lt;400&gt;</td><td> 256</td><td></td>

acattgaagg tccccacacc gcctggacac ctgctggcaa ggcctggtta tggcttccca tcaacccacc cttgagcaca actggcatta gcaagaacat aagtctaact aaaccatcca cagttatgac cctggtttgt tcagggtagg agggataccc taatgcaccc caggacagac ggggatgggg cctaagttan cctctagcct agataggccc tcatctctat gggcaagtgt tcgtgttagt

120

180

240

300

301 gttgtggagg tccccactta tcttacctag gtcacattac tcttaatctt c

<td colspan="2">&lt;21O&gt; 257 &lt;211&gt; 301 &lt;212&gt; DNA &lt;213&gt; Homo sapienS</td>

<td> &lt;400&gt;</td><td> 257</td>

aactctggct tttttgtctt tccagtctac tcccttcagt cacatcttta tgctcattaa tcactatcgc cccctggagt gatctcttgt atcttatctc gtcctactga aggccttaga tagaatggcc agaagtgcca tttgactcct ttttcactat agaggtctac atcctgaagt atccctgaat ctttacaccg cccctgaatt ctgcctccag gaaaagtaat gccaccaaga gagaaggctc

120

180

240

300

301 cagcagtagt aggggcccag cccagggcaa atgtctcggg tggtgatccc t

<td> &lt;210&gt;</td><td> 258</td><td></td>

<td> &lt;211&gt;</td><td> 301</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>wheezing</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td>(1Ϊ</td><td> 7.(301)</td>

<td> &lt;223&gt;</td><td>n * j</td><td>», T, c iu (&gt;</td>

<td> &lt;400&gt;</td><td> 258</td><td></td>

agatgccgta ccaccaggcg caagaatcca catcgaggct tgggagcgcc tgccagcacg cagaagcaag ataccaggac gtcaataana ggtggagtaa cccagcactc ataaacagta tgggcaaaat cgctgatccc cgttggtcca ccaggatcag ggctcaagac cttcaaagat ctgctgtatg tggaaagcag caccagcacc cagagccacc cttaacactg gtggtgtcat cgcccacaac

120

180

240

300

301 &lt;210&gt; 259 &lt;211&gt; 301 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;220&gt;

&lt;22l&gt; misc_feature &lt;222&gt; &lt;l) ... (301) &lt;223&gt; n = A, T, C, and Jci G &lt;400&gt; 259

PL 200 772 Β1

139 tcatatatgc aaacaaatgc agactangcc tcaggcagag actaaaggac atctcttggg 60 gtgtcctgaa gtgatttgga cccctgaggg cagacaccta agtaggaatc ccagtgggaa 120 gcaaagccat aaggaagccc aggattcctt gtgatcagga agtgggccag gaaggtctgt 180 tccagctcac atctcatctg catgcagcac ggaccggatg cgcccactgg gtcttggctt 240 ccctcccatc ttctcaagca gtgtccttgt tgagccattt gcatccttgg ctccaggtgg 300 c 301 &lt;210&gt; 260 &lt;211&gt; 301 &lt;212&gt; DNA &lt; 213&gt; Homo sapiens &lt;400&gt; 260 ttttttttct ccctaaggaa aaagaaggaa caagtctcat aaaaccaaat aagcaatggt 60 aaggtgtctt aacttgaaaa agactaggag tcactggttt acaagttata attgaatgaa 120 agaactgtaa cagccacagt tggccatttc atgccaatgg cagcaaacaa caggattaac 180 tagggcaaaa taaataagtg tgtggaagcc ctgataagtg cttaataaac agactgattc 240 actgagacat cagtacctgc ccgggcggcc gctcgagccg aattctgcag atatccatca 300 c 301 &lt;210&gt; 261 &lt;211&gt; 301 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 261 aaatattcga gcaaatcctg taactaatgt gtctccataa aaggctttga actcagtgaa 60 tctgcttcca tccacgattc tagcaatgac ctctcggaca tcaaagctcc tcttaaggtt 120 agcaccaact attccataca attcatcagc aggaaataaa ggctcttcag aaggttcaat 180 ggtgacatcc aatttcttct gataatctag attcctcaca accttcctag ttaagtgaag 240 ggcatgatga tcatccaaag cccagtggtc acttactcca gactttctgc aatgaagatc 300 and 301 &lt;210&gt; 262 &lt;211&gt; 301 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 262 gaggagagcc tgttacagca tttgtaagca cagaatactc caggagtatt tgtaattgtc 60 tgtgagcttc ttgccgcaag tctctcagaa atttaaaaag atgcaaatcc ctgagtcacc 120 cctagacttc ctaaaccaga tcctctgggg ctggaacctg gcactctgca tttgtaatga 180 gggctttctg gtgcacacct aattttgtgc atctttgccc taaatcctgg attagtgccc 240 catcattacc cccacattat aatgggatag attcagagca gatactctcc agcaaagaat 300 c 301

<td> &lt;210&gt;</td><td> 263</td><td></td>

<td>&lt;2ll&gt;</td><td> 301</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td>&lt;2l3&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc.</td><td>.feature</td>

<td> &lt;222&gt;</td><td>ii) /</td><td> ..(301)</td>

<td> &lt;223&gt;</td><td>n = _vol</td><td>ATC | uL</td>

140

GB 200 772 B1 &lt;400&gt; 263 tttagcctgt ggtaaatgac tcacaaaact gattttaaaa tcaagttaat gtgaatcttg 60 aaaateacta cttaatccta attcacaata acaatggcat taaggtttga ctcgagttgg 120 tccttagcat tatttatggt aaataggctc ttaccacttg caaataactg gccacatcat 180 taatgactga cttcccagta aggctctcta aggggtaagt angaggatcc acaggacttg 240 agatgctaag gccccagaga tcgttcgatc caaccctctt attttcagag gggaaaatgg 300 g 301 &lt;210&gt; 264 &lt; 211&gt; 301 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 264 ccagacgttc aaccactcta ctaccacttg tggaactctc accgggccac tgacaaascc 60 aatgaatgac tctaaaaccc atatttacat ttaatggttt gtagacaata ccccccccag 120 gtggatcgct caagaatcga aacatttcaa gaaaaccata scatttgaca gatgagaaag 180 ctcaattata gatgcaaagt tataactaaa ctactatagt agtaaagaaa tacatttcac 240 acccttcata taaattcact atctcggctt gaggcactcc ataaaatgta tcacgtgcat 300 and 301 &lt;210&gt; 265 &lt;211&gt; 301 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt; 400&gt; 265 tgcccaagtc atgtgtaagt gtatccgcac ccagaggtaa aactacactg tcatctttgt 60 cttcttgtga cgcagtattt cttctctggg gagaagccgg gaagtcttct cctggctcta 120 catattcttg gaagtctcta atcaactttt gttccatttg attcatatca tcaggaggga 180 atttcagεta gtcaacatgt tctctaacaa cacttgccca tttctgtaaa gaatccaaag 240 cagtccaagg ctttgacatg tcaacaacca gcacaactag agtatccetc agagatacgg 300 c 301 &lt;210&gt; 266 &lt;211&gt; 301 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 266 taccgtctgc ccttcctccc atccaggcca cctgcgaatc tacatgggtc ctcctattcg 60 acaccagatc actctatcca ctacccacag gcttgctatg agcaagagac acaacctcct 120 ctcttctgtg atccagcacc cctcccaccc cataagεtca attcctgggg 180 atagagacac caatacccaa aacctctcac ctaagcctcc ttataaccca gggtgcacag 240 cacegactcc tgacaactgg taaggccaac gaaccgggag ctcacagctg gctgtgcctg 300 a 301

<td>&lt;2l0&gt;</td><td> 267</td>

<td> &lt;211&gt;</td><td> 301</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo gasps</td>

<td> &lt;400&gt;</td><td> 267</td>

aaagagcaca ggccagccca gcctgccctg gccatctaga ctcagcctgg ctccatgggg 60

PL 200 772 Β1

141 gttctcagtg ctgagtccat ccaggaaaag ctcacctaga ccttctgagg ctgaaccttc 120 atcctcacag gcagcttctg agagcctgat attcctagcc ttgatggtct ggagtaaagc 180 ctcattctga ttcctctcct tcttttcttC caagctggct ttcctcacat ccctctgttc 240 aattcgcttc agctcgtctg ctttagccct catttccaga agcttcttct ctttggcatc 300 t 301 &lt;210 »268 &lt;211&gt; 301 &lt;212» DNA &lt;213 »Homo sapiens &lt;400» 268 aatgtctcac tcaactactt cccagcctac cgtggcctaa tcctgggagt tttcttctta 60 gatcttggga gagctggttc ttctaaggag aaggaggaag gacagatgta actttggatc 120 tcgaagagga agtctaatgg aagtaattag tcaacggtcc ttgttcagac tcttggaata 180 tgctgggtgg ctcagtgagc ccttttggag aaagcaagta ttattcttaa ggagtaacca 240 cttcccattg ttctactttc taccatcatc aattgtatat tatgtattct ttggagaact 300 and 301 &lt;210 »269 &lt;211» 301 &lt;212 »DNA &lt;213» Homo sapiens &lt;400 »269 taacaatata cactagctat ctttttaact gtccatcatt agcaccaatg aagattcaat 60 aaaattacct ttattcacac atctcaaaac aattctgcaa attcttagtg aagtttaact 120 atagtcacag accttaaata ttcacattgt tctctatgtc tactgaaaat aagttcacta 180 cttttctgga tattctctac aaaatcttat taaaattcct ggtattatca cccccaatta 240 tacagtagca caaccacctt atgtagtttt tacatgatag ctctgtagaa gtttcacatc 300 t 301 &lt;210 »270 &lt;211» 301 &lt;212 »DNA &lt;213» Homo sapiens &lt;400 »270 cattgaagag cttttgcgaa acatcagaac acaagtgctt ataaaattaa ttaagcctta 60 cacaagaata catattcctt ttatttctaa ggagttaaac atagatgtag ctgatgtgga 120 gagctcgctg gtgcagtgca tattggataa cactattcat ggccgaattg atcaagtcaa 180 ccaactcctt gaactggatc atcagaagaa gggtggtgca cgatatactg cactagataa 240 tggaccaacc aactaaattc tctcaccagg ctgtatcagt aaactggctt aacagaaaac 300 a 301

<td>&lt;21O&gt;</td><td> 271</td><td></td>

<td> &lt;211&gt;</td><td> 301</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapienS</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>_feature</td>

<td> &lt;222&gt;</td><td> (1) .</td><td> . . (301)</td>

<td> &lt;223&gt;</td><td>n »</td><td>A, T, C luJo</td>

142

PL 200 772 Β1 &lt;400? 271 aaaaggttct cataagatta acaatttaaa taaatatttg atagaacatt ctttctcatt 60 ttcatagctc atctttaggg ttgatattca gttcatgctt cccttgctgt tcttgatcca 120 gaattgcaat cacttcatca gcctgtattc gctccaattc tctataaagt gggtccaagg 180 tgaaccacag agccacagca cacctctttc ccctggtgac tgccttcacc ccatganggt 240 tctctcctcc agatganaac tgatcatgcg cccacatttt gggtttcata gaagcagtca 300 c 301 &lt;210? 272 &lt;211? 301 &lt;212? DNA &lt;213? Homo sapienj &lt;400? 272 taaattgcta agccacagat aacaccaatc aaatggaaca aatcactgtc ttcaaatgtc 60 ttatcagaaa accaaatgag cctggaatct tcataatacc taaacatgcc gtatttagga 120 tccaataatt ccctcatgat gagcaagaaa aattctttgc gcacccctcc tgcatccaca 180 gcatcttctc caacaaacat aaccttgagt ggcttcttgt aatctatgtt ctttgtttcc 240 ctaaggactt ccattgcatc tcctacaata ttttctctac gcaccactag aattaagcag 300 9 301

<td> &lt;210&gt;</td><td> 273</td><td></td>

<td> &lt;211&gt;</td><td> 301</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapienj</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1) . .</td><td> .(301)</td>

<td> &lt;223&gt;</td><td>n = A</td><td>, T, C lufo</td>

<td> &lt;400&gt;</td><td> 273</td><td></td>

acatgtgtgt atgtgtatct ttgggaaaan aanaagacat cttgtttayt atttttttgg 60 agagangctg ggacatggat aatcacwtaa tttgctayta tyactttaat ctgactygaa 120 gaaccgtcta aaaataaaat ttaccatgtc dtacattcct tatagtatgc ttatttcacc 180 ttytttctgt ccagagagag tatcagtgac ananatttma gggtgaamac atgmattggt 240 gggacttnty tttacngagra accctgcccg sgcgccctcg makcngantt ccgcsananc 301 300 t &lt;210? 274 &lt;211? 301 &lt;212? DNA &lt;213? Homo sapienS &lt;220?

&lt;221? misc_feature &lt;222? (1). .. (301) &lt;223? n = ATC lufo G &lt;400? 274 cttatatact ctttctcaga ggcaaaagag gagatgggta atgtagacaa ttctttgagg 60 aacagtaaat gattattaga gagaangaat ggaccaagga gacagaaact aacttgtaaa 120 tgattctctt tggaatccga atgagatcaa gaggccagct ttagcttgtg gaaaagtcca 180 tctaggtatg gttgcatcct cgccttcttt tccgcagcag ataatgaggt aaccgaaggc 240 aattgtgctt cttttgacaa gaagctttct tggtcatatc aggaaattcc aganaaagtc 300

PL 200 772 Β1

143

<td> &lt;210&gt;</td><td> 275</td><td></td>

<td> &lt;211&gt;</td><td> 301</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapien?</td>

<td>&lt;22O&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>_feature</td>

<td> &lt;222?</td><td> (1)</td><td> . . (301)</td>

<td> &lt;223&gt;</td><td>n =.</td><td>A, T, C hatch</td>

<td> &lt;400?</td><td> 275</td><td></td>

tcggtgtcag cagcacgtgg cattgaacat tgcaatgtgg agcccaaacc acagaaaatg gggtgaaatt ggccaacttt ctattaactt atgttggcaa ttttgccacc aacagtaagc tggcccttct aataaaagaa aattgaaagg tttctcacta aacggaatta agtagtggag tcaagagact cccaggcctc agcgtacccg cccgggcggc cgctcgaagc cgaattctgc agatatccat cacactggcg gncgctcgan catgcatcta gaaggnccaa and ttcgccctat

<td colspan="2">&lt;210&gt; 276 &lt;211&gt; 301 &lt;212&gt; DNA &lt;213&gt; Homo sapien ^</td>

<td> &lt;400&gt;</td><td> 276</td>

tgtacacata ctcaataaat aaatgactgc attgtggtat tattactaca ctgattacat ttatcacgtg acctctaatt agaaaatgta tccaaaagca aaacagcaga catacaaaat taaagagaca gaagatagac attaacagat aaggcaactt atacattgag aatccaaatc caatacatct aaacatttgg gaaatgaggg ggacaaatgg aagccagatc aaatttgtgt aaaactattc agtatgtttc ccttgcttca tgtctgagaa ggctctcctt caatggggac 9

<td> &lt;210&gt;</td><td> 277</td><td></td>

<td> &lt;211?</td><td> 301</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapien $</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>_feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (301)</td>

<td> &lt;223?</td><td>n =,</td><td>ATC who</td>

<td> &lt;400&gt;</td><td> 277</td><td></td>

ttcgttgatg tcagtatctt attacttgcg ttatgagtgc tcacctggga aatcctaaag acacagagga cttggaggaa gcagagcaac tgaatttaat ttaaaagaag gaaaacattg gaatcatggc actcctgata ctttcccaaa ccaacactct caatgcccca ccctcgtcct caccatagtg gggagactaa agtggccacg gatttgcctt angtgcgcag tgcgttctga gttcnctgtc gattacatct gaccagtctc ctttttccga agtccntccg ttcaatcttg c &lt;210&gt; 278 &lt;211&gt; 301 &lt;212&gt; DNA &lt;213&gt; Homo sapien ^

144

PL 200 772 Β1 &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (301) &lt;223&gt; n = A, T, C (c &lt;b G &lt;400&gt; 278 taccactaca ctccagcctg ggcaacagag caagacctgt ctcaaagcat aaaatggaat 60 aacatatcaa atgaaacagca cgaaacattagg cgagctacaatgaagggaaacattagg gggctacaatgacaggggctacaattca atgaaaacagg ggaaaacagca atgaaacagca 120 tgttattatg cattacctgg gaatttatat aagcccttaa taataatgcc 180 aatgaacatc tcatgtgtgc tcacaatgtt ctggcactat tataagtgct tcacaggttt 240 tatgtgttct tcgtaacttt atggantagg tactcga210gccg &lt;121&gt; &lt;12&gt; &lt;12&gt; &lt;12&gt; Homohome&gt; &lt;&gt; 301&gt; &lt;&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (301) &lt;223&gt; n = IUB ATC G &lt;400&gt; 279 aaagcaggaa Cgacaaagct tgcttttctg gtacgttcta ggtgtattgt gacttttact 60 gttatattaa ttgccaatat aagtaaatat agattatata tgtatagtgt ttcacaaagc 120 ttagaccttt accttccagc caccccacag tgctcgatat ttcagagtca gtcattggtt 180 atacatgtgt agttccaaag cacataagct agaanaanaa atatttcCag ggagcactac 240 catctgtttt cacatgaaat gccacacaca tagaactcca acatcaattt cattgcacag 300 a 301

<td> &lt;210&gt;</td><td> 280</td>

<td> &lt;211&gt;</td><td> 301</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapien&gt;</td>

<td> &lt;400&gt;</td><td> 280</td>

ggtactggag ttttcctccc ctgtgaaaac gtaactactg ttgggagtga attgaggatg 60 tagaaaggtg gtggaaccaa attgtggtca atggaaatag gagaatatgg ttctcactct 120 tgagaaaaaa acctaagatt agcccaggta gttgcctgta acttcagttt ttctgcctgg 180 gtttgatata gtttagggtt ggggtcagat taagatctaa attacatcag gacaaagaga 240 cagactatta actccacagt taattaagga ggtatgttcc atgtttattt gttaaagcag 300 t 301

<td> &lt;210&gt;</td><td> 281</td>

<td> &lt;211&gt;</td><td> 301</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo sapiens</td>

<td> &lt;400&gt;</td><td> 281</td>

aggtacaaga aggggaatgg gaaagagctg ctgctgtggc attgttcaac tcggatattc 60 gccgagcaat ccaaatcctg aatgaagggg catcttctga aaaaggagat ctgaatctca 120 atgtggtagc aatggcttta tcgggttata cggatgagaa gaactccctt tggagagaaa 180 tgtgtagcac actgcgatta cagctaaata acccgtattt gtgtgtcatg tttgcatttc 240

PL 200 772 Β1

145 tgacaagtga aacaggatct tacgatggag ttttgtatga aaacaaagtt gcagtacctc 300

301 &lt;210 »282 &lt;211» 301 &lt;212 »DNA &lt;213» Homo sapiens &lt;400 »282 caggtactac agaattaaaa tactgacaag caagtagttt cttggcgtgc acgaattgca 60 tccagaaccc aaaaattaag aaattcaaaa agacattttg tgggcacctg ctagcacaga 120 agcgcagaag caaagcccag gcagaaccat gctaacctta cagctcagcc tgcacagaag 180 cgcagaagca aagcccaggc agaaccatgc taaccttaca gctcagcctg cacagaagcg 240 cagaagcaaa gcccaggcag aacatgctaa ccttacagct cagcctgcac agaagcacag 300 a 301 &lt;210 »283 &lt;211» 301 &lt;212 »DNA &lt;213» Homo sapienS &lt;400 »283 atctgtatac ggcagacaaa ctttatarag tgtagagagg tgagcgaaag gatgcaaaag 60 cactttgagg gctttataat aatatgctgc ttgaaaaaaa aaatgtgtag ttgatactca 120 gtgcatctcc agacatagta aggggttgct ctgaccaatc aggtgatcat tttttctatc 180 acttcccagg ttttatgcaa aaattttgtt aaattctata atggtgatat gcatctttta 240 ggaaacatat acatttttaa aaatctattt tatgtaagaa ctgacagacg aatttgcttt 300 g 301 &lt;210 »284 &lt;211» 301 &lt;212 »DNA &lt;213» Homo sapienS &lt;400 »284 caggtacaaa acgctattaa gtggcttaga atttgaacat ttgtggtctt tatttacttt 60 gcttcgtgtg tgggcaaagc aacatcttcc ctaaatatat attaccaaga aaagcaagaa 120 gcagattagg tttttgacaa aacaaacagg ccaaaagggg gctgacctgg agcagagcat 180 ggtgagaggc aaggcatgag agggcaagtt tgttgtggac agatctgtgaga ccaaaaggaga aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa

<td> &lt;210»</td><td> 285</td><td></td>

<td> &lt;211»</td><td> 301</td><td></td>

<td> &lt;212»</td><td>GOUT</td><td></td>

<td> &lt;213»</td><td>Homo</td><td>sapienfe</td>

<td> &lt;220»</td><td></td><td></td>

<td> &lt;221»</td><td>misc</td><td>_feature</td>

<td> &lt;222»</td><td>(li.</td><td> . . (301)</td>

<td> &lt;223»</td><td>n =.</td><td>A, T, C or</td>

<td> &lt;400»</td><td> 285</td><td></td>

acatcaccat gatcggatcc cccacccatt atacgttgta tgtttacaca aatactcttc 60 aatgatcatt agtgttttaa aaaaaacact gaaaactcct tctgcatccc aatctctaac 120

146

GB 200 772 Β1 caggaaagca aatgctactc acagacctgc aagccctccc tcaaacnaaa ctatttctgg 180 atcaaatatg tctgacttct tttgaggtca cacgactagg caaatgctac ttacgatctg 240 caaaagctgt ttgaagagtc aaagccccca tgtgaacacg atttctggac cctgtaacag 300 t 301 &lt;210&gt; 286 &lt;211&gt; 301 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 286 taccaccgca ttccagcctg ggtgacagag tgagactccg tctccaaaaa aaactttgct 60 tgtataccat ttttgcctta cagtggatca ttctagtagg aaaggacagt aagatttttt 120 atcaaaatgt gtcatgccag taagagatgt tatattcttt tccctcattcctca 180 aaaataagct accacatagc ttataagtct caaactcttg ccttctacta aaatgtgatt 240 gtttctgttc attgcgtatg cttcatcacc tatattaggc aaattccatc ttttcccttg 300 t 301 &lt;210&gt; 287 &lt;211&gt; 301 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 287 tacagatccg ggaactaaat attaaaaatg agtgtggctg gatatatgga gaatgttggg 60 cccagaagga acgtagagat cagatattac aacagctttg ttttgagggc taaaaatatg 120 aaatgatttg gttacgaacg cacagtctag gcagcagggc cagaatcctg accctctgcc 180 ccgtggttat ctcctcccca gcttggctgc ctcatgttat cacagtattc catctcgctc 240 gttgcatgtc ttgtgaagcc atcaagattt tctcgtctgt tttcctccca ttggtaatgc 300 t 301 &lt;210&gt; 288 &lt;211&gt; 301 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 288 gtacacctaa ctgcaaggac agctgaggaa cgtaatgggc agccgctctt aaagaagtag 60 agtcaacagg aagacaaact ccagttccag ctcagtctgg gcatctgcaa agctgcaaaa 120 gatcttcaaa gacaatttca agagaatatt tccttaaagt tggcaatttg gagatcatac 180 aaaagcatct gcctctgtga tttaatttag ctcatctggc cactggaaga atccaaacag 240 tctgccttaa ttttggatga atgcatgacg gaaattcaat aatttagaaa gttaaaaaaa 300 a 301

<td> &lt;210&gt;</td><td> 289</td><td></td>

<td> &lt;211&gt;</td><td> 301</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>_f eature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> ..(301)</td>

<td> &lt;223&gt;</td><td>n - j</td><td>at.c or</td>

&lt;400&gt; 289

PL 200 772 Β1

147 ggtacactgt ttccatgtta tgtttctaca cattgctacc tcagtgctcc tggaaactta 60 gcttttgatg tctccaagta gtccaccttc atttaactct ttgaaactgt atcatctttg 120 ccaagtaaga gtggtggcct atttcagctg ctttgacaaa atgactggct cctgacttaa 180 cgttctataa atgaatgtgc tgaagcaaag tgcccatggt ggcggcgaan aagagaaaga 240 tgtgttttgt tttggactct ctgtggtccc ttccaatgct gtgggtttcc aaccagngga 301 300 and &lt;210? 290 &lt;211? 301 &lt;212? DNA &lt;213? Homo sapienS &lt;220?

&lt;221? misc_feature &lt;222? (1). . . (301) &lt;223? n = A, T, C, or G &lt;400? 290 acactgagct cttcttgata aatatacaga atgcttggca tacacaagat tctatactac 60 tgactgatct gttcatttct ctcacagctc ttacccccaa aagctttccc accctaagtg 120 ttctgacctc cttttctaat cacagtaggg atagaggcag anccacctac aatgaacatg 180 gagttctatc aagaggcaga aacagcacag aatcccagtt ttaccactcg ctagcagtgc 240 tgcccCgaac aaaaacattt ccccacgtct cattttcttc atgccccaag taacagtgag 301 300 and &lt;210? 291 &lt;211? 301 &lt;212? DNA &lt;213? Homo sapienS &lt;400? 291 caggtaccaa tttcttctat cctagaaaca tttcatttta tgttgttgaa acataacaac 60 tatatcagct agattttttt tctatgcttt acctgctatg gaaaatttga cacattctgc 120 tttactcctt tgtttatagg tgaatcacaa aatgtatttt tatgtattct gtagttcaat 180 agccatggct gtttacttca tttaatttat ttagcataaa gacattatga aaaggcctaa 240 acatgagctt cacttcccca ctaactaatt agcatctgtt atttcttaac cgtaatgcct 301 300 and &lt;210? 292 &lt;211? 301 &lt;212? DNA &lt;213? Homo sapiens &lt;220?

&lt;221? misc_feature &lt;222? (1). . . (301) &lt;223? n = A, T, C, or G &lt;400? 292 acctttcagt agtaatgtct aataataaac aagaaatcaa ttttacaagg tccatatagc 60 tgtattaaat aacttttaag cttaaaagat aaaataccat catttcaaat gttggcattc 120 aaaaccaaag natataaccg aaaggaaaaa cagatgagac ataaaatgat ttgcnagatg 180 ggaaatatag tasctyacga atgttnatta aattccagtt ataatagtgg ctacacactc 240 tcaccacaca cacagacccc acagtcctat atgccacaaa cacatctcca taacttgaaa 300 and 301

148

PL 200 772 Β1 &lt;210? 293 &lt;211? 301 &lt;212? DNA &lt;213? Homo sapien&gt;

&lt;400? 293 ggtaccaagt gctggtgcca gcctgttacc Cgttctcacc gaaaagtctg gctaatgctc 60 ttgtgtagtc acttctgatt ctgacaatca atcaatcaac ggcccagagc actgactgtt 120 aacacaaacg tcactagcaa agtagcaaca gctttaagtc taaatacaaa gctgttctgt 180 gtgagaattt tttaaaaggc tacttgtata ataacccttg tcatttttaa Cgtacctcgg 240 ccgcgaccac gctaagccga attctgcaga tatccatcac actggcggcc gctcgagcat 300 9 301

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td>294 301 GOUT Homo</td><td>sapienS</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td>U). .</td><td> .(301)</td>

<td> &lt;223&gt;</td><td>π = A</td><td>i, T, C lu.t&gt;</td>

<td> &lt;400&gt;</td><td> 294</td><td></td>

tgacccataa caatatacac tagctatctt ttcaactgtc catcattagc accaatgaag 60 attcaataaa attaccttta ttcacacatc tcaaaacaat tctgcaaatt cttagtgaag 120 tttaactata gtcacaganc ttaaatattc acattgtttt ctatgtctac tgaaaataag 180 ttcactactt ttctgggata ttctttacaa aatcttatta aaattcctgg tattatcacc 240 cccaattata cagtagcaca accaccttat gtagttttta catgatagct ctgtagaggt 301 300 t &lt;210? 295 &lt;211? 305 &lt;212? DNA &lt;213? Homo sapien ^ &lt;400? 295 gtactctttc tctcccctcc tctgaattta attctttcaa cttgcaattt gcaaggatta 60 cacatttcac tgtgatgtat attgtgttgc aaaaaaaaaa gtgtctttgt ttaaaattac 120 ttggtttgtg aatccatctt gctttttccc cattggaact agtcattaac ccatctctga 180 actggtagaa aaacrtctga agagctagtc tatcagcatc tgacaggtga attggatggt 240 tctcagaacc atttcaccca gacagcctgt ttctatcctg tttaataaat tagtttgggt 300 305 tctct

<td colspan="2">&lt;210? 296 &lt;211? 301 &lt;212? GOUT &lt;213? Homo sapien *</td>

<td> &lt;400&gt;</td><td> 296</td>

aggtactatg ggaagctgct aaaataatat ttgatagtaa aagtatgtaa tgtgctatct 60 cacctagtag taaactaaaa ataaactgaa actttatgga atctgaagtt attttccttg 120 attaaataga attaataaac caatatgagagg aaacgatgaaca attaataaac caatatgagga attaaataga attaataaac caatatgatcaa 180

PL 200 772 Β1

149 tgtcattact ataaatttta aaatctgtta ataagatggc ctatagggag gaaaaagggg c

300

301

<td> &lt;210»</td><td> 297</td><td></td>

<td> &lt;211»</td><td> 300</td><td></td>

<td> &lt;212»</td><td>GOUT</td><td></td>

<td> &lt;213»</td><td>Homo</td><td>sapien ^</td>

<td> &lt;220»</td><td></td><td></td>

<td> &lt;221»</td><td>misc__</td><td>feature</td>

<td> &lt;222»</td><td> (1)</td><td> ‘.(300)</td>

<td> &lt;223»</td><td>n = /</td><td>i, t, c or</td>

<td> &lt;400»</td><td> 297</td><td></td>

actgagtttt aactggacgc caagcaggca aggctggaag gttttgctct ctttgtgcta aaggttttga aaaccttgaa ggagaatcat tttgacaaga agtacttaag agtctagaga acaaagangt gaaccagctg aaagctctcg ggggaanctt acatgtgttg ttaggcctgt tccatcattg ggagtgcact ggccatccct caaaatttgt ctgggctggc ctgagtggtc accgcacctc ggccgcgacc acgctaagcc gaatcctgca gatatccatc acactggcgg

120

180

240

300

<td> &lt;210»</td><td> 298</td><td></td>

<td> &lt;211»</td><td> 301</td><td></td>

<td> &lt;212»</td><td>GOUT</td><td></td>

<td> &lt;213»</td><td>Homo</td><td>sapien ^</td>

<td> &lt;220»</td><td></td><td></td>

<td> &lt;221»</td><td>misc</td><td>^ feature</td>

<td> &lt;222»</td><td> (1)</td><td> (301)</td>

<td> &lt;223»</td><td>n - j</td><td>A, T, C or</td>

<td> &lt;400»</td><td> 298</td><td></td>

tatggggttt gtcacccaaa agctgatgct gagaaaggcc cccctggggc ccctcccgcg ggcacctgag agacctggtg ttccagtgtt tctggaaatg ggtcccagtg ccgccggctg tgaagctctc agatcaatca cgggaagggc ccggcggtgg tggccacctg gaaccaccct gtcctgtctg tttacattcc actaycaggt tttctctggg cattacnatc cgttccccta caacagtgac ctgtgcattc tgctgtggcc tgctgcgtct gcaggtggct ctcagcgagg t

120

180

240

300

301

<td colspan="2">&lt;210 »299 &lt;211 »301 &lt;212 »DNA &lt;213 »Homo sapiens</td>

<td> &lt;400&gt;</td><td> 299</td>

gttttgagac ggagttccac tcttgttgcc cagactggac tgcaatggca gggcctctgc tcactgcacc ctctgcctcc caggttcgag caattctcct gcctcagcct cccaggtagc tgggattgca ggctcacgcc accataccca gctaattttt ttgtattttt agtagagacg gagtttcgcc atgtcggcca gctggtctca aactcctgac ctcaagcgac ctgcctgccc cggcctccca aagtgctgga attataggca tgagtcaaca cgcccagcct aaagatattt t

120

180

240

300

301 &lt;210 »300 &lt;211» 301 &lt;212 »DNA &lt;213» Homo sapienS

150

GB 200 772 Β1 &lt;400&gt; 300 attcagtttt atttgctgcc ccagtatctg taaccaggag tgccacaaaa tcttgccaga 60 tatgtcccac acccactggg aaaggctccc acctggctac ttcctctatc agctgggcca 120 gctgcattcc acaaggtcct cagcctaatg agtttcacta cctgccagtc tcaaaactta 180 gtaaagcaag accatgacat tcccccacgg aaatcagagt ttgccccacc gtcttgttac 240 tataaagcct gcctctaaca gtccttgctt cttcacacca atcccgagcg catcccccat 300 9 301 &lt;2L0&gt; 301 &lt; 211? 301 &lt;212&gt; DNA &lt;213&gt; Homo sapienS &lt;400&gt; 301 ttaaattttt gagaggataa aaaggacaaa taatctagaa atgtgtcttc ttcagtctgc 60 agaggacccc aggtctccaa gcaaccacac ggtcaagggc atgaataatt aaaagttggt 120 gggaactcac aaagaccctc agagctgaga cacccacaac agtgggagct cacaaagacc 180 cccagagctg agacacccac aacagcggga gctcacaaag accctcagag ctgagacacc 240 cacaacagca cctcgttcag ctgccacatg tgtgaataag gatgcaatgt ccagaagtgt 300 t 301 &lt;2L0&gt; 302 &lt;211? 301 &lt;212&gt; DNA &lt;213? Homo sapien »&lt;400? 302 aggtacacat ttagcttgtg gtaaatgact cacaaaactg attttaaaat caagttaacg 60 tgaattttga aaattaccac ttaatcctaa ttcacaataa caatggcatt aaggtttgac 120 ttgagttggt tcttagtatt atttatggta aataggctcc taccacttgc aaataactgg 180 ccacatcatt aatgactgac ttcccagtaa ggctctctaa ggggtaagta ggaggatcca 240 caggatttga gatgctaagta2 ccctagta 300 ccctagta2 a ccctagta 300? 301 &lt;212? DNA &lt;213? Homo puffers &lt;400? 303 aggtaccaac tgtggaaata ggtagaggat cattttttct ttccatatca actaagttgt 60 atattgtttt tCgacagttt aacacatctt cctctgtcag agattctttc acaatagcac 120 tggctaatgg aactaccgct cgagatgctaga aactaccgct cgagatgctaga 180 tgtatggctaga atgtttttct aaccgatctt ttgctcgttc caaagggacc tcaagacttc 240 catcgatctt atacctgggg tctagaaaag gagttaatct gttctccctc ataaattcac 300 c 301

<td> &lt;210&gt;</td><td> 304</td>

<td>&lt;2ll&gt;</td><td> 301</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td>&lt;2l3&gt;</td><td>Homo sapien S.</td>

<td> &lt;400&gt;</td><td> 304</td>

acatggatgt tatttcgcag actgtcaacc tgaatttgca cttgcttgac atcgcctaat 60

PL 200 772 Β1

151 tattagtttc agtttcagct tacccacttt ttgtctgcaa catgcaraas agacagtgcc 120 ctttttagtg tatcatatca ggaatcatct cacattggtt tgtgccatta ctggtgcagt 180 gactttcagc cacttgggta aggtggagtt ggccatatgt ctccactgca aaattactga 240 ttttcctttt gtaattaata agtgtgtgtg tgaagattct ttgagatgag gtatatatcc 300 c 301 &lt;210? 305 &lt;211? 301 &lt;212? DNA &lt;213? Homo sapienj &lt;220?

&lt;221? misc_feature &lt;222? (1). . . (301) &lt;223? n = A, T, C IulU G &lt;400? 305 gangtacagc gtggtcaagg taacaagaag aaaaaaatgt gagtggcatc ctgggacgag 60 cagggggaca gacctggaca gacacgttgt catttgctgc tgtgggtagg aaaatgggcg 120 taaaggagga gaaacagata caaaacctcc aactcagtat taaggtattc tcatgcctag 180 aatattggta gaaacaagaa tacattcata tggcaaataa ctaaccatgg tggaacaaaa 240 ttctgggatt taagttggat accaangaaa ttgtattaaa agagctgttc atggaataag 301 300 and &lt;210? 306 &lt;211? 8 &lt;212? PRT &lt;213? Homo sapiens &lt;400? 306

Val Leu Gly Trp Val Ala Glu Leu 1 5 &lt;210? 307 &lt;211? 637 &lt;212? DNA &lt;213? Homo wheezing &lt;400? 307 acagggratg aagggaaagg gagaggatga ggaagccccc ctggggattt ggtttggtcc 60 ttgtgatcag gtggtctatg gggcttatcc ctacaaagaa gaatccagaa ataggggcac 120 attgaggaat gatacttgag cccaaagagc attcaatcat cgttttattt gccttmtttt 180 cacaccattg gtgagggagg gattaccacc ctggggttat gaagatggtt gaacacccca 240 cacatagcac cggagatatg agatcaacag cttcttagcc atagagattc acagcccaga 300 gcaggaggac gcttgcacac catgcaggat gacatggggg atgcgctcgg gattggtgtg 360 aagaagcaag gactgttaga ggcaggcttt atagtaacaa gacggtgggg caaactctga 420 tttccgtggg gaaatgtcat ggtcttgctt tactaagttt tgagactggc aggtagtgaa 480 actcattagg ccgagaacct tgtggaatgc acttgaccca sctgatagag gaagtagcca 540 ggtgggagcc tttcccagtg ggtgtgggac atatctggca agattttgtg gcactcctgg 600 ttacagatac tggggcagca aataaaactg aatcttg 637 &lt;210? 308 &lt;211? 647 &lt;212? DNA &lt;213? Homo sapiens

152

PL 200 772 Β1 &lt;220 »&lt;221» misc_feature &lt;222&gt; (1). . . (647) &amp; lt; 223 &amp; gt; n = A, T, Cl_atb G &lt;400 »308 acgattttca ttatcatgta aatcgggtca ctcaaggggc caaccacagc tgggagccac 60 tgctcagggg aaggttcata tgggactttc tactgcccaa ggttctatac aggatataaa 120 ggngcctcac agtatagatc tggtagcaaa gaagaagaaa caaacactga tctctttctg 180 ccacccctct gaccctttgg aactcctctg accctttaga acaagcctac ctaatatctg 240 ctagagaaaa gaccaacaac ggcctcaaag gatctcttac catgaaggtc tcagctaatt 300 cttggctaag atgtgggtcc cacattaggt tctgaatatg gggggaaggg tcaatttgct 360 cattttgtgt gtggataaag tcaggatgcc caggggccag agcagggggc tgcttgcttt 420 gggaacaatg gctgagcata taaccatagg ttatggggaa caaaacaaca tcaaagtcac 480 tgtatcaatt gccatgaaga cttgagggac ctgaatctac cgattcatct taaggcagca 540 ggaccagttt gagtggcaac aatgcagcag cagaatcaat ggaaacaaca gaatgattgc 600 aatgtcctct tctttctcct gcttctgact tgataaaagg ggaccgt 647 &lt;210 »309 &lt;211» 460 &lt;212 »DNA &lt;213» Homo sapiens &lt;400 »309 actttacagt ttaggctgga cattggaaoa aaaaaaaagc cagaacaaca tgtgafagac 60 aatatgattg gctgcacact tccagactga tgaatgatga acgtgatgga ctattgtatg 120 gagcacatct tcagcaagag ggggaaatac tcatcatttt tggccagcag ttyttcgacc 180 accaaacatc atgccagaat actcagcaaa ccttcttagc tcttgagaag tcaaagtccg 240 ggggaattta ttcctggcaa ttttaattgg actccttatg tgagagcagc ggctacccag 300 ctggggtggt ggagcgaacc cgtcactagt ggacatgcag tggcagagct cctggtaacc 360 acctagagga atacacaggc acatgtgtga tgccaagcgt gacacctgta gcactcaaat 420 ttgtcttgtt tttgtctttc ggtgtgtaag attcctaagt 460 &lt;210 »310 &lt;211» 539 &lt;212 »DNA &lt;213 »Homo sapienS &lt;400» 310 acgggactta tcaaataaag ataggaaaag aagaaaactc aaatattata ggcagaaatg 60 ctaaaggttt taaaatatgt caggattgga agaaggcatg gataaagaac aaagttcagt 120 taggaaagag aaacacagaa ggaagagaca caataaaagt cattatgtat tctgtgagaa 180 gtcagacagt aagatttgtg ggaaatgggt tggtttgttg tatggtatgt attttagcaa 240 taatctttat ggcagagaaa gctaaaatcc tttagcttgc gtgaatgatc acttgctgaa 300 ttcctcaagg taggcatgat gaaggagggt ttagaggaga cacagacaca atgaactgac 360 ctagatagaa agccttagta tactcagcta ggaatagtga ttctgagggc acactgtgac 420 atgattatgt cattacatgt atggtagtga tggggatgat aggaaggaag aacttatggc 480 atatcttcac ccccacaaaa gtcagttaaa tatcgggaca ctaaccaccc aggtcaaga 539 &lt;210 »311 &lt;211» 526 &lt;212 »DNA &lt;213» Homo sapiens

PL 200 772 Β1

153 &lt;220&gt;

&lt;221? misc_feature &lt;222&gt; (1) ... (526) &lt;223? n = ATC / or a G &lt;400&gt; 311 caaatttgag ccaatgacat agaattttac aaatcaagaa gcttattctg gggccatttc 60 ttttgacgtt ttctctaaac tactaaagag gcattaatga tccataaatt atattatcta 120 catttacagc atttaaaatg tgttcagcat gaaatattag ctacagggga agctaaataa 180 attaaacatg gaataaagat ttgtccttaa atataatcta caagaagact ttgatatttg 240 tttttcacaa gtgaagcatt cttataaagt gtcataacct ttttggggaa actatgggaa 300 aaaatgggga aactctgaag ggttttaagt atcttacctg aagctacaga ctccataacc 360 tctctttaca gggagctcct gcagccccta cagaaatgag tggctgagat tcttgattgc 420 acagcaagag cttctcatct aaaccctttc cctttttagt atctgtgtat caagtataaa 480 agttctataa actgtagtnt acttatttta atccccaaag 526

<td> &lt;210&gt;</td><td> 312</td><td></td>

<td> &lt;211&gt;</td><td> 500</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>sapiens</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1) .7</td><td> (500)</td>

<td> &lt;223&gt;</td><td colspan="2">n = ATC luli G.</td>

<td>&lt;4O0&gt;</td><td> 312</td><td></td>

cctctctctc cccaccccct gactctagag aactgggttt tctcccagta ctccagcaat 60 tcatttctga aagcagttga gccactttat tccaaagtac actgcagatg ttcaaactct 120 ccatttctct ttcccttcca cctgccagtt ttgctgactc tcaacttgtc atgagtgtaa 180 gcattaagga cattatgctt cttcgattct gaagacaggc cctgctcatg gatgactctg 240 gcttcttagg aaaatatttt tcttccaaaa tcagtaggaa atctaaactt atcccctctt 300 tgcagatgtc tagcagcttc agacatttgg ttaagaaccc atgggaaaaa aaaaaatcct 360 tgctaatgtg gtttcctttg taaaccanga ttcttatttg nctggtatag aatatcagct 420 ctgaacgtgt ggtaaagatt tttgtgtttg aatataggag aaatcagttt gctgaaaagt 480 tagtcttaat tatctattgg 500 &lt;210? 313 &lt;211? 718 &lt;212&gt; DNA &lt;213? Homo sapienS &lt;220&gt;

&lt;221? misc_feature &lt;222? (1). .. (718) &lt;223? n = ATC or G &lt;400? 313 ggagatttgt gtggtttgca gccgagggag accaggaaga tctgcatggt gggaaggacc 60 tgatgataca gaggtgagaa ataagaaagg ctgctgactt taccatctga ggccacacat 120 ctgctgaaat ggagataatt aacatcacta gaaacagcaa gatgacaata taatgtctaa 180 gtagtgacat gtttttgcac atttccagcc cttttaaata tccacacaca caggaagcac 240 aaaaggaagc acagagatcc ctgggagaaa tgcccggccg ccatcttggg tcatcgatga 300 gcctcgccct gtgcctgntc ccgcttgtga gggaaggaca ttagaaaatg aattgatgtg 360 ttccttaaag gatggcagga aaacagatcc tgttgtggat atttatttga acgggattac 420

154

GB 200 772 Β1 agattcgaaa tgaagtcaca aagtgagcat taccaatgag aggaaaacag acgagaaaat 480 cttgatggtt cacaagacat gcaacaaaca aaatggaaca ctgtgatgac acgagcagcc 540 aactggggag gagataccac ggggcagagg tcaggattct ggccctgctg cctaactgtg 600 cgttatacca atcatttcta tttctaccct caaacaagct gtngaatatc tgacttacgg 660 ctcttntggc ccacattttc atnatccacc ccntcntttt aannttantc caaantgt 718 &lt;210&gt; 314 &lt;211? 358 &lt;212? DNA &lt;213? Homo sapiena &lt;400? 314 gttcatttac attacagaaa aaacatcaag acaatgtata ctatttcaaa tatatccata 60 cataatcaaa tatagctgta gcacatgttt ccattggtgt agattaccac aaatgcaagg 120 caacatgtgt agatctcttg tcttattctt ttgtctataa tactgtattg tgcagtccaa 180 gctctcggta gtccagccac tgtgaaacat gctcccttta gattaacctc gtggacgctc 240 ttgttgtatt gctgaactgt agtgccctgt attttgcttc tgCctgtgaa ttctgttgct 300 tctggggcac ttccttgtga tgcagaggac caccacacag atgacagcaa tctgaatt 358 &lt;210? 315 &lt;211&gt; 341 &lt;212? DNA &lt;213? Homo sapienS &lt;400? 315 taccacctcc ccgctggcac tgatgagccg catcaccatg gtcaccagca ccatgaaggc 60 ataggtgatg atgaggacat ggaatgggcc cccaaggatg gtctgtccaa agaagcgagt 120 gacccccatt ctgaagaCgt ctggaacctc taccagcagg atgatgatag ccccaatgac 180 agtcaccagc tccccgacca gccggatatc gtccttaggg gtcacgtagg cttcctgaag 240 tagcttctgc tgtaagaggg tgttgtcccg ggggctcgtg cggttattgg tcctgggctt 300 gagggggcgg tagatgcagc acatggtgaa gcagatgatg t 341

<td> &lt;210?</td><td> 316</td>

<td> &lt;211?</td><td> 151</td>

<td> &lt;212?</td><td>GOUT</td>

<td> &lt;213?</td><td>Homo sapien?</td>

<td> &lt;400&gt;</td><td> 316</td>

agactgggca agactcttac gccccacace gcaatttggt cttgttgccg tatccattta 60 tgtgggcctt tctcgagttt ccgattataa acaccactgg agcgatgtgt tgactggact 120 catccaggga gctctggttg &lt;210 catccaggga gctctggttg &lt;210 caat? 317 &lt;211? 151 &lt;212? DNA &lt;213? Homo sapiens &lt;400? 317 agaactagtg gatcctaatg aaatacctga aacacatatt ggcatttatc aatggctcaa 60 atcttcattt atctctggcc ttaaccctgg ctcctgaggc tgcggccagc agatcccagg 120 ccagggctct gttacctgctcagg 120 ccagggctct gttacctggctca gttacctggtca 318 &lt;211? 151 &lt;212? GOUT

PL 200 772 Β1

155 &lt;213? Homo sapiens &lt;400&gt; 318 actggtggga ggcgctgttt agttggctgt tttcagaggg gtctttcgga gggacctcct gctgcaggct ggagtgtctt tattcctggc gggagaccgc acattccact gacagaggggg tggca tgtccact gacagagggcggca

<td colspan="2">&lt;21O&gt; 319 &lt;211&gt; 151 &lt;212&gt; DNA &lt;213&gt; Homo sapiens</td>

<td> &lt;400&gt;</td><td> 319</td>

aactagtgga tccagagcta taggtacagt gtgatctcag ctttgcaaac acattttcta catagatagt actaggtatt aatagatatg taaagaaaga aatcacacca ttaataatgg taagattggg tttatgtgat tttagtgggt a &lt;210? 320 &lt;211&gt; 150 &lt;212? DNA &lt;213&gt; Homo sapiens &lt;400&gt; 320 aactagtgga tccactagtc cagtgtggtg gaattccatt gtgttggggt tctagatcgc gagcggctgc cctttttttt tttttttttg ggggggaatt tttttttttt aatttacagtta gagtgttatta gagtctcat

<td colspan="2">&lt;210&gt; 321 &lt;211&gt; 151 &lt;212&gt; DNA &lt;213&gt; Homo sapiens</td>

<td> &lt;400&gt;</td><td> 321</td>

agcaactttg tttttcatcc aggttatttt aggcttagga tttcctctca cactgcagtt tagggtggca ttgtaaccag ctatggcata ggtgttaacc aaaggctgag taaacatggg tgcctctgag aaatcaaagt cttcat2ac2 &lt;2i&gt; sunday &lt;211&gt; Homemade

&lt;22l&gt; misc_feature &lt;222? (1). . . (151) &lt;223&gt; n = A, T, Clut G &lt;400&gt; 322 atccagcatc ttctcctgtt tcttgccttc ctttttcttc ttcttasatt ctgcttgagg tttgggcttg gtcagtttgc cacagggctt ggagtggtc ggctgctcg ggagtgctgc ggagtgctgc

120

151

120

151

120

150

120

151

120

151 &lt;210&gt; 323 &lt;211? 151 &lt;212&gt; DNA

156

PL 200 772 Β1 &lt;213? Homo puffers &lt;220?

&lt;221? misc_feature &lt;222? (1). . . (151) &lt;223? n = A, T, C (ab G &lt;400? 323 tgaggacttg tkttcttttt ctttattttt aatcctctta ckttgtaaat atattgccta 60 nagactcant tactacccag tttgtggttt twtgggagaa atgtaactgg acagttagct 120 gttaggactta &lt;211 gttagtacta &lt;211? &lt;220?

&lt;221? misc_feature &lt;222? (1) ... (461) &lt;223? n »A, T, C or G &lt;400? 324 acctgtgtgg aatttcagct ttcctcatgc aaaaggattt tgtatccccg gcctacttga 60 agaagtggtc agctaaagga atccaggttg ttggttggac tgttaatacc tttgatgaaa 120 agagttacta cgaatcccat cttggttcca gctatatcac tgacagcatg gtagaagact 180 gcgaacctca cttctagact ttcacggtgg gacgaaacgg gttcagaaac tgccaggggc 240 ctcatacagg gatatcaaaa taccctttgt gctacccagg ccctggggaa tcaggtgact 300 cacacaaatg caatagttgg tcactgcatt tttacctgaa ccaaagctaa acccggtgtt 360 gccaccatgc accatggcat gccagagttc aacactgttg ctcttgaaaa ttgggtctga 420 aaaaacgcac aagagcccct gccctgccct agctgangca c 461 &lt;210? 325 &lt;211? 400 &lt;212? DNA &lt;213? Homo sapienS &lt;400? 325 acactgtttc catgttatgt ttctacacat tgctacctca gtgctcctgg aaacttagct 60 tttgatgtct ccaagtagtc caccttcatt taactctttg aaactgtatc atctttgcca 120 agtaagagtg gtggcctatt tcagctgctt tgacaaaatg actggctcct gacttaacgt 180 tctataaatg aatgtgctga agcaaagtgc ccatggtggc ggcgaagaag agaaagatgt 240 gttttgtttt ggactctctg tggtcccttc caatgctgtg ggtttccaac caggggaagg 300 gtcccttttg cattgccaag tgccataacc atgagcacta cgctaccatg gttctgcctc 360 ctggccaagc aggctggttt gcaagaatga aacgaatgat 400

<td>&lt;21O&gt;</td><td> 326</td>

<td>&lt;2L1&gt;</td><td> 1215</td>

<td> &lt;212&gt;</td><td>GOUT</td>

<td> &lt;213&gt;</td><td>Homo gasps</td>

<td> &lt;400&gt;</td><td> 326</td>

ggaggactgc agcccgcact cgcagccctg gcaggcggca ctggtcatgg aaaacgaatt 60 gttctgctcg ggcgtcctgg tgcatccgca gtgggtgctg tcagccgcac actgtttcca 120 gaactcctacg caggggcca 120 gaactcctacgggggcagcaggggcca 120 gaactcctacgggggcca

PL 200 772 B1

157 ccagatggtg gaggccagcc tctccgtacg gcacccagag tacaacagac ccttgctcgc taacgacctc atgctcatca agttggacga atccgtgtcc gagtctgaca ccatccggag catcagcatt gcttcgcagt gccctaccgc ggggaactct tgcctcgttt ctggctgggg tctgctggcg aacggcagaa tgcctaccgt gctgcagtgc gtgaacgtgt cggtggtgtc tgaggaggtc tgcagtaagc tctatgaccc gctgtaccac cccagcatgt tctgcgccgg cggagggcaa gaccagaagg actcctgcaa cggtgactct ggggggcccc tgatctgcaa cgggtacttg cagggccttg tgtctttcgg aaaagccccg tgtggccaag ttggcgtgcc aggtgtctac accaacctct gcaaactcac tgagtggata gagaaaaccg tccaggccag ttaactctgg ggactgggaa cccatgaaat tgacccccaa atacatcctg cggaaggaat tcaggaatat ctgttcccag cccctcctcc ctcaggccca ggagtccagg cccccagccc ctcctccctc aaaccaaggg tacagatccc cagcccctcc tccctcagac ccaggagtcc agacccccca gcccctcctc cctcagaccc aggagtccag cccctcctcc ctcagaccca ggagtccaga ccccccagcc cctcctccct cagacccagg ggtccaggcc cccaacccct cctccctcag actcagaggt ccaagccccc aacccctcct tccccagacc cagaggtcca ggtcccagcc cctcctccct cagacccagc ggtccaatgc cacctagact ctccctgtac acagtgcccc cttgtggcac gttgacccaa ccttaccagt tggtttttca ttttttgtcc ctttccccta gatccagaaa taaagtctaa tagaagcgta aaaaaaaaaa aaaaaaaaaa aaaaaa2aa2 &lt;Tap&gt; &lt;

240

300

360

420

480

540

600

660

720

780

840

900

960

1020

1080

1140

1200

1215

<td></td><td colspan="2"> &lt;400&gt;</td><td colspan="13"> 327</td>

<td>Glu</td><td>Asp</td><td>Cys</td><td>Cheese</td><td>Pro</td><td>His</td><td>Cheese</td><td>Gin</td><td>Pro</td><td>Trp</td><td>Gin</td><td>Ala</td><td>Ala</td><td>Leu</td><td>Val</td><td>Underworld</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td>Glu</td><td>Asn</td><td>Glu</td><td>Leu</td><td>Phe</td><td>Cys</td><td>Cheese</td><td>Gly</td><td>Val</td><td>Leu</td><td>Val</td><td>His</td><td>Pro</td><td>Gin</td><td>Trp</td><td>Val</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td>Leu</td><td>Cheese</td><td>Ala</td><td>Ala</td><td>His</td><td>Cys</td><td>Phe</td><td>Gin</td><td>Asn</td><td>Cheese</td><td>Tyr</td><td>Thr</td><td>How much</td><td>Gly</td><td>Leu</td><td>Gly</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td>Leu</td><td>His</td><td>Cheese</td><td>Leu</td><td>Glu</td><td>Ala</td><td>Asp</td><td>Gin</td><td>Glu</td><td>Pro</td><td>Gly</td><td>Cheese</td><td>Gin</td><td>Underworld</td><td>Val</td><td>Glu</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td>Ala</td><td>Cheese</td><td>Leu</td><td>Cheese</td><td>Val</td><td>Arg</td><td>His</td><td>Pro</td><td>Glu</td><td>Tyr</td><td>Asn</td><td>Arg</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Ala</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td>Asn</td><td>Asp</td><td>Leu</td><td>Attorney</td><td>Leu</td><td>How much</td><td>Lys</td><td>Leu</td><td>Asp</td><td>Glu</td><td>Cheese</td><td>Val</td><td>Cheese</td><td>Glu</td><td>Cheese</td><td>Asp</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td>Thr</td><td>How much</td><td>Arg</td><td>Cheese</td><td>How much</td><td>Cheese</td><td>How much</td><td>Ala</td><td>Cheese</td><td>Gin</td><td>Cys</td><td>Pro</td><td>Thr</td><td>Ala</td><td>Gly</td><td>Asn</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td>Cheese</td><td>Cys</td><td>Leu</td><td>Val</td><td>Cheese</td><td>Gly</td><td>Trp</td><td>Gly</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Asn</td><td>Gly</td><td>Arg</td><td>Underworld</td><td>Pro</td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<td>Thr</td><td>Val</td><td>Leu</td><td>Gin</td><td>Cys</td><td>Val</td><td>Asn</td><td>Val</td><td>Cheese</td><td>Val</td><td>Val</td><td>Cheese</td><td>Glu</td><td>GLu</td><td>Val</td><td>Cys</td>

<td></td><td> 130</td><td></td><td></td><td></td><td></td><td> 135</td><td></td><td></td><td></td><td></td><td> 140</td><td></td><td></td><td></td><td></td>

<td>Cheese</td><td>Lys</td><td>Leu</td><td>Tyr</td><td>Asp</td><td>Pro</td><td>Leu</td><td>Tyr</td><td>His</td><td>Pro</td><td>Cheese</td><td>Underworld</td><td>Phe</td><td>Cys</td><td>Ala</td><td>Gly</td>

<td> 145</td><td></td><td></td><td></td><td></td><td> 150</td><td></td><td></td><td></td><td></td><td> 155</td><td></td><td></td><td></td><td></td><td> 160</td>

<td>Gly</td><td>Gly</td><td>Gin</td><td>Asp</td><td>Gin</td><td>Lys</td><td>Asp</td><td>Cheese</td><td>Cys</td><td>Asn</td><td>Gly</td><td>Asp</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Pro</td>

<td></td><td></td><td></td><td></td><td> 165</td><td></td><td></td><td></td><td></td><td> 170</td><td></td><td></td><td></td><td></td><td> 175</td><td></td>

<td>Leu</td><td>How much</td><td>Cys</td><td>Asn</td><td>Gly</td><td>Tyr</td><td>Leu</td><td>Gin</td><td>Gly</td><td>Leu</td><td>Val</td><td>Cheese</td><td>Phe</td><td>Gly</td><td>Lys</td><td>Ala</td>

<td></td><td></td><td></td><td> 180</td><td></td><td></td><td></td><td></td><td> 185</td><td></td><td></td><td></td><td></td><td> 190</td><td></td><td></td>

<td>Pro</td><td>Cys</td><td>Gly</td><td>Gin</td><td>Val</td><td>GLy</td><td>Val</td><td>Pro</td><td>Gly</td><td>Val</td><td>Tyr</td><td>Thr</td><td>Asn</td><td>Leu</td><td>Cys</td><td>Lys</td>

<td></td><td></td><td> 195</td><td></td><td></td><td></td><td></td><td> 200</td><td></td><td></td><td></td><td></td><td> 205</td><td></td><td></td><td></td>

<td>Phe</td><td>Thr</td><td>Glu</td><td>Trp</td><td>How much</td><td>Glu</td><td>Lys</td><td>Thr</td><td>Val</td><td>Gin</td><td>Ala</td><td>Cheese</td><td></td><td></td><td></td><td></td>

<td></td><td> 210</td><td></td><td></td><td></td><td></td><td> 215</td><td></td><td></td><td></td><td></td><td> 220</td><td></td><td></td><td></td><td></td>

&lt;210&gt; 328

158

GB 200 772 B1 &lt;211&gt; 234 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 328 cgctcgtctc tggtagctgc agccaaatca taaacggcga ggactgcagc ccgcactcgc 60 agccctggca ggcggcactg gtcatgggaa acgaattgtt ctgctcgggc gtcctggtgc 120 atccgcagtg ggtgctgtca gccacacact gtttccagaa ctcctacacc atcgggctgg 180 gcctgcacag tcttgaggcc gaccaagagc cagggagcca gatggtggag GCCA 234 &lt; 210&gt; 329 &lt;211&gt; 77 &lt;212&gt; PRT &lt;213&gt; Homo sapienS &lt;400&gt; 329

<td>Leu</td><td>Val</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>Cys</td><td>Cheese</td><td>Main</td><td>How much</td><td>How much</td><td>Asn</td><td>Gly</td><td>Glu</td><td>Asp</td><td>Cys</td><td>Cheese</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td>Pro</td><td>His</td><td>Cheese</td><td>Main</td><td>Pro</td><td>Trp</td><td>Main</td><td>Ala</td><td>Ala</td><td>Leu</td><td>Val</td><td>Underworld</td><td>Glu</td><td>Asn</td><td>Glu</td><td>Leu</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td>Phe</td><td>Cys</td><td>Cheese</td><td>Gly</td><td>Val</td><td>Leu</td><td>Val</td><td>His</td><td>Pro</td><td>Main</td><td>Trp</td><td>Val</td><td>Leu</td><td>Cheese</td><td>Ala</td><td>Thr</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td>His</td><td>Cys</td><td>Phe</td><td>Main</td><td>Asn</td><td>Cheese</td><td>Tyr</td><td>Thr</td><td>How much</td><td>Gly</td><td>Leu</td><td>Gly</td><td>Leu</td><td>His</td><td>Cheese</td><td>Leu</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td>Glu</td><td>Ala</td><td>Asp</td><td>Main</td><td>Glu</td><td>Pro</td><td>Gly</td><td>Cheese</td><td>Main</td><td>Underworld</td><td>Val</td><td>Glu</td><td>Ala</td><td></td><td></td><td></td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 330 &lt;211&gt; 70 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 330 cccaacacaa tggcccgatc ccatccctga ctccgccctc aggatcgctc gtctctggta 60 gctgcagcca 70 &lt;210&gt; 331 &lt;211&gt; 22 &lt;212&gt; PRT sapieni &lt;400&gt; Homo sapieni &lt;400&gt; 331

Gin His Asn Gly Pro Ile Pro Ser Leu Thr Pro Pro Ser Gly Ser Leu 15 10 15

Val Ser Gly Ser Cys Ser 20 &lt;210&gt; 332 &lt;211&gt; 2507 &lt;212&gt; DNA &lt;213&gt; Homo sapienS &lt;400&gt; 332 tggtgccgct gcagccggca gagatggttg agctcatgtt cccgctgttg ctcctcctgtc 60 tgcccttcct tctacgggtcct actacgggtcct actacgggtcct actacgggatgta

PL 200 772 Β1

159 gtacatcaac tgttcagctt cctgggaaag tagttgtggt cacaggagct aatacaggta 180 tcgggaagga gacagccaaa gagctggctc agagaggagc tcgagtatat ttagcttgcc 240 gggatgtgga aaagggggaa ttggtggcca aagagatcca gaccacgaca gggaaccagc 300 aggtgttggt gcggaaactg gacctgtctg atactaagtc tattcgagct tttgctaagg 360 gcttcttagc tgaggaaaag cacctccacg ttttgatcaa caatgcagga gtgatgatgt 420 gtccgtactc gaagacagca gatggctttg agatgcacat aggagtcaac cacttgggtc 480 acttcctcct aacccatctg ctgctagaga aaccaaagga atcagcccca tcaaggatag 540 taaatgtgtc ttccctcgca catcacctgg gaaggaCcca cttccataac ctgcagggcg 600 agaaattcta caatgcaggc ctggcctact gtcacagcaa gctagccaac atcctcttca 660 cccaggaact ggcccggaga ctaaaaggct ctggcgttac gacgtattct gtacaccctg 720 gcacagccca atctgaactg gttcggcact catctttcat gagatggatg tggtggcttt 780 tctcctttCt catcaagact cctcagcagg gagcccagac cagcctgcac tgtgccttaa 840 cagaaggtct tgagattcta agtgggaatc atttcagtga ctgtcatgtg gcatgggtct 900 ccgcccaagc tcgtaatgag actatagcaa ggcggctgtg ggacgtcagt tgtgacctgc 960 tgggcctccc aatagactaa caggcagtgc cagttggacc caagagaaga ctgcagcaga 1020 ctacacagta cttcttgtca aaatgattct ccttcaaggt tttcaaaacc tttagcacaa 1080 agagagcaaa accttccagc cttgcctgct tggtgtccag ttaaaactca gtgtactgcc 1140 agattcgtct aaatgtctgt catgtccaga tttactttgc ttctgttact gccagagtta 1200 ctagagatat cataatagga taagaagacc ctcatatgac ctgcacagct cattttcctt 1260 ctgaaagaaa ctactaccta ggagaatcta agctatagca gggatgattt atgcaaattt 1320 gaactagctt ctttgttcac aattcagttc ctcccaacca accagtcttc acttcaagag 1380 ggccacactg caacctcagc ttaacatgaa taacaaagac tggctcagga gcagggcttg 1440 cccaggcatg gtggatcacc ggaggtcagt agttcaagac cagcctggcc aacatggtga 1500 aaccccacct ctactaaaaa ttgtgtatat ctttatgtgt cttcctgttt atgt.gtgcca 1560 agggagtatt ttcacaaagt tcaaaacagc cacaataatc agagatggag caaaccagta 1620 ccatccagtc tttatgcaaa tgaaatgctg caaagggaag cagattctgt atatgttggt 1680 aactacccac caagagcaca tgggtagcag ggaagaagta aaaaaagaga aggagaatac 1740 tggaagataa tgcacaaaat gaagggacta gttaaggatt aactagccct ttaaggatta 1800 actagttaag gattaatagc aaaagayatt aaatatgcta acatagctat ggaggaattg 1860 agggcaagca cccaggactg atgaggtctt aacaaaaacc agtgtggcaa aaaaaaaaaa 1920 aaaaaaaaaa aaaaatccta aaaacaaaca aacaaaaaaa acaattcttc attcagaaaa 1980 attatcttag ggactgatat tggtaattat ggtcaattta ataatatttt ggggcatttc 2040 cttacattgt cttgacaaga ttaaaatgtc tgtgccaaaa ttttgtattt tatttggaga 2100 cttcttatca aaagtaatgc tgccaaagga agtctaagga attagtagtg ttcccatcac 2160 ttgtttagag tgtgctattc taaaagattt tgatttcctg gaatgacaat tatattttaa 2220 ctttggtggg ggaaagagtt ataggaccac agtcttcact tctgatactt gtaaattaat 2280 cttttattgc acttgttttg accattaagc tatatgttta gaaatggtca ttttacggaa 2340 aaattagaaa aattctgata atagtgcaga ataaatgaat taatgtttta cttaatttat 2400 attgaactgt caatgacaaa taaaaattct ttttgattat tttttgtttt catttaccag 2460 aataaaaacg taagaattaa aagtttgatt acaaaaaaaa aaaaaaa 2507 &lt;210&gt; 333 &lt;211&gt; 3030 &lt;212&gt; DNA &lt;213&gt; Homo sapienS &lt;400&gt; 333 gcaggcgact tgcgagctgg gagcgactta aaacgctttg gattcccccg gcctgggtgg 60 ggagagcgag ctgggtgccc cctagatccc ccgcccccgc acctcatgag ccgacccccg 120 gctccatgga gcccggcaat tatgccacct tggatggagc caaggatatc gaaggcttgc 180 tgggagcggg aggggggcgg aatctggtcg cccactcccc tctgaccagc cacccagcgg 240 cgcctacgct gatgcctgct gtcaactatg cccccttgga tctgccaggc tcggcggagc 300 cgccaaagca atgccaccca tgccctgggg tgccccaggg gacgtcccca gctcccgtgc 360 cttatggtta ctttggaggc gggtactact cctgccgagt gtcccggagc tcgctgaaac 420 cctgtgccca ggcagccacc ctggccgcgt accccgcgga gacccccacg gccggggaag 480

160

GB 200 772 Β1 agtaccccag ycgccccact gagtttgcct tctatccggg atatccggga acctaccagc 540 ctatggccag ttacctggac gtgtctgtgg tgcagactct gggtgctcct ggagaaccgc 600 gacatgactc cctgttgcct gtggacagtt accagtcttg ggctctcgct ggtggctgga 660 acagccagat gtgttgccag ggagaacaga acccaccagg tcccttttgg aaggcagcat 720 ttgcagactc cagcgggcag caccctcctg acgcctgcgc ctttcgtcgc ggccgcaaga 780 aacgcattcc gtacagcaag gggcagttgc gggagctgga gcgggagtat gcggctaaca 840 agttcatcac caaggacaag aggcgcaaga tctcggcagc caccagcctc tcggagcgcc 900 agattaccat ctggtttcag aaccgccggg tcaaagagaa gaaggttccc gccaaggtga 960 agaacagcgc taccccttaa gagatctcct tgcctgggtg ggaggagcga aagtgggggt 1020 gtcctgggga gaccaggaac ctgccaagcc caggctgggg ccaaggactc tgctgagagg 1080 cccctagaga caacaccctt cccaggccac tggctgctgg actgttcctc aggagcggcc 1140 tgggtaccca gtatgtgcag ggagacggaa ccccatgtga cagcccactc caccagggtt 1200 cccaaagaac ctggcccagt cataatcatt catcctgaca gtggcaataa tcacgataac 1260 cagtactagc tgccatgatc gttagcctca tattttctat ctagagctct gtagagcact 1320 ttagaaaccg ctttcatgaa ttgagctaat tatgaataaa tttggaaggc gatccctttg 1380 cagggaagct ttctctcaga cccccetcca ttacacctct caccctggta acagcaggaa 1440 gactgaggag aggggaacgg gcagattcgt tgtgtggctg tgatgtccgt ttagcatttt 1500 tctcagctga cagctgggta ggtggacaat tgtagaggct gtctcttcct ccctccttgt 1560 ccaccccata gggtgtaccc actggtctcg gaagcaccca tccttaatac gatgactttt 1620 ctgtcgtgtg aaaatgaagc cagcaggctg cccctagtca gtccttcctt ccagagaaaa 1680 agagatttga gaaagtgcct gggtaattca ccattaattt cctcccccaa actctctgag 1740 tcttccctta atatttctgg tggttctgac caaagcaggt catggtttgt tgagcatttg 1800 ggatcccagt gaagtagatg tttgtagcct tgcatactta gcccttccca ggcacaaacg 1860 gagtggcaga gtggtgccaa ccctgttttc ccagtccacg tagacag3tt cacagtgcgg 1920 aattctggaa gctggagaca gacgggctct ttgcagagcc gggactctga gagggacatg 1980 agggcctctg cctctgtgtt cattctctga tgtcctgtac ctgggctcag tgcccggtgg 2040 gactcatctc ctggccgcgc agcaaagcca gcgggttcgt gctggtcctt cctgcacctt 2100 aggctggggg tggggggcct gccggcgcat tctccacgat tgagcgcaca ggcctgaagt 2160 ctggacaacc cgcagaaccg aagctccgag cagcgggtcg gtggcgagta gtggggtcgg 2220 tggcgagcag ttggtggtgg gccgcggccg ccactacctc gaggacattt ccctcccgga 2280 gccagctctc ctagaaaccc cgcggcggcc gccgcagcca agtgtttatg gcccgcggtc 2340 gggtgggatc ctagccctgt ctcctctcct gggaaggagt gagggtggga cgtgacttag 2400 acacctacaa atctatttac caaagaggag cccgggactg agggaaaagg ccaaagagtg 2460 tgagtgcatg cggactgggg gttcagggga agaggacgag gaggaggaag atgaggtcga 2520 tttcctgatt taaaaaatcg tccaagcccc gtggtccagc ttaaggtcct cggttacatg 2580 cgccgctcag agcaggtcac tttctgcctt ccacgtcctc cttcaaggaa gccccatgtg 2640 ggtagctttc aatatcgcag gttcttactc ctctgcctct ataagctcaa acccaccaac 2700 gatcgggcaa gtaaaccccc tccctcgccg acttcggaac tggcgagagt tcagcgcaga 2760 tgggcctgtg gggagggggc aagatagatg agggggagcg gcatggtgcg gggtgacccc 2820 ttggagagag gaaaaaggcc acaagagggg ctgccaccgc cactaacgga gatggccctg 2880 gtagagacct ttgggggtct ggaacctctg gactccccat gctctaactc ccacactctg 2940 ctatcagaaa cttaaacttg aggattttct ctgtttttca ctcgcaataa aytcagagca 3000 aacaaaaaaa aaaaaaaaaa aaaactcgag 3030 &lt;210? 334 &lt;211&gt; 2417 &lt;212? DNA &lt;213&gt; Homo sapiens &lt;400? 334 ggcggccgct ctagagctag tgggatcccc cgggctgcac gaattcggca cgagtgagtt 60 ggagttttac ctgtattgtt ttaatttcaa caagcctgag gactagccac aaatgtaccc 120 agtttacaaa tgaggaaaca ggtgcaaaaa ggttgttacc tgtcaaaggt cgtatgtggc 180 agagccaaga tttgagccca gttatgtctg atgaacttag cctatgctct tcaaacttct 240 gaatgctgac cattgaggat atctaaactt agatcaattg cattttccct ccaagactat 300

PL 200 772 Β1

161 ttacttatca atacaataat accaccttta ccaatctatt gttttgatac gagactcaaa 360 tatgccagat atatgtaaaa gcaacctaca agctctctaa tcatgctcac ctaaaagatt 420 cccgggatct aataggctca aagaaacttc ttctagaaat ataaaagaga aaattggatt 480 atgcaaaaat tcattattaa tttttttcat ccatccttta attcagcaaa catttatctg 540 ttgttgactt tatgcagtat ggccttttaa ggattggggg acaggtgaag aacggggtgc 600 cagaatgcat cctcctacta atgaggtcag tacacatttg cattttaaaa tgccctgtcc 660 agctgggcat ggtggatcat gcctgtaatc tcaacattgg aaggccaagg caggaggatt 720 gcttcagccc aggagttcaa gaccagcctg ggcaacatag aaagacccca tctctcaatc 780 aatcaatcaa tgccctgtct tcgaaaataa aactctttaa gaaaggttta atgggcaggg 840 tgtggtagct catgcctata atacagcact ttgggaggct gaggcaggag gatcacttta 900 gcccagaagt tcaagaccag cctgggcaac aagtgacacc tcatctcaat tttttaataa 960 aatgaataca tacataagga aagataaaaa gaaaagttta atgaaagaat acagtataaa 1020 acaaatctct tggacctaaa agtatttttg ttcaagccaa atattgtgaa tcacctctct 1080 gtgttgagga tacagaatat ctaagcccag gaaactgagc agaaagttca tgtactaact 1140 aatcaacccg aggcaaggca aaaatgagac taactaatca atccgaggca aggggcaaat 1200 tagacggaac ctgactctgg tctattaagc gacaacttcc cctccgttgt atttttcttt 1260 tattcaatgt aaaaggataa aaactctcta aaactaaaaa caatgtttgt caggagttac 1320 aaaccatgac caactaatta cggggaatca taaaatatga ctgtatgaga tcttgatggt 1380 ttacaaagtg tacccactgt taatcacttt aaacattaat gaacttaaaa atgaatttac 1440 ggagactgga atgtttcttt cctgttgtat tagttggctc aggctgccat aacaaaatac 1500 cacagactgg gaggcttaag taacagaaat tcatttctca cagttctggg ggctggaagt 1560 ccacgatcaa ggtgcaggaa aggcaggctt cattctgagg cccctctctt ggctcacatg 1620 tggccaccct cccactgcgt gctcacatga cctctttgtg ctcctggaaa gagggtgtgg 1680 gggacagagg gaaagagaag gagagggaac tctctggtgt ctcgtctttc aaggacccta 1740 acctgggcca ccttggccca ggcactgtgg ggtggggggt tgtggct.gct ctgctctgag 1800 tggccaaaat aaagcaacag aaaaatgtcc aaagctgtgc agcaaagaca agccaccgaa 1860 cagggatctg ctcatcagtg tggggacctc caagtcggcc accctggagg caagccccca 1920 cagagcccat gcaaggtggc agcagcagaa gaagggaatt gtccctgtcc ttggcacatt 1980 cctcaccgac ctggtgatgc tggacactgc gatgaatggt aatgtggatg agaatatgat 2040 ggactcccag aaaaggagac ccagctgctc aggtggctgc aaatcattac agccttcatc 2100 ctggggagga actgggggcc tggttctggg tcagagagca gcccagtgag ggtgagagct 2160 acagcctgtc ctgccagctg gatccccagt cccggtcaac cagtaatcaa ggctgagcag 2220 atcaggcttc ccggagctgg tcttgggaag ccagccctgg ggtgagttgg ctcctgctgt 2280 ggtactgaga caatattgtc ataaattcaa tgcgcccttg tatccctttt tcttttttat 2340 ctgtctacat ctataatcac tatgcatact agtctttgtt agtgtttcta ttcmacttaa 2400 tagagatatg ttatact 2417 &lt;210? 335 &lt;211&gt; 2984 &lt;212&gt; DNA &lt;213? Homo Sapiens &lt;400&gt; 335 atccctcctt ccccactctc ctttccagaa ggcacttggg gtcttatctg ttggactctg 60 aaaacacttc aggcgccctt ccaaggcttc cccaaacccc taagcagccg cagaagcgct 120 cccgagctgc cttctcccac actcaggtga tcgagttgga gaggaagttc agccatcaga 180 agtacctgtc ggcccctgaa cgggcccacc tggccaagaa cctcaagctc acggagaccc 240 aagtgaagat atggttccag aacagacgct ataagactaa gcgaaagcag ctctcctcgg 300 agctgggaga cttggagaag cactcctctt tgccggcccC gaaagaggag gccttctccc 360 gggcctccct ggtctccgtg tataacagct atccttacta cccatacctg cactgcgtgg 420 gcagctggag cccagctttt tggtaatgcc agctcaggtg acaaccatta tgatcaaaaa 480 ctgcctcccc cagggtgtct ctatgaaaag cacaaggggc caaggtcagg gagcaagagg 540 tgtgcacacc aaagctattg gagatttgcg tggaaatctc asattcttca ctggtgagac 600 aatgaaacaa cagagacagc gaaagtttta atacctaagt cattccccca gtgcatactg 660 taggtcattt tttttgcttc tggctacctg tttgaagggg agagagggaa aatcaagtgg 720

162

GB 200 772 B1 tatttcccag cacttcgtat gattctggat gagctgtaca cccaaggatt ctgttctgca 780 actccatcct cccgtgtctc tgaatatcca ccctgaaaga gcaaacctca caggagaaag 840 gtcttcctgg atgaggacgc caccaactga aataaactta agtccagaag cctcctgttg 900 gccttggaat atggccaagg ctctctctgt ccccgtaaaa gagaggggca aatagagaat 960 ctcctagtga ccgccctcat gczcagcaca ggagggggag atgggtggga 1020 tgagttgata atatcagcct ttctztattcc tt ^ Cttattcc ttttaaaatg gtatgccaac 1080 ttatgcatitt tctgtgtggt ccaaatagaa ctagttgcac tttttgttat ttccagai ^^. ^ 1140 gccgŁatata ccgcactcca c.tggctgtgg ggggggcggg ccaggagaat ctccgtttgt 1200 ctttgacagg tgcttaagga gggggtccac accgccggca ^ g ^ e ^ ggcc titg cattttttta 1260 ttagtagacc taggcttggc ctcttcccca cctlLtetccc ttgggctgga ggattitaga 1320 tcttaagttt ^ ^^ ^ p gag ^ rcaga clc atatatactg tttcctgaaa ggtcttttaa 1380 atcεtcctat cctcctttta aaattttggg tccctti · t! ^ cagcaattac tcactatagg 1440 gcttcatttt attcttgatt tttagtctgt ctgcacttaa cttctgttat gcctacttag 1500 tttgagatct ggccctctct tttttttttt tttctccgcc ttcttatagt tttatctgtc 1560 ttgacttttt ccacaagttc ggggtttcat tctgaattgg ctattcgcca tgccttttta 1620 aaacttttaa ttcEεattac ttŁcccttat aattacatag tattaattct catatcccat 1680 ttacagacct ttcagctagt gatggttcct actttattta atggacctac εggtgttact 1740 ttatttacgt aegaagattg aceacccccg agtttctatg tttgcagatg aggtaagagg 1800 atttggaaεt acacagtggt agaacacagc gttcttcgaa ttctgtgctg 1860 acctttgtct tg^cttctggt tgggacatgg aaaagaaęjgc ctctttgttt ctggggagcc 1920 ctgtctactg cgctctttct ggactgagtg aggctεaεtc cgtattttgt tctgaaaaag 1980 gcaaaccatt ttaatctcct acaagagttt gtccaaatgc attgggccca gtggttattg 2040 ccattactgt tactctcctc tgggtaaccc agtctt1taga tcgaatgtgc agagagcaaa 2100 tgtgttttct ggcŁgŁcίtfca ccattatacc tc ^ the ^ td ^ tc ^ t ccggtgagct ggcagagggg 2160 cccttcagcc acaacaaaac aattaccaat gcggttcgtt gaggcccggg 2220 tgttattctc taettccctt tagtgagaaa εεσ ^ εεβεε 2,280 cgctgttttc t^{c |}attttgtt gttgttttcc'ttgccaacac tcgtacctat aaagtttgcc 2340 cctεtcactc cattttctgt ggttεgtt^cε ccaacttgca tεgatcactg ccacgggctg 2400 cagttctttt tcggagtcca agccagcaca aaaggcaggg aagcctgctt cgctttccgc 2460 tctttatctt acataca^andat taagcactta gt :: gct &lt;tagt1t ctεccagcta β ^^ εε ^ ο 2520 ic ^ ccccic tcttacactt tgcaacattc ccggattccc οβε ^^ ο ^ 2580 agctgttttt agagttgcat aag ^^^^ cttgatta ^ cM acttgctaag ^^^^ cttgttt ^ cM acttgccag ^^^^ ctt gttttt ^ cM acttgcta ^^^^ vol^andcgttttcg tctacttcta tctgacaggt gaatatgcag gatctctgaa 2760 ctatatcatc ttttccgcct gcttccatcc tgt ^ titaataa tttatattgg gttctcatct 2820 atcctgttcc aatctgtctc ataaaaggct gtttagactg 2880 ccttcttttt aaactttcεa ttactaagtc tatEttgctc ttattgtteg tcttgttaat 2940 accttatttc agtctttatt cgcacacaac ccccaccatc atac 2984 &lt;210&gt; 336 &lt;211&gt; 147 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 336

<td>Pro</td><td>Cheese</td><td>Phe</td><td>Pro</td><td>Thr</td><td>Leu</td><td>Leu</td><td>Cheese</td><td>Arg</td><td>Arg</td><td>His</td><td>Leu</td><td>Gly</td><td>Cheese</td><td>Tyr</td><td>Leu</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td>Leu</td><td>Asp</td><td>Cheese</td><td>GLu</td><td>Asn</td><td>Thr</td><td>Cheese</td><td>Gly</td><td>Alc</td><td>Leu</td><td>Pro</td><td>Arg</td><td>Leu</td><td>Pro</td><td>Main</td><td>Thr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td>Pro</td><td>Lys</td><td>Gin</td><td>Pro</td><td>Main</td><td>Lys</td><td>Arg</td><td>Cheese</td><td>Arg</td><td>Ala</td><td>Alt</td><td>Phe</td><td>Cheese</td><td>His</td><td>Thr</td><td>Main</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td>Val</td><td>How much</td><td>GLu</td><td>Leu</td><td>Glu</td><td>Arg</td><td>Lys</td><td>Phe</td><td>Cheese</td><td>His</td><td>Main</td><td>Lys</td><td>Tyr</td><td>Leu</td><td>Cheese</td><td>Ala</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td>Pro</td><td>Glu</td><td>Arg</td><td>Alt</td><td>His</td><td>Leu</td><td>Alc</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Lys</td><td>Leu</td><td>Thr</td><td>Glu</td><td>Thr</td><td>Main</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

PL 200 772 Β1

163

<td rowspan="2">Val</td><td rowspan="2">Lys</td><td colspan="2" rowspan="2">How much Trp</td><td colspan="11">Phe Gin Asn Arg Arg Tyr Lys Thr Lys Arg Lys</td><td rowspan="2">Gin</td>

<td colspan="3"> 85</td><td colspan="3"> 90</td><td colspan="5"> 95</td>

<td>Leu</td><td>Cheese</td><td>Cheese</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Asp</td><td>Leu</td><td>Glu</td><td>Lys</td><td>His</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Pro</td><td>Ala</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td>Leu</td><td>Lys</td><td>Glu</td><td>Glu</td><td>Ala</td><td>Phe</td><td>Cheese</td><td>Arg</td><td>Ala</td><td>Cheese</td><td>Leu</td><td>Val</td><td>Cheese</td><td>Val</td><td>Tyr</td><td>Asn</td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<td>Cheese</td><td>Tyr</td><td>Pro</td><td>Tyr</td><td>Tyr</td><td>Pro</td><td>Tyr</td><td>Leu</td><td>Tyr</td><td>Cys</td><td>Val</td><td>Gly</td><td>Cheese</td><td>Trp</td><td>Cheese</td><td>Pro</td>

<td></td><td> 130</td><td></td><td></td><td></td><td></td><td> 135</td><td></td><td></td><td></td><td></td><td> 140</td><td></td><td></td><td></td><td></td>

<td>Ala</td><td>Phe</td><td>Trp</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

145 &lt;2l0&gt; 337 &lt;211&gt; 9 &lt;212&gt; PRT &lt;213&gt; Homo sapierfe &lt;400&gt; 337

Ala Leu Thr Gly Phe Thr Phe Ser Ala l 5 &lt;210&gt; 338 &lt;211&gt; 9 &lt;212&gt; PRT &lt;213&gt; Homo sapienS &lt;400&gt; 338

Leu Leu Ala Asn Asp Leu Met Leu Ile 1 5 &lt;21O&gt; 339 &lt;211&gt; 318 &lt;212&gt; PRT &lt;213&gt; Homo sapienS &lt;400&gt; 339

<td>Underworld</td><td>Val</td><td>Glu</td><td>Leu</td><td>Underworld</td><td>Phe</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Leu</td><td>Leu</td><td>Leu</td><td>Leu</td><td>Pro</td><td>Phe</td><td>Leu</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td>Leu</td><td>Tyr</td><td>Underworld</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Gin</td><td>How much</td><td>Arg</td><td>Lys</td><td>Underworld</td><td>Leu</td><td>Cheese</td><td>Cheese</td><td>Gly</td><td>Val</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td>Cys</td><td>Thr</td><td>Cheese</td><td>Thr</td><td>Val</td><td>Gin</td><td>Leu</td><td>Pro</td><td>Gly</td><td>Lys</td><td>Val</td><td>Val</td><td>Val</td><td>Val</td><td>Thr</td><td>Gly</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td>Ala</td><td>Asn</td><td>Thr</td><td>Gly</td><td>How much</td><td>Gly</td><td>Lys</td><td>Glu</td><td>Thr</td><td>Ala</td><td>Lys</td><td>Glu</td><td>Leu</td><td>Ala</td><td>Gin</td><td>Arg</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td>Gly</td><td>Ala</td><td>Arg</td><td>Val</td><td>Tyr</td><td>Leu</td><td>Ala</td><td>Cys</td><td>Arg</td><td>Asp</td><td>Val</td><td>Glu</td><td>Lys</td><td>Gly</td><td>Glu</td><td>Leu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td>Val</td><td>Ala</td><td>Lys</td><td>Glu</td><td>How much</td><td>Gin</td><td>Thr</td><td>Thr</td><td>Thr</td><td>Gly</td><td>Asn</td><td>Gin</td><td>Gin</td><td>Val</td><td>Leu</td><td>Val</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td>Arg</td><td>Lys</td><td>Leu</td><td>Asp</td><td>Leu</td><td>Cheese</td><td>Asp</td><td>Thr</td><td>Lys</td><td>Cheese</td><td>How much</td><td>Arg</td><td>Ala</td><td>Phe</td><td>Ala</td><td>Lys</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td>10S</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td>Gly</td><td>Phe</td><td>Leu</td><td>Ala</td><td>Glu</td><td>Glu</td><td>Lys</td><td>His</td><td>Leu</td><td>His</td><td>Val</td><td>Leu</td><td>How much</td><td>Asn</td><td>Asn</td><td>Ala</td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<td>Gly</td><td>Val</td><td>Underworld</td><td>Underworld</td><td>cys</td><td>Pro</td><td>Tyr</td><td>Cheese</td><td>Lys</td><td>Thr</td><td>Ala</td><td>Asp</td><td>Gly</td><td>Phe</td><td>Glu</td><td>Underworld</td>

<td></td><td> 130</td><td></td><td></td><td></td><td></td><td> 135</td><td></td><td></td><td></td><td></td><td> 140</td><td></td><td></td><td></td><td></td>

<td>His</td><td>How much</td><td>Gly</td><td>Val</td><td>Asn</td><td>His</td><td>Leu</td><td>Gly</td><td>His</td><td>Phe</td><td>Leu</td><td>Leu</td><td>Thr</td><td>His</td><td>Leu</td><td>Leu</td>

164

PL 200 772 B1

<td colspan="4"> 145</td><td colspan="5"> 150</td><td colspan="6"> 155</td><td> 160</td>

<td>Leu</td><td>Glu</td><td>Lys</td><td>Leu</td><td>Lys</td><td>Glu</td><td>Cheese</td><td>Ala</td><td>Pro</td><td>Cheese</td><td>Arg</td><td>How much</td><td>Val</td><td>Asn</td><td>Val</td><td>Cheese</td>

<td></td><td></td><td></td><td></td><td> 165</td><td></td><td></td><td></td><td></td><td> 170</td><td></td><td></td><td></td><td></td><td> 175</td><td></td>

<td>Cheese</td><td>Leu</td><td>Ala</td><td>His</td><td>His</td><td>Leu</td><td>Gly</td><td>Arg</td><td>How much</td><td>His</td><td>Phe</td><td>His</td><td>Asn</td><td>Leu</td><td>Gin</td><td>Gly</td>

<td></td><td></td><td></td><td> 160</td><td></td><td></td><td></td><td></td><td> 185</td><td></td><td></td><td></td><td></td><td> 190</td><td></td><td></td>

<td>Glu</td><td>Lys</td><td>Phe</td><td>Tyr</td><td>Asn</td><td>Ala</td><td>Gly</td><td>Leu</td><td>Ala</td><td>Tyr</td><td>Cys</td><td>His</td><td>Cheese</td><td>Lys</td><td>Leu</td><td>Ala</td>

<td></td><td></td><td> 195</td><td></td><td></td><td></td><td></td><td> 200</td><td></td><td></td><td></td><td></td><td> 205</td><td></td><td></td><td></td>

<td>Asn</td><td>How much</td><td>Leu</td><td>Phe</td><td>Thr</td><td>Gin</td><td>Glu</td><td>Leu</td><td>Ala</td><td>Arg</td><td>Arg</td><td>Leu</td><td>Lys</td><td>Gly</td><td>Cheese</td><td>Gly</td>

<td></td><td> 210</td><td></td><td></td><td></td><td></td><td> 215</td><td></td><td></td><td></td><td></td><td> 220</td><td></td><td></td><td></td><td></td>

<td>Val</td><td>Thr</td><td>Thr</td><td>Tyr</td><td>Cheese</td><td>Val</td><td>His</td><td>Pro</td><td>Gly</td><td>Thr</td><td>Val</td><td>Gin</td><td>Cheese</td><td>Glu</td><td>Leu</td><td>Val</td>

<td> 225</td><td></td><td></td><td></td><td></td><td> 230</td><td></td><td></td><td></td><td></td><td> 235</td><td></td><td></td><td></td><td></td><td> 240</td>

<td>Arg</td><td>His</td><td>Cheese</td><td>Cheese</td><td>Phe</td><td>Underworld</td><td>Arg</td><td>Trp</td><td>Underworld</td><td>Trp</td><td>Trp</td><td>Leu</td><td>Phe</td><td>Cheese</td><td>Phe</td><td>Phe</td>

<td></td><td></td><td></td><td></td><td> 245</td><td></td><td></td><td></td><td></td><td> 250</td><td></td><td></td><td></td><td></td><td> 255</td><td></td>

<td>How much</td><td>Lys</td><td>Thr</td><td>Pro</td><td>Gin</td><td>Gin</td><td>Gly</td><td>Ala</td><td>Gin</td><td>Thr</td><td>Cheese</td><td>Leu</td><td>His</td><td>Cys</td><td>Ala</td><td>Leu</td>

<td></td><td></td><td></td><td> 260</td><td></td><td></td><td></td><td></td><td> 265</td><td></td><td></td><td></td><td></td><td> 270</td><td></td><td></td>

<td>Thr</td><td>Glu</td><td>Gly</td><td>Leu</td><td>Glu</td><td>How much</td><td>Leu</td><td>Cheese</td><td>Gly</td><td>Asn</td><td>His</td><td>Phe</td><td>Cheese</td><td>Asp</td><td>Cys</td><td>His</td>

<td></td><td></td><td> 275</td><td></td><td></td><td></td><td></td><td> 280</td><td></td><td></td><td></td><td></td><td> 285</td><td></td><td></td><td></td>

<td>Val</td><td>Ala</td><td>Trp</td><td>Val</td><td>Cheese</td><td>Ala</td><td>Gin</td><td>Ala</td><td>Arg</td><td>Asn</td><td>Glu</td><td>Thr</td><td>How much</td><td>Ala</td><td>Arg</td><td>Arg</td>

<td></td><td> 290</td><td></td><td></td><td></td><td></td><td> 295</td><td></td><td></td><td></td><td></td><td> 300</td><td></td><td></td><td></td><td></td>

<td>Leu</td><td>Trp</td><td>Asp</td><td>Val</td><td>Cheese</td><td>Cys</td><td>Asp</td><td>Leu</td><td>Leu</td><td>Gly</td><td>Leu</td><td>Pro</td><td>How much</td><td>Asp</td><td></td><td></td>

<td> 305</td><td></td><td></td><td></td><td></td><td> 310</td><td></td><td></td><td></td><td></td><td> 315</td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 340 &lt;211&gt; 483 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 340 gccgaggcct gccttcacac ggaggacacg agactgcttc ctcaagggct cctgcctgcc 60 tggacactgg Cgggaggcgc tgtttagtcg gctgttttca gagggggctt tcggagggac 120 ctcctgctgc aggccggagt gtccttattc ctggcgggag accgcacatt ccactgctga 180 ggttgtgggg gcggtttatc aggcagtgat aaacataaga tgtcatttcc ttgactccgg 240 ccttcaattt tctctttggc tgacgacgga gtccgtggtg ccccgatgta actgacccct 300 gctccaaacg tgacatcact gatgctcttc tcgggggtgc tgatggcccg cttggtcacg 360 tgctcaatct cgccattcga ctctcgcccc aaactgtatg aagacacctg actgcacgtt 420 ttttctgggc ttccagaact taaagtgaaa ggcagcactc ctaagctccg actccgatgc 480 ctg 483

<td colspan="2">&lt;210&gt; 341 &lt;2ll&gt; 344 &lt;212&gt; DNA &lt;213&gt; Homo sapiens</td>

<td> &lt;400&gt;</td><td> 341</td>

g ^ c ^^ ga gccacagatt tcattataaa tagcctccct aaggaaaata caatgaatgc 60 tatttttact taccattctt tttttatagg aatagctgag tttctctaaa ctcactctct 120 gcc ^^ ^ ac tagttttatt tattttaatc ctttccataa ttagtagttc aaaataagca 180 atttatttat taatttctga cgergę ^^ atctgcagta atttgtttat cttctatttg 24 0 aarztŁactta acgaaaaact gaagagaaca aaatttgcaa ctttttgttt ttaagtactc 300 «^ ga ctta acattgtctt taatgaccac M ^ ca ^ ca acag 344 &lt;210&gt; 342 &lt;211&gt; 592 &lt;212&gt; DNA &lt;213&gt; Homo sapiens

PL 200 772 B1

165 &lt;400&gt; 342 acagcaaaaa agaaactgag aagcccaaty tgccttcttg ttaacatcca cttatccaac 60 caatgtggaa acttcttata cttggttcca tcaegaagtt ggacaattgc tgccatcaca 120 cctggcaggt aaaccaatgc caagagagtg atggaaacca ttggcaagac tttgttgatg 180 accaggattg gaattttata aaaatattgt tgatgggaag ttgctaaagg gtgaattact 240 tccctcagaa gagtgtaaag aaaagtcaga gaegctataa tagcagctat tttaattggc 300 aagtgccact gtggaaagag ttcctgtgtg tgctgaagct ctgaagggca gtcaaattca 360 tcagcatggg ctgtttggtg caaacgcaaa agcacaggtc ttttcagcat gctggtctct 420 cccgtgccct tacgcaaata atcgtcttct tctaaatttc tcctaggctt cattttccaa 480 agttcttctt ggtttgtgat gtcttttctg ctttccatta attctataaa atagtatggc 5₄0 tecagccacc cactcttcgc cttagcttga ccgtgagcct cggctgccgc cg 592 &lt;210&gt; 343 &lt;211&gt; 382 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 343 ttcttgacct cctcctcctt caagctcaaa caccaccccc cttattcagg accggcactt 60 cccaatgttt gtggctttct ctccagcctc tcttaggagg ggtaatggtg gagttggcat 120 ctcgcaactc tcctttctcc tttcttcccc ttcctctgcc cgcctttccc atcctgctgt 180 agacttcttg attgtcagtc tgcgŁcacat ccagtgattg ctttggtttc tgttcccttt 240 ctgactgccc aaggggcttt g ^^^ agc tattccttcc ttcttttttg 300 ggggtagccg g ^ gęgaccg aaattgtggg gggaaggtag gtggcacatt tataaagtgg 360 ttatctttat gctgtataat aa 332 &lt;210&gt; 344 &lt;211&gt; 536 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 344 ttgggtttgt agctgtaggg taaatcagag gcaggcttct gagcgatgag agtccŁgaga 60 ttttatcttg gccggatgga tcctctttat aaggtggtca cctcttgctt 120 gttaaggggg ^ g ^^ GGA tBeggccagc tcagctatac gatgtgaągt tgtattatca 180 agtccctcag agtaatggat gctatttgag Łgęgatcccg g ^ acaŁc ^ ggttacattc 240 ttctttcttg tgtctgtatg gttgttaggt ttgaaaaatt cacccctttt gagtgcgcgcta ^ attcttctta gŁagctatta 360 atttgatcta gaaattgcct tccttttacc cctaccatga gcc ^ aca ^ 420 ttactaactt gccactaata g ^ acętc ^ aattatcttc ciagcc ^^ 480 gtccggccta tgagigacta ctaataggtt1 &lt;tb&gt; 5135 &lt;sub&gt; tagactgagac &lt;12&gt; &lt;sub&gt; &lt;p&gt; 345 accctttgag gtctctctca ccatctccat agccaccgtc accgcgg ^^ t gcgctggatg 60 tgaatgttgt gttgcctccŁg ataagagtgt ggatgtgttt gac ^ ę ^ a ^ ccttg 120 gcgtagtaggcaccgacgtaggcacgacgtagg180 gcac ggtag ^ a ^ a ^ ccttg 120 gcg ^^ ggagatttat ccggacaccg 240 gtgttatttc c 251

166

PL 200 772 Β1

<td> &lt;210&gt;</td><td> 346</td><td></td>

<td>&lt;2ll&gt;</td><td> 282</td><td></td>

<td> &lt;212&gt;</td><td>GOUT</td><td></td>

<td> &lt;213&gt;</td><td>Homo</td><td>I'm wheezing</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1) . .</td><td> .(282)</td>

<td> &lt;223&gt;</td><td>n = A</td><td>"T, C kb</td>

&lt;400? 346 cgcgtctctg acactgtgat catgacaggg gttcaaacag aaagcgcctg ggccctcctt 60 ctaagtcttg ctaccaaaaa aaggaaaaag aaaagatctt ctcagttaca aattctggga 120 agggagacta cacctggccc ttgccctaag tgagaggtct tccctcccgc accaaaaaat 180 agaaaggctt tctatttcac tggcccaggt agggggaagg agagtaactt tgagtctgtg 240 ggcctcattt cccaaggtgc cttcaatgct cacnaaaacc aa 282

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td>347 201 GOUT Homo</td><td>sapienS</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td>misc_</td><td>_feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td>λ (201)</td>

<td> &lt;223&gt;</td><td colspan="2">n = A, T, C or</td>

<td> &lt;400&gt;</td><td> 347</td><td></td>

acacacataa tattataaaa tgccatctaa ttggaaggag ctttctatca ttgcaagtca 60 taaatataac ttttaaaana ntactancag cctttaccta ngctcctaaa tgcttgtaaa 120 tctgagactg actggacccca cccgtctacca ggggacccca cccgtctacca ggggaccca 251 &lt;212? DNA &lt;213&gt; Homo sapienS &lt;400&gt; 348 ctgttaatca caacattcgt gcatcacttg tgccaagtga gaaaatgttc taaaatcaca 60 agagagaaca gtgccagaat gaaactgacc ctaagtccca ggtgcccctg ggcaggcttcag ggtgcccctg ggcagctcttcag ggtgcccctg ggcagctcttcag ggtgcccctg ggcagctgcaga 120 ggtgcccctg ggcagctgcaga gtctacaatg 180 ggggaaggtt ttactataga actcccaaca gcccacctca ctcctgccac ccacccgatg 240 gccctgcccc c 251

<td colspan="2">&lt;210&gt; 349 &lt;211&gt; 251 &lt;212&gt; DNA &lt;213&gt; Homo sapienS</td>

<td> &lt;400&gt;</td><td> 349</td>

taaaaatcaa gccacttaat tgtatctttg aaggtaaaca atatatggga gctggatcac 60 aacccctgag gatgccagag ccatgggtcc agaacatggt gtggtattat caacagagtt 120 cagaagggtc tgaactattac gtgacata gattagca 180 cagaagggtc tgaactattac gtgacata caccagca

PL 200 772 Β1

167 actcctggtt t 251 &lt;210? 350 &lt;211? 908 &lt;212? DNA &lt;213? Homo sapiens &lt;400? 350 ctggacactt tgcgagggct tttgctggct gctgctgctg cccgtcatgc tactcatcgt 60 agcccgcccg gtgaagctcg ctgctttccc tacctcctta agtgactgcc aaacgcccac 120 cggctggaat tgctctggtt atgatgacag agaaaatgat ctcttcctct gtgacaccaa 180 cacctgtaaa tttgatgggg aatgtttaag aattggagac actgtgactt gcgtctgtca 240 gttcaagtgc aacaatgact atgtgcctgt gtgtggctcc aatggggaga gctaccagaa 300 tgagtgttac ctgcgacagg ctgcatgcaa acagcagagt gagatacttg tggtgtcaga 360 aggatcatgt gccacagtcc atgaaggctc tggagaaact agtcaaaagg agacatccac 420 ctgtgatatt tgccagttcg gtgcagaatg tgacgaagat gccgaggatg tccggtgtgt 480 gtgtaatatt gactgttctc aaaccaactt caatcccctc tgcgcttctg atgggaaatc 540 ttatgataat gcatgccaaa tcaaagaagc atcgtgtcag aaacaggaga aaattgaagt 600 catgtctttg ggccgatgtc aagataacac aactacaact actaagtctg aagatgggca 660 ttatgcaaga acagattatg cagagaacgc taacaaatta gaagaaagtg ccagagaaca 720 ccacatacct tgtccggaac attacaatgg cttctgcatg catgggaagt gtgagcattc 780 tatcaatatg caggagccat cttgcaggtg tgatgctggt tatactggac aacactgtga 840 aaaaaaggac tacagcgttc tatacgttgt tcccggtcct gtacgatttc agtatgtctt 900 aaccgcag 908 &lt;210? 351 &lt;211? 472 &lt;212? DNA &lt;213? Homo sapienS &lt;400? 351 ccagttattt gcaagcggta agagcctatt taccataaat aatactaaga accaactcaa 60 gtcaaacctt aatgccattg ttattgtgaa ttaggattaa gtagtaattt tcaaaattca 120 cattaactcg attttaaaac cagwtttgyg agtcatttac cacaagctaa atgtgtacac 180 tatgataaaa acaaccattg tattcctgtt tttctaaaca gtcctaattt ctaacactgt 240 atatatcctt cgacatcaat gaacttcgtt ttcttttact ccagtaataa agtaggcaca 300 gatctgtcca caacaaactt gccctctcat gccctgcctc tcaccatgct ctgctccagg 360 tcagccccct tttggcctgc ttgttttgtc aaaaacctaa tctgctcctt gcttttcttg 420 gtaatatata tttagggaag atgttgcttt gcccacacac gaagcaaagt aa 472 &lt;210? 352 &lt;211? 251 &lt;212? DNA &lt;213? Homo sapienS &lt;400? 352 ctcaaagcta atctctcggg aatcaaacca gaaaagggca aggatcttag gcatggtgga 60 tgtggacaag gccaggtcaa tggctgcaag catgcagaga aagaggtaca tcggagcgtg 120 caggctgcctta tccgtcgt cgatgaagac cacgacgcag tttccaaaca ttgccactac 180 atacacggaa aggaggggga agccaaccca gaaatgggct ttctctaatc ctgggatacc 240 aataagcaca a 251 &lt;210? 353 &lt;211? 436 &lt;212? GOUT