Compositions and methods for therapy and diagnosis of ovarian cancer

(12) PATENT DESCRIPTION (19) PL (11) 201529 (13) B1 (21) Application number: 349322 ⁽¹³⁾ (22) Filing date: 17.12.1999 (86) Date and number of the international application:

17.12.1999, PCT / US99 / 30270 (87) Date and publication number of the international application:

June 22, 2000, WO00 / 36107 PCT Gazette No. 25/00 (51) Int.Cl.

C12N 15/12 (2006.01) C07K 14/47 (2006.01) C12N 15/62 (2006.01) C12Q 1/68 (2006.01) C07K 16/18 (2006.01)

A pharmaceutical composition and its use in the manufacture of a medicament for the treatment of an ovarian cancer in a patient

<td>(30) Priority:</td><td>(73) The right holder of the patent:</td>

<td>1998-12-17, US, 09 / 215,681</td><td>CORIXA CORPORATION, Seattle, US</td>

<td>12/17/1998, US, 09 / 216.003 1999-06-23, US, 09 / 338,933 1999-09-24, US, 09 / 404,879</td><td>(72) Inventor (s):</td>

<td>(43) Application announced:</td><td>Jennifer L. Mitcham, Redmond, US Gordon E. King, Seattle, US Paul A. Algate, Seattle, US</td>

<td>15.07.2002 BUP 15/02</td><td>Tony N. Frudakis, Sarasoto, US</td>

<td>(45) The grant of the patent was announced:</td><td>(74) Representative:</td>

<td>April 30, 2009 WUP 04/09</td><td>Janina Kossowska, PATPOL Sp. z o. o</td>

⁽⁵⁷⁾ The invention relates to a pharmaceutical composition comprising a) an antibody or antigen-binding fragment that specifically binds to an ovarian cancer protein, wherein the ovarian cancer protein comprises an amino acid sequence that is encoded by the polynucleotide sequence shown in Id. Seq. NO: 391 or the complement thereof, b) a polypeptide which is encoded by the polynucleotide sequence set forth in SEQ ID NO. Seq. NO: 391 or the complement thereof; and a physiologically acceptable carrier, for use in the manufacture of a medicament for the treatment of ovarian cancer; and its uses for the manufacture of medicaments for killing a cancer cell, for treating ovarian cancer, or for preventing and treating ovarian cancer.

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Description of the invention

The invention relates to a pharmaceutical composition and its use in the manufacture of a medicament for the treatment of an ovarian cancer in a patient.

The present invention relates generally to the treatment of ovarian cancer. More particularly, the invention relates to a polypeptide comprising at least a portion of an ovarian cancer protein and to a polynucleotide encoding such a polypeptide, as well as antibodies that specifically recognize such polypeptides. Such polypeptides, polynucleotides, antibodies can be used in pharmaceutical compositions for the treatment of ovarian cancer.

Ovarian cancer is a significant health problem for women in the United States and around the world. While progress has been made in the detection and treatment of this cancer, no vaccines or other universally effective methods of preventing or treating this cancer are currently available. The management of this disease currently consists of combining early diagnosis with aggressive treatment, which may include one or more of a variety of treatments such as surgery, radiation, chemotherapy, and hormone therapy. The treatment of a particular tumor is often selected based on a variety of prognostic parameters, including the analysis of tumor-specific markers. However, the use of established markers often leads to a result that is difficult to interpret and still high mortality is observed among many cancer patients.

Immunotherapies have the potential to substantially improve cancer treatment and increase survival. Such treatments may include inducing or enhancing an immune response to an ovarian cancer antigen. However, so far relatively few ovarian cancer antigens have been known, and eliciting an immune response against such antigens has not been shown to be therapeutically beneficial.

Accordingly, there is a need in the art for improved methods of identifying ovarian cancer antigens for the use of such antigens in the treatment of ovarian cancer. The present invention meets these needs and provides further related advantages.

Briefly, the invention relates to compositions and their use in the treatment of cancer such as ovarian cancer.

The pharmaceutical composition of the invention comprises (a) an antibody or antigen-binding fragment that specifically binds to an ovarian cancer protein, wherein the ovarian cancer protein comprises an amino acid sequence that is encoded by the polynucleotide sequence set forth in Id. Seq. NO: 391 or the complement thereof.

(b) a polypeptide that is encoded by the polynucleotide sequence set forth in Id. Seq. NO: 391 or the complement thereof; and a physiologically acceptable carrier, for use in the manufacture of a medicament for the treatment of ovarian cancer.

Preferably, the antibody or antigen-binding fragment thereof is conjugated to a toxin.

Preferably the toxin is selected from the group consisting of ricin, abrin, diphtheria toxin, cholera toxin, gelonin, Pseudomonas exotoxin, Shigella toxin, and an anti-viral pokeweed protein.

Preferably the antibody or antigen binding fragment thereof is conjugated to a radionuclide.

More preferably, the radionuclide is selected from the group consisting of ⁹⁰Y, ¹²³AND, ¹²⁵AND, ¹³¹AND, ¹⁸⁶Re, ¹⁸⁸RE, ²¹¹At i ²¹²Bi.

Preferably, the antibody or antigen-binding fragment thereof binds to a polypeptide encoded by sequence Id. Seq. NO: 391, and expressed on the cell surface of an ovarian tumor cell.

Preferably, the antibody or antigen-binding fragment thereof induces internalization in an in vitro cytotoxicity assay upon binding to the polypeptide encoded by Id. Seq. NO: 391 expressed on the cell surface.

Preferably, the antibody or antigen-binding fragment thereof is an isolated humanized antibody or an antigen-binding fragment thereof.

It is also within the scope of the invention to use a composition of the invention comprising an isolated antibody, or antigen-binding fragment thereof, in the manufacture of a medicament for killing a tumor cell that expresses a polypeptide encoded by Id. Seq. NO: 391, or inhibiting its growth, comprising contacting the tumor cell with the isolated antibody or antigen-binding fragment thereof in an amount sufficient to kill or inhibit the growth of the tumor cell.

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The invention also relates to the use of a composition of the invention comprising an isolated antibody or antigen-binding fragment thereof in the manufacture of a medicament for the treatment of an ovarian cancer in a patient, wherein the cancer expresses a polypeptide encoded by Id. Seq. NO: 391 comprising a therapeutically effective amount of an isolated antibody or antigen-binding fragment thereof in an amount sufficient to treat ovarian cancer.

Furthermore, the invention relates to the use of a composition of the invention comprising a polypeptide in the manufacture of a medicament for the prevention of the development of ovarian cancer or for the treatment of ovarian cancer.

Also disclosed are fusion proteins that contain at least one polypeptide as described above, as well as polynucleotides encoding such fusion protein, and pharmaceutical compositions containing such a fusion protein or a polynucleotide encoding such a fusion protein in combination with a non-specific immune response enhancer.

Vaccines are also disclosed that contain a fusion protein or a polynucleotide encoding such a fusion protein in combination with a non-specific immune response enhancer.

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 individually incorporated.

Brief description of the drawings:

Figures 1A-1S (SEQ ID NOs: 1-71) show partial sequences of polynucleotides encoding representative secreted ovarian cancer antigens.

Fig. 2 shows the complete sequences for the three clones of Fig. 1. Fig. 2A shows the sequence labeled 07E (11731; SEQ ID NO: 72), Fig. 2B shows the sequence labeled 09E (11785; SEQ ID NO: 72). SEQ ID NO: 73) and Fig. 2C shows the sequence labeled 08E (13695; SEQ ID NO: 74).

Fig. 3 shows the results of the expression analysis of the ovarian cancer sequence labeled 08E in microplates.

Figure 4 shows a partial sequence of a polynucleotide (designated 3g; SEQ ID NO: 75) encoding an ovarian carcinoma sequence that is a splicing fusion between the TAX oncoprotein of the human T cell leukemia virus type I and osteonectin.

Fig. 5 shows the ovarian cancer polynucleotide designated 3f (SEQ ID NO: 76).

Fig. 6 shows the ovarian cancer polynucleotide designated 6b (SEQ ID NO: 77).

Figures 7A and 7B show the ovarian cancer polynucleotides designated 8e (SEQ ID NO: 78) and 8h (SEQ ID NO: 79).

Fig. 8 shows the ovarian cancer polynucleotide designated 12c (SEQ ID NO: 80).

Fig. 9 shows the ovarian cancer polynucleotide designated 12h (SEQ ID NO: 81).

Fig. 10 shows the results of the expression analysis of the ovarian cancer sequence labeled 3f in microplates.

Fig. 11 shows the results of the expression analysis of the ovarian cancer sequence labeled 6b on microplates.

Fig. 12 shows the results of the expression analysis of the ovarian cancer sequence labeled 8e in microplates.

Fig. 13 shows the results of the expression analysis of the ovarian cancer sequence labeled 12c in microplates.

Fig. 14 shows the results of the analysis of the expression in microplates of the ovarian cancer sequence labeled 12h.

Figures 15A-15EEE are partial sequences of additional polynucleotides encoding representative secreted ovarian cancer antigens (SEQ ID NOs: 82-310).

Fig. 16 is a diagram illustrating the position of various partial sequences within the full length sequence.

As noted above, the present invention relates generally to compositions and their use in immunotherapy and the diagnosis of cancer, such as ovarian cancer. Compositions described herein may include immunogenic polypeptides, polynucleotides encoding such polypeptides, binding agents such as antibodies that bind to the polypeptide.

The polypeptide of the present invention generally comprises at least an immunogenic portion of an ovarian cancer protein or variant thereof. Certain ovarian cancer proteins have been identified using an immunoassay and are referred to herein as ovarian cancer antigens. "An ovarian cancer antigen is a protein that is expressed by ovarian cancer cells (preferably human cells) at a level that is at least twice that in normal ovarian cells.

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Certain ovarian cancer antigens react at detectable levels (in immunoassays such as ELISA) with antisera produced against the serum of immunocompromised animals implanted with human ovarian cancer. Such ovarian cancer antigens are either ejected or secreted from the ovarian cancer into the serum of non-immune animals. Accordingly, some of the ovarian cancer antigens provided herein are secreted antigens. Certain nucleic acid sequences of the invention generally contain DNA or RNA sequences that code for all or part of such a polypeptide, or which are complementary to such a sequence.

The present invention further provides an ovarian cancer sequence which is identified using techniques to assess altered expression in an ovarian cancer. Such sequences can be polynucleotide or protein sequences. Ovarian cancer sequences are generally expressed in ovarian cancer at a level that is at least twice, and preferably at least five times, the expression level in normal ovarian tissue as determined using the representative assay provided herein. Certain partial ovarian cancer polynucleotide sequences are presented herein. Proteins encoded by genes containing such polynucleotide sequences (or the complement thereof) are also considered ovarian cancer proteins.

Antibodies are generally proteins of the immune system, or antigen-binding fragments thereof, that have the ability to bind to at least a portion of an ovarian cancer polypeptide as described herein. T cells that can be used in the provided compositions are generally T cells (e.g. CD4⁺ and / or CD8⁺) that are specific for such a polypeptide.

Ovarian cancer polynucleotides

Preferably, the 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 an ovarian cancer protein. Polynucleotides can be single-stranded (encoding or antisense) or double-stranded, and can be DNA (genomic, cDNA, or synthetic) or RNA molecules. 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 a native sequence (ie, an endogenous sequence that encodes an ovarian cancer protein or a portion thereof) or may contain a variant of such sequence. Ovarian cancer protein polynucleotide variants may contain one or more substitutions, additions, deletions, and / or insertions such that the immunogenicity of the encoded protein is not reduced relative to native ovarian cancer protein.

The effect on the immunogenicity of the encoded polypeptide can generally be tested as described herein. The variants preferably have at least 70% identity, preferably at least about 80% identity, and most preferably at least about 90% identity with the polynucleotide sequence that encodes a native ovarian cancer protein or a portion thereof.

The percent identity of two polynucleotide or polypeptide sequences can be readily determined by comparing the sequences using computer algorithms well known to those skilled in the art such as Megalign using standard parameters. 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 of the same number of consecutive positions after the two sequences have been optimally aligned. Optimal sequence alignment for comparison can be performed using the Megalign program from the Lasergene software suite (DNASTAR, Inc., Madison, WI), using standard parameters. Preferably, the percent sequence identity is determined by comparing two optimally matched sequences over 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). The percent identity can be calculated by determining the number of positions where both sequences have identical nucleic acid bases or amino acid residues 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, yielding 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 have the ability

Hybridizing under moderately stringent conditions to a naturally occurring DNA sequence encoding a native ovarian cancer 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.

One skilled in the art will understand that as a result of the degeneracy of the genetic code, there may be multiple nucleotide sequences that code for 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 be have altered structure or function. The alleles can be identified using standard techniques (such as hybridization, amplification and / or database sequence comparison and).

Polynucleotides can be produced using a variety of techniques. For example, an ovarian cancer polynucleotide can be identified as described in more detail below by screening a late passage ovarian cancer expression library with anti-serum produced against immunocompetent mouse serum after injection of such mouse with SCID mouse serum implanted with late passage ovarian tumors. Ovarian cancer polynucleotides can also be identified using a variety of techniques designed to assess differential gene expression. Alternatively, the polynucleotides can be amplified with cDNA made from ovarian cancer cells. Such polynucleotides can be amplified by the polymerase chain reaction (PCR). In this approach, primers specific for the sequence provided herein can be designed and purchased or synthesized.

The amplified portion can be used to isolate a full-length gene from an appropriate library (e.g., an ovarian cancer cDNA library) using well-known techniques. Among these techniques, a 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 using random primers can also be beneficial for identifying the 5 'and upstream regions of genes. Genomic libraries are preferred for obtaining introns and sequences extending in the 5 'direction.

For hybridization techniques, partial sequences can be labeled (e.g., by nick-translation or end-labeling). ³²P) using well-known techniques. The 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 prepared 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, amplifications are generally performed 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 50%, 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.

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One such amplification technique is reverse PCR (see Triglia et al., Nucl. Acids Res. 16: 8186, 1988), which uses restriction enzymes to generate a fragment in a known region of the gene. This fragment is then recirculated by intracellular ligation and used as a template for PCR with various primers derived from a known region. In an alternative approach, sequences adjacent to a partial sequence may 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. A variation of this procedure which uses two primers that initiate extension in opposite directions from the known sequence is described in WO 96/38591. Additional techniques include catch PCR (Lagerstrom et al., PCR Methods Applic. 1: 111-19, 1991) and rolling PCR (Parker et al., Nuci. Acids. Res. 19: 3055-60, 1991). Other amplification methods can also be used to obtain full-length cDNA sequences.

In some instances, 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), 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 an ovarian cancer protein are shown in Figures 1A-1S (SEQ ID NOS: 1 to 71) and Figures 15A to 15EEE (SEQ ID NOS: 82 to 310). The sequences shown in Figs. 1A-1S appear to be new. For the sequences in Fig. 15A15EEE, a database search revealed sequences of significant identity. These polynucleotides were isolated by serological screening of an ovarian cancer DNA expression library using a technique designed to identify secreted cancer antigens.

Briefly, an expression library for late passage ovarian cancer was prepared from derived from

SCID of human ovarian carcinoma (OV9334) in the λ-screen vector (Novagen). Sera used for screening were obtained by injecting immunocompetent mice with sera from SCID mice implanted with one late passage of an ovarian tumor. This technique makes it possible to identify DNA molecules that code for the immunogenic part of secreted cancer antigens.

Polynucleotides presented herein, as well as full-length polynucleotides comprising such sequences, other portions of such full-length polynucleotides, and sequences complementary to all portions of such full-length molecules are all encompassed by the present invention. It will be apparent to one of skill in the art that this technique can also be used to identify antigens that are secreted from other types of tumors.

Other nucleic acid sequences of DNA molecules encoding portions of ovarian cancer proteins are shown in Figures 4-9 (SEQ ID NO: 75-81), as well as in ID NO. Seq. No: 313-384. These sequences were identified by screening cDNA microplates for tumor associated expression (ie, an expression that is at least five times greater in ovarian cancer than in normal ovarian tissue as determined using a representative assay provided herein). Such searches can be performed using Syneteni 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). Id. Seq. Nos .: 311 and 391 provide full-length sequences containing some of these nucleic acids.

Any of a number of known techniques can be used to assess tumor associated cDNA expression. For example, hybridization techniques using labeled polynucleotide probes can be used. Alternatively or additionally, amplification techniques such as real-time PCR can be used (see Gibson et al., Genome Research 6: 995-1001, 1996; Heid et al. Genome Research 6: 986-994, 1996). Real-time PCR is a technique that assesses the level of PCR product accumulation during amplification. This technique allows the quantification of mRNA levels in multiple samples. Briefly, mRNA is extracted from tumor and normal tissue and cDNA is generated using standard techniques. Real-time PCR can be performed, for example, on a 7000 Prism Perkin Elmer / Applied Biosystems machine (Foster City, CA). Matching primers and fluorescent probes can be designed for genes of interest using, for example, the Primer express program provided by Perkin Elmer / Applied Biosystems (Foster City, CA). Optimal concentrations of primers and probes can be predetermined by those skilled in the art and control (e.g., for (β-actin) primers and probes can be purchased from, for example, Perkin Elmer / Applied Biosystems (Foster City, CA).

In order to evaluate the amount of specific RNA in a sample, a standard curve is prepared using a plasmid containing the gene of interest. Standard curves can be generated using Ct values ​​determined by real-time PCR, which are dependent on the starting cDNA concentration used in the assay. Standard dilutions in the range of 10-10⁶ copies of the gene of interest are generally sufficient. In addition, a standard curve is drawn up for the control sequence. This enables the starting RNA content of the tissue samples to be standardized against the control amounts for comparison purposes.

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 an ovarian cancer antigen or a portion thereof, provided that the DNA is incorporated into the vector with an appropriate RNA polymerase promoter (such as T7 or SP6). Certain portions can be used to generate an encoded polypeptide as described herein. Additionally, or alternatively, a portion may be administered to a patient such that the encoded polypeptide is produced in vivo.

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 cells or tissues 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 open up sufficiently to bind 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 ribosomes.

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 in place of phosphodiesterase linkages in the carbon backbone; 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 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. Such formulations are especially useful for therapeutic purposes. One skilled in the art will understand 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 can be inserted into a viral vector such as, but not limited to, adenovirus, adeno-associated virus, retrovirus, or vaccinia virus, or other pox viruses (e.g., avipox). Techniques for inserting DNA into such vectors are well known to those skilled in the art. Retroviral vectors may additionally carry or insert a gene for a selectable marker (to help identify or select 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.

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Other formulations for therapeutic 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 (i.e. an artificial membrane vesicle). The preparation and use of such systems is well known in the art.

Ovarian Cancer Polypeptides

The polypeptides may include at least an immunogenic portion of an ovarian cancer protein or a variant thereof as described herein. As noted above, certain ovarian cancer proteins are ovarian cancer antigens that are expressed by ovarian cancer cells and react at a detectable level in immunoassays (such as ELISA) with antisera produced against the serum of an immunocompromised animal implanted with a human ovarian cancer. Other ovarian cancer proteins are encoded by the ovarian cancer polynucleotides presented herein. 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 (but need not) have additional immunogenic or antigenic properties.

As used herein, the term "immunogenic portion is that portion of an antigen that is recognized (i.e. bound specifically) by the surface receptor of the B-lymphocyte and / or T-lymphocyte antigen. Such immunogenic portions generally contain at least 5 amino acid residues, more preferably at least 10, more more preferably at least 20 amino acid residues of an ovarian cancer protein or a variant thereof. Preferred immunogenic fragments are encoded by cDNA molecules isolated as described herein. Further immunogenic portions can generally be identified using well-known techniques, such as those summarized in Paul, Fundamental Immunology, 3rd Edition, 243-247 (Raven Press, 1993) and references cited therein. Such techniques include screening the polypeptides for the ability to react with ovarian cancer protein-specific antibodies, antisera, and / or T cell lines or clones. As used herein, antisera and antibodies are "antigen-specific if they bind specifically to an ovarian cancer antigen (ie, they react with an ovarian cancer protein in an ELISA or other immunoassay and do not detectably react with unrelated proteins). Such antisera, antibodies, and T cells can be generated as described herein using well known techniques. An immunogenic fragment of a native ovarian cancer protein is a fragment that reacts with such antiserum, antibodies, and / or T cells at a level that is not significantly less than the reactivity of a full-length polypeptide (e.g., in an ELISA and / or T-cell reactivity assay). Such immunogenic fragments may react in such assays at levels that are similar to or greater than the reactivity of the full-length protein. Such searches can generally 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 can be immobilized on a solid support and brought into contact with the serum. patient 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 A ¹²⁵AND.

The composition may include a native ovarian cancer protein variant. The term "variant polypeptide as used herein" means a polypeptide that differs from native ovarian cancer protein in one or more substitutions, deletions, 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 an ovarian cancer protein specific antiserum may be enhanced or unchanged relative to native ovarian cancer protein or it may be reduced less than 50%, preferably less than 20% relative to native ovarian cancer protein. Such variants can generally be identified by modifying one of the above polypeptide sequences and evaluating the reactivity of the modified polypeptide with the ovarian cancer protein-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 portions of the mature protein have been removed from the N- and / or C-terminus (e.g. 1-30 amino acids, preferably 5-15 amino acids).

Preferably, the polypeptide variants have about 70%, more preferably at least about 90%, and most preferably at least about 95% identity with the native polypeptide. 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 hyropathic nature of a polypeptide to remain substantially unchanged." Amino acid substitutions can generally be made on the basis of 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. 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 the 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 may 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 prokaryotic, 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 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 solid phase synthesis method such as Merrifield where amino acids are added sequentially to a growing amino acid chain. See Merrifield, J. Am. Chem. Soc. 85: 2149-2146, 1963. Automatic polypeptide synthesis devices are commercially available from suppliers such as Perkin Elmer / Applied BioSystems, Inc. (Foster City, CA) and may be operated according to the manufacturers' instructions.

In some specific embodiments, the polypeptide may be a fusion protein that comprises a plurality of polypeptides as described herein or comprises at least one polypeptide as described herein and a known tumor antigen, such as an ovarian cancer protein or a variant of such a 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 protein expression (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.

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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: 82,588,262,186; 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 non-essential 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 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.

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, for example, 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 epitope to the T lymphocyte 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 LytA gene; Gene 43: 265292, 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.

In general, the polypeptides (including fusion proteins) and polynucleotides described herein are isolated. "An isolated polypeptide or polynucleotide is one that is removed from its original surroundings. For example, a naturally occurring protein is isolated if it is separated from some or all of its coexisting material in the natural system. Preferably 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 which is not part of its natural environment.

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Binding factors

The present invention further provides agents, such as antibodies, and antigen-binding fragments thereof, that specifically bind to an ovarian cancer protein. As used herein, an antibody or antigen-binding fragment thereof is said to "bind specifically to an ovarian cancer protein if it responds at a detectable level (e.g., by an ELISA) to the ovarian cancer protein and does not detectably react with unrelated proteins in similar conditions. The term "bond as used herein" means a non-covalent connection between two distinct molecules such that a complex is formed. The ability to bind can be assessed, for example, by determining the 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. Generally, it is said in the context of the present invention that two components "are linked when the binding constant for complex formation exceeds about 10.³ l / mol. The binding constant can be determined using methods well known in the art.

Binding agents may furthermore be capable of distinguishing between cancer-free and cancer-like patients with ovarian cancer using the representative assays provided herein. In other words, antibodies or other binding agents that bind to an ovarian cancer protein will generate 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 cancer-free subjects. To determine if a binding agent meets these requirements, biological samples (e.g., blood, serum, leukophoresis, urine, and / or cancer biopsies) from patients with and without cancer (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 made by any of a variety of techniques known to those skilled 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 a polypeptide is initially injected into any of a wide variety of mammals (e.g., mice, rats, rabbits, sheep, or goats). In this step, a polypeptide 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 capstone hemocyanin. The immunogen is injected into the host, preferably according to a predetermined schedule that includes one or more booster immunizations, and the animals will bleed periodically. 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, these methods involve 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 combined with a non-ionic detergent for several minutes and then plated at low density onto selective media that supports the growth of hybrid cells but not myeloma cells. A preferred selection technique uses HAT (hypoxanine, 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.

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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 polypeptide of the invention may 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 matrix (Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988) and digested with papain to obtain Fab and Fc fragments. The Fab and Fc fragments can be separated by affinity chromatography on a protein A matrix column.

Monoclonal antibodies 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 include⁹⁰Y, ¹²³AND, ¹²⁵AND, ¹³¹AND, ¹⁸⁶Re, ¹⁸⁸Re, ²¹¹At i ²¹²Bi. Preferred drugs include methotrexate, pyrimidine and purine analogs. Preferred differential inducers include phorbolic esters and butyric acid. Preferred toxins include ricin, abrin, diphtheria toxin, cholera, gelonin, Pseudomonas exotoxin, Shigella toxin, and an anti-viral pokeweed protein.

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 necessary to link the therapeutic agent and the antibody through 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 also facilitate the use of agents or functional groups of the agents, 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 heterofunctional (such as those described in the Pierce Chemical Co., Rockford, IL catalog) catalog, can be used as linking groups. Linking can be performed through, for example, amino, carboxyl, silphhydryl groups, or oxidized carbohydrate moieties. There are a number of references 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 necessary 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 for 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 derivatized amino acid side chains (e.g., U.S. Patent No. 4,638,045 to Kohn et al.) by hydrolysis via serum complement (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 necessary 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 albuPL 201 529 B1 mines (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 by non-covalent bonding or by encapsulation, as in the case of lipid vesicles (e.g. U.S. 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, US 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 into the placenta of a resected cancer. 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 antibody disappears.

Also provided herein are anti-idiotopic antibodies that mimic the immunogenic portion of the ovarian cancer protein. Such antibodies can be raised against an antibody, or a binding fragment thereof, that binds specifically to an immunogenic portion of an ovarian cancer protein using well-known techniques. Anti-idiotype antibodies that mimic an immunogenic portion of an ovarian cancer protein are those antibodies that bind to the antibody, or a binding fragment thereof, that binds specifically to an immunogenic portion of an ovarian cancer protein as described herein.

T lymphocytes

The immunotherapeutic compositions can also include T cells specific for an ovarian cancer protein. Such lymphocytes can generally be produced in vitro or ex vivo using standard procedures. For example, T cells can be present (or isolated from) bone marrow, peripheral blood, or a fraction of the bone marrow or peripheral blood of a mammal, such as a patient, using a commercially available cell separation system such as the CEPRATE ™ system available from CellPro 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 can be derived from related or unrelated humans, non-human mammals, lineages, or cell cultures.

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

T cells are considered to be specific for ovarian cancer polypeptides if the T cells kill target cells coated with or expressing an ovarian cancer 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 is indicative of T cell specificity. 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, detection of T cell proliferation can be achieved by a number of known techniques. For example, proliferation can be detected by measuring an increase in the rate of DNA synthesis (e.g., by plus labeling a T cell culture with tritiated thymidine and measuring the amount of tritiated thymidine incorporated into DNA). Contact with an ovarian cancer polypeptide (200 ng / ml 100 µg / ml, preferably 100 ng / ml - 25 µg / ml) for 3-7 days should lead to at least a twofold increase in T cell proliferation and / or contact as described above 2- 3 hours should lead to T cell activation as measured by a standard cytokine assay in which a 2-fold increase in cytokine release (e.g. TNF or IFN-λ) is an indicator 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 an ovarian cancer polypeptide, polynucleotide, or APC expressing an ovarian cancer polypeptide may be CD4⁺ and / or CD8⁺. Ovarian cancer protein specific T cells can be expanded using standard techniques. In preferred embodiments, T cells from the patient or a related or unrelated donor are administered to the patient after stimulation and expansion.

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For therapeutic purposes, CD4 T cells⁺ or CD8⁺ that proliferate in response to a polypeptide, ovarian cancer polynucleotide or APC can be propagated 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 an ovarian cancer polypeptide with or without the addition of T cell growth factors such as interleukin 2 and / or stimulator cells that synthesize an ovarian cancer polypeptide. Alternatively, one or more T cells that proliferate in the presence of an ovarian cancer protein may be expanded by cloning. Methods for cloning cells are well known in the art and include limited dilution. After expansion, cells can be returned to the patient as described by Chang et al. Crit. Rev. Oncol. Hematol. 22: 213, 1996.

Pharmaceutical compositions and vaccines

In certain aspects, the polypeptides, polynucleotides, binding agents, and / or cells of the immune system disclosed herein may be included in pharmaceutical compositions or vaccines. Pharmaceutical compositions include one or more of such compounds or cells and a physiologically acceptable carrier. Vaccines may contain one or more of these compounds or cells and a non-specific immune response enhancer. The non-specific immune response enhancer can be any substance that enhances the immune response to an exogenous antigen. Examples of nonspecific immune response enhancers include adjuvants, biodegradable microspheres (e.g., polylactate galactide), and liposomes (into which the compound can be incorporated; see, e.g., Fullerton, US Patent No. 4,235,877). Vaccine preparation is generally described, e.g., in MF Powell and MJ Newman, ed., Vaccine Design (the subunit and adjuvant approach) Plenum Press (NY, 1995). Pharmaceutical compositions within the scope of the present invention may also contain other compounds that may be biologically active or inactive. A pharmaceutical composition or vaccine may contain DNA encoding one or more of the polypeptides described above, such as an in situ generated polypeptide. 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.

Suitable nucleic acid expression systems contain the necessary DNA sequences 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 a polypeptide on its surface. 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: 28382848, 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 article, Science 259: 1691-1692, 1993. Naked DNA uptake can be enhanced by coating the DNA on biodegradable beads that 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 by 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, talc, cellulose, glucose, sucrose, and magnesium carbonate can be used. Biodegradable microspheres (e.g. polylactate polyglycolate). Suitable biodegradable microspheres are disclosed, for example, in US Patents 4,897,268 and 5,075,109.

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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 can be used in vaccines. 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 Freund's Incomplete Adjuvant and Freund's Complete 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. Upon administration of the vaccine provided herein, the patient will develop an immune response that will include Th1 and Th2 type 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 predominantly Th1-type responses include, for example, combinations of monophosphoryl lipid A, preferably 3 de-O-acylated monophosphoryl lipid A (3DMPL), 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 sponge that causes the ingredient to be released slowly after administration). Such preparations generally can be prepared using well known technology and administered, for example, by oral, rectal or subcutaneous implantation, or by implantation at a desired target site. Slow-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 for use in such compositions are biocompatible and can also be biodegradable; it is preferred that the formulations provide a relatively constant release of the active ingredient. The amount of active ingredient contained in the slow release composition depends on the site of implantation, the rate and time of release expected, 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 lymphocytes, monocytes, and other cells that

The PL 201 529 B1 can be changed 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 a T cell response, to have anti-tumor activity per se, and / or to be immunologically compatible with the donor (i.e., 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 embodiments of the present invention use dendritic cells or their precursors as antigen presenting cells. Dendritic cells are highly efficient APC cells (Banchereau 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 (stellate in situ, with marked in vitro cytoplasmic extensions (dendrites)) and by the absence of markers for B lymphocyte differentiation (CD19 and CD20), T lymphocytes (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, antigen-charged vesicles secreted from dendritic cells (called exosomes) can be used (see Zitvogel et al., Nature Med. 4: 594-600, 1998).

Dendritic cells and precursors can be obtained from peripheral blood, bone marrow, tumor infiltrating cells, peritumor infiltrating cells, 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

TNFa for the cultivation of monocytes collected from peripheral blood. Alternatively, CD34 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 proliferation of dendritic cells.

It is convenient to divide the dendritic cells into "immature and" mature, which allows a simple distinction between two well-characterized phenotypes. However, this nomenclature should not be considered to exclude all possible 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 cell surface molecules responsible for T cell activation, such as MHC class I and II, adhesion molecules (e.g. CD54 and CD11), and costimulatory molecules (e.g. CD40, CD80 and CD86). ).

APCs generally can be transfected with a polynucleotide encoding an ovarian cancer antigen (or a portion or other variant thereof) such that the antigen or an immunogenic portion thereof is expressed on the cell surface. Such transfection can take place ex vivo, and a composition containing such transfected cells can then be used for therapeutic purposes as described herein. Alternatively, the patient may be administered a gene delivery vehicle that targets 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 shotgun approach described by Mahvi et al., Immunology and Cell Biology 75: 456-460,1997. . Antigen loading of dendritic cells can be achieved by incubating the dendritic cells or precursor cells with a polypeptide, DNA (naked or on a plasmid vector), or RNA; or a recombinant bacterium or antigen-expressing virus (e.g. vectors based on vaccinia, fowlpox, adenoviruses or lentiviruses). Prior to loading, the polypeptide may be covalently linked to an immune partner that supports T cells (e.g., a carrier molecule). Alternatively, the dendritic 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 present invention, the compositions described herein may be used for immunotherapy of a cancer, such as ovarian cancer. Within such uses, the pharmaceutical compositions are typically administered to a patient. The term "patient as used herein" refers to any

A warm-blooded animal, preferably a human. The patient may or may not be affected by the cancer. Thus, the above pharmaceutical compositions can be used to prevent tumor growth or to treat a patient afflicted with cancer. In some preferred embodiments, the patient is suffering from ovarian cancer. Such a neoplasm can be diagnosed using criteria generally accepted in the art, including the presence of malignant neoplasm. The pharmaceutical compositions can be administered before or after surgical removal of the primary tumor and / or after treatment such as radiation therapy or administration of conventional chemotherapeutic drugs.

In some 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 modifiers (such as tumor vaccines, bacterial adjuvants, and / or cytokines).

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⁺ and tumor-infiltrating CD4 T cells⁺), killer cells (such as NK (Natural Killers) cells and lymphokine activated killer cells), B lymphocytes, and antigen presenting cells (such as dendritic cells and macrophages) expressing a polypeptide provided herein. T cell receptors and antibody receptors specific for the polypeptides presented 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 usually be obtained in amounts sufficient for adoptive immunotherapy by in vitro cultivation as described herein. The culture conditions for growing 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 cell cultures to create a sufficient number of cells for immunotherapy. In particular, antigen presenting cells such as dendritic cells, macrophages, monocytes, fibroblasts or B lymphocytes 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 growth and wide spread, 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-2 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 collected from a patient and cloned ex vivo for autologous transplantation back into the same patient.

The route and frequency of administration of the therapeutic compositions disclosed herein, as well as the dosage, will vary from patient to patient and can readily be determined using standard techniques. In general, the pharmaceutical compositions can be administered by injection (e.g., intradermal, intramuscular, intravenous, or subcutaneous), intranasally (e.g., by aspiration), or orally, or at the site of an excised tumor. Preferably, 1 to 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. Different protocols may be appropriate for individual patients. A suitable dose is that amount of a component that, when administered as described above, has the ability to promote an immune response against cancer and is at least 10-50% higher than the baseline level (i.e. without administration). Such a response can be monitored 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

To induce an immune response that leads to an improved clinical picture (e.g., more frequent remissions, complete or partial, or longer disease-free survival) in vaccinated patients as 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 levels will vary with patient size but will typically range from about 0.1 ml to about 5 ml.

In general, an appropriate regimen of dosing and treatment will provide the active ingredient (s) in an amount sufficient to provide a therapeutic and / or prophylactic benefit. Such a response can be monitored by establishing an improvement in the clinical picture (e.g., more frequent remissions, complete or partial, or longer disease-free survival) in treated patients compared to untreated patients. An increase in a pre-existing immune response to an ovarian cancer antigen generally correlates with improvement in the clinical picture. 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.

Search to identify secreted ovarian cancer antigens

In methods for identifying secreted tumor antigens, tumors are implanted into immunodeficient animals, such as SCID mice, and maintained for a time sufficient to allow the secretion of the tumor antigens into the serum. In general, tumors can be implanted subcutaneously or into the gonadal fat flap of immunocompromised animals and last for 1-9 months, preferably 1-4 months. Implantation can generally be performed as described in WO97 / 18300. The serum containing the secreted antigens is then used to obtain the antiserum in an immunocompetent mouse using standard techniques as described herein. Briefly, 50-100 μl of serum (collected from three groups of immunocompromised mice, each group with a different SCID-derived human ovarian cancer) can be mixed 1: 1 (v: v) with a suitable adjuvant such as RIBI-MPL or MPL + TDM (Sigma Chemical Co., St. Louis, MO) and inject intraperitoneally into the syngeneic immunocompetent animal monthly for a total of 5 months. Antisera from animals immunized in this way can be obtained by drawing blood after the third, fourth, and fifth immunizations. The resulting antiserum is pre-purified from E. coli and phage antigens and used (generally diluted, such as 1: 200) in a serological expression assay.

The library is usually an expression library containing DNA from one or more tumors of the type that have been implanted in SCID mice. Such expression library can be prepared in any suitable vector, such as λ-screen (Navagen). cDNAs that encode a polypeptide that reacts with the antiserum can be identified using standard techniques and sequenced. Such cDNA molecules can be further characterized to assess expression in tumor cells and normal tissue, and to assess antigen secretion in patients.

The methods provided herein have advantages over other methods for identifying tumor antigens. In particular, all antigens identified by such methods should be secreted or released by tumor cell necrosis. Such antigens may be present on the surface of the tumor cells for a period of time sufficient to allow the immune system to reach and kill after inoculation.

Methods of tumor detection

Generally, a tumor can be detected in a patient based on the presence of one or more proteins and / or polynucleotides encoding ovarian cancer proteins in a biological sample (such as 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 ovarian cancer. Moreover, such proteins may be useful in the detection of 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 encoding a tumor protein, which also indicates the presence or absence of a tumor. In general, the ovarian cancer-related sequence should be present at a level at least three times higher in neoplastic tissue than in normal tissue.

There are a variety of assay methods known to those skilled in the art that employ a binding agent to detect polypeptide markers in a sample. See, e.g., Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988. Generally, the presence or absence of a tumor in a patient can be determined by a) contacting a biological sample

Obtained from a 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 a preferred embodiment, 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 specifically binds to the binding agent / 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 can be used in which the polypeptide is labeled with a reporter group and allows it 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 ovarian 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 the tumor protein can be attached. For example, the solid support may be a well of 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, for example, in US 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: a non-covalent association such as adsorption and a covalent bond (which may be a direct link between an agent and functional groups on a substrate or a linkage via a cross-linking agent). Immobilization by adsorption to a well of 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 ng to about 10 µg, and preferably about 100 ng to about 1 µg, 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 a suitable polymer coating using a benzoquinone or by condensation of the aldehyde group on the substrate with an amine and the active hydrogen of the binding partner (see, e.g., Pierce Immunotechnology Catalog and Handbook, 1991, in A12-A13).

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 that remains 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 (i.e., incubation time) is sufficient to detect the presence of the polypeptide in a sample obtained from an ovarian cancer subject. Preferably, the contact time is sufficient to achieve a binding level of at least 95% that is achieved at an equilibrium between bound and unbound polypeptide. Professionals in this field will realize that the time required for the axis20

Equilibrium strikes can be easily determined by determining the level of binding achieved over 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 that contains the reporter group can then be added to the solid support. Preferred indicator groups include the aforementioned groups.

The detection reagent 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 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 (usually a radioactive or fluorescent group or an enzyme). Enzyme pointer groups can generally be detected by adding substrate (generally for a specific time) followed by spectroscopic or other analysis of the reaction products.

To determine the presence or absence of a tumor, such as ovarian cancer, the signal detected from the indicator group that remains bound to the solid support is usually compared to a signal corresponding to a predetermined cut-off. In one preferred embodiment, the cutoff 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 plotted against a pair of true positives (ie, sensitivity) and false positives (100% specificity), which corresponds to each possible cutoff value 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 embodiments, the test is performed as a flow or strip test 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 polypeptide binding agent complex as the solution containing the second binding agent passes through the membrane. Detection of the bound second binding agent can then be performed as described above. With the strip 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 that location produces a pattern, such as a line, that can be read visually. The absence 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 polypeptide levels 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 accomplished

Be modified to use ovarian cancer polypeptides to detect antibodies that bind such polypeptides in a biological sample. The detection of such antibodies specific for ovarian cancer 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 ovarian cancer proteins in the biological sample. In some methods, a biological sample containing CD4 T cells⁺ and / or CD8⁺ isolated from the patient is incubated with an ovarian cancer polypeptide, a polynucleotide encoding such a polypeptide, and / or APC cells expressing at least an immunogenic portion of such polypeptide, and the presence or absence of specific activation of T cells is detected. Suitable biological samples include, but are not limited to, isolated T cells.

For example, T cells can be isolated from the patient by routine techniques (such as centrifugation of peripheral blood lymphocytes on a Ficoll / Hypaque density gradient). T cells can be incubated in vitro for 2-9 days (typically 4 days) at 37 ° C with an ovarian cancer polypeptide (eg, 5-25 µg / ml). It may be necessary to incubate another T cell sample in the absence of the ovarian cancer polypeptide as a control. For CD4 T cells⁺ activation is preferably detected by assessing proliferation of T cells. For CD8 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 disease-free patients, indicates the presence of a tumor in the patient.

As noted above, a cancer may also or alternatively be detected based on the level of mRNA encoding an ovarian cancer protein in a biological sample. For example, at least two oligonucleotide primers may be used in a polymerase chain reaction (PCR) assay to amplify a portion of an ovarian cancer cDNA derived from a biological sample, wherein at least one oligonucleotide primer is specific (i.e. hybridizes to) a polynucleotide encoding an ovarian cancer 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 an ovarian cancer 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 an ovarian cancer protein that is at least 10 nucleotides in length, and preferably at least 20 nucleotides. Preferably, the oligonucleotide primers and / or probes hybridize to a polynucleotide encoding a polypeptide disclosed herein under moderately stringent conditions as defined above. Oligonucleotide primers and / or probes which 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 set out herein. 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 a test patient and from an individual who is not cancerous. The amplification reaction can be performed on several cDNA dilutions over 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 to track tumor development. In this embodiment, 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.

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Certain in vivo diagnostic tests 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, multiple ovarian cancer marker proteins can be determined in a given tissue to improve sensitivity. It will be appreciated that binding agents specific for 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 protein markers 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.

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

Examples

Example 1

Identification of cDNA for representative ovarian cancer proteins

This example illustrates the identification of cDNA molecules encoding ovarian cancer proteins.

Sera against SCID mice (generated against sera from SCID mice with late passage ovarian tumor) were pre-purified from E. coli and phage antigens and used at a dilution of 1: 200 for serological expression screening. A screening library was generated from SCID-derived human ovarian carcinoma (OV9334) using the RH targeted cDNA library construction kit (oligo dT) and the λ vector, Screen (Novagen). Screening for bacteriophage lambda was performed.

Approximately 400,000 pfu of the amplified OV9334 library were screened.

196 positive clones were isolated. Certain sequences that have been found to be new are shown in Figures 1A-1S and in Id. Seq. Nos. 1 to 71. Three complete insert sequences are shown in Figures 2A-2C (SEQ ID NOS: 72 to 74). Other clones having known sequences are shown in Figures 15A-15EEE (SEQ ID NOs: 82 to 310). Database searches identified the following sequences that are substantially identical to the sequences shown in Figs. 15A-15EEE.

These clones were further characterized using microplate technology to determine mRNA expression levels in a variety of tumors and normal tissues. Such analyzes were performed using Synteni microplates (Palo Alto, CA) according to the manufacturer's instructions. The PCR amplification products were arranged in an orderly manner on the slides, each occupying a specific place in the array. mRNA was extracted from the tissue sample to be tested, reverse transcribed, and fluorescently labeled probes were prepared. Microplates were screened with labeled cDNA probes and slides scanned to measure fluorescence intensity. Data were analyzed using the GEMtools software provided by Synteni. The results for one clone (13695, also referred to as 08E) are shown in Fig. 3.

Example 2

Ovarian cancer cDNA identification using microplate technology

This example illustrates the identification of ovarian cancer polynucleotides using PCR elimination and microplate analysis. The cDNA microplates were analyzed for ovarian tumor specific expression using Synteni microplates (Palo Alto, CA) according to the manufacturer's instructions (and essentially as described in Schena et al., Proc. Natl. Acad Sci. USA 93: 10614-10619, 1996 and Heller et al., Proc. Natl. Acad. Sci. USA 94: 2150-2155,1997).

PCR elimination was performed using test cDNA from four ovarian tumors (three of which were metastatic tumors) and eliminating cDNA from five normal tissues (adrenal gland, lung, pancreas, spleen and brain). The DNA fragments recovered after elimination were analyzed on microplates, where the fragments were amplified by PCR, placed on microplates, and hybridized with fluorescently labeled probes derived from human ovarian cancer mRNA and various normal human tissues. In this analysis, the slides were scanned and the fluorescence intensity was measured, and the data was analyzed using the GEMtools software from Synteni. In general, sequences showing at least a 5-fold increase in tumor expression (relative to normal cells) were considered ovarian cancer antigens. The results of the fluorescence measurement were analyzed and clones that showed an increase

The expression in ovarian cancers was further analyzed by DNA sequencing and searching databases to determine if they were new sequences.

Using such assays, an ovarian cancer antigen was identified, which is a fusion of the TAX oncoprotein of the human T-cell leukemia virus type I (see Jin et al., Cell 93: 81-91, 1998) and an extracellular protein called osteonectin. There is an intron cutout at their junction. The sequence of this clone is shown in Fig. 4 and in Id. Seq. No .: 75. Osteonectin, unspliced ​​and unchanged, was also identified independently in these tests.

Further clones identified by this method are referred to herein as 3f, 6b, 8e, 8h, 12c and 12h. The sequences of these clones are shown in Figures 5 to 9 and in Id. Seq. Nos .: 76 to 81. Microplate analyzes were performed as described above and are shown in Figures 10 to 14. Full length sequences including clones 3f, 6b, 8e and 12h were obtained by screening an ovarian cancer DNA library (derived from SCID). This 2296 bp sequence (designated 0772P) is shown in Id. Seq. No. 311, and its encoded protein sequence of 914 amino acids is shown in SEQ ID NO. Seq. No: 312. PSORT analysis indicates a Type 1a transmembrane protein located in the plasma membrane.

In addition to some of the sequences described above, the following sequences were identified as a result of this search:

<td>Sequence</td><td>Comments</td>

<td>OV4vG11 (Seq ID No: 313)</td><td>human clone 1119D9 on chromosome 20p12</td>

<td>OV4vB11 (Seq ID No: 314)</td><td>human UWGC: y14c094 from chromosome 6p21</td>

<td>OV4vD9 (Seq ID No: 315)</td><td>human clone 1049G16, chromosome 20q12-13.2</td>

<td>OV4vD5 (Seq ID No: 316)</td><td>the human KIAA0014 gene</td>

<td>OV4vC2 (Seq ID No: 317)</td><td>the human KIAA0084 gene</td>

<td>OV4vF3 (Seq ID No: 318)</td><td>The human cosmid R31167 from chromosome 19</td>

<td>OV4vVC1 (Seq ID No: 319)</td><td>new</td>

<td>OV4vH3 (Seq ID No: 320)</td><td>new</td>

<td>OV4vD2 (Seq ID No: 321)</td><td>new</td>

<td>0815P (Seq ID No: 322)</td><td>new</td>

<td>OV4vC12 (Seq ID No: 323)</td><td>new</td>

<td>OV4vA4 (Seq ID No: 324)</td><td>new</td>

<td>OV4vA3 (Seq ID No: 325)</td><td>new</td>

<td>OV4v2A5 (Seq ID No: 326)</td><td>new</td>

<td>0819P (Seq ID No: 327)</td><td>new</td>

<td>0818P (Seq ID No: 328)</td><td>new</td>

<td>0817P (Seq ID No: 329)</td><td>new</td>

<td>0816P (Seq ID No: 330)</td><td>new</td>

<td>Ov4vC5 (Seq ID No: 331)</td><td>new</td>

<td>21721 (Seq ID No: 332)</td><td>human lumican</td>

<td>21719 (Seq ID No: 333)</td><td>human retinoic acid binding protein II</td>

<td>21717 (Seq ID No: 334)</td><td>human ATPase subunit of the 26S proteasome</td>

<td>21654 (Seq ID No: 335)</td><td>human kick I</td>

<td>21627 (Seq ID No: 336)</td><td>human gamma-2 enolase specific to neuron</td>

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<td>21623 (Seq ID No: 337)</td><td>human geranylgeranyltransferase II</td>

<td>21621 (Seq ID No: 338)</td><td>human cyclin-dependent protein kinase</td>

<td>21616 (Seq ID No: 339)</td><td>Human prepro-megakaryocytic helper factor</td>

<td>21612 (Seq ID No: 340)</td><td>human UPH1</td>

<td>21558 (Seq ID No: 341)</td><td>human RalGDS-like 2 (RGL2)</td>

<td>21555 (Seq ID No: 342)</td><td>human autoantigen P542</td>

<td>21548 (Seq ID No: 343)</td><td>human actin-related protein (ARP2)</td>

<td>21462 (Seq ID No: 344)</td><td>human protein that interacts with huntingtin</td>

<td>21441 (Seq ID No: 345)</td><td>human product 90K (tumor associated antigen)</td>

<td>21439 (Seq ID No: 346)</td><td>human guanine nucleotide protein regulator (tim1)</td>

<td>21438 (Seq ID No: 347)</td><td>human autoimmune Ku antigen (p70 / p80)</td>

<td>21237 (Seq ID No: 348)</td><td>human laminin-S</td>

<td>21436 (Seq ID No: 349)</td><td>human ribophorin I.</td>

<td>21435 (Seq ID No: 350)</td><td>human cytoplasmic chaperonin hTRiC5</td>

<td>21425 (Seq ID No: 351)</td><td>human EMX2</td>

<td>21423 (Seq ID No: 352)</td><td>the human p87 / p89 gene</td>

<td>21419 (Seq ID No: 353)</td><td>human HPBRII-7</td>

<td>21252 (Seq ID No: 354)</td><td>human T1-227H</td>

<td>21251 (Seq ID No: 355)</td><td>The Human Cultures I.</td>

<td>21247 (Seq ID No: 356)</td><td>human kunitz protease inhibitor (KOP)</td>

<td>21244-1 (Seq ID No: 357)</td><td>human F tyrosine phosphatase receptor (PTPRF)</td>

<td>21718 (Seq ID No: 358)</td><td>human LTR repeat</td>

<td>OV2-90 (Seq ID No: 359)</td><td>new</td>

<td colspan="2">The human zinc finger (SEQ ID NO: 360)</td>

<td colspan="2">Human polyA binding protein (SEQ ID NO: 361)</td>

<td colspan="2">Human Pleitropin (SEQ ID NO: 362)</td>

<td colspan="2">PAC 278C19 human clone (SEQ ID NO: 363)</td>

<td colspan="2">Human LLRep3 (SEQ ID NO: 364)</td>

<td colspan="2">Human Kunitz Protease Inhibitor (SEQ ID NO: 365)</td>

<td colspan="2">The human KIAA0106 gene (SEQ ID NO: 366)</td>

<td colspan="2">Human Keratin (SEQ ID NO: 367)</td>

<td colspan="2">Human HIV-1TAR (SEQ ID NO: 368)</td>

<td colspan="2">Human neuroglyle derived nexin (SEQ ID NO: 369)</td>

<td colspan="2">Human Fibronectin (SEQ ID NO: 370)</td>

<td colspan="2">Human ECMproBM40 (SEQ ID NO: 371)</td>

<td colspan="2">Human Collagen (SEQ ID NO: 372)</td>

<td colspan="2">Human alpha enolase (SEQ ID NO: 373)</td>

<td colspan="2">Human aldolase (SEQ ID NO: 374)</td>

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Human Transforming Growth Factor BIG H3 (SEQ ID NO: 375) Human Osteonectin SPARC (SEQ ID NO: 376)

Human SLP1 leukocyte protease (SEQ ID NO: 377)

Human Mitochondrial ATP Synthase (SEQ ID NO: 378)

Human DNA sequence of clone 461P17 (SEQ ID NO: 379)

Human dbpB pro Y box (Seq ID No: 380)

Human keratin 40 kDa (SEQ ID NO: 381)

Human arginosuccinate synthase (SEQ ID NO: 382)

Human acid ribosomal phosphoprotein (SEQ ID NO: 383)

Human Laminin Binding Protein from Colon Cancer (SEQ ID NO: 384)

As a result of this search, multiple forms of the 0777P clone, referred to herein as 21013, 21003 and 21008, were identified. PSORT analysis indicated that 21003 (SEQ ID NO: 386, translated as SEQ ID NO: 389) and 21008 (SEQ ID NO: 389) and 21008 (SEQ ID NO: 389) and 21008 (SEQ ID NO: 389) and 21008 (SEQ ID NO: NO: 387, translated as SEQ ID NO: 390) represents the type 1a transmembrane form of the 0772P protein. 21013 (SEQ ID NO: 385, translated as SEQ ID NO: 388) appears to be a truncated form of the protein and is predicted by PSORT analysis to be a secreted protein.

Additional sequence analysis resulted in a full length clone for 08E (2627 bp, which is in agreement with the mRNA size observed in Northern analysis; SEQ ID NO: 391). This nucleotide sequence was obtained as follows: the starting O8E sequence (OrigO8Econs) was found to overlap by 33 nucleotides on the sequence from the EST clone (IMAGE # 1987589). This clone provided an additional 1042 nucleotides upstream of the original O8E sequence. The association between EST and 08E was confirmed by sequencing multiple PCR fragments generated from a primary ovarian carcinoma library using primers for the unique EST and 08E sequences (ESTx08EPCR). The full length was also indicated that the anchored PCR reaction from the ovarian cancer library produced several clones (AnchoredPCR cons) which all ended above the methionine being the putative start site but carried no additional sequence information. Fig. 16 is a diagram that illustrates the position of each partial sequence within the full length 08E sequence.

Two protein sequences may be translated from full-length O8E. Form a (SEQ ID NO: 393) starts with a putative starting methionine. The second form of b (SEQ ID NO: 392) includes 27 additional residues upstream of the 5 'end of the nucleotide sequence.

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.

Summary of the sequence list

Id. Seq. Nos. 1-71 are the polynucleotides for the ovarian cancer antigen shown in Figs. 1A-1S.

Id. Seq. Nos .: 72-74 are the polynucleotides for the ovarian cancer antigen shown in Figs. 2A-2C.

Id. Seq. NO: 75 is a 3g polynucleotide of ovarian cancer (Fig. 4).

Id. Seq. NO: 76 is an ovarian carcinoma 3f polynucleotide (Figure 5).

Id. Seq. NO: 77 is an ovarian carcinoma polynucleotide 6b (Fig. 6).

Id. Seq. NO: 78 is an ovarian carcinoma polynucleotide 8e (Fig. 7A).

Id. Seq. NO: 79 is an 8h polynucleotide for ovarian carcinoma (Fig. 7B).

Id. Seq. NO: 80 is an ovarian carcinoma polynucleotide 12e (Figure 8).

Id. Seq. NO: 81 is an ovarian cancer 12h polynucleotide (Fig. 9).

Id. Seq. Nos. 82-310 are the polynucleotides for the ovarian cancer antigen shown in Figs. 15A-15EEE.

Id. Seq. ID NO: 311 is the sequence for the full length polynucleotide 0772P of ovarian cancer.

Id. Seq. ID NO: 312 is the amino acid sequence 0772P.

Id. Seq. Nos .: 313-384 are polynucleotides for the ovarian cancer antigen.

Id. Seq. NO: 385-390 shows the sequence of Form 0772P.

Id. Seq. NO: 391 is the sequence for the full length 08E ovarian carcinoma polynucleotide.

Id. Seq. Nos .: 392-393 are the protein sequences encoded by 08E.

PL 201 529 B1

Sequence List &lt;110&gt; Coriza Corporation

Compositions and methods for the treatment and diagnosis of ovarian cancer

<td>&lt;13O&gt;</td><td> 210121.</td><td>462P</td>

<td> &lt;140&gt;</td><td>PCT</td><td></td>

<td> &lt;141&gt;</td><td> 1999-12</td><td> -17</td>

<td> &lt;160&gt;</td><td> 393</td><td></td>

<td> &lt;170&gt;</td><td>FastSEQ</td><td>for</td>

<td> &lt;210&gt;</td><td> 1</td><td></td>

<td> &lt;211&gt;</td><td> 461</td><td></td>

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

<td> &lt;213&gt;</td><td colspan="2">Homo sapien</td>

<td> &lt;400&gt;</td><td> 1</td><td></td>

ttagagaggc tttgttttgt catgatctca ctcccaagta tttagtagag tgatccaccc gcccccaaag taactgacgt acagaaggaa tttgttttga gctcgctgca gctgggatta acagggtttc gcctcggcct ctgtttcttt gactgccagc gaagagttaa gatggagtct acctccgcct caggcgcccg accaggttgg cccaaagtgc tgtctttagc aagctcagtc aagcagcaaa cactctgttg cccacgttca ccaccacgct ccaggctgct tgggattaca gtaaagctct actccgtggt gccgggtttt cccaagctgg agtgattctc cagctaattt cttgaactcc ggcgtgagcc cctgccatgc c

tttgttttgt agtacaacgg ctgcctcagc tttttgtatt tgacctcagg accacgcccg agtatctaca

120

180

240

300

360

420

461

<td> &lt;210&gt;</td><td> 2</td>

<td> &lt;211&gt;</td><td> 540</td>

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

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

<td> &lt;400&gt;</td><td> 2</td>

taggatgtgt agaagaagat attaattatt aggaggttgg tggcctttct ggaccggcag gttaaagcag gtttgtacta aggagacatt tggaccctct gcatttaaaa gtgtcagaag cagcaagaac gcatgggaac actgtgtcta ggttacatga aaacccaaca ctcttggatg gtgtcaaaaa tatgggttat agattgaata aatttgaaca ttattgagct tggcaattąa tgaaaaaggg taatttctta aaaattgctg aaacctcaca tttcaacttt cctgcttaag tcataaaatc tattggaaat tgaagtcttt ccacagacgg ctatgtgagt tgtagagtcc aagaatcccc ttatctgagg aagcttacag aactttgatg ggacagttta aatgaactta aaaaactgga gaggatctga ttgcctgaca tgctcattac acaagtatcc aagctatggg acagtaaaaa gcaaaggcat tattagatgt ctgaaagatg aggataagaa aagatggaaa

120

180

240

300

360

420

480

540

<td> &lt;210&gt;</td><td> 3</td>

<td> &lt;211&gt;</td><td> 461</td>

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

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

<td> &lt;400&gt;</td><td> 3</td>

GB 201 529 B1 ttagagaggc tttgttttgt catgatctca ctcccaagta tttagtagag tgatccaccc gcccccaaag taactgacgt acagaaggaa tttgttttga gctcgctgca gctgggatta acagggtttc gcctcggcct ctgtttcttt gactgccagc gaagagttaa gatggagtct acctccgcct caggcgcccg accaggttgg cccaaagtgc tgtctttagc aagctcagtc aagcagcaaa cactctgttg cccacgttca ccaccacgct ccaggctgct tgggattaca gtaaagctct actccgtggt gccgggtttt cccaagctgg agtgattctc cagctaattt cttgaactcc ggcgtgagcc cctgccatgc c

tttgttttgt agtacaacgg ctgcctcagc tttttgtatt tgacctcagg accacgcccg agtatctaca

120

180

240

300

360

420

461

<td> &lt;210&gt;</td><td> 4</td><td></td>

<td> &lt;211&gt;</td><td> 531</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>mi sc</td><td>feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> ' ⁽⁵³V /</td>

<td> &lt;223&gt;</td><td>n »Z</td><td></td>

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

<td>&lt;4OO&gt;</td><td> &lt;3</td><td></td>

tctttttctt tcgatttcct tcaatttgtc acgtttgatt ttatgaagtt gttcaagggc 60 taactgctgt gtattatagc tttctctgag ttccttcagc tgattgttaa atgaatccat 120 ttctgagagc ttagatgcag tttctttttc aagagcatct aattgttctt taagtctttg 180 gcataattct tccttttctg atgacttttt atgaagtaaa ctgatccctg aatcaggtgt 240 gttactgagc tgcatgtttt taattctttc gtttaatagc rgcttctcag ggaccagata 300 gataagctta ttttgatatt ccttaagctc ttgttgaagt tgtttgattt ccataatttc 360 caggtcacac tgtttatcca aaacttctag ctcagtcttt tgtgtttgct ttctgatttg 420 gacatcttgt agtctgcctg agatctgctg atgntttcca ttcactgctt ccagttccag 480 gtggagactt tnctttctgg agctcagcct gacaatgcct tcttgntccc t 531

<td> &lt;210&gt;</td><td> 5</td>

<td> &lt;211&gt;</td><td> 531</td>

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

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

<td> &lt;400&gt;</td><td> 5</td>

agccagatgg cgatgaatgg aacagtttga ttttcctaca tgaaeaagga taaagttgca tgttctctcc atcagccatt ccagtattcc ctgagagctg agggccaaat taacctcaaa gtcaggtctg tgggaagatg gggccaacag.

actaatctct gcctccagtt tcccctaatg caagaagaag atgtgggcra ccttcaggag ccggccccgg gaccagcaag ctgcctgtag gctcgttttg gcacctatag atgcctgctc tcaggatcat ttacatctga gttacataac ttttagctga agttctctat tcctccctcc ggatgggaag caacaccctt ccctagtgcc gatggctcag agaacgtact aggtgatcaa aatatgggcc agctatgaaa tatcatgaaa catgcccaat gtcttctgct ttctgttagt tttcccacag aagcatgata gcccgtactt ttatcagatc ctcatcaagt caacccccta ctgtccattc acttcaggga and

120

180

240

300

360

420

480

531

<td> &lt;210&gt;</td><td> 6</td>

<td> &lt;211&gt;</td><td> 531</td>

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

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

<td> &lt;400&gt;</td><td> 6</td>

aatagattta atgcagagtg tcaacttcaa ttgattgata gtggctgcct agagtgctgt 60 gttgagtagg tttctgagga tgcaccctgg cttgaagaga aagactggca ggattaacaa 120 tatctaaaat ctcacttaccagta gggcaaccagta gggccctcagta

GB 201 529 B1 ccagctccac caaggccagc gaagagccca aatgtgagag tggcggtcag gctggcacca gcactgaagc caccactggt gctggcactg gcactggcac tgttattggt actggtactg gcaccagtgc tggcactgcc actctcttgg gctttggctt tagcttctgc tcccgcctgg atccgggctt tggcccaggg tccgatatca gcttcgtccc agttgcaggg cccggcagca ttctccgagc cgagcccaat gcccattcga gctctaatct cggccctagc cttggcttca gctgcagcct cagctgcagc cttcaaatcc gcttccatcg cctctcggta c

240

300

360

420

480

531

<td> &lt;210&gt;</td><td> 7</td>

<td> &lt;211&gt;</td><td> 531</td>

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

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

<td> &lt;400&gt;</td><td> 7</td>

gccaagaaag cccgaaaggt gaagcatctg gatggggaag aggatggcag cagtgatcag agtcaggctt ctggaaccac aggtggccga agggtotcaa aggccctaat ggcctcaatg gcccgcaggg cttcaagggg tcccatagcc ttttgggccc gcagggcatc aaggactcgg ttggctgctt gggcccggag agccttgctc tccctgagat cacctaaagc ccgtaggggc aaggctcgcc gtagagctgc caagctccag tcatcccaag agcctgaagc accaccacct cgggatgtgg cccttttgca agggagggca aatgatttgg tgaagtacct tttggctaaa gaccagacga agattcccat caagcgctcg gacatgctga aggacatcat caaagaatac accgatgtgt accccgaaat cattgaacga gcaggctatt ccttggagaa ggtatttggg attcaattga aggaaattga taagaatgac cacttgtaca ttcttcrcag c &lt;210? 8 &lt;211? 531 &lt;212? DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221? misc ^ feature &lt;222? (1) ... (531) &lt;223? n - A, T, C, Lula G &lt;400&gt; 8 gaggtctcac tatgttgccc aggctgttct tgaactcctg ggatcaagca atccacccat gttggtctcc aaaagtgctg ggatcatagg cgtgagccac ctcacccagc caccaatttt caatcaggaa gactttttcc ttcttcaaga agtgaagggt ttccagagta tagctacact attgcttgcc tgagggtgac tacaaaattg cttgctaaaa ggttaggatg ggtaaagaat tagattttct gaatgcaaaa ataaaatgtg aactaatgaa ctttaggtaa tacatattca taaaataatt attcacatat ttcctgattt atcacagaaa taatgtatga aatgctttga gtttcttgga gtaaactcca ttactcatcc caagaaacca tattataagt atcactgata ataagaacaa caggaccttg tcataaattc tggataagag aaatagtctc tgggtgtttg ntcttaattg ataaaattta cttgtccatc ttttagttca gaatcacaaa a &lt;210&gt; 9 &lt;211&gt; 531 &lt;212? DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (531) &lt;223&gt; n = A, T, C Ue G &lt;400&gt; 9

120

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240

300

360

420

480

531

120

180

240

300

360

420

480

531

GB 201 529 B1 aagcggaaat agggctcagt ggtgcacaga atacactgag tgtgcagtga atgttctgag aagttaaaaa tccacccaag aggtacttga gagaaaggag cctgttggag ccagcacggc tataagggtt atctaagaaa ttacctattt caaagcaggt gagccaggga gttggaattg ggaaaatcat aactctgggt tctgtgacct ggtttagaaa aaaattgggg ttattgcatt cctttatcac gctgggctaa ttttaatccc gtggtattga ggtgctgtag gtttgttaca ctcttacagc ctgtatttgt ttacaaaagc agcactgtcg accaaagaat atcattacca

<td>gcggaaaact</td><td>gctggatgac</td><td> 60</td>

<td>aacagggcca</td><td>ctcacagtgg</td><td> 120</td>

<td>ggtccatgat</td><td>gaggtaaaca</td><td> 180</td>

<td>aatttgacaa</td><td>agtaatcttc</td><td> 240</td>

<td>atgttccttt</td><td>ttttcatttc</td><td> 300</td>

<td>atccttccat</td><td>gaaggaccgg</td><td> 360</td>

<td>tagaacacag</td><td>ttcagagtta</td><td> 420</td>

<td>tttgcttttg</td><td>gttaatcstc</td><td> 480</td>

<td>ggctggangt</td><td>g</td><td> 531</td>

<td> &lt;210&gt;</td><td> 10</td>

<td> &lt;211&gt;</td><td> 861</td>

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

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

<td> &lt;400&gt;</td><td> 10</td>

ccgcggctcc gccagccttg tggagacatt atcagaaaag gatcagataa tttttggacc tcagaacatt gaatatcata cgatagagaa gaaatgagga gtcatgactg aatcacaata ttatgattca actgttaatt actcaaagta tgtccagacc tactgatgtc caagcaaagg gtgactaata aacagtttaa gtgttagaga gcttacagaa ttcagcagaa gtcctgatgg ctcatctgat tttggcaaat gaaggtctta gcagcttggt ttaaagcaac aaataaatgg ctgaccctcc ggctgcgaga ttggacaact aaggtaccag ggaattcctg cttcacaaca atatttaaaa tgaagęcctg atgaactttt agaatcccct ggaaaccgct ttgttcagtg cacttgatta ttatgtgttc and

<td>ctcccaaggc</td><td>tcaaccgtcc</td><td>cccaacaacc</td><td> 60</td>

<td>gcctgtgctt</td><td>aagtaagaat</td><td>caggccttat</td><td> 120</td>

<td>acttttccag</td><td>aacagaaagg</td><td>aaactcatgc</td><td> 180</td>

<td>aagaatatgg</td><td>ctgcacaaat</td><td>accagaatct</td><td> 240</td>

<td>gggacctaca</td><td>ataaacttac</td><td>agagacccgc</td><td> 300</td>

<td>agagaagtaa</td><td>aacctgaaga</td><td>gaccacctgt</td><td> 360</td>

<td>atgacacaaa</td><td>gaatatccat</td><td>gagatttcag</td><td> 420</td>

<td>gcagccaaag</td><td>caggactcct</td><td>tggccaacca</td><td> 480</td>

<td>gatgaaagat</td><td>tgccaacagc</td><td>tgctttattg</td><td> 540</td>

<td>gaaagcagta</td><td>gccaccatgt</td><td>tcaaccatct</td><td> 600</td>

<td>ggagaaacaa</td><td>aattgctatt</td><td>taccaggaat</td><td> 660</td>

<td>aaataacaag</td><td>atgcaacatt</td><td>tgttgaggcc</td><td> 720</td>

<td>gaaaaataaa</td><td>ccattgtttc</td><td>ttcaattgtg</td><td> 780</td>

<td>gatcatgtat</td><td>gagatagaaa</td><td>aatttttatt</td><td> 840</td>

<td></td><td></td><td></td><td> 861</td>

&lt;210&gt; 11 &lt;211&gt; 541 &lt;212&gt; DNA &lt;213&gt; Homo saoien &lt;400&gt;

gaaaaaaaat caccaatata atgaagctag tggcataaga tgaaagcgtt agagtaacag caaaacgaac acaaggcacc gaaaatcaga a

ataaaacaca aatccaattt caagtgatga tatatccact cctgatcttg aaaaagaaaa aaagtgtcat gtgatttttg tgagaaaact cttttgcgaa tatgaaaact tatgataaaa tttgatatta cttgttctcc aagacatttt gtctaattct taattctaac gtggtctttc aacggtggcc gacaatttaa taaacgtgga aacttgtgaa atttcaaata tgcattttga agcctctgaa ctgaagaaat caaagcctga

<td>ctaaaagagg</td><td>aaaagaattt</td><td> 60</td>

<td>tccaagaatc</td><td>acttttgtaa</td><td> 120</td>

<td>ggaaataaaa</td><td>acacaagact</td><td> 180</td>

<td>gcatattctt</td><td>cgacaaattg</td><td> 240</td>

<td>aggaggcata</td><td>tcacatccca</td><td> 300</td>

<td>gatgaaccaa</td><td>agacacaaaa</td><td> 360</td>

<td>ataaaccttg</td><td>aacatctcct</td><td> 420</td>

<td>gtgatgactt</td><td>ttgtggacat</td><td> 480</td>

<td>actcccctga</td><td>aaacctttgc</td><td> 540</td>

<td></td><td></td><td> 541</td>

<td> &lt;210&gt;</td><td> 12</td>

<td> &lt;211&gt;</td><td> 541</td>

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

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

<td> &lt;400&gt;</td><td> 12</td>

PL 201 529 B1 ctgggatcat catcctcttc aagatgatgc tggctgtttc cagcttccac ctgattcaga ctttgctgtc ttggtcgatt ttggtgaatt t

ttctcttgat tgtacagtgc ttctgtttct tctgacttca agcatcttca ggtcgaagag tgtgctctca aagtggcctg tccaggaaac gtcataaaag tgccgggtac cctaccataa ccttctttgt tctggatgtt tcactgtgat ggcaacccat ggtgtcccag ataacaccat actcttcttc aacggctatc ctgaagaaat caaacctgag tatttttcaa ttttctcctc ttgttgtcat gcccatttat tcattcgatt ttcctcttca tttgtcttta ttcgctggaa tctttttacc agggctcact attttgctgc gggggctgac attagacctc taaactattg tcctcttctt tcctgagatg gtcgtttgac tcatgcccct gaggaaactt aaatttgcct aaagaaacct tcagtatagc gaattggttt

120

180

240

300

360

420

480

540

541

<td> &lt;210&gt;</td><td> 13</td>

<td> &lt;211&gt;</td><td> 441</td>

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

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

<td> &lt;400&gt;</td><td> 13</td>

gagggttggt ggtagcggct tggggaggtg ctcgctctgt cggtcttgct cttcccccgg ctcccttcgt ttcccccccc cggtcgcctg cgtgccggag ggagggggag ggcgtcgggg gggtgggggg aggcgttccg gtccccaaga gggaggcgga ggctgtgagg gactccggga agccatggac gtcgagaggc gctgaaagat tttgagaaga gggggaaaaa ggaagtttgt cctgtcctgg ttgtcatgta gccaagactg gagaaacaat gattcagtgg tcccaattta tattttcaaa ctggagaaag tgatggatga tttcagaact tcagctcctg tcctcccaac cctaatgtcg and ctctcgcacg tgtgcgcgag gacccgcgga tccaggaggc atcagtttct aaggctattt agccaagagg

120

180

240

300

360

420

441 &lt;210&gt; 14 &lt;211&gt; 131 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; ¢ 1) ... (131) &lt;223&gt; n = A, T, CG &lt;400&gt; 14 aagcaggcgg ctcccgcgct cgcagggccg tgccacctgc ccgcccgccc tgccacctgc ccgcccgccc gctcgctcgc 60 tcgccccaccggg cgccgcgccggcgc 60 tcgccccaccgggcgcgc gccgc 60 tcgcccgccg

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

<td> &lt;211&gt;</td><td> 692</td>

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

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

<td> &lt;400&gt;</td><td> 15</td>

atctcttgta tgccaaatat ttaatataaa tctttgaaac aagttcagat tcaaagtttg caaaaacgtg aagattaact taattgtcaa atattcctca tcagtatttt ttttatttct atgcaaaagt atgccttcaa actgcttaaa tatgatacac aaaccagttt tcaaatagta aagccagtca tcttgcaatt ggtaaaagat tataagacac cttacacaca cacacacaca cacacacgtg tgacaaaaaa caatttggcc tctcctaaaa taagaacatg aagaccctta ggagggaaca ctgtgtcacc cctccctaca atccaggtag tttcctttaa aatctgggca tatttgagag gagtgattct gacagccacg ttgaaatcct gaaataaaaa ttgccccaaa tgatatatga gtaagaaata tgcacgccaa attgctgcca tccaatagca gtggggaacc

120

180

240

300

360

420

480

PL 201 529 B1 attcatgtcc acccactggt gccctgaaaa aatgccaata atttttcgct cccacttctg 540 ctgctgtctc ttccacatcc tcacatagac cccagacccg ctggcccctg gctgggcata ctggccctgg gctggtcata ctagggtgtcata ctagggtgcgtc 600 gcattgccta ctagggtgcgtc 600 gcattgccta

<td> &lt;210&gt;</td><td> 16</td>

<td> &lt;211&gt;</td><td> 728</td>

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

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

<td> &lt;400&gt;</td><td> 16</td>

cagacggggt ttcactatgt cctgccttgg cctcccaaag tgatggtttc ataaggcttt gaagaaggac ccggccatgc ggtatgtctt agaggattct ctttaaactg gccaagctat gtgctgccac atgtttgctt tgaactgtga tattagtaga tcctggatcc ggagatagaa agatgacatg ccaccccacc tactagcctc aagtgtcccc tctgccctac ttctcttacc tccaaagg tggctaggct tgctgggatt tccccctttt ccccttccac gtcaattaaa atgagaacag cagcacttcc aacagattcc ggcagcctcc agggccaagt aagccacagt tttacccctc

<td>ggtcttgaac</td><td>tcctgacttc</td><td>aggtgatctg</td><td> 60</td>

<td>acaggcataa</td><td>gccactgcgc</td><td>ccggctgatc</td><td> 120</td>

<td>gctcagcact</td><td>tctccttcct</td><td>gccgccatgt</td><td> 180</td>

<td>cacgattgta</td><td>agttgtttcc</td><td>tgaggcctcc</td><td> 240</td>

<td>cctctttcct</td><td>ttataaatta</td><td>tccagttttg</td><td> 300</td>

<td>actaatacaa</td><td>cccttaaagg</td><td>agactgacgg</td><td> 360</td>

<td>tctgaatgct</td><td>actgacattc</td><td>ttcttgagga</td><td> 420</td>

<td>atggctcagc</td><td>agcctgagag</td><td>cagggaggga</td><td> 480</td>

<td>cctgaggcca</td><td>ggtgtggccg</td><td>aacctgggca</td><td> 540</td>

<td>cctgtccutg</td><td>gagagccaag</td><td>cctcaatcac</td><td> 600</td>

<td>ggctaggggg</td><td>actcagggaa</td><td>cagttcccag</td><td> 660</td>

<td>atacctccaa</td><td>agtagaccat</td><td>grtcatgagg</td><td> 720</td>

<td></td><td></td><td></td><td> 728</td>

&lt;210&gt; 17 &lt;211&gt; 531 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220 &lt;221&gt; misc_feature &lt;222&gt; (1) ... (531) &lt;223&gt; n = A, T, CG &lt;400 aagcgaggaa aacgcgaaga agctggcccg agcaggaggc agaaagagga aaaagcactt taatgaagag ccgcagctaa cttccagaaa&gt; 17 gccactgcgg acaggagcgg ggaggctgaa tcgagagaag agccgaagcc tcagaaggag gactcggaaa caattccggc ggattctatt ctcctggctg aagctgcagg gcccgggctg gcgcaggctg cggtcccggg gaacaggaga tcagaagccg ccagaccctt gcagaaagga aaaagcggcg ctgaaaggga aacgtgaggc agcaggagga aagaagctga gacaagagca ccgaaaccaa gtgaaagctg aggagctngg cćaggctcgg caagcgaatg cgaggcgcgg gcaggagcga gcgccagcgc aaaaaagęgg gaagcaggat tagagactcg ccccccangg gaacagaagg cgagaggagc agacggagacaggg ctgcaggg gagctaggagg ctgcaggg ctgcaggg gagctaggagg

120

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240

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531

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

<td> &lt;211&gt;</td><td> 1041</td>

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

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

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

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

<td> &lt;222&gt;</td><td> ¢1)...(1041)</td>

<td> &lt;223&gt;</td><td>η ~ A, T, C | oh</td>

GB 201 529 B1 &lt;40Q&gt; 18 ctctgtggaa aactgatgag gaatgaattt accattaccc atgttctcat ccccaagcaa agtgctgggt ctgattactg caacacagag aacgaagaag aacttttcct catacaggat cagcagggcc tcatcacact gggctggatt catactcacc ccacacagac cgcgtttctc tccagtgtcg acctacacac tcactgctct taccagatga tgttgccaga gtcagtagcc attgtttgct cccccaagtt ccaggaaact ggattcttta aactaactga ccatggacta gaggagattt cttcctgtcg ccagaaagga tttcatccac acagcaagga tccacctctg ttctgtagct gcagccacgt gactgttgtg gacagagcag tgaccatcac agaccttcga tgagcgtttg agtccaacac cttccaagaa caacaaaacc atatcagtgt actgtagccc cttaatttaa gctttctaga aagctttgga agtttttgta gatagtagaa aggggggcat cacntgagaa agagctgatt ttgtatttca ggtttgaaaa gaaataactg aacatatttt ttaggcaagt cagaaagaga acatggtcac ccaaaagcaa ctgtaactca gaaattaagt tactcagaaa ttaagtagct cagaaattaa gaaagaatgg tataatgaac ccccatatac ccttccttct ggattcacca attgttaaca tttttttcct ctcagctatc cttctaattt ctctctaatt tcaatttgtt tatatttacc tctgggctca ataagggcat ctgtgcagaa atttggaagc catttagaaa atcttttgga ttttcctgtg gtttatggca atatgaatgg agcttattac tggggtgagg gacagcttac tccatttgac cagattgttt ggctaacaca tcccgaagaa tgattttgtc aggaattatt gctatttaat aaatatttca ggatactttc cccctacaat aaagtaacaa tc

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840

900

960

1020

1041

<td> &lt;210&gt;</td><td> 19</td>

<td> &lt;211&gt;</td><td> 1043</td>

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

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

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

ctctgtggaa aactgatgag gaatgaattt accattaccc atgttctcat ccccaagcaa agtgctgggt ctgattactg caacacagag aacgaagaag aacttttcct catacaggat cagcagggcc tcatcacact gggctggatt catactcacc ccacacagac cgcgtttctc tccagtgtcg acctacacac tcactgctct taccagatga tgttgccaga gtcagtagcc attgtttgct cccccaagtt ccaggaaact ggattcttta aactaactga ccatggacta gaggagattt cttcctgtcg ccagaaagga tttcatccac acagcaagga tccacctctg ttctgtagct gcagccacgt gactgttgtg gacagagcag tgaccatcac agaccttcga tgagcgtttg agtccaacac cttccaagaa caacaaaacc atatcagtgt actgtagccc cctaatttaa gctttctaga aagctttgga agtttttgta gatagtagaa aggggggcat cacctga.gaa agagctgatt ttgtatttca ggtttgaaaa gaaataactg aacatatttt ttaggcaagt cagaaagaga acatggtcac ccaaaagcaa ctgtaactca gaaattaagt tactcagaaa ttaagtagct cagaaattaa gaaagaatgg tataatgaac ccccatatac ccttccttct ggattcacca attgttaaca tttttttcct ctcagctatc cttctaattt ctctctaatt tcaatttgtt tatatttacc tctgggctca ataagggcat ctgtgcagaa atttggaagc catttagaaa atcttttgga ttttcctgtg gtttatggca atatgaatgg agcttattac tggggtgagg gacagcttac tccatttgac cagattgttt ggctaacaca tcccgaagaa tgattttgtc aggaattatt gttatttaat aaatatttca agatattttt cctctacaat aaagtaacaa tta

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720

780

840

900

960

1020

1043

<td> &lt;210&gt;</td><td> 20</td>

<td> &lt;211&gt;</td><td> 448</td>

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

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

<td> &lt;400&gt;</td><td> 20</td>

ggacgacaag gccatggcga tatcggatcc gaattcaagc ctttggaatt aaataaacct ggaacaggga aggtgaaagt tggagtgaga tgtcttccat atctatacct ttgtgcacag ttgaatggga actgtttggg tttaggaggcat cgttagtta attaca

120

180

GB 201 529 B1 ggaactggtg ggaggtcaag tggggaagtt ggtgaatgtg gaataactta ccacttaaac cagatgtgtt gcagctttcc tgacatgcaa ggatctactt ctctcattaa taaattgaat aaaagggaat gttttggcac ctgatataat atgtgacagt aggaaggaat ggtttcccct aacaagccca atgcactggt aaattattta ataaaatgaa ctattatc

<td> &lt;210&gt;</td><td> 21</td>

<td> &lt;211&gt;</td><td> 411</td>

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

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

<td> &lt;400&gt;</td><td> 21</td>

ggcagtgaca ttcaccatca tgggaaccac cttccctttt cttcaggatt gaagagagca cccagtgttg ggctgaaaac atctgaaagt agggagaaga atcagtatct cagagggctc taaggtgcca agaagtctca ctggacattt aaaggcatac tttcggaatc gccaagtcaa aactttctaa cttctgtctc aagtgagact caagagtcta ctgctttagt ggcaactaca gaaaactggt aaaacaggag caattagaaa tggttccaat atttcaaagc tccgcaaaca tcctttgccc atttagggtt tcttctcttt cctttctctt tattaaccac &lt;210&gt; 22 &lt;211&gt; 896 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc__feature &lt;222&gt; (1). . . (896) &lt;223&gt; n - A, T, C, the gaps G &lt;400&gt; 22 tgcgctgaaa acaacggcct cctttactgt taaaatgcag ccacaggtgc gcatctcaac caccagcctc tgtggggggc aggtgggcgt ccctgtgggc acgtccagcc tctgtcctct gccttccgtt cttcgacagt gttcccggca cttggtactt ggcgtgggcc tcctgtgctg ctccagcagc tcctccaggn cttcaccgca gcctcatgtt gtgtccggag gctgctcacg gcctcctcct ggctgtcttc accctccggn gcacctcctc cagctccagc tgctggcggg ggccagctcg gccttggcct gccgcgtctc ctcctcarag gctgccagcc ctcctggcgg atcacctggg ccaggttgct gcgctcgcta gaaagctgct ctgcgcatcc tccagcgccc gctccttctg ccgcacaagg ccctgcagac gccctcggcc tccccaagct ggcccttcag ctccgagcac cgctcctgaa cgactgctcc agctcggaga gctcagcctc gtacttgtcę cgtaagcgct ctcggcagcc ttctcactct cctccttggc cagcgccatg tcggcctcca gaccagctca atctccttgt cccggccttt ccggatttct tccctcagct gttcagcagc cacgcctcct ccttcctggt gcggccggcc tcccacgcct ctccagctgc tgcttcaggg tattcagctc catctggcgg gcctgcagcg

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

<td> &lt;211&gt;</td><td> 111</td>

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

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

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

caacttatta cttgaaatta taatatagcc tgtccgtttg ctgtttccag attttcctag tggtttgact ttaaaaataa ataaggttta attttctccc cctttgtgct taattccaca ctgccaggct ctgactttat

240 300 360 420 4 4 8 ctctgtagtg acctaaaata aagtgccaac tctcagagac gttacccaga ggatgtgctt t

120

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240

300

360

411 ttagccgtgg ctctgggccc tccctggtca ggtcggcccg tcctcgcgag cctgcagcgt ggtcctcgaa cgttcaccgc gcagattctc gcttccgctc tgatgcgggct gccggttcccag tggctctccag tggctcgtccag

120

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240

300

360

420

480

540

600

660

720

780

840

896 gctgtgatat c

111

PL 201 529 B1

<td> &lt;210&gt;</td><td> 24</td>

<td> &lt;211&gt;</td><td> 531</td>

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

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

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

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

<td> &lt;222&gt;</td><td> (1) . .. (531}</td>

<td> &lt;223&gt;</td><td>η = A, T, C |</td>

<td> &lt;400&gt;</td><td> 24</td>

Lgeaagicac gggaguLLaL LLatttaatE tttttcccca ggctggagtg caatggtgtg atcttggctc actgcaacct attctcctgc cacagcctcc cgagtagctg ggattacagg taatttttat atttttagta aagacagggt ttccccatgt ttctgacctc aggtgatcca cctgcctcgg cctcccaaag gctacccgtg cctggccagc cactggagtt taaaggacag ggcggcattt tcccccatca gaaagcccac ggctcctgta aaagtcagcc agtgaagtct ctgctctaac tggccacccg agccttacca ggangccrgc atctgcaaaa gaaaagttca gatggagact ccacctcctg tgcccgccac tggccaggct tgttgggatt tcatgttggc cctcaaaata gggccattgg cttcctttcc ctgtcgccca ggttcaagcg cacacccagc ggtcttgaac acaggcgtga tccagcctaa gggcacctgt cntctgacac α

120

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240

300

360

420

480

531

<td> &lt;210&gt;</td><td> 25</td>

<td> &lt;211&gt;</td><td> 471</td>

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

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

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

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

<td> &lt;222&gt;</td><td> (1).-.(471)</td>

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

<td> &lt;400&gt;</td><td> 25</td>

cagagaatct ccctgaatca gggacttggg cctggggagc actccttgcc ggttctcact cctgtgttgg gtaatagtgg kagaaagata ttgagaaaag gagcgtgcag agatggaccc tgataattga tcagtatgct atgttgngtc gttcaatgaa rcgcgttttc gcggcggtgg agacctctag tactggaagt agattctcag atctegacac caatccttga catttgaaag ttttaatgaa cgacagcgac ctcgagcgcg cagttggatt cctgaaagcc cttcctaatc acaaacagct aaaaccaggt tgagagaagc gacctaggga agggacctcc cagatttctc aggttctaaa tccagacgca ggagaagaac tgcagaccct ccatttgtat tcgatctgga cgccgggata tcagcaagat ggatgattct caaagaaaat gaggagaccg g

120

180

240

300

360

420

471

<td> &lt;210&gt;</td><td> 26</td>

<td> &lt;211&gt;</td><td> 541</td>

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

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

<td> &lt;400&gt;</td><td> 26</td>

gactgtcctg gagtggaagc atactgtttt gtgacttctg cttccatagc gtggattttg ccttgctgga aacaagggac caaagaacac attgctctgg aatctgcagt agcaacagat ctcttttaca ctgttctgct ctctgaccag ccaccttcct tcaaacaagt ccactttcca gctttggggc acatgtacat atggggatat agagctgcag cccttgaagg cttcctgagt taagttcttg taaaaggcat ccttactggg

Cttcgttgga gagatgcaga agtagagcaa tgacaaaacc tgcagacaac gtcctctgac ctgtgctgtc ctgttcttca gtggtggcag ccatcagaag tcaggctctg tgttcttttg cttgcaggtg acagggatgt

120

180

240

300

360

420

PL 201 529 B1 cagtattagc atccacatca gacagcctgg tataaccaga attggtggtt gctgctcttt gtccacttca tatggcacaa gtattttcct caacatcctg g &lt;21Ó&gt; 27 &lt;211&gt; 461 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (461) &lt;223&gt; n = A, T, C LC G &lt;400&gt; 27 gaaatgtata tttaatcatt ctcttgaacg atcagaactc traaatcagt arcatgtaat acagtcaccg tggctccaag gtccaggaag gcagtggtta agtgtgggaa gggggctaga aacaaagtat tcttttcctt caaagcttca cctcaattca agcagtcatt gtccttgctt tcaaaagtct gtgtgtgctt atatgtttgt tgccttaatt tgaattgtgg ccaggaaggg tctggagatc gtaagaaaac ctgagctaga actcaggcat ttctcttaca gaacttggct aatgaangga aagaaactta gaagctcaac aagctgaaga taatcccatc cataggcctt gcaactctgt tcactgagag atgttatcct g actgattgta gctctgggaa tttctataac acacatgaag ttcctcaagg catggaaggr

Caaattcaga tgcagggtag aggcatttcc

480

540

541

120 180 240 300 360 420 4 61

<td> &lt;210&gt;</td><td> 28</td>

<td> &lt;211&gt;</td><td> 541</td>

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

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

<td> &lt;400&gt;</td><td> 28</td>

agtctgaagt gagcaaacaa gagcaagaaa caarragaag ccaaaagcag tatgaacaag ataaatctat cttcaaagac atattagaag ttgggaaaat aactagacaa gtgtgttaag agtgataagt aaaatgcacg tggagacaag gatctcaggg acctccccct gcctgtcacc tggggagtga gaggacagga tctttgtctc tgaattttta gttatatgtg ctgtaatgtt gctctgagga aagtctatcc caacatatcc acatcttata Ltccacaaat taagctgtag aagacgctgc taattgactg ccacttcgca actcaggggc ggćtgcattt tcaaatgatt cactttttat gatgcttccc aaggtgcctt ggcttctctt aaatgcccaa gttgagaaaa atgatcataa ttttagcata aaccgagcaa c aaggctccaa aattcatgtg tgcatcccca tagtgcargt agcccctgga tatgtaccct tagtaatggg cccaactgac tcggcgaccc

120

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240

300

360

420

480

540

541

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

<td> &lt;211&gt;</td><td> 411</td>

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

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

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

tagctgtctt cctcactctt atggcaatga ccccatatct taatggatta agtgtatttc ttacactctg tatctatcac cagaagctga ggtgatagcc tgtcatccat attctgggac tcaggcggga actttctgga atattgccag agaggggcac agtgcattct gggggaatgc acattggctc agcctgggta tacattacct ctgttcacaa ctcattgccc agcaccagtc acaaggcccc agagcccaag aaatgtagtc ctgttgatat ggttttgctg tgtcccaacc cttgaattgt aagctcccat aattcccatg tgttgtggga gggacctggt agataatgaa cgcttgtcat ggagcatggc atgagtgata accaaatacc caaatctcat g

120

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240

300

360

411

PL 201 529 B1

<td> &lt;210&gt;</td><td> 30</td>

<td> &lt;211&gt;</td><td> 511</td>

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

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

<td> &lt;400&gt;</td><td> 30</td>

atcatgagga tgctttgaag acagttctgc ggagcaaggc ttataaacca tcatgatcca attagaggga AATC agctcc gatggggaca tgttaccaaa atactacctg atggctgaag atgtcttaca ttcagatctc atcacctccc cacagagaca taccaggccc cagattcaaa gggatggtac agactgggta aggcctcagg tgtcagtagg ataactccct gccaggtccc aaccatatca cacctccaac ccatatcata taaaccattt atttataaac aaacttacag agagagagcg atcatgagaa tccctcgaca tcattcatga actggggatt c

gtattcgtct aaaagagatt tcatggtgga agagcaggag aaacatggag cgtggggatt gaaatccacc gcaattcaac gttttcacac taattgactc aggcaaagga aacctgccac gaaaccaccc ataattcagg ctcatagtcc atgagatttg

120 180 240 300 3 60' 420 480 511

<td> &lt;210&gt;</td><td> 31</td>

<td> &lt;211&gt;</td><td> 827</td>

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

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

<td> &lt;400&gt;</td><td> 31</td>

catggccttt ctaccagctt tcacagtgtc ccctgggaac acctagtgtc agatacaagc gaggaagcag tccctctggt ctggccacgc tggcttacaa aacagtcttc gctttctaaa agataagtaa agactgcatg ctccttagag tcctgatttt cactcaaggg ttgacccggg cgtcctcctc tccttgtggc aggccccttg gctcccacgt gggggcagtg agtagagttg cttgccctgc cacagccaca aatgacttgc tsaacaactg gccagaggtg cccgtttggt cagcttggtc aacaacaggt tctcctggag tggaaaaaca ggggtgccct ctgttcctca gaggcacagg gcccagtttc catcatctgg ggaggcttgt ctaaggcctc gaaccgaaaa ctgccctggc ccatgtgaag ctcttgtcct ggcccagagt ccagtcttga cccctctgct cctgaagaga ccctccatct ctcagggtgg cttccacctg ggtggctggc agggcatctt ccagcaccct catgcctcag tgggagtgaa agctaccacg gcagaggcag gagtgtggcc gtttaaaggc gataaagctc gcgtcaggcc ctgggagcag ccgggctacc aggggagcac tgtcaagaaa ccaggtgggg tgatcttgga tataaaa gctccaggca agccccagcc gctggtgtga tggcccctca attaagtgtt agggggcact atcagctctg ctgcacctga tggcacccta tctgactccc ggccgggcat aaacagtctt gtctcacagc

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540

600

660

720

780

827

<td> &lt;210&gt;</td><td> 32</td>

<td> &lt;211&gt;</td><td> 291</td>

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

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

<td> &lt;400&gt;</td><td> 32</td>

ccagaacctc cttctctttg gagaatgggg ctggatgacc tctagagaaa ttgcccaaga ccacagcagt cagttggtca ggccctgctg ccaaccaatg ggcaggagag aaggccttta acctccgttt tcagtcagyg ttgtccagca aggcctcttg gagacacaga gggtttcacc 60 agcccacctt ctggtcccaa cctgcagacc 120 tagaaggtca cttggctcca ttgcctgctt 180 tttctcgccc acccattctc ctgtaccagc 240 and 291 acggtaccgt ttacacagtc

<td> &lt;210&gt;</td><td> 33</td>

<td> &lt;211&gt;</td><td> 491</td>

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

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

<td> &lt;400&gt;</td><td> 33</td>

GB 201 529 B1 tgcatgtagt tttatttatg tgttttsgtc tggaaaacca agtgtcccag cagcatgact 60 gaacatcact cacttcccct acttgatcta caaggccaac gccgagagcc cagaccagga 120 ttccaaacac actgcacgag aatattgtgg atccgctgtc aggtaagtgt ccgtcactga 180 cccaracgct gttacgtggc acatgactgt acagtgccac gtaacagcac tgtacttttc 240 tcccatgaac agttacctgc catgtatcta catgattcag aacattttga acagttaatt 300 ctgacacttg aataatccca tcaaaaaccg taaaatcact ttgatgtttg taacgacaac 360 atagcatcac tttacgacag aatcatctgg aaaaacagaa caacgaatac atacatctta 420 aaaaatgctg gagtgggcca ggcacagctt cacgcctgta atcccagcac tttgggaggc 480 ttaagcgggt g ₄₉₁ &lt;210&gt; 34 &lt;211&gt; 521 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ..- (521) &lt;223&gt; n = A, T, CG &lt;400&gt; 34.

tggggcggaa agaagccaag gccaaggagc tggtgcggca gctgcagctg gaggccgagg 60 agcagaggaa gcagaagaag cggcagagtg tgtcgggcct gcacagatac cttcacttgc 120 tggatggaaa tgaaaattac ccgtgtcttg tggatgcaga cggtgatgtg atttccttcc 180 caccaataac caacagtgag aagacaaagg ttaagaaaac gacttctgat ttgtttttgg 240 aagtaacaag tgccaccagt ctgcagattt gcaaggatgt catggatgcc ctcattctga 300 aaatggcaag aaatgaaaaa gtacacttta gaaaataaag aggaaggatc actctcagat 360 actgaagccg atgcagtcrc tggacaactt ccagatccca caacgaatcc cagtgctgga 420 aaggacgggc ccttccttct ggtggtggaa cangtcccgg tggtggatct tggaanggaa 480 cctgaangtg gtgtaccccg tccaaggccg accttggcca c 521

<td> &lt;210&gt;</td><td> 35</td><td></td><td></td><td></td><td></td>

<td> &lt;211&gt;</td><td> 161</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 sapien</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> &lt;221&gt;</td><td>misc feature</td><td></td><td></td><td></td><td></td>

<td> &lt;222&gt;</td><td> (1)-..(161)</td><td></td><td></td><td></td><td></td>

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

<td> &lt;400&gt;</td><td> 35</td><td></td><td></td><td></td><td></td>

<td colspan="2">tcccgcgctc gcagggcncg tgccacctgc</td><td>cygtccgccc</td><td>gctcgctcgc</td><td>tcgcccgccg</td><td> 60</td>

<td colspan="2">cgccgcgctg ccgaccgyca gcatgctgcc</td><td>gagagtgggc</td><td>tgccccgcgc</td><td>tgccgctgcc</td><td> 120</td>

<td colspan="2">gccgccgccg ctgctgccgc tgctgccgct</td><td>gctgctgctg</td><td>c</td><td></td><td> 161</td>

<td> &lt;210&gt;</td><td> 36</td>

<td> &lt;211&gt;</td><td> 341</td>

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

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

<td> &lt;400&gt;</td><td> 36</td>

ggcgggtagg catggaactg agaagaacga agaagctttc agactacgtg gggaagaatg 60 aaaaaaccaa aattatcgcc aagattcagc aaaggggaca gggagctcca gcccgagagc 120 ctattattag cagtgctaggaca cagatgcagcag cagatgcagcag cagatgcagaca 180

PL 201 529 B1 agctcaagag attggaagaa aatgatgatg atgcctattt acactgcttt gaaaagacat tttcatggag tgaaagacat gttcaccagc tgatgacact tccaaagaga ttagctcacc &lt;210&gt; 37 &lt;211&gt; 521 &lt;212&gt; sapien &lt;220&gt; DNA &lt;213&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). .. (521) &lt;223&gt; n = A, T, C (UGG &lt;400&gt; 37 tctgaaggtt aaatgtttca tctaaatagg gataatgrta gtttgagatt aaatgagata atacatgtaa aattatgtgc tgttgttgtt gatgatgatg atgatgatga taatattttt cttgaaccta ttagataatc aatacatgtt tcttgaactg tctgactgat gaagccctac attttcttct agaggagatg agaaaatcag atgccttcac ctgaccactg cttggtgatc ctccattagc tctcatctca ccagcccatc attattgtat cagctggcta ccatcmggca gaataaaaat catcctttca tttatttgca tttcccaaag ccaagcaccg tggganggta aaactcacca aaagtggaga t

tgggcggata ccaagatgaa

240

300

341

<td> &lt;210&gt;</td><td> 38</td>

<td>&lt;2U&gt;</td><td> 461</td>

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

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

<td> &lt;400&gt;</td><td> 38</td>

tatgaagaag ggaaaagaag ataatttgtg aaagaaatgg aaagggtcag tctgtagctc ttcttaatga gaataggcag gatttcctta gtggtgtatc taatcacagg aaacatctgt tgggggactt gggcccactt ctcatttcat ttaattaaag atttactgtt gtttaacaat gccacaaaga catggttggg aaaatgctgt ttttgtgtgc tcataatggt tccaaaaatt tactgttaca gaagccagca agaagacctc tgttcattca attgactcca gtgtgtgcaa atccagtttg gcctatcttc

<td> &lt;210&gt;</td><td> 39</td>

<td> &lt;211&gt;</td><td> 769</td>

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

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

<td> &lt;400&gt;</td><td> 39</td>

tgagggactg attggtttgc tctctgctat tcaattcccc cgtcctcctt ctcattccct ttagttgtac cctctctttc gatgtcgcct tttcttcttc ttgctttttc tgatgttctg tctcatctgc atcattcctt tcagatgctg tagcttcttc tctttttctt ttttttgggg ggcttgctct ctgactgcag ggcctttgag acgagccagg aaggcctgct cctgggcctc tcattgtgat cccaagacgg gcagccttgt gtgctgttcg gcatctcatc agtcagaatc tttggggact tggacccctg tctccaagtc tttgtttggc ttctctccac ctgaagtcaa aacacctata ctggcataca ctatccccag agatcaattt acatttgagc ccatggcact gtgctgcctt taaaatagtg g

gtccagttac ctttcagttg ggttccctcc gaaatagaac agctatttct gggtgctggc cacccccggg t

aagcccactt atctgagacc ctcagcatgt ctcctctttc ttgaggggcc taggcgagca cccctcacag gttgtcgtca tgtagccatc gcatagagtt gcaagattgt tgcacaactg ccccatgttg aagatcttaa ttgtacatct ctgaagcttg accctccttt tagtctttga ctcagggtca agtctctttc tcaaagtaca tgatttgtgt caaagagaga gatatcagga gttcctgcag tttccttctt tctgggtgct tgcctccttt ccagggtcct agcttggcct gcttggagca tcactgcagc ttcacaaact

120

180

240

300

360

420

480

521

120

180

240

300

360

420

461

120

180

240

300

360

420

480

540

GB 201 529 B1 tctgatacag caagttgggc ttgggatgat tataacgggt ggtctcctta gaaaggctcc 600 ttatctgtac tccatcctgc ccagtttcca ctaccaagtt ggccgcagtc ttgttgaaga 660 gctcattcca ccagtggttt gtgaactcct tggcagggtc atgtcctacc ccatgagtgt 720 cttgcttcag ygtcaccctg agagcctgag tgataccatt ctccttccg 769

<td> &lt;210&gt;</td><td> 40</td>

<td> &lt;211&gt;</td><td> 292</td>

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

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

<td> &lt;400</td><td> 40</td>

gacaacatga aataaatcct aaactcgaaa aatgaacaag tgggcctcct gatcttaaca cctttacgca ggaaacaggg ctaacctacc tgccgggtag agaggacaaa attaaactca atagagtgta gtctagttaa 60 tctggtggga gtggaggaag ggctatacta taaatccaag 120 agccatgctc attatacaca tctctgaact ggacatacca 180 cttggaactt ctaagggaaa ttaacatgca ccacccacat 240 gtaccatccc tgcttcgctg aaatcagtgc tc 292

<td> &lt;210</td><td> 41</td>

<td> &lt;211&gt;</td><td> 406</td>

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

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

<td> &lt;400&gt;</td><td> 41</td>

ttggaattaa ctataccttt tgatggaaaa ataacttacc atctacttta gatataatct gcactggtct ataaacctgg gtgcacagtt agcagacagg tttgtgctcc attccacact gccaggctat gactttataa aacagggaag gaatgggaac aactggtggg acttaaacca ctcattaata gtgacagtag attatttaat gtgaaagttg tgtttgggtt aggtcaagtg gatgtgttgc aattgaataa gaaggaargg aaaatgaact gagtgagatg tagggcatct gggaagttgg agctttcctg aagggaatgt tttcccctaa attatc tcttccatat tagagttgat tgaatgtgga acatgcaagg tttggcacct caagcccaat

120

180

240

300

360

406

<td> &lt;210</td><td> 42</td>

<td> &lt;211&gt;</td><td> 381</td>

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

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

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

aaactggacc tgcaacaggg acatgaattt actgcarggt ctgagcaagc tcagcccctc 60 tacctcaggg ccccacagcc atgactacct cccccaggag cgggagggtg aagggggcct 120 gtctctgcaa gtggagccag agtggaggaa tgagctctga agacacagca cccagccttc 180 tcgcaccagc caagccttaa ctgcctgcct gaccctgaac cagaacccag ctgaactgcc 240 cctccaaggg acaggaaggc tgggggaggg agtttacaac ccaagccatt ccaccccctc 300 ccctgctggg gagaatgaca catcaagctg ctaacaattg ggggaagggg aaggaagaaa 360 actctgaaaa caaaatcttg t 381.

<td> &lt;210&gt;</td><td> 43</td>

<td> &lt;211&gt;</td><td> 451</td>

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

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

<td> &lt;400&gt;</td><td> 43</td>

catgcgtttc accactgttg gccaggctgg tctcgaactc ctggcctcaa gcaatccacc 60 cgcctcagcc tccaaaagtg ctgggattac agatgtgagc catggcacca tgccaaaagg 120 ctatattcct ggctctgtgt ttccgagact gcttttaatc ccaacttctc tacatttaga 180 ttaaaaaata ttttattcat ggtcaatctg gaacataatt actgcatctt aagtttccac 240

PL 201 529 B1 tgatgtatat agaaggctaa aggcacaatt tttatcaaat ctagtagagt aaccaaacat aaaatcatta attactttca acttaataac taattgacat tcctcaaaag agctgttttc aatcctgata ggttctttat tttttcaacca aatcctgata ggttctttat tttttcaacca agatgatcata atgatgatcatta tttttcaacca a tgggtcata

300

360

420

451

<td> &lt;210&gt;</td><td> 44</td>

<td> &lt;211&gt;</td><td> 521</td>

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

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

<td> &lt;400&gt;</td><td> 44</td>

gttggacccc cagggactgg aaagacactt cttgcccgag gttccttttt attatgcttc tggatccgaa tttgatgaga agccgtatca gaaatctttt tagggaagca aaggcgaatg gatgaattag attctgttgg tgggaagaga attgaatctc cagaccataa atcaacttct tgctgaaatg gatggtttta ataataggag ccacaaactt cccagaggca ttagataatg ttttgacatg caagttacag ttccaaggcc agatgtaaaa atggtatctc aataaaataa agtttgatca atcccgttga ggtacrggtg gcttttccgg aagcagagtt gggagaatct ctgtggcggg tgtttgtggg ctccttgtgt caatgcatcc aacccaatga ccttaatacc ggtcgaacag tccagaaatt t

agaagctgat tgtgggagcc tatatttatt atattcaagg aggagttatc gtcctggtcg aaattttgaa atagcctcga

120

180

240

300

360

420

480

521

<td> &lt;210&gt;</td><td> 45</td>

<td> &lt;211&gt;</td><td> 585</td>

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

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

<td> &lt;400&gt;</td><td> 45</td>

gcctacaaca cagatcttcg accatygaga aggttgatct cagaaagagt aagaccctga gtcaaggcaa gctgggaaac actctgcact acaaatttca tccagaaaga tgaagaccct acgtcaaagc ttgccggaaa cyaccctgca ctggtaagac agatccaaga agctggaaga tggtcctgcg ttgcactttc gtctaccctg gactggtaag aaagatccar gcagctggaa cctggtgctc catcaccctc taaggaaggc tggacgcacc cttgaggggg ctttcaataa cacctggtgc accatcactc gacaaggaag gatggdcgca cgtctcagag gaggtggagc atccctcctg ctgtctgact ggtgtctaag agttgttgca tscgtctcag tcgaagtgga gcrtycctcc ccctgtctga gtgggatgca ccagtgacac atcagcagag acaacatcca tttccccttt ttccc aggtgggatg gccgagtgac tgaccagcag ctacaacatc ratcttcgtg catcgagaat gttgatcttt gaaagagtcc taaggtttcm

120

180

240

300

360

420

480

540

5B5

<td> &lt;210&gt;</td><td> 46</td>

<td> &lt;211&gt;</td><td> 481</td>

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

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

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

gaactgggcc ctgcccctca cttcctgcaa gtaggagaga gcagcagacc gcacctgatg ggcacctggg aactcctcaa a

ctgagcccaa cccctccctc atcacacaca tgaatagagg cagcggcagc ggcctcatct ccgagcagag tcttgcctgc gtcatgcctt ctggtcttct catgcgggcc cccatacatt tgaggtgcat cgtgaatcct caggagactg cccctagtat gtgtccgcat gagccagcac acacatacct gtacagaagg ggagcacggt cgaggcagcg agggtcagag gaagccccct ctgccgtgtc catctccaaa gctgccctgg aggggcaggt tggggccggc ccacagcaga tggaggctaa tcctgcccct acctctgtkc tagcctattc agatggggaa gcagataaaa attgggctga ggagttaagt gctgccctgg acaattcctg

120

180

240

300

360

420

480

481 &lt;210&gt; 47

PL 201 529 B1

<td> &lt;211&gt;</td><td> 461</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> &lt;1&gt;- -. (461)</td>

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

<td> &lt;400&gt;</td><td> 47</td>

<td>atggatctta</td><td>ctttgccacc caggttggag tgcagtgctg caatcttggc tcactgcagc</td><td> 60</td>

<td>cttaacctcc</td><td>caggctcaag ctatcctcct gccaaagcct tccacatagc tgggactaca</td><td> 120</td>

<td>ggtacacngc</td><td>caccacaccc agctaaaatt tttgtatttt ttgtagagac gggatctcgc</td><td> 180</td>

<td>cacgttgccc</td><td>aggctggtcc catcctgacc tcaagcagat ctgcccacct cagcccccca</td><td> 240</td>

<td>acgtgctagg</td><td>attacaggcg tgagccaccg cacccagcct ttgttttgct tttaatggaa</td><td> 300</td>

<td>tcaccagttc</td><td>ccctccgtgt ctcagcagca gctgtgagaa atgctttgca tctgtgacct</td><td> 360</td>

<td>ttatgaaggg</td><td>gaacttccat gctgaatgag ggtaggatta catgctcctg tttcccgggg</td><td> 420</td>

<td>gtcaagaaag</td><td>cctcagacrc cagcatgara agcagggtga g</td><td> 461</td>

<td>&lt;21O&gt;</td><td> 43</td><td></td>

<td> &lt;211&gt;</td><td> 571</td><td></td>

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

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

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

<td>ataggggctt</td><td>taaggaggga attcaggttc aatgaggtca taaggccagg gctcttatcc</td><td> 60</td>

<td>agtaagactg</td><td>gggtccttag atgagaaaga gacacccgag gtccttctct ctgccgtgtg</td><td> 120</td>

<td>aggatgcatc</td><td>aagaaggcgg ccgtctgcaa gcgaaggaga ggccgcacca gaaaccgaca</td><td> 180</td>

<td>ccttcatctt</td><td>ggacttgcag cctctagaac tgagaaaata actgtctgtt ggttaagcca</td><td> 240</td>

<td>cccagtttgt</td><td>agtattctct tatggcttcc taagcagact aacaaacaaa cacccaaaat</td><td> 300</td>

<td>taactgatgg</td><td>cttcgctgtc ttctgtaaaa attgctatga gagaactttt cactcactgt</td><td> 360</td>

<td>tttgcagttt</td><td>ctccctcagt ccctggttct ttcttctcac ataatcccaa tttcaattta</td><td> 420</td>

<td>tagttcatgg</td><td>cccaggcaga gcieattcatc acggcatctc ctgagctaaa ccagcacctg</td><td> 480</td>

<td>ctctgctcac</td><td>ttcttgactg gctgctcatc atcagccctc ttacagagat ttcatttcct</td><td> 540</td>

<td>cccgtgccag</td><td>gtacttcacg caecaagctc a</td><td> 571</td>

<td> &lt;210&gt;</td><td> , 49</td><td></td>

<td> &lt;211&gt;</td><td> 511</td><td></td>

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

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

<td> &lt;400&gt;</td><td> 49 .</td><td></td>

<td>ggataatgaa</td><td>gttgttttat ttagcttgga caaaaaggca tattcctcta ttttcttata</td><td> 60</td>

<td>caacaaatat</td><td>ccccaaaata aagcaagcat atatatcttg aatgtgtaat aatccagtga</td><td> 120</td>

<td>taaacaagag</td><td>cagtacttta aaagaaaaaa aaatatgtat ttctgtcagg ttaaaatgag</td><td> 180</td>

<td>aatcaaaacc</td><td>atttactctg ctaactcatt attttttgct ttctttttgg ttaagagagg</td><td> 240</td>

<td>caatgcaata</td><td>cactgaaaaa ggtttttatc ttatctggca ttggaattag acatattcaa</td><td> 300</td>

<td>accccagccc</td><td>ccatttccaa actttaagac cacaaacaag taatttactt ttctgaacat</td><td> 360</td>

<td>tggttttttc</td><td>tggaaaargg gaattataaa atagactttg cagactctta tgagattaaa</td><td> 420</td>

<td>taagataatg</td><td>tatgaaattc tttcttcttt tttacttctt tttccttttt gagatggagt</td><td> 480</td>

<td>ctcaccccgt</td><td>cacccaggct ggagtacagt g</td><td> 511</td>

<td> &lt;210&gt;</td><td> 50</td><td></td>

<td> &lt;211&gt;</td><td> 561</td><td></td>

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

GB 201 529 B1 &lt;213&gt; Homo sapien &lt;400 ccactgcact acaaacaaaa tcaacagatt caagaggttc ccaggcatgg acttgggccc gggcaacaga gtgctgtaaa ggctcacgcc gaattttggc&gt; 50 ccagcctggg aactgaaaag gttgatcacc tgcagaactt ttgctcacac aggagttcaa gcaagaccct ggaagtaaat tgtggtctaa caggcatggt tgacggagtg gaaatagagt taccatatgc catggagcat ctttagtccc ggctgcagtg gtctcagggg aggttgatat cgctttggga g

agactctgtc tcctctttcc ttggtattgt gaaagtaaat agcactttgg agccaagatt gaacaaaaag tcaagagagc agcccgagcg tcaaaaaaac tcatatatga tctaattgct aaacaaagtt gaggctgagg gtgccactac ttaatttcag acctgaaggc ggcggatcac aaacaaacaa atatattatt ggggatacag aatttcaagg caggtggatc tctccaggct attttgttaa caggcgtggt aaggtcagga

120

180

240

300

360

420

480

540

561

<td> &lt;210&gt;</td><td> 51</td>

<td> &lt;211&gt;</td><td> 451</td>

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

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

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

agaatccatt tattgggttt taaactagtt acacaactga aatcagtttg gcactacttt 60 atacagggat tacgcctgtg tatgccgaca cttaaatact gtaccaggac cactgctgtg 120 cttaggtctg tattcagtca ttcagcatgt agatactaaa aatatactgt agtgttcctt 180 taaggaagac tgtacagggt gtgttgcaag atgacattca ccaatttgtg aattatttca 240 acccagaaga tacctttcac tctataaact tgtcataggc aaacatgtgg tgttagcatt 300 gagagatgca cacaaaaatg ttacataaaa gttcagacat tctaatgata agtgaactga 360 aaaaaaaaaa aaccccacat ctcaattttt gtaacaagat aaagaaaata atttaaaaac 420 acaaaaaatg gcattcagtg ggtacaaagc c 451

<td> &lt;210&gt;</td><td> 52</td>

<td> &lt;211&gt;</td><td> 682</td>

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

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

<td> &lt;400&gt;</td><td> 52</td>

caaatattta atataaatct ttgaaacaag ttcagakgaa ataaaaatca aagtttacaa 60 aaacgtgaag attaacttaa ttgtcaaata ttcctcattg ccccaaatca gtattttttt 120 tatttctatg caaaagtatg ccttcaaact gcttaaatga tatatgatat gatacacaaa 180 ccagttttca aatagtaaag ccagtcatct tgcaattgta agaaataggt aaaagattat 240 aagacacctt acacacacac acacacacac acacacacgt gtgcaccgcc aatgacaaaa 300 aacaatttgg cctctcctaa aataagaaca tgaagaccct taattgctgc caggagggaa 360 cactgtgtca cccctcccta caatccaggt agtttccttt aatccaatag caaatctggg 420 catatttgag aggagtgatt ctgacagcca csgttgaaat cctgtgggga accatteatg 480 tccacccact ggtgccctga. aaaaatgcca ataatttttc gctcccactt ctgctgctgt 540 ctcttccaca tcctcacata gaccccagac ccgctggccc ctggctgggc atcgcattgc 600 tggtagagca agtcataggt ctcgtacttacgcgtgtcata 6 agtcata 6cca gtgtcata 6

<td> &lt;210</td><td> 53</td><td></td>

<td> &lt;211&gt;</td><td> 311</td><td></td>

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

<td> &lt;2±3&gt;</td><td>Homo</td><td>sapien</td>

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

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

PL 201 529 B1 &lt;222&gt; (1) ... (311) &lt;223&gt; η = A, Τ, C ^G. &lt;400&gt; 53 tttgacttta gtaggggtct gaactattta ttttactttg tatatctttc attatgccat cttatcttct aatgbcaagg tctgcattwa tcacattaaa aatggctttc ttggaaaatc tcttttavag ccatcattta aagcmggntt ctctccaaca gagctgtgaa ctctggctga aggctttccc atacacactg agbgtgagtt and ccmgtaatat gaacagwtgc ttcttgatat cgagtctgct caatgacmtg ttaraccyta taamctggct gaataaagga sasggggggk gtttctgacc

120

180

240

300

311

<td> &lt;210&gt;</td><td> 54</td>

<td> &lt;211&gt;</td><td> 561</td>

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

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

<td> &lt;400&gt;</td><td> 54</td>

agagaagccc cataaatgca atcagtgtgg gaaggccttc agtcagagct caagcctttt 60 cctccatcat cgggttcata ctggagagaa accctatgta tgtaatgaat gcggcagagc 120 ctttggtttt aactctcatc ttactaaaca cgtaaggatt cacacaggag aaaaacccta 180 tgtttgtaat gagtgcggca aagcctttcg tcggagttcc actcttgttc agcatcaaag 240 agttcacact ggggagaagc cctaccagtg cgttgaatgt gggaaagctt tcagccagag 300 ctcccagctc accctacatc agccgagttc acactggaga gaagccctat gactgtggtg 360 actgtgggaa ggccttcagc cggaggtcaa ccctcattca gcatcagaaa gttcacagcg 420 gagagactcg taagtgcaga aaacatggtc cagcctttgt tcatggctcc agcctcacag 480 cagatggaca gattcccact ggagagaagc acggcaaaac ctttaaccat ggtgcaaatc 540 tcattctgcg ctggacagtt c 561

<td> &lt;210&gt;</td><td> 55</td>

<td> &lt;211&gt;</td><td> 311</td>

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

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

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

gagacagggt ctcactttgt cacccaggct ggaatgcagt ggtgcgatct tacgtagctc 60 actgcaaccc tgacctcctg gactcaaaca attctcctgc ctcaaccctg caagtagctg 120 ggactgtggg tgcatgccac catgcctggc taacttttgt agtttttgta aagatggggt 180 tttgccatgt tgcacatgct ggtcttgaac tcctgagctc aaacgatctg cccacctcgg 240 cctcccagaa tgttgggatt acaggggtaa accaccacgc ctggccccat tagggtattc 300 ttagcatcca cttgctcact gagattaatc ataagagatg ataagcactg gaagaaaaaa 360 atttttacta ggctttggat atttttttcc tttttcagct ttatacagag gattggatct 420 ttagttttcc tttaactgat aataaaacat tgaaaggaaa taagtttacc tgagattcac 480 agagataacc ggcatcactc ccttgctcaa ttccagtctt taccacatca attattttca 540 gaggtgcagg ataaaggcct ttagtctgct ttcgcacttt ttcttccact tttttgtaaa 600 cctgttgcct gacaaatgga attgacagcg tatgccatga ctattccatt tgtcaggcat 660 acgctgtcaa tttttccacc aatcccttgt ctctctttgg agagatcttc ttatcagcta 720 gtcctttggc aaaagtaatt gcaacttctt ctaggtattc tattgtccgt tccactggtg 780 gaacccctgg gaccaggact aaaacctcca 811 g

<td> &lt;210&gt;</td><td> 56</td>

<td> &lt;211&gt;</td><td> 591</td>

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

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

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

PL 201 529 B1

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

<td> &lt;222&gt;</td><td> (1) ..</td><td> . (591)</td>

<td> &lt;223&gt;</td><td>n = A</td><td>»T, CG</td>

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

atctcatata tcacagagac acaaaactag tacaaagagc catcctagga ctgttcccag tcacagggca tggcctggaa cgtgccccan gcaggccctt tatatttctt caaaatagag ggggctctgt tactctatct agaaagaatg ggaccactac agtgccaggg gataaggaga gagcttccca ttgggtgggg cctgacttta cggctttctg cttctcatac gaaaaaaaat ggaagaaaga cttcctgcca taggtgggga aagtctcaga cctgctgctg nccaactggg tttgcttgct gtggaacgca atcatacaat taaaaaataa acggggcagt ctgagttccc ccagtggaga aacacactgg gctccctggg cctttgggcc tctgncacgc tggcagtcac tttcaagtat atgagacaag tgggtacaga ccacagcctc caggaaccag tgggaagcaa tggctttggg cgtgtggaaa atttaaaata aggacaaaat tttttttatg atagtttatg ttcctgtccc acccatcatg caacatactt tcccacnggc aacagcttgg g

120

180

240

300

360

420

480

540

591

<td> &lt;210&gt;</td><td> 57</td>

<td>&lt;2il&gt;</td><td> 481</td>

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

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

<td> &lt;400&gt;</td><td> 57</td>

aaacattgag aattatgatt tttacctctt attttttctg aataaacagg aaacaatctg ctgtattcca agcagggccg a

atggaatgat tatagccttc tacaaattaa tattaaacct tttaaaatca aatgcttaag gacttcttaa ggaggcaaca agggtttccc tcaaatacct ataagcaagt ctatcatagt cctcaatagg attttccact attatagaaa tcatctacca agaatcaggt gccatacttg aactggatcc ttaagcctat caactgccct ttgggtgcta aaggaatgta tggtagggac ccatatttta atatctcaac acaatt-dad tagggtactt tctggttttc gcagtacaca cactttttgt ttgtatgcat actaaatgaa cagagctaat atacctgtca aatccttaca ttctttgact gtgttacacr attctttctg ggactacttt

120

180

240

300

360

420

480

481

<td> &lt;210&gt;</td><td> 58</td>

<td> &lt;211&gt;</td><td> 141</td>

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

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

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

actctgtcgc ccaggctgga gcccabtggm gcgatctcga ctccctgcaa gctmcgcctc 60 acaggwtcat gccattctcc tgcctcagca tctggagtag ctgggactac aggcgccagc 120 caccatgtt t 141

<td> &lt;210&gt;</td><td> 59</td>

<td> &lt;211&gt;</td><td> 191</td>

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

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

<td> &lt;400&gt;</td><td> 59</td>

caggcaattc a

<td>gagagaaagc</td><td>ttacaaatgt</td><td>aaggtttctg</td><td> 60</td>

<td>caacatactg</td><td>gacttcacac</td><td>tggabagaaa</td><td> 120</td>

<td>tttggcaagc</td><td>agtcaacact</td><td>tattcaccat</td><td>1B0</td>

<td></td><td></td><td></td><td> 191</td>

&lt;210&gt; 60 &lt;211&gt; 480

GB 201 529 B1 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;400&gt; 60 agtcaggatc atgatggctc agtttcccac agcgatgaat ggagggccaa tattacatct gaagaacgta ctaagcatga taaacagttt gataacctca aggttacata acaggtgatc aagcccgtac ttttttccta cagtcaggtc ggttttagct gaaatatggg ccttatcaga tctgaacaag gatgggaaga agagttctct atagctatga aactcatcaa gttaaagctg cagggccaac agtcctccct cctatcatga aacaaccccc tatgttctct ccactaatct tgggatggga agcatgccca atctgtccat tcatcagcca ttgcctccag agcaacaccc ttgtcttctg ctacttcagg gaccagtatt cctccctaat

<td> &lt;210&gt;</td><td> 61</td>

<td> &lt;211&gt;</td><td> 381</td>

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

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

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

ctttcgattt ccttcaattt gtcacgtttg attttatgaa gttgttcaag tgtgtattat agctttctct gagttccttc agctgattgt taaatgaatc agcttagatg cagtttcttt ttcaagagca tctaattgtt ctttaagtct tcttcctttt ctgatgactt tctatgaagt aaactgatcc ctgaatcagg agctgcatgt ttttaaćtct ttcgtttaat agctgcttct cagggaccag ttattttgat attccttaag ctcttggtga agttgttcga tttccataat cactggttat cccaaacttc t

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

<td> &lt;211&gt;</td><td> 906</td>

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

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

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

gtggaggtga aacggaggca aaaaaggggg ctacctcagg agcgagggac tgaggcacct aggccgcggc accccggcga caggaagccg tcctgaaccg taggggaagg gcccgcgtag tcctcgcagg gccccagagc tggagtcggc cgggccgtcg gcttctcact tcctggacct ccccggcgcc cgggcctgag gcggagggag aagaggaaac agacttgagc agctccccgt tgtctcgcaa gaggaactct catttcttcc ctcgctcctt caccccccac ctcatgtaga agcgtccgga gggaagaaga acctgggcta ccgtcctggc cttcccmccc gcgctttggt gggcgtggag ttggggttgg gggggtgggt gggggttctt rtnnnriAACr tfttfTCCtt r.anrrl · t rA ΓΤΓΤΓΤΓΤΛΛΛ rtrtrt λ a ł- aa tf - - 3 3 3 3 ---- ~ -------- ~ ------ 3 3-— - 3333 --- 33 ^ sk.

atgggggcaa gaaggacggg agtggaggag cttctggaac tttgcagccg gcggcagctc taacagcaga gagcgtcacc gcttggtatc gaagcacaag ccaaacactc caaagacatg gggttggtga cccccgaagc agcatccctg tcaaaccttt ggtggagtat gatgatatca gctctgattc cgacaccttc tggccttcaa actagaccga agggagaacg acgaacgtcg tggatcagat gcctgcacaa acatcgtcac caccagcaca ggcgttcccg ggacttacta agaccg &lt;210&gt; 63 &lt;211&gt; 491 &lt;212&gt; DNA &lt;213&gt; Homo sapien atatgtgggc aaccttcagg tgccggcccc tggaccagca agctgcctgt ctgctcgttt ttgcacctat gatgcctgct

120 180 240 300 3 60 420 480 ggctaactgc catttctgaa ttggcataat tgtgttactg atagataagc ttccaggtca

120

180

240

300

360

381 aaagggggcg ggctaccggg tccacagccc gactggctcg ctccactgcc aaggtgctga ccttcccggg ttttggagtg tcatcgggag cggcataagt ggcacagtta tccgatgaca cggagctaacc aaccgatgaca cggagctaacc aa

120 180 240 300 360 420 480 54 0 600 660 720 780 840 900 906

GB 201 529 B1 &lt;400&gt; 63 gacatgtttg cctgcagggg accagagaca atgggattag tgcttccaga gaggatgggg acagctctca ggtcagaatc ggttgggggc ccccggaagc acggtccgga tcctccctgg tcaggcttgg ggtaccaaac tcatgctctg tactgttttg aacctagaaa aagattggtc gtgctaagga atcagctgcc tgctggtgac aacatattcc ctctcccagg acacagactc agtggcctct ggaggctcgt ggcctaaggc agggctccgt ggtggggtga gggtttctga cccttcgctt cccatcccat cactgtggtc and ccagtgctca caggctgaga catcagcgta gccccatgcg ccctcatcct ggtgactcca aaggctgatc aaccgctgtc ctgttcttta aggccatgct gacccgctgc gtgagaggaa ccgcatccaa cactgggctg ggctgaactg aatgagctca

120

180

240

300

360

420

480

491

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

<td> &lt;211&gt;</td><td> 511</td>

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

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

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

gatggcatgg tcgttgctaa tgtgcctgct gggatggagc gggacccgcc tgtccctgga gcttggggca aggagggaag gctgcagcca ggggccagag tcagttcagg gagtggtcct gggactgctc aggagtgatg grgccctgga gtttgcccca aggtgcctgg ctgctccagg cctctaggct gggctgatgg tcattaaagc caccctctcc tcagettgtc aggccgcaca caaccccctc gcctgccctg ccetccatca ggaggagcca ccagcatctc agcagccctc aaaagtcgtc ctggggcaag ggtcatctgg gcttggcctg ctctctctcg c acttcctcct agtgatacca cggccctcaa actrccctgg gtttctccag tgtgggacag gtggaacctt ctctggttct gtgagcccag agaaggtggg agctcctccg ccaccctgga gacacaagta gctgtgctca cggaaagctc cctgactgga

120

180

240

300

360

420

480

511

<td> &lt;210&gt;</td><td> 65</td>

<td> &lt;211&gt;</td><td> 394</td>

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

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

<td> &lt;400&gt;</td><td> 65</td>

taaaaaagtg taacaaaggt ttatttagac tttcttcatg atgtaaaccg ttatcttaca aagaaaacac aatatttggt gcttaactga aatagcgtcc atccaaaagt aggtttaagg ggcggggatc ctgcagtttg gac-tgcttgc cgggtttgtc tggcactcat ggggacaggc atcctgctcg tctgtggggc aagctgaagg tatcgaccst agggggctct agggcagtgg aagggtcggg gagaggcctc ttgggctatg tggg cccccagatc ataaactaag taaaactacc cagggttccg cccgctggag gaccttcatc caggatgtct tcagtgactt tgacgatatt ggtctgttct cccttacgtg cggaactaac

120

180

240

300

360

394

<td> &lt;210&gt;</td><td> 66</td>

<td> &lt;211&gt;</td><td> 359</td>

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

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

<td> &lt;400&gt;</td><td> 66</td>

caagcgttcc tttatggatg taaattcaaa cagtcatgct tcacgttwaa gacactaggt cgggcgccac agtgccaccc atttttccat gaagatgtac ggaaatctga tgttgaatat attccaaaag gttaccacag gggctgtaag acctagtgac aatggagaat agtatttctg atgcatcaag aacatcagaa gaaggaaaat tccatatcca a-tatgagttt actcagagac &lt;210&gt; 67 &lt;211&gt; 450 gagccatccc aaggagaaga gaaaatggcc cctcctaagt tataaaactg agtagaaact gggctgacag agaatttgga cccaaatgga gggaaagagg agatcataat attcccagg

120

180

240

300

359

PL 201 529 B1 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... {450&gt;

&lt;223&gt; n = A, T, C (UFO G &lt;400&gt; 61 taggaataac aaatgtttat tcagaaatgg ataagtaata cataatcacc taatgcccct tcctctcctt ctgcacagga gacacagatg ggtaacatag agtggaggag gacacaggac tagcccacca ccttctcttc ccggtctccc cttatagagt ggaggaggca aacaggtccc ctcaatgtac cagatggtca cagctccaga tggccacgtg gttgcagctg gactcaatga aactctgtga atacctgctt tgggatgaga gggaggataa agccatgcag ggaggatatt accctaagca cagtgcaagc agtgagcccc cggctcccag tacctgaaaa actgnctttt ggatgctctc ttgggccacg

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

<td> &lt;211&gt;</td><td> 511</td>

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

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

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

aagcctcctg ccctggaaat ctggagcccc ttggagctga gctggacggg gctgagaggc aagaccgtct ccctcctgct gcagctgctt ccccagcagc cacagcagaa acgccagcag agaaaatggg agccgagagt ccttagccct ctgcctctgg gctgacccgc tggctgtaca tggccagaac tggggttggc catttgaggc cagggtggag gaaagggagg ccaacagagg aaaacctatt caacacagcc cttgtcccac gcagcctaag tgcagggagc gtgatgaagt gtcggggagg acgaggtaac tcagcagcaa tgtcaccttg tagcctatgc ccggaggggc agcaaccccc cgcacacgtc agccaacagc agcgcctctg gagagcgatg atggacttga gcgccgtgtt c

<td> &lt;210&gt;</td><td> 69</td>

<td> &lt;211&gt;</td><td> 511</td>

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

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

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

gtttggcaga agacatgttt aataacattt tcatatttaa aaaatacagc tatctgtcca ccatcttgcc ttgcccttcc tggggctgag gcagacaaag gaggttaggg cccccaggcg ggctaagtgc tattggcctg ctcctgctca tagccagctg ggcacggccc cctagcccct ccaggttgct gaggcggcag gttcttcact gagccgtggg ctgcagtctc gcagggagaa cttctgcacc ctacggcccg aaagaggtgg agccctgaga accggaggaa aacatccatc cctccagggc ttcctcctct tcctggcctg ccagttcacc tgccagccgg ccaggtagtc agcgttgtag aagcagccct ccgcagaagc ctgccggtca ctataggagc cccccgggag gggtcagcac c &lt;210&gt; 70 &lt;211 &gt; 511 &lt;212&gt; DNA &lt;213&gt; Homo sapien cttcatctct aggcatggga aagatgactg cctatagcac caaccagaag taccatccct accaaggcct

120

180

240

300

360

420

450 gcagggaggg cactgctggg ggagctgagg atctggcatc cctgctgtga caggcagcca gctcaatggc caggcaccaa

120

180

240

300

360

420

480

511 aacaattctc gaaaggtaat aagagagcca ^{C (}3gtggtaga agccctggct acctccagcc gctcgggccg aatctccccg

120

180

240

300

360

420

480

511

GB 201 529 B1 &lt;400&gt; 70 caagttgaac gtcaggcttg gcagaggtgg agtgtagatg aaaacaaagg tgtgattatg aagaggatgt gagtcctttg ggtgtaggag agaaaggctg ttgagcttct atttcaagat acttttacct gtgcaaaaag cacattttcc acctccttct catggcattt gtgtaaggtg agtatgattc ctattccatc tgcattttag aggtgaagaa taacgtacaa gggattcagt gattagcaag ggacccctca ctaagtgttg atggagttag gacagagctc agctgtttga atctcagagc ccaggcagct ggagctgggt aggatcctgg agctggcact aatgtgaggt gcattccctc caacccaggc tcagatccgg aacctgaccg tgctgacccc cgaaggggag gcagggctga gctggcccgt tgggctccct gctcctttca caccacactc tcgctttgag gtgctgggct gggactactt cacagagcag c

120

180

240

300

360

420

480

511

<td> &lt;210&gt;</td><td> 71</td>

<td> &lt;211&gt;</td><td> 511</td>

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

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

<td> &lt;400&gt;</td><td> 71</td>

tggcctgggc aggattggga gagaggtagc tacccggatg cagtcctttg ggatgaagac tatagggtat gaccccatca cttccccaga ggtctcggcc tcctttggtg ttcagcagct gcccctggag gagatctggc ctctctgtga tttcatcact gtgcacactc ctctcctgcc ctccacaaca ggcttgctga atgacaacac ctttgcccag tgcaagaagg gggtgcgtgt ggtgaactgt gcccgtggag ggatcgtgga cgaaggcgcc ctgctccggg ccctgcagtc tggccagtgt gccggggctg cactggacgt gtttacggaa gagccgccac gggaccgggc cttggtggac catgagaatg tcatcagctg tccccacctg ggtgccagca ccaaggaggc tcagagccgc tgtggggagg aaattgctgt tcagttcgtg gacatggtga aggggaaatc tctcacgggg gttgtgaatg cccaggccct t

120

180

240

300

360

420

480

511

<td> &lt;210&gt;</td><td> 72</td>

<td> &lt;211&gt;</td><td> 2017</td>

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

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

<td> &lt;400&gt;</td><td> 72</td>

agccagatgg ctgagagctg caagaagaag tcaggatcat gatggctcag tttcccacag cgatgaatgg agggccaaat atgtgggcta ttacatctga agaacgtact aagcatgata aacagtttga taacctcaaa ccttcaggag gttacataac aggtgatcaa gcccgtactt ttttcctaca gtcaggtctg ccggccccgg ttttagctga aatatgggcc ttatcagatc tgaacaagga tgggaagatg gaccagcaag agttctctat agctatgaaa ctcatcaagt taaagttgca gggccaacag ctgcctgtag tcctccctcc tatcatgaaa caacccccta tgttctctcc actaatctct gctcgttttg ggatgggaag catgcccaat ctgtccattc atcagccatt gcctccagtt gcacc.tatag caacaccctt gtcttctgct acttcaggga ccagtattcc tcccctaatg atgcctgctc ccctagtgcc ttctgttagt acatcctcat taccaaatgg aactgccagt ctcattcagc ctttatccat tccttattct tcttcaacat tgcctcatgc atcatcttac agcctgatga tgggaggatt tggtggtgct agtatccaga aggcccagtc tctgattgat ttaggatcta gtagctcaac ttcctcaact gcttccctct cagggaactc acctaagaca gggacctcag agtgggcagt tcctcagcct tcaagattaa agtatcggca aaaatttaat agtctagaca aaggcatgag cggatacctc tcaggttttc aagctagaaa tgcccttctt cagtcaaatc tctctcaaac tcagctagct actatttgga ctctggctga catcgatggt gacggacagt tgaaagctga agaatttatt ctggcgatgc acctcactga catggccaaa gctggacagc cactaccact gacgttgcct cccgagcttg tccctccatc tttcagaggg ggaaagcaag ttgattctgt taatggaact ctgccttcat atcagaaaac acaagaagaa gagcctcaga agaaactgcc agttactttt gaggacaaac ggaaagccaa ctatgaacga ggaaacatgg agctggagaa gcgacgccaa gtgttgatgg agcagcagca gagggaggct gaacgcaaag cccagaaaga gaaggaagag tgggagcgga aacagagaga actgcaagag caagaatgga agaagcagct ggagttggag aaacgcttgg

120

180

240

300

360

420

480

540

600

660

720

780

840

900

960

1020

1080

1140

1200

1260

1320

GB 201 529 B1 agaaacagag gagaggcagc ggcaggagct gaaagaaaag gcagactaca ataaacagtg atcaaaataa acatgcagct aaaaggaaga catctaagct ataatacaca aaatcgaaag agagctggag aaaacaggag gctcagtcag tctccacctg agatgtccaa tgacctggaa gcttatctat cagtaacaca attatgccaa ctcagaaatg gcagttagcc aaaaagatta agacagcggg cttgagagac aagaccaggg gaactggaag atcagaaagc attatggaaa ctggtccctg cctgattcag agacttaaag gattcattta cttgaacaac gagcaaaaaa aggaagagag aacgccgttt aacaagaaga cagtgaatgg aaacacaaaa tcaaacaact agaagcagct ggatcagttt aacaattaga acaatcagct ttcataaaat aaaaaaa gagaaaggag agaatgggaa cattgtcagg aaaacatcag gactgagcta tcaacaagag attaaacgaa acttcataaa tgctcttgaa gaaggaactc caaacgtgac atagaaagac agactccgtc ctgagctcca cagatctcag gaagttttgg cttaaggaat agaattaaaa aagtcatcag aaagaaactg agagaaagct aaattgaagg

1380

1440

1500

1560

1620

1680

1740

1800

1860

1920

1980

2017

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

<td>&lt;21zł&gt;</td><td> 414</td>

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

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

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

atggcagtga cattcaccat catgggaacc accttccctt ttcttcagga ttctctgtag 60 tggaagagag cacccagtgt tgggctgaaa acatctgaaa gtagggagaa gaacctaaaa 120 taatcagtat ctcagagggc tctaaggtgc caagaagtct cactggacat ttaagtgcca 180 acaaaggcat actttcggaa tcgccaagtc aaaactttct aacttctgtc tctctcagag 240 acaagtgaga ctcaagagtc tactgcttta gtggcaacta cagaaaactg gtgttaccca 300 gaaaaacagg agcaattaga aatggttcca atatttcaaa gctccgcaaa caggatgtgc 360 tttcctttgc ccatttaggg tttcttctct ttcctttctc tttattaacc Acta 414

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

<td> &lt;211&gt;</td><td> 1567</td>

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

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

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

atatctagaa gtctggagtg aggctccaat atgaacaaga attcatgtga actagacaag gcatccccag atctcaggga agtgcatgtt ctttgtctct gcccctggaa atgtacccta agtaatgggt ccaactgaca cggcgacacc ttatttctca tatggcatta agacctcagt catctccggg acagtgctac acaggacgtc aaccctggtt cctcacatta gagccagaac tatgggaaat cattctaccc agtctatccc agacgctgct caaatgattc aatgccaaag gattttataa gatgatgttc tgtcatcaca tttcaatagc ggaatgtctg taccaactag tccccattac ttgagtagaa gtcattggca tctatcgggc gcctgatggg tgcaagccaa .tactctgaa tttagatctc agcaaacaag taaatctatc tgtgttaaga cctccccctg gaatttttag aacatatcca aattgactgc actttttatg ttgagaaaaa ataaactgag at.ccgtgaat agctctgagg atctagagca aagacaattt tggataaagg aactacccaa aagggcctgg aataagcatt accaggataa attatcttca gttctgtaag cagacccttc agcaagaaac ttcaaagaca gtgataagta cctgtcacct ttatatgtgc catcttatat cacttcgcaa atgcttccaa tgatcataat caccttcttt ggtccaggga cttctccttt gtgggactca tgttacctca ccagggatgc tccgaagtgt aaagagggga ctgtctcttt catctctcag gcttgttgag agaaatgcct ctggccacaa aaaaagaagc tattagaagt aaatgcacgt ggggagtgag tgtaatgttg tccacaaatt ctcaggggcg aggtgccttg tttagcataa ttaaacaaac aggacctttc ccatcctgcg gctggggtga atgagggagt tgctcaacct caactgtgtc gccaacaaat ggctgctgcc tgaacagagt cttctaagtt gagttctagc ttcaaattaa caaaagcaga tgggaaaata ggagacaagt aggacaggat ctctgaggaa aagctgtagt gctgcatttt gcttctcttc acagagcagt aaatgcgggt accttgacta tggacagcta tttcgccccc ggaggaggat cctaccatgt aggactaaga ctgtctgctt tcagcacaga tgacaaggcc tctttccctt tcaggttttc ggcaacaaac

120 180 240 300 360 4 20 480 540 600 660 720 760 840 900 960 1020 1080 1140 1200 1260 1320

GB 201 529 B1 atataccttc catgaagcac acacagactt ttgaaagcaa ggacaatgac tgcttgaatt gaggccttga ggaatgaagc tttgaaggaa aagaatactt tgtttccagc ccccttccca cactcttcat gtgttaacca ctgccttcct ggaccttgga gccacggtga ctgtattaca tgttgttata gaaaactgat tttagagttc tgatcgttca agagaatgat taaatataca tttccta

1380

1440

1500

1560

1567

<td> &lt;210&gt;</td><td> 75</td>

<td> &lt;211&gt;</td><td> 240</td>

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

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

<td> &lt;400&gt;</td><td> 75</td>

uuydycyyuL yuuuyyyudy yuccLccaga curggactgt gtcacactgc caggcttcca gggctccaac ttgcagacgg cctgttgtgg gacagtctct gtaatcgcga aagcaaccat ggaagacctg ggggaaaaca ccatggtttt atccaccctg agatctttga acaacttcat ctctcagcgt gcggagggag gctctggact ggatatttct acctcggccg cgaccacgct &lt;210&gt; 76 &lt;211&gt; 330.

&lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (330) &lt;223&gt; n = A, T, C k ^ G

120

180

240 &lt;400&gt; 76 tagcgyggtc gcggccgagg yctgcttytc ggtgggtgca gatggcatcc actccggtgg tcagcctgca gccagagtac agagggccaa ggccctgaag grccctctct gtagtgttga cataccgcag gytagygatg gtgaagttga caracctgcc cgggcggccg ctcsaaatcc tgtccagccc agggcctgtg gggtcagggc cttccccatc tttctctggc ctgagcaagg cactggtgtt cttgaacaag ggccttagca acttcctgga gccaggccac atgttctcct gggtgaaata gtattmangr agatggctgg

120

180

240

300

330

<td> &lt;210&gt;</td><td> 77</td>

<td> &lt;211&gt;</td><td> 361</td>

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

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

<td> &lt;400&gt;</td><td> 77</td>

agcgtggtcg gtgtcagctc cagccaccag acagagagcg cctacaccct ccaccaccag a

cggccgaggt tctgtactct agtggatgct gctgtactgg ggacagggac caccggggtg gtccttcagg ggttgcagac gtctgcaccc aagctgagcc agtctctatg gtcagcgagg gtctgcttat tgaccttgct atcgtcctga agctgaccca tcaatggttt agccattcaa gcccttgttc caggcctgag ccccaaaagc cggcatcact cacccatcgg cctgcccggg aagaacacca aaggatgggg cctggactgg gagctgggcc agctctgtac cggccgctcg

120

180

240

300

360

361

<td> &lt;210&gt;</td><td> 78</td>

<td> &lt;211&gt;</td><td> 356</td>

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

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

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

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (356) &lt;223&gt; n = A, T, C, UC G &lt;400&gt; 78 ttggggnttt mgagcggccg cccgggcagg actgaacttc accatcaaca acctgcggta gaagttcaac accacggaga gggtccttca cagtgttggc cctctgtact ctggctgcag ggcagccact ggagtggacg ccatctgcac ggacagagag cggctatact gggagctgag taccggggtg tgaggagaac gggcctgctc actgactttg cctccgcctt ccagtcctct gtcagcgagg atgcagcacc aggtccctgt ctcagacttg gatcccactg ggcggngacn agccattcac ctggctccag tcaagagcac agaaacatgg gtcctggact ccnctt

120

180

240

300

356

<td>&lt;21u&gt;</td><td> 79</td>

<td> &lt;211&gt;</td><td> 226</td>

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

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

<td> &lt;400&gt;</td><td> 79</td>

agcgtggtcg cggccgaggt ccagrcgcag catgctcttt ctcctgccca ctggcacagt gaggaagatc tctgctgtca gtgagaaggc tgtcatccac tgagatggca gtcaaaagtg catttaatac acctaacgta tcgaacatca tagcttggcc caggttatct catatgtgct cagaacactt acaatagccc gcagacctgc ccgggcggcc gctcga &lt;210&gt; 80 - &lt;211&gt; 444 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (444) &lt;223&gt; n = A, T, C |_at(about G.

120

180

226 &lt;400&gt; 80 tgtggtgttg aacttcctgg agncagggtg acccatgtcc gatggtgaag ttgagggtga atggtaccag gagagggcca gsmgmssgag gmwggwgtyy cwgaggttcy rarrtccact ggtggtgggc acagagstcy gatgggtgaa accattgaca ggtgtagggg cccagctctt yratgycatt ggycagttkg ctctckgyyg mgwccagsgc ttttggggtc aagatgatgg agtggctgct ccatccttct cggacctgag agaggtcagt gccaacacta atottcttta aata tccccatact gcagccataa gtggaggtcc tagagactgt ctyagctccc atgcagatgg ctgcagccag gcaggttggt ttgtsgrgck caggagtgct tcctgtccag agtacagccr catccactcc agtacagagg

120

180

240

300

360

420

<td> &lt;210&gt;</td><td> 81</td>

<td> &lt;211&gt;</td><td> 310</td>

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

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

<td> &lt;400&gt;</td><td> 81</td>

tcgagcggcc gcccgggcag ttccacctgt gctgcggaca gatcagtcag actggctgtt acagagggcc aacactggtg tccgtggtgt tgaacttcct ttggtgatgg gtcaggaagc acattggtct tagagccact tctccaggga gtgcagaagg gaagcaggtc ctcagttctc acctgagcaa ggtcagtctg ttcttgaaca agggcttgag cagaccctgc ggaaaccagg gtgttgcatg tttttcctca gcctcctgga aaactgctca cagccagagt agaaccctct taatgcaagg

120

180

240

300

310

PL 201 529 B1 &lt;210&gt; 82 &lt;211&gt; 571 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ..- (571) &lt;223&gt; η = A, T C February G &lt;400&gt; 82 acggtttcaa tggacacttt tattgtttac ttaatggatc atcaattttg tacaaatgga atttcatctt gtttccatgc tgagtagtga aacagtgaca taataaccta catcaaaaga gaactaagct aacactgctc actttctttt aatataaata tatgcactct anaatgcaca atggtttagt cactaaaaaa atcttgaaga atgtatgcaa atccagggtg cagtgaagat gagctgagat tgtttaaggg ttcctggcac tgcatctctt ggccactagc tgaatcttga tttagctaat gccaagtgga gatgcagaaa atgctaagtt gacttagggg gaactaaaag gcaggaaagt actaaatatt gctgagagca tccaccccag accttccagg agctccaaac tggcaccacc cccagtgctc acatggctga cgtgttccat ttggcacagc aagtggcagt g tctcactacc aagctaatca taacaggcaa ttcaaatggg gctgtgcaac catggaaggt ctgtgcacag gaaggacttt ctttatcctc

120

180

240

300

360

420

480

540

571

<td> &lt;210&gt;</td><td> 83</td>

<td> &lt;211&gt;</td><td> 551</td>

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

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

<td> &lt;400&gt;</td><td> 83</td>

aaggctggtg ggtttttgat cctgctggag aacctccgct ttcatgtgga aagggaaaag atgcttctgg gaacaaggtt aaagccgagc cagccaaaat cgagcttcac tttccaagct aggggatgtc tatgtcaatg atgcttttgg agagcccaca gctccatggt aggagtcaat ctgccacaga aggctggtgg aagaaggagc tgaactactt tacaaaggcc ttggagagcc cagagcgacc atcctgggcg gagctaaagt tgcagacaag atccagctca tcaataatat gtcaatgaga tgattattgg tggtggaatg gcttttacct tccttaaggt atggagattg gcacttctct gtttgatgaa gagggagcca agattgtcaa tccaaagctg agaagaatgg tgtgaagatt accttgcctg ttgactttgt aagtttgatg a ggaagaaggg agaagctttc cactgctcac gtttttgatg cttcctggcc gctggacaaa gctcaacaac agacctaatg cactgctgac

120

180

240

300

360

420

480

540

551

<td> &lt;210&gt;</td><td> 84</td>

<td> &lt;211&gt;</td><td> 571</td>

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

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

<td> &lt;400&gt;</td><td> 84</td>

tttgttcctt acatttttct aaagagttac ttaaatcagt caactggtct taagttctga ttccaactta gctaattcat tctgagaact gtggtatagg cttctagctg ggacaaaagt tctttgtttt ccccctgtag agtatcacag gaagctggac ctctgtctgg gccttggact cccaaatctg cttgtcatgt aaatgttaat ctttaattct tccatatgga tggacatctg tctaagttga cactgcaatt atcttctttg agtctaattt cttcttcttt gctttgaatc acttcctctc ccatttctta gcttcatcta tcaccctgtc acgatcatcc acatgctctt agtaaaggct gcaagctggg tcacagtact gtccaagttt gctgaacttc cttgtctttc ttgttcaaag taacctgaat ctctccaatt ttgagactct tggcgtgtct accttctgct tcaagcctgg tcctttagaa gcatcactaa tggagggaag tcctgaagtt gtctcttcca

120

180

240

300

360

420

480

540

Agtggacttt ttctctgcgc aaagcatcca g

571

<td> &lt;210&gt;</td><td> 85</td>

<td> &lt;211&gt;</td><td> 561</td>

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

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

<td> &lt;400&gt;</td><td> 85</td>

tcattgcctg tgatggcatc tggaatgtga tgagcagcca aatcaaagga ttcagcatgt ggtggaagct gtgaggcaag aagttaagaa gcacagaggc aaacaagaag gagacagaaa caagaaatgg aggaaatgaa agaaaagatg agaaagtttg atcctagagc tggaagaaga gaatgaccgg cttagggcag acagctaaag agtgtatgga aacacttctt tcttccaatg gaaagggtca aaatggagta tgaaaccctt tctaagaagt aaagactctc taagtgaaga ggttcaagat ttaaagcatc aaacaagcta acctagaggc caccgagaaa catgataacc ggaacacagt ctataccagg t ggaagttgta agaaacaaga agcagttgca ctaaatctaa aggtgcaccc ccagcatgaa ttcagtcttt agatagaagg aaacgaatgt gatttcattc actgtatggc ggaagctgag acagcagaaa tgcaggagat ggaagaactt aatgtctgag taatgtatct cactgaagag

120

180

240

300

360

420

480

540

561

<td> &lt;210&gt;</td><td> 86</td>

<td> &lt;211&gt;</td><td> 795</td>

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

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

<td> &lt;400&gt;</td><td> 86</td>

aagccaataa tcaccattta ttacttaata tatgccaacc aattctcacc gttacaacaa ccccatgagg tatttattcc cacagctcaa gtaagttagg aaactgagcc aagtatacac tagaaggaaa gactgacact gctatctgct ggcctccagt ggttcaatgt ctccagcgct gctgctgctg ctgcattacc cctctggtgt tcaactgcat ccttcaaaga atctaactca tttctctctt tctgaaatta cttttaataa ttcttcatga ttggtagttt tgttgtttaa gctgctcaat ttgggactta tacatcctgt aacagctgtg ttttgctaga aagatcactc ttctaacctc "ttcaattcat tttccttttc tttcaacaca tgatgcagaa gaggcctctt tcaagttatg ttgtgctact agattcattt tcttcttgaa gatcctgtaa ccacttccct tttctcttcc aaaacagcct tcatggtatt catctgttcc caggagcttc agaac actgtacttg cattctatag agaatacgaa gtcctggctc atgccctcat ttccagagac gggggaaaag aacaatttgt tccctctctt atctcaagtt tcctgaacat gtattggcta tcttttcctt gcagttcaca atagggaaac gtggcaaaac ttttcacacg tgtttttctt cacttatttc aagatgcctg tttcatcttg ttagcatggc cttcaaactg gtgcttztas ggtctttctc ttaataagtt

120

180

240

300

360

420

480

540

600

660

720

780

795

<td> &lt;210&gt;</td><td> 87</td>

<td> &lt;211&gt;</td><td> 594</td>

<td> &lt;212&gt;</td><td>DNA. '</td>

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

<td> &lt;400&gt;</td><td> 87 .</td>

caagcttttt tttttttttt aaaaagtgtt agcattaatg caactgggtt tatgtcttca tattttatat ttttgtaaat aatagccaat ggctggttat attttcagaa aacatgatta cttcaagctt ttccttattg gctccagaaa attcacccac actggaatgt tggcatgcat ttgacttcac actctgaagc catctacttc aaggaatatc acgttggaat acttttcaga tgatcatttt gcaaggccca caccacgtgg ctgagaagtc ctgcagcgtc caaggcttcc tgaaaagcag tcttgctctc ctgctggagt ctgacgagcg gctgtaagga ccgatggaaa ttttattgtc taaaaaaatt gactaattca cttttgtccc aacatcctga gagggaatga aactactaca gatctgcttc tggatccaaa acgcagatgg 'acaagtttta ttaatggtgg ttcttaaaaa cagtcatcca aagaaaggct agtttatcac accatcttgg gcaccaaaca

120

180

240

300

360

420

480

540

PL 201 529 B1 gagcttcaag actcgctgct tggcttgaat tcggatccga

<td> &lt;210&gt;</td><td> 88</td>

<td> &lt;211&gt;</td><td> 557</td>

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

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

<td> &lt;400&gt;</td><td> 88</td>

aagtgttagc attaatgttt tattgtcacg cagatggcaa tttatatttt tgtaaattaa aaaaattmca agttttaaat ttcagaaaac atgattagac taattcatta atggtggctt ccagaaaatt cacccacctt ttgtcccttc ttaaaaaact acttcacact ctgaagcaac atcctgacag tcatccacat ttggaatact tttcagagag ggaatgaaag aaaggcttga cacgtggctg agaagtcaac tactacaagt ttatcacctg aaagcagtct tgctctcgat ctgcttcacc atcttggctg gtaaggaccg atggaaatgg atccaaagca ccaaacagag catgaattcg gatccga

<td>tatcgccatg</td><td>gcct</td><td> 594</td>

<td>ctgggtttat</td><td>gtcttcatat</td><td> 60</td>

<td>agccaatggc</td><td>tggttatatt</td><td> 120</td>

<td>caagcttttc</td><td>cttattggct</td><td> 180</td>

<td>ggaatgttgg</td><td>catgcatttg</td><td> 240</td>

<td>ctacttcaag</td><td>gaatatcacg</td><td> 300</td>

<td>tcattttgca</td><td>aggcccacac</td><td> 360</td>

<td>cagcgtccaa</td><td>ggcttcctga</td><td> 420</td>

<td>ctggagtctg</td><td>acgagcggct</td><td> 480</td>

<td>cttcaagact</td><td>cgctgcttgg</td><td> 540</td>

<td> &lt;210&gt;</td><td> 89</td>

<td> &lt;211&gt;</td><td> 561</td>

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

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

&lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (I) ... (561) &lt;223&gt; n = A, T, C her. G &lt;400&gt; 89 tacaaacttt attgaaacgc acacgcgcac acacacaaac acccctgtgg atagggaaaa 60 gcacctggcc acagggtcca ctgaaacggg gaggggatgg cagcttgtaa tgtggctttt 120 gccacaaccc ccttctgaca gggaaggcct tagattgagg ccccacctcc catggtgatg 180 gggagctcag aatggggtcc agggagaatt tggttagggg gaggtgctag ggaggcatga 240 gcagagggca ccctccgagt ggggtcccga gggctgcaga gtcttcagta ctgtccctca 300 cagcagctgt ctcaaggctg ggtccctcaa aggggcgtcc cagcgcgggg cctccctgcg 360 caaacacttg gtacccctgg ctgcgcagcg gaagccagca ggacagcagt ggcgccgatc 420 agcacaacag acgccctggc ggtagggaca gcaggcccag ccctgtcggt tgtctcggca 480 gcaggtctgg ttatcatggc agaagtgtcc ttcccacact tcacgtcctt cacacccacg 540 tganggctga ngg 561

<td> &lt;210&gt;</td><td> 90</td>

<td> &lt;211&gt;</td><td> 561</td>

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

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

<td> &lt;400&gt;</td><td> 90</td>

cccgtgggtg ccatccacgg agttgttacc tgatctttgg aagcaggatc gcccgtctgc 60 actgcagtgg aagccccgtg ggcagcagtg atggccatcc ccgcatgcca cggcctctgg 120 gaagactgggagcag ggga cggcctgggg 120 gaagactgggaggg gggga 120 gaagactgggaggggga 180^{t (}999^catca acctggcagg ggccacccag atgcctgctc agtgttgtgg gccatttgtc 240 cagaagggga cggcagcagc tgtagctggc tcctccgggg tccaggcagc aggccacagg 300 gcagaactga ccatctgggc accgcgttcc agccaccagc cctgctgtta aggccaccca 360 gctcaccagg gtccacatgg tctgcctgcg tccgactccg cggtccttgg gccctgatgg 420 ttctacctgc tgtgagctgc ccagtgggaa gtatggctgc tgccaatgcc caacgccacc 480

PL 201 529 B1 tgctgctccg atcacctgca ctgctgcccc aagacactgt gtgtgacctg agtgcctctc caaggagaac g &lt;210&gt; 91 &lt;211&gt; 541 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc__f eature &lt;222&gt; (1). .. (541) &lt;223&gt; n = A, T, C lu &lt;o G &lt;400&gt; 91 gaatcacctt tctggtttag ctagtacttt gtacagaaca atgaggtttc gtctccctgg gctctgtttg gctctcggta aggcaggcct acaccttttc tggagagggg aatatgcatt aaggtgaaaa gtcaccttcc aaaagtgaga attgctgctt caggactgtg gaattatttg gaatgtttta caaatggttg acaaaaaagg taattacaaa atgtgtacat cacaacatgc tttttaaaaa tgtgctcaca ttcccttaaa tgttgtttcc aaaggtgctc agcctctagc tctccgggaa gaggcagaga cagtttggcg aaaaagacac agggaaggag aaggagaaag cagccttcca gttaaagatc agccctcagt taaaggtcag gctggcctca ngcggagtct gggtcagagg gaggagcagc agcagggtgg t atccagagta ccacagcgga ctctcctcta aagggattcg ctacaaaaca cattatgcat ccagctggat ggggtggtga cttcccgcan gactggggcg

540

561

120

180

240

300

360

420

480

540

541

<td> &lt;210&gt;</td><td> 92</td>

<td> &lt;211&gt;</td><td> 551</td>

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

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

<td> &lt;400&gt;</td><td> 92</td>

aaccggagcg cgagcagtag ctgggtgggc accatggctg ggatcaccac gtgaagcgca agatccaggt tctgcagcag caggcagatg atgcagagga cgcctccagc gagaagttga gggagaaagg cgggcccggg aacaggctga gcctccttga accgtaggat ccagctggtt gaagaagagc tggaccgtgc ctggccactg ccctgcaaaa gotggaagaa gctgaaaaag ctgctgatga ggtatgaagg ttattgaaaa ccgggcctta aaagatgaag aaaagatgga atccaactca aagaagctaa gcacattgca gaagaggcag ataggaagta gctcgtaagt tggtgatcat tgaaggagac ttggaacgca cagaggaacg gcagagtccc gttgccgaga gatggatgag cagattagac tgatggacca tgtctgagtg c catcgaggcg gcgagctgag ggctgaggtg tcaggagcgc gagtgaaaga actccaggaa tgaagaggtg agctgagctg gaacctgaag

120

180

240

300

360

420

480

540

551

<td>&lt;210&gt; 93 &lt;211&gt; 531 &lt;212&gt; DNA &lt;213&gt; Homo sapien</td>

<td> &lt;400&gt; 93</td>

gagaacttgg cctttattgt gggcccagga gggcacaaag gtcaggaggc gatctggttt tctggatagc caggtcatag catgggtatc agtaggaatc gcacaggcct cacttgctgc agttccgggg agaacacctg cactgcatgg ctcgtggtac acgacagagc cattggtgca gtgcaagggc acgcgcatgg cgagggcagg cagcaggagc attgctcctg cacatcctcg atgtcaatgg tttgctggca cactttccct ggcagtaatg aatgtccact tcctcttggg tcccactttg atgtactgca ccttggctgt gatgtctttg caatcaggct ccaagggagg cgctgtagct cgttgatgac gctccgtcct agtacacagc acttacaatc cctcacatgt

120

180

240

300

360

420

PL 201 529 B1 gtcacagcag gtgcctggaa ttttcacgat tttgcctcct tcagccagac acttgtgttc 480 atcaaatggt gggcagcccg tgaccctctt ctcccagatg tactctcctc t 531

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td>94 531 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> (1) - -</td><td> . (531)</td>

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

<td> &lt;400&gt;</td><td> 94</td><td></td>

gcctggacct ctgcagagtc tctcctgttc ggcagttcca tgctcctatg gcctgcagcc gtcrctgctg ccgtacgttg tttacccatc tgccggatca atcgtgtcaa gggtggagga ctcggcacat tcatctttca ccggggcaaa agctgcacag gtgaaaacat ttggccacat gtgccacaca ttgtgaccat gacgtgtggc cgtcaccttc aaacaaggag acaagcctgc taacatggag ggaagtcagc cctcacatac gtgacttgct ggaccccggc tgccgctgga gatgggcaga caggacctgg atgaagtccs atggcagtgg atctacggcg accgccncaa tggcaaatgg cttcatgtgc cctgcccttg atttcaagct aagtgctcct ttgagattaa atgggagact ctatcatgta aacaacgagt ccagaccttg caacagccag tgtgtgcacg tactggtagc ccacaatggg gcatgctggc ggtccttgcc tgaagtcagg t

120

180

240

300

360

420

480

531

<td> &lt;210&gt;</td><td> 95</td>

<td> &lt;211&gt;</td><td> 605</td>

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

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

<td> &lt;400&gt;</td><td> 95</td>

agatcaacct ctgctggtca tctcgatagt rsgraraytt tggatgttgt ctctgctgat gtgtcactgg tgcatcccac tcagacaggg aggaggratg ctccacttcg TCTA rwcaactkkr agacaycccm agtcagacag caggagggat gctccacctc ctctgagacg tgcgyccatc ccttccttgt agagtgatgg ggaggaatgc ytsrams KMA cctcwgagac ggtgcgtcca gccttcctta gagggtgatg gagcaęcagg ttccagctgc cytggatctt tcttaccagt cttccttgtc agkgyratgr gsagkaccar tcttccagct tcttggatct gtcttaccag tgcagggtrg tttccsagca tgcyttgacr cagggtcttc ttggatcttt wmttksywgw gtgcagaggt gtttcccagc ttgccttgac tcagggtctt actctttctg aagatcaacc ttctcratgg acgaagatct actttgacgt rasaktmwwm ggactctttc aaagatcaac attctcgatg cacgaagaty gatgttgtag tctgctggtc tgtcactcaccg gcats

120

180

240

300

360

420

480

540

600

605

<td> &lt;210&gt;</td><td> 96</td>

<td> &lt;211&gt;</td><td> 531</td>

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

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

<td> &lt;400&gt;</td><td> 96</td>

aagtcacaaa gacagaggtc gaggaggtga caagacatgc aaacttaaat gctcgtttaa atggaaaaaa cagacaaaga atgattctga agcatctcaa ttaatcactc cattacaaca ctgacaaaca agctgaaaga ttattaccag gatgattgga acataatctc agaaaaggaa acggttagaa tcaatctatt agaaagagaa ctgcaagcta gaccttcaag gaaaaagtgg aagaataatt caagaggtaa gaagaggcaa gctcgagaga tattagaagc ctcgaattac aaggagaaag tagagataga atgaacacaa agtctgtggc aggctgaaaa tgaacgaaga atctttacaa aaaagaggct tttaaactac agtaaccaaa aatgtgtgag tcgggttgtt

120

1B0

240

300

360

420

PL 201 529 B1 cagattgaga aacagtgttc catgctagac gttgatctga agcaatctca gcagaaacta gaacatttga ctggaaataa agaaaggatg gaggatgaag ttaagaatct a &lt;210&gt; 97 &lt;211&gt; 1017 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc__feature &lt;222&gt; (1) ... (1017) &lt;223&gt; π * A, T, C łu ^ G

480

531 &lt;400&gt; 97 cgcctccacc atgtccatca ccgggccttc agcagccgct cttctcccga gtgggcagca cagcggcatg ggaggcatca cctggaggtg gaccccaaca cctcaacaac aagtttgcct gatgctggag accaagtgga caacatgttc gagagctaca gaagctgaag ctggaggcgg caagtatgag gatgagatca gaaggatgtg gatgaagctt gaccgacgag atcaacttcc ccagatctcg gacacatctg cagcatcatt gctgaggtca ggctgagagc atgtaccagg ggatgacctg cggcgcacaa ctncaggctg agattgaggg gggtgaccca cctacacgag gcaactttcg ccgcagttac tccaggccgt ccttcataga gcctcctgca tcaacarcct agcttggcaa ataagcgtac acatgaacaa tcaggcagct tggtgctgtc aggcacagta tcaagtatga agactgagat cctcaaaggc gaagtcctac tgggcccggt cggtggcctg ggtcaaccag gcgcacccag caaggtacgg gcagcagaag taggcggcag catgcagggg agagatggag ggtagagctg gtatgaagag catggacaac cgaggatatt ggagctgcag ctctgagatg caganggctt aaggtgtcca tcccgcatca ggcggcggct agcctgctga gagaaggagc ttcctggagc acggctcgaa ctggagactc ctggtggagg aacgaatttg gagtctcgcc gagatccggg agccgctccc gccaaccgca agcctggctg aacccggaac ncctggangn cctctggccc gctcctcgag atggtggggc gcccccttgt agatcaagac agcagaacaa gcaacatgga tgggccagga acttcaagaa tcctcatcaa tggaagggct agctgcagtc tggacatgga gccgggctga ggaagcacgg atcagcccgg ccgccat

120

180

240

300

360

420

480

540

600

660

720

780

840

900

960

1017

<td> &lt;210&gt;</td><td> 98</td>

<td> &lt;211&gt;</td><td> 561</td>

<td> &lt;212&gt;</td><td>DNA.</td>

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

<td> &lt;400&gt;</td><td> 98</td>

cccggagcca gccaacgagc ggaaaatggc agacaatttt tcgctccatg atgcgttatc 60 tgggtctgga aacccaaacc ctcaaggatg gcctggcgca tgggggaacc agcctgctgg 120 ggcagggggc tacccagggg cttcctatcc tggggcctac cccgggcagg cacccccagg 180 ggcttatcct ggacaggcac ctccaggcgc ctaccctgga gcacctggag cttatcccgg 240 agcacctgca cctggagtct acccagggcc acccagcggc cctggggcct acccatcttc 300 tggacagcca agtgccaccg gagcctaccc tgccactggc ccctatggcg cccctgctgg 360 gccactgatt gtgccttata acctgccttt gcctggggga gtggtgcctc gcatgctgat 420 aacaattctg ggcacggtga agcccaatgc aaacagaatt gctttagatt tccaaagagg 480 gaatgatgtt gccttccact ttaacccacg cttcaatgag aacaacagga gagtcattgg 540 ttgcaataca aagctggata a 561

<td> &lt;210&gt;</td><td> 99</td>

<td> &lt;211&gt;</td><td> 636</td>

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

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

<td> &lt;400&gt;</td><td> 99</td>

PL 201 529 B1

<td>gggaatgcaa caactttatt gaaaggaaag</td><td>tgcaatgaaa</td><td>tttgttgaaa</td><td>ccttaaaagg</td><td> 60</td>

<td>ggaaacttag acaccccccc tcragcgmag</td><td>kaccargtgc</td><td>araggtggac</td><td>tctttctgga</td><td> 120</td>

<td>tgttgtagtc agacagggtr cgwccatctt</td><td>ccagctgttt</td><td>yccrgcaaag</td><td>atcaacctct</td><td> 180</td>

<td>gctgatcagg aggratgcct tccttatctt</td><td>ggatctttgc</td><td>cttgacattc</td><td>tcgatggtgt</td><td> 240</td>

<td>cactgggctc cacctcgagg gtgatggtct</td><td>taccagtcag</td><td>ggtcttcacg</td><td>aagatytgca</td><td> 300</td>

<td>tcccacctct gagacggagc accaggtgca</td><td>gggtrgactc</td><td>tttctggatg</td><td>ttgtagtcag</td><td> 360</td>

<td>acagggtgcg yccatcttcc agctgctttc</td><td>csagcaaaga</td><td>tcaacctctg</td><td>ctggtcagga</td><td> 420</td>

<td>ggratgcctt ccttgtcytg gatctttgcy</td><td>ttgacrttct</td><td>caatggtgtc</td><td>actcggctcc</td><td> 480</td>

<td>acttcgagag tgatggtctt accagtcagg</td><td>gtcttcacga</td><td>agatctgcat</td><td>cccaccta</td><td> 540</td>

<td>agacggagca ccaggtgcag ggtggactct</td><td>ttctggatgg</td><td>ttgtagtcag</td><td>acagggtgcg</td><td> 600</td>

<td>tccatcttcc agctgtttcc cagcaaagat</td><td>caacct</td><td></td><td></td><td> 636</td>

<td> &lt;210&gt; 100</td><td></td><td></td><td></td><td></td>

<td> &lt;211&gt; 697</td><td></td><td></td><td></td><td></td>

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

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

<td> &lt;400&gt; 100</td><td></td><td></td><td></td><td></td>

<td>aggttgatct ttgctgggaa acagctggaa</td><td>gatggacgca</td><td>ccctgtctga</td><td>ctacaaccat</td><td> 60</td>

<td>ccagaaagag tccaccctgc accrggtgct</td><td>ccgtcttaga</td><td>ggtgggatgc</td><td>agatcttcgt</td><td> 120</td>

<td>gaagaccctg actggtaaaa ccatcactct</td><td>cgaagtggag</td><td>ccgagtgaca</td><td>ccattgagaa</td><td> 180</td>

<td>ygtcaargca aagatccarg acaaggaagg</td><td>catycctcct</td><td>gaccagcaga</td><td>ggttgatctt</td><td> 240</td>

<td>tgctsggaaa gcagctggaa aatggręgca</td><td>ccctgtctga</td><td>ctacaacatc</td><td>cagaaagagt</td><td> 300</td>

<td>cyaccctgca cctggtgctc cgtctcagag</td><td>gtgggatgca</td><td>ratcttcgtg</td><td>aagaccctga</td><td> 360</td>

<td>ctggtaagac catcaccctc gaggtggagc</td><td>ccagtgacac</td><td>catcgagaat</td><td>gtcaaggcaa</td><td> 420</td>

<td>agatccaaga taaggaaggc atccctcctg</td><td>atcagcagag</td><td>gttgatcttt</td><td>gctgggaaac</td><td> 480</td>

<td>agctggaaga tggacgcacc ctgtctgact</td><td>acaacatcca</td><td>gaaagagtcc</td><td>acctytgcac</td><td> 540</td>

<td>ytggtmctbc gtctyagagg kgggrtgcaa</td><td>atctwmgtkw</td><td>agacactcac</td><td>tkkyaagryy</td><td> 600</td>

<td>atcamcmwtg akktcgakys castkwcact</td><td>wtcrakaamg</td><td>tyrwwgcawa</td><td>gatccmagac</td><td> 660</td>

<td>aaggaaggca ttcctcctga ccagcagagg</td><td>ttgatct</td><td></td><td></td><td> 697</td>

<td> &lt;210&gt; 101</td><td></td><td></td><td></td><td></td>

<td> &lt;211&gt; 451</td><td></td><td></td><td></td><td></td>

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

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

<td> &lt;400&gt; 101 · </td><td></td><td></td><td></td><td></td>

<td>atggagtctc actctgtcga ccaggctgga</td><td>gcgctgtggt</td><td>gcgatatcgg</td><td>ctcactgcag</td><td> 60</td>

<td>tctccacttc ctgggttcaa gcgatcctcc</td><td>tgcctcagcc</td><td>tcccgagtag</td><td>ctgggactac</td><td> 120</td>

<td>aggcaggcgt caccataatt tttgtatttt</td><td>tagtagagac</td><td>atggtttcgc</td><td>catgttggct</td><td> 180</td>

<td>gggctggtct cgaactcctg acctcaagtg</td><td>atctgtcctg</td><td>gcctcccaaa</td><td>gtgttgggat</td><td> 240</td>

<td>tacaggcgaa agccaacgct cccggęcagg</td><td>gaacaacttt</td><td>agaatgaagg</td><td>aaatatgcaa</td><td> 300</td>

<td>aagaacatca catcaaggat caattaatta</td><td>ccatctatta</td><td>attactatat</td><td>gtgggtaatt</td><td> 360</td>

<td>atgactattt cccaagcatt ctacgttgac</td><td>tgcttgagaa</td><td>gatgtttgtc</td><td>ctgcatggtg</td><td> 420</td>

<td>gagagtggag aagggccagg attcttaggt</td><td>vol</td><td></td><td></td><td> 451</td>

<td> &lt;210&gt; 102 .</td><td></td><td></td><td></td><td></td>

<td> &lt;211&gt; 571</td><td></td><td></td><td></td><td></td>

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

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

<td> &lt;400&gt; 102</td><td></td><td></td><td></td><td></td>

<td>agcgcggtct tccggcgcga gaaagctgaa</td><td>ggtgatgtgg</td><td>ccgccctcaa</td><td>ccgacgcatc</td><td> 60</td>

<td>cagctcgttg aggaggagtt ggacagggct</td><td>caggaacgac</td><td>tggccacggc</td><td>cctgcagaag</td><td> 120</td>

<td>ctggaggagg cagaaaaagc tgcagatgag</td><td>agtgagagag</td><td>gaatgaaggt</td><td>gatagaaaac</td><td> 180</td>

GB 201 529 B1 cgggccatga cacattgcgg gagggtgagc ctggaagaag aagtattctg aaagaggctg attgatgacc aggatgagga aagaggctga tggagagggc aactcaagaa aaaaggagga agacccgtgc tggaagagaa gaagatggag ccgcaaatac agaggagcgt tgttactaac caaatatgaa tgaatttgca acttgcccag attcaggaga gaggaggtag gcggaggtgt aatctgaaat gaagaaatta gagagaacgg c

tgcagctcaa ctcgtaagct ctgaactaaa ctctggaggc aacttctgtc ttgcaaaact agaggccaag ggtcatcctg atgtggtgac tgcatctgaa tgacaaactg ggaaaagaca

240

300

360

420

480

540

571

<td> &lt;210&gt;</td><td> 103</td>

<td> &lt;211&gt;</td><td> 451</td>

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

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

<td> &lt;400&gt;</td><td> 103</td>

gtgcacaggt taaattacaa gaagctgtcc aggactcaga ctgaggccac caaacctatt cccaggcagg aggcacagtc cccatttatt aacagaaacc cctcctccct ggggatcagt agagctgggc tacagcacct tgggtgggcc ccagaggtga gtagaaaata acaaagaagg gccaccctcc ctccaggggc aacctgagcc tcgcccctcc aggcctcagc tatcaaggcc ataataatta aagaggaaaa caggctcatt cctgggctga gcctctctgg cctctaaacc catactcctg t

cagtgatgaa accccaggac agtgtccttg agcgggtgag ccccctcccc cgtccatcca ggcgcgggtt tagctcttct ttccaagggt gaaggggcag gcagagagtc caccactgcc ctctgcactt tcggtgagcc

120

180

240

300

360

420

451

<td> &lt;210&gt;</td><td> 104</td>

<td> &lt;211&gt;</td><td> 441</td>

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

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

<td> &lt;400&gt;</td><td> 104</td>

gcaaggaact actcacggtg acggccccca caatggcctc ccgtcatgct ttgtcacctc gccagatgca cccgcgccct ggtctgctca caaaggtgca cagccggatc catggggcta gtgctgcgcg gcagaccatc gtgcaaggtg cgtcatcatc cacttgctgg ctctgcgaac ccctcagcct caggtaatgg ctgcccatgt tgggagggcc and tacgactcgc

cttgcgcatc gttaagtccg tccaggtcct gcatcgcgct ggcgcgtgac tatggatgaa tgctggcact aggactggct tccccagcgc caactcccgt ggccgtcctg ggccttcatc ctgcgtggtg gccgcaggac ttatctcctg ttggaatcct ggacgctgaa ggctggcrgg ggcagcaaca cagagcaccg ctgcaggcgg

120

180

240

300

360

420

441 &lt;210&gt; 105 &lt;211&gt; 509 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (509) &lt;223&gt; n = A, T, CG &lt;400&gt; 105 tgcaaaaggg acacaggggt tcaaaaataa aaatttctct tccccctccc ccccagętcc ccgaccacaa cccccttcct cccccgggga aagcaagaag ggcatctgca gctgggaaga gagaggccgg ggaggtgccg agctcggtgc ccaaatataa atacntgtgt cagaactgga aaatcctcca gcacccacca ctccgttttc tgccggtgtt tggagagggg cggggggcag gggcgccagg ctgcggtcta ctgcatccgc tgggtgtgca ccccgcgagc ctcctgctgc caaacctgta gagcaggtgt tggtctcttt cccaagcact caccggctgg tcattgtaga

120

180

240

300

360

PL 201 529 B1 agagatgaca ctcggggtcc ccccggatgg tgggggctcc tggggttcac acaccagcac tccccacgct gcccgttcag ggttgtacag gccatgcttg tcacagttg ctggatcagttc agacatgtgtga

420

480

509

<td> &lt;210&gt;</td><td> 106</td>

<td> &lt;211&gt;</td><td> 571</td>

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

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

<td> &lt;400&gt;</td><td> 106</td>

gggttggagg gactggttct ttatttcaaa aagacacttg agttgcacta ttgatttctc tttctcccaa tcggccccaa gtacatttta agccaataag ctgcaggatg tacacctaac cagaaaatgg ggactgggta gggaaggaaa cttaaaagat gactgcagag gctgtcacag ccagatgggg tggccagggt tttcaaaata atataaaatt taaaaagttt tgtacataag actgactgat acaaagcaca attgagatgg cacttctaga aaaagggtga tgagatgagt ttcacatggc taaatcagtg ctttctttct ttcaaggagg caggaaagca attaagtggt atgatccatt ctgtaagcag ttgtgaaggg g tcaatattca agagaccaca agacctccta caacaaactg gccacaaacc ctattcaaga gacagcagct gcaaaaacac cacctcaaca gtatcaaaac taaaaggaga gaaaccttac ccagcccacg caaagcaaag tttctccagc tcaaacccag agtcttcttt taagggggac

120

180

240

300

360

420

480

540

571

<td> &lt;210&gt;</td><td> 107</td>

<td> &lt;211&gt;</td><td> 555</td>

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

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

<td> &lt;400&gt;</td><td> 107</td>

caggaaccgg agcgcgagca gtagctgggt gggcaccatg ggcggtgaag cgcaagatcc aggttctgca gcagcaggca tgagcgcctc cagcgagaag ttgagggaga aaggcgggcc ggtggcctcc ttgaaccgta ggatccagct ggttgaagaa gcgcctggcc actgccctgc aaaagctgga agaagctgaa gagaggtatg aaggttattg aaaaccgggc cttaaaagat ggaaatccaa ctcaaagaag ctaagcacat tgcagaagag ggtggctcgt aagttggtga tcattgaagg agacttggaa gctggcagag tcccgttgcc gagagatgga tgagcagatt gaagtgtctg agtgc gctgggatca gatgatgcag cgggaacagg gagctggacc aaagctgctg □ aagaaaaga gcagatagga cacacagagg agactgatgg ccaccatcga aggagcgagc ctgaggctga gtgctcagga atgagagtga tggaactcca agtatgaaga aacgagctga accagaacct

120

180

240

300

360

420

480

540

555

<td> &lt;210&gt;</td><td> 108</td>

<td> &lt;211&gt;</td><td> 541</td>

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

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

<td> &lt;400&gt;</td><td> 108</td>

atctacgtca tcaatęaggc tggagacacc atgttcaatc ggctttcaag aggccttgaa ggactatgat tacaactgct ctcattccga tggacgaccg taatgcctac aggtgttttt gttgcaatgg acaagttcgg gtttagcctg ccatatgttc gctctcagta aacaacagtt tcttgccatc aatggattcc ggaggagaag atgacgacat ttttaacaga ttagttcata ccaaatgctg tagtagggag gtgtcgaatg atccggcatt cccaatcctc agaggtttga ccggatcgca catacaaagg ttgaactcac ttacctacaa ggtgttggat gtcagagata c gagctaagct ttgtgttcag cgcagccacg agtattttgg ctaataatta aaggcatgtc caagagacaa aaacgatgcg cccgttatat gctcaatatt tgatgtggac gcacatttct aggtgtctct ttggggttgg tatatcacgt gaaaaatgag cttcgatggt acccaaatca

120

180

240

300

360

420

480

540

541

PL 201 529 B1

<td> &lt;210&gt;</td><td> 109</td>

<td> &lt;211&gt;</td><td> 411</td>

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

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

<td> &lt;400&gt;</td><td> 109</td>

ctagacctct aattaaaagg cacaatcatg ctggagaatg aacagtctga cacagcgaat tttagggaag gaggcaaaga ggtgagaagg gaaaggaaag ggagaacaat aagaactgga gacgttgggt gggtcaggga gtgtggtgga gatggtaaac aaacctgact gctatgagtt ttcaacccca tagtctaggg gtcagttctt ggtggctgag ggtccttcca cccagcccac ctgggggagt gttctgccag gtaagcagat gttgtctccc aagttcctga cccagatgtc acgctgacct gttccctcaa caagggacct gaaagtaatt ttgctcttta ccccgagggc aaggaaggaa ggctcggaga ccatgagggc ggagtgggga tggcaggata c

120

180

240

300

360

411

<td> &lt;210&gt;</td><td> 110</td>

<td> &lt;211&gt;</td><td> 451</td>

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

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

<td> &lt;400&gt;</td><td> 110</td>

ccgaattcaa tgaacctacg attattccta gattgaagcc ccccacatta cgctacacga tttcatgccc taccctatag gcgtcaacga agtacaccga gaaccaggcg cccattcgta ggcttaaaaa ccgggggtat atcgtcctag caccccctct tccytccctt ctacgggcgg acctgcgact taataattac cagatgcaat actacggtca aattaattcc accccctcta accatcaaat actaatcttc ccttgacgtt atcacaagac tcccggacgt atgctctgaa cctaaaaatc caattggcca aactcctaca gacaatcgag gtcttgcact ctaagccaaa atctgtggag tttgaaatag ccaatggtac tacttccccc tagtactccc catgagctgt ccactttcac caaaccacag ggcccgtatt

120

180

240

300

360

420

451

<td> &lt;210&gt;</td><td> 111</td>

<td> &lt;211&gt;</td><td> 541</td>

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

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

<td> &lt;400&gt;</td><td> 111</td>

gctcttcaca cttttattgt agaccaccac tgaccaggaa aacagttttc aaaggagtga cttgccaggt ctgagaggcc ggataaggaa ggattccagt aaactgtgat c

ctgaccgtct ccccaaggcc ttggggttcg ggggtatgct cagccacagc ttatgaaaat gtcggccaat taattctctt atgccacttt gggagcgttg tcaaccacac tgagctttcc tcatgagtgt acttcatgct ttaaagcaaa gaccaccatt cacatggcag tacaaaatca aagggtgacc ttcccagagc ttgctgctgc taacatttac tgtgagggtt caacggtttt tttctgccca atacagagct tccccccttt agcacatttg tcaccatggg ggtggggagg gggacaaaag agctgtagga tagctgggtg tgtgaaggtc gtcgtcttga tcatgattgg cacatgcaaa ctgcaggtga ccctcaagaa cgcatcatta gcgggtgaaa ggaaacagga cccatgaaac

120

180

240

300

360

420

480

540

541

<td> &lt;210&gt;</td><td> 112</td>

<td> &lt;211&gt;</td><td> 521</td>

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

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

<td> &lt;400&gt;</td><td> 112</td>

caagcgcttg gcgtttggac ccagttcagt gaggttcttg ggttttgtgc ctttggggat 60 tttggtttga cccaggggtc agccttagga aggtcttcag gaggaggccg agttcccctt 120 cctttctcccaccc cctggcctt 120 cctttctcccaccc cccggcctt 120 cctctcccccacc

GB 201 529 B1 atattgacac ccttccttgc tcatcagtcc aagactttgt ggtgtatgga acatctttag gttggagccg ctaaggtgtc attgctcttg ccccacttac ggggaaggga tgtctgagct agcctgaaca tgagtttctg agtctttgca agatctatct tctcctgcgc tctcaaatta tgcccctcgg gctcttgagg gagaacctca cctcccttgg ccttcattgc ctgcaatagg ccccagcaca catttccaga gatcaggtgc gaagggcagg cacacttggt and

tggaaaaccc cttgaaattc acctgggaga gaatggggac gggaccatga

240

300

360

420

480

521

<td> &lt;210&gt;</td><td> 113</td>

<td>&lt;2il&gt;</td><td> 568</td>

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

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

<td> &lt;400&gt;</td><td> 113</td>

agcgtcaaat cagaatggaa aagactcaaa agratccttc aagaaacagg aaaaaactcc agacattaaa gcaaaaatgc aagcaagtat agccaaattc atcaattatg tgaagaattg agatctctgg cagtggagga agtctcttta ttttccgtct tatttcattt ctgtaacagt agtgagaact ttccctaccg tgtttgataa gttgtccaaa atgcctgttt agtttttaaa gtatgtatgg aatgttatga taggacatag ggsmgacaaa aatatacatg tgaaataa accatcatca taaaacacca agaaaaaggt cttccggatg agaaaatagt tgatatctgg atgttgtcca gatggaactc tagtagcggt acaccaagat aaaggaccta ggttctcttc actgaccaag ttaaacaatt ctgtcctttt ggttctattg caccctttgc ggtcagacat caaaaggaca gttctgtaga ccaaagtgga aggctattca tgttaaaaaa tataatgcag ccaagaatgt ttggttttaa ggaaatggtg

120

180

240

300

360

420

480

540

568

<td> &lt;210&gt;</td><td> 114</td>

<td> &lt;211&gt;</td><td> 483</td>

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

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

<td> &lt;400&gt;</td><td> 114</td>

tccgaattcc aagcgaatta tggacaaacg attcctttta gaggattact tcggttttag taatctaggc tttgcctgta aagaatacaa cgatggattt ttgtggaatg tgtttaaagg attgattcta gaacctttgt atatttgata ctttcatttc tttactgttt gcagttaatg ttcatgttct gctatgcaat cacgtttctt taattttttt agattttcct ggatgtatag tttaaacaac tttaaaactg tagcagtagt ttacagttct agcaaagagg aaagttgtgg tgtattttct ttcttataga ggcttctaaa aaggtatttt tatatgttct tattgtgtac aacctttaaa acatcaatgt ttggatcaaa acaagaccca TGC

<td> &lt;210&gt;</td><td> 115</td>

<td> &lt;211&gt;</td><td> 521 .</td>

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

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

<td> &lt;400&gt;</td><td> 115</td>

tgtggtggcg cgggctgagg tggaggccca ggactctgac cctgcccctg ggcccccggc agcgccggcc actacgaact gccgtgggtt gaaaaatata gctgaatgaa attgtcggga atgaagacac cgtgagcagg ctagaggtct aggaaatgtg cccaacatca tcattgcggg ccctccagga accggcaaga tctgtgcttg gcccgggccc tgctgggccc agcactcaaa gatgccatgt tgcttcaaat gacaggggca ttgacgttgt gaggaataaa attaaaatgt aaaagtcact cttcccaaag gccgacataa gatcatcatt ctggatgaag gaccgacgga gcccagcaag ccttgaggag aaccatggaa atctactcta ttcgcccttg cttgtaatgc ttcggataag atcatcgagc c tttttcaatt taaatactgt gtatttctaa cgtttatatg aaaaagtcta ggttaaactt ttttaacaaa gcttattttc

120

180

240

300

360

420

480

483 ccttcagcaa ggccagtaaa ttgcaaggga ccacaagcat tggaactcaa ttgctcaaca cagacagcat aaaccactcg

120

180

240

300

360

420

480

521

PL 201 529 B1

<td>&lt;210&gt; 116 &lt;211&gt; 501 &lt;212&gt; DNA &lt;213&gt; Homo sapien</td>

<td> &lt;400&gt; 116</td>

ctttgcaaag cttttatttc atgtctgcgg catggaatcc acctgcacat ctgtgaagga gaaagcagtg cacgagaagg aatgagtggg cggaaccaac agctgccttc cagcagcctg ccaaggccat ggcagagaga gactgcaaac aaacagagtc tcttcacagc tggagtctga aagctcatag tggcatgtgt aaattaaaag tgtgcatagt ccattacatg cataaaacac taataataat cgtgactgca gcaggcaggt ccagctccac cactgccctc ctgccacatc ccatggttta gagggttttt catatgtaat tcttttattc tgtaaaaggt acagaacaaa actttccctt tttaaaacta atgttacaaa tctgtattat taaatagtat ataagctgat c &lt;210&gt; 117 &lt;211&gt; 451 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (451) &lt;223&gt; n = A, T, C JuJ, G &lt;400&gt; 117 caagggatat atgttgaggg tacrgrgtga cactgaacag atcacaaagc ttagttctct ccctgatgatgca gtagtgatagca cttagtctccttcttagtcctccttcttagtcctccttcttagtcctccttcttagtcctccttcttagtctccttctt. cttcatcaaa tgccgttttt gccaggctac aggagagttt agaatctcat agtaaaagac tgagaaattt agtgccagac tgggtgtgta ggctgcattn ctttcttact aatttcaaat gcttcctggtcagtcctaa tagtcctaagaca tcc acttagcta acattcctaagaca

<td> &lt;210&gt;</td><td> 118</td>

<td> &lt;211&gt;</td><td> 501</td>

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

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

<td> &lt;400&gt;</td><td> 118</td>

tccggagccg gggtagtcgc cgccgccgcc gccggtgcag ccactgcagg gccgcctgag tagtgggctt aggaaggaag aggtcatctc gctcggagct gggtctttgt tccctgcagc cctcccacgg gaatgacaat ggataaaagt agaaagccaa actcgctgag caggctgagc gatatgatga tatggctgca cagtcacaga acaggggcat gaactctcca acgaagagag aaatctgctc acaagaatgt ggtaaggccg cccgccgctc ttcctggcgt gtcatctcca gaaaacagag aggaatgaga agaagcagca gatgggcaaa gagtaccgtg ggcagaactg caggacatct gcaatgatgt tctggagctt gttggacaaa caatgctaca caacccagaa a &lt;210&gt; 119 &lt;211&gt; 391 ggcatcttag ggcctccaca aaacacaagc gaatctgaca cctgtttaca acatcaagtg aacaaaatat cacttggata

120

180

240

300

360

420

480

501 acgagaaaca tccacagagt cttcattcag aggccttttc caagacgaat aagcctgctg gatacctaaa

120

180

240

300

360

420

451 caccgctgcc tcgctcggaa gagctggtac gccatgaagg tctgttgcct gcattgagca agaagataga tatcttattc

120

180

240

300

360

420

480

501

GB 201 529 B1 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;400 aaaaagcagc tgtgtgaggg agggttcccc agagtcaggg tctggaggct tctctgatca cacttgacag&gt; 119 argttcaaca gggaagcaac tctcctctgg gtgttcattc tagggaccaa ggggaaagga aatgggacag caaaata.gaa agcaaaagga ggactgactc ttttttggga ggctggtctc gctcgaatga actccttccc atctcaaatg agaaatgaga aaacactgat gtaagaaaag tttcccccct gggaggtaga and

taggatagaa tgttgcaaaa gtggcagtat gtggggatta cccaaccccc gttggaaagg caaaaccaag aagatggagg acaccattcc agaagacgtt ttgatccctt gaaaggattc

120

180

240

300

360

391

<td> &lt;210&gt;</td><td> 120</td><td></td>

<td> &lt;211&gt;</td><td> 421</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> (421)</td>

<td> &lt;223&gt;</td><td>n = fi</td><td>i, T, CG</td>

<td> &lt;400&gt;</td><td> 120</td><td></td>

tggcaatagc acagccatcc aggagctctt cargcgcatc tcggagcagt tcactgccat 60 gttccgccgg aaggccttcc tccactggta cacaggcgag ggcatggacg agatggagtt 120 caccgaggct gagagcaaca tgaacgacct cgtctctgag tatcaagcag taccaggatg 180 ccaccgcaga agaggaggag gatttcggtg aggaggccga agaggaggcc taaggcagag 240 cccccatcac ctcaggcttc tcagttccct tagccgtctt actcaactgc ccctttcctc 300 tccctcagaa tttgtgtttg ctgcctctat cttgtttttt gttttttctt ctgggggggt 360 ctagaacagt gcctggcaca tagtaggcgc tcaataaata cttggttgnt gaatgtctcc 420 t 421

<td> &lt;210&gt;</td><td> 121</td>

<td> &lt;211&gt;</td><td> 206</td>

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

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

<td> &lt;400&gt;</td><td> 121</td>

agctggcgct agggctcggt tgtgaaatac agcgtrgtca gcccttgcgc tcagtgtaga 60 aacccacgcc tgtaaggtcg gtcttcgtcc atctgctttt ttctgaaata cactaagagc 120 agccacaaacta cttactacaatta ctaggtaaccta ctaggtaacctaa ctagtaagtaa ctagtaaaaaa ctagtaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa

<td> &lt;210&gt;</td><td> 122</td>

<td> &lt;211&gt;</td><td> 131</td>

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

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

<td> &lt;400&gt;</td><td> 122</td>

ggagatgaag atgaggaagc tgagtcagct acgggcargc gggcagctga agatgatgag 60 gatgacgatg tcgataccaa gaagcagaag accgacgagg atgactagac agcaaaaaag 120 gaaaagttaa a 131 &lt;210&gt; 123 &lt;21i&gt; 231

PL 201 529 B1 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (231) &lt;223&gt; n = A, T, C LUL G &lt;400&gt; 123 gatgaaaatt aaatacttaa attaatcaaa aggcactacg ataccaccta aaacctactg 60 cctcagtggc agtakgctaa kgaagatcaa gctacagsac atyatctaat atgaatgtta 120 gcaattacat akcargaagc atgtttgctt tccagaagac tatggnacaa tggtcattwg 180 ggcccaagag gatatttggc cnggaaagga tcaagataga tnaangtaaa g 231 &lt;210&gt; 12 4 &lt;211&gt; 521 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature · &lt;222&gt; (1) - - - (521) &lt;223&gt; n = A, T, CG &lt;400&gt;

gagtagcaac agcagccgtg atcttcagca ggagctaggc tgaaagtgta acaatttaat ttactgcagt gccgccaatc atcaccatgg

124 .

gcaaagcgct atcgcttagt ggcagctccc aaggtggtga ccgtggagag ggagcttttg catcccatgc tcagccaagc acctacatgc tggtattgag ggagtgctta accaggactt ctaagaaatt gatgtctaca atcatgatta ttcccttatg ttggtgcaaa ttctcaaatt tctgtgggsg gggtagttgg atctcasaaa cagcaaccag ttgttcagag atgcctgcaa ccccggcagg tatgctatct canggctttt acttcggttc ccaggatgcc attgctgacc gagacctgtg tggntgtggc gattgcttca ataagaaaga gtagcagtgc t

cggtctctgc gaatatcaaa gcctgggcct tggaaattgg gaaatcaatg gccagccggg tnagagccgg agatcatatt

120

180

240

300

360

420

480

521 &lt;210&gt; 125 &lt;211&gt; 341 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (341) &lt;223&gt; n = A, T_rCG &lt;400&gt; 125 atgcaaaagg ggacacaggg gtaccccagc tccccgacca tgtggcatct gcagctggga tttccaaata taaatacgtg actctccgtt ttctgccggt tggctgcggt ctactgcatc ggttcaaaaa caaccccctt agagagaggc tgtcagaact gtttggagag cgctgggtgt taaaaatttc cctcccccgg cggggaggtg ggaaaatcct gggcggnggg gcaccccgcg tcttccccct ggaaagcaag ccgagctcgg ccagcaccca caggggcgcc ccccaaacct aaggagcagg tgctggtctc ccacccaagc aggcaccggc

120

180

240

300

341 &lt;210&gt; 126 &lt;211&gt; 521

PL 201 529 B1 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (521) &lt;223&gt; n = A, T, C Lfc G &lt;400&gt; 126 aggttggaga aggtcatgca ggtgcagatt gtccaggskc caggcccaga gtggcactgg acagaccatg caggtgatgc ggagagatcc agcagatccc ggtgcagctg aatgccggcc gcccagcctg tatcaggcac tcaagttgtg cagggacaga gctcaacaga ttacacagac agaggtccag caaggacagc aagatggaca gcagctctac cagatccagc aagtcaccat ccagcccatg ttcatccagt caagccaacc agcccttcna ccggcgactg aagggcctga gctggcaagg ccaangacac cagcccccag gcaatgggca cagcctttct tcccagagga agccacaggg agcagatcat agctgcagta tccagacact agcagttcaa gcctgcgggc cgggcaggcc ccaacacaat c

tcaagcccaa cactaacaca tatccgctta tgccaccaat gccagttcac cangacctcg ccccaggtga ttttgccata

120

180

240

300

360

420

480

521

<td> &lt;210&gt;</td><td> 127</td>

<td> &lt;211&gt;</td><td> 351</td>

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

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

<td> &lt;400&gt;</td><td> 127</td>

tgagatttat tgcatttcat gcagcttgaa gtccatgcaa aatgcattta aaaaataaaa gggaggtggg cagcaaacac gtccctggga gaaaagagtg tggcaatgaa tccacccact tctcttaaat gcaaagaatg trtccatggc ctctggatgc tcagagcaag ggatggggag aggaccacga gtgaaaaagc ttccatctga gggcaagaac aacgtggcaa gtcttggggg aggrgactag acaaagtcct ctccacaggg aaatacacag agctacacac tagcagctgt cacagttttt agtttcctgg aataaatctg agctctgggg attcacctaa t

120

180

240

300

351

<td> &lt;210&gt;</td><td> 128</td>

<td> &lt;211&gt;</td><td> 521</td>

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

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

<td> &lt;400&gt;</td><td> 128</td>

tccagacatg ctcctgtcct aggcggggag caggaaccag agagttaagg gaaggtttcc tttcattcct gttccttctc taaatatact aatagctaag tcatttgcca gccaggtccc gagcttgcta agaattaatt ttgctgtttt tcaccccatt cctgatggag ttccattcct gccagggcac ggctgagtaa gcgggtgtga aatcactgcc accccatgga cagacccctc gcgctactta ataaatatat ttatactttg aaattatgat catcctaagg gcacttgcca gctcttatcc ggacagtcaa ataaaggaaa agaaaaagaa gaaaacaacc gcaacttctg acctgctatg ttttgctttt ggtgaacagt caaacagagc cacgaagcca actcttcctt aaccgatttt gcactgttgt t

ggaagcagaa gaacagtttt agagaacaag tgccctgttc ttcaagaaag cttagccgca tcccatgcgg tggacaacag

120

180

240

300

360

420

480

521

<td> &lt;210&gt;</td><td> 129</td>

<td> &lt;211&gt;</td><td> 521</td>

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

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

<td> &lt;400&gt;</td><td> 129</td>

tgagacggac cactggcctg gtcccccctc atktgctgtc gtaggacctg acatgaaacg

GB 201 529 B1 cagatctagt agagcaatta gaaagagagc agcttcacat tcaccggcct agtgcgagat agtgtctatg caacagaggg ggcagagagg atgaagctta cgggaaaggt attccatcat gtttctaccg taccagacac cccaacatgt ccgaaaccaa aagatgatga actcaggcct catctctgtt ctaaaactgc acttcgctca ttccagatgg tggaaccaaa atctcagaga ggaacttctg gggacagttg agccagtcgc atctctccct gtataacagc ccacatgcct gatatttcca ggtggacaga agacgtcggc atcttgaaag tacgattctc ggctatggaa tatggggatg gcaatgagaa tatgaaatgc and

agcttcaaga aagagatgga ccatcaactc gaaatgggct tcagcggggg tggaccgagg tcatggtgac

120

180

240

300

360

420

480

521

<td> &lt;210&gt;</td><td> 130</td>

<td> &lt;211&gt;</td><td> 270</td>

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

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

<td> &lt;400&gt;</td><td> 130</td>

tcactttatt tttcttgtat aaaaacccta tgttgtagcc acagctggag cctgagtccg 60 ctgcacggag actctggtgt gggtcttgac gaggtggtca gtgaactcct gatagggaga 120 cttggtgaat acagtctcct tccagaggtc gggggtcagg tagctgtagg tcttagaaat 180 ggcatcaaag gtggccttgg cgaagttgcc cagggtggca gtgcagcccc gggctgaggt 240 gtaacagtca tcgataccag ccatcatgag 270

<td> &lt;210&gt;</td><td> 131</td>

<td> &lt;211&gt;</td><td> 341</td>

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

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

<td> &lt;400&gt;</td><td> 131</td>

ctggaatata ccagccattc ttatgtataa ctggggaaga aacccagtgg ataaaactgg gacccgtgat gctcctactg tagctcatgc aggagtacat ccagggagcg gcacagctct cgacaaaact atgagacaag atgtgtccat tgaagggaga tggcacttac taaataaaat ttgaacgagg atgtggtgat gtcataactg ttggcaccta ctttgtccct ataaatgaac ctgactgtgc gacagaatca tcttcatacg gtggctggga tgcttcattc caccgtcccg acttttgtaa cttctgcact gcttgccagg ttgtgagatg

120

180

240

300

341

<td> &lt;210&gt;</td><td> 132</td>

<td> &lt;211&gt;</td><td> 844</td>

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

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

&lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ,,. (844) &lt;223&gt; n = A, T, C [ul G &lt;400 tgaatgggga gaaccttcca gccatgtgga ctccttcatc tggtcatcct aaggagggga gtaaagtgtg tcctgtgaca ctgcgggctc ccctgcactg&gt; 132 ggagctgacc gaagtgggca acatgagggg caccaagact tggagctgtg ctatgctctg aagacagctg tccagagacc aaagtgaaga ccctgtgttc caggaaatgg tctgtggtgg ctgcctgagc aacacagtaa atggcttttg gctccaggct cctggtgtgg tcagttctct actgtggagc ccttccacag agcttgngga tgcctcttgg ccctcaccct tcattgctgt tgatgaagag cccagagctc acttggtgac ttagtcaagt ccagtccacc ccaaccttgc gaccaggcct gaaggagcag gagatggggc tccggttgtc gaggagaaac tgatatgtct agacaatgtc gtctgatgtt cctgcacacc tgctccagcc acaggggatg aagtacacat aaggaggagc cttggagctg acaggtggaa ctcccagatt ttcacacatgtagtac

120

180

240

300

360

420

480

540

600

GB 201 529 B1 ggacatctgc agcctgtcag ctccatgcta ccctgacctt caactcctca cttccacact gagaataata atttgaatgt gggtggctgg agagatggct cagcgctgac tgctcttcca aaggtcctga gttcaaatcc cagcaaccac atggtggctc acaaccatct gtaatgggat ctaataccct cttctgcagt gtctgaagac asctacagtg tacttacata taataataaa TAAG

660

720

780

840

844

<td> &lt;210&gt;</td><td> 133</td>

<td> &lt;211&gt;</td><td> 601</td>

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

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

<td> &lt;400&gt;</td><td> 133</td>

ggccgggcgc gcgcgccccc gccacacgca cgccgggcgt gccagtttat agcaagcagc gagtcttgaa gctctgtttg gtgctttgga tccatttcca cagccgctcg tcagactcca gcagccaaga tggtgaagca gatcgagagc ttcaggaagc cttggacgct gcaggtgata aacttgtagt agttgacttc ggtgtgggcc ttgcaaaatg atcaagcctt tctttcattc cctctctgaa acgtgatatt ccttgaagta gatgtggatg actgtcagga tgttgcttca tcaaatgcat gccaacattc cagtttttta agaagggaca aaaggtgggt gagccaataa ggaaaagctt gaagccacca ttaatgaatt agtctaatca aaatataacc agccattgac tatttaaaac ttgtaatttt tttaatttac aatatgaaga cataaacccm gttgccatct gcgtgacaac aaaacattaa aaagggagag tcggtcctta aagactgctt tcagccacgt aagtattcca gagtgtgaag gaattttctg tgttttctga aaaaatataa cgctaacact

120

180

240

300

360

420

480

540

600

601

<td> &lt;210&gt;</td><td> 134</td>

<td> &lt;211&gt;</td><td> 421</td>

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

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

<td> &lt;400&gt;</td><td> 134</td>

tcacataaga aatttaagca agagaaaccc agagaagaag gtgattaggt attgcttatt tccctcacag gggcaatctt ttccctccct taaccataaa taatattgcc acaaaaaaat caccgtttta caaattacac agttacrcta ccacctccct accaagtttt ttcttacaaa tcagtacaaa tatatagcag caagacgcac tcttaaaaaa cccccaccct gtggaatcca atttctattt agttcaatat agaataarga agtggtttat cacaacgaat cctcatgaat tcatccagag taaaaaaaat attgaaaaat agagattgct ttaccctccc gcattttaat taagaatcta tgcttacarg tataacctta gcttttcccc agtctagatg cttctcacaa

120

180

240

300

360

420

421

<td> &lt;210&gt;</td><td> 135</td>

<td> &lt;211&gt;</td><td> 511</td>

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

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

<td> &lt;400&gt;</td><td> 135</td>

ggaaaggatt caagaattag aggacttgct tgctrragaa gctgacagac aaagagagag agatggcgga aataagggat tgactatgaa cagcttcttg atgtaaagtt agccctggac gaaactctta gaaggcgaag aagagaggtt gaagctgtct gacagtatcc cgagcatcct caagtcgtag tgtaccgtac gggttgatgt ggaagaatca gaggcgaagt agtagtgtta accactggaa atgtttgcat cgaagaaatt gatgttgatg gaacacttct gaacaggatc aaccaatggg aaggcttggg gacacatcag tcagttataa atatacctca and aaagacaact caaatgcagc atggaaatca ccaagccctt aactagagga gcatctctca ggaaatttat agatgatcag ctcgtcgcat aacagctgaa gtgcttacag cttcccgtgr aagcggaaga ttccgcctca cccgcttgsa aaaaat tgga

120

180

240

300

360

420

480

511

PL 201 529 B1

<td> &lt;210&gt;</td><td> 136</td>

<td> &lt;211&gt;</td><td> 341</td>

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

<td> &lt;213&gt;</td><td>Home sapien</td>

<td> &lt;400&gt;</td><td> 136</td>

catgggtttc accaggttgg ccaggctgct cttgaactsc gcctcggcct cccaaagtgc tgggattaca ggcgtgagcc ctgtttcttt tgtctttagc gtaaagctct cctgccatgc gactgccagc aagctcagtc actccgtggt ctttttctct ttcaagttct gcctcagtga aagctgcagg tccccagtta ttgaacctgg ttctatcagt cgaattaatc cttcatgatg tgacctcagg accacgcccg agtatctaca ttccagttct agtgatcagg g

tgatccaccc gcccccaaag taactgacgt tctctctctc tgagggttct

120

180

240

300

341

<td> &lt;210&gt;</td><td> 137</td>

<td> &lt;211&gt;</td><td> 551</td>

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

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

<td> &lt;400&gt;</td><td> 137</td>

gatgtgttgg accctctgtg tcaaaaaaaa cctcacaaag agaagatgca cttaaaatat gggttatttt caacttttta aattattgtg tcagaagaga ttgaatacct gcttaagaag aggttggcag caagaacaat ttgaacatta taaaatcaac cctttctgca tgggaactta ttgagcttat tggaaatgga ccggcagact gtgtctatgg caattaatga agtctttaat aaagcagggt tacatgatga aaaagggcca cagacggaaa tgtactaaaa cccaacataa tttcttacta tgtgagtgag agacattctc ttggatgaaa attgctgtgt agaagtcctt aaatgccttt t &lt;210&gt; 138 &lt;211&gt; 531 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (531) &lt;223&gt; n- = A, T, C Lb G &lt;400&gt; 138 gactggttct ttatttcaaa aagacacttg tcaatattca ttgatttctc tttctcccaa tcggccccaa agagaccaca agaccagataag cgtactgacgctaagacgacgctaaga cggccccaa agagaccaca agaccagataag cactga ccagatgggg tggccagggt gccacaaacc atataaaatt taaaaagttt tgtacataag ctattcaaga acaaagcaca attgagatgg cacttctaga gacagcagct tgagatgaag tttcacatgg ctaaatcagt ggttcaaagggana&gt; tagtaa2aagggana&gt; tagtaaaaga21 gtaaaaagggana &lt;5 &lt;213&gt; Homo sapien aatcccctgc tctgaggaca cttacagaag tttgatgaca cagtttagca gaacttatat aactggactg gatctgaagg gcctgacaaa t cattacaga agtatccatt ctatgggagg gtaaaaatgg aaggcatttgga tagaatgga

120

180

240

300

360

420

4B0

540

551 gtrtcaaaac taaaaggaga gaaaccttac ccagcccacg caaagcaaag tttctccagc tcaaacccag cagtcttctt ataaggggga agttgęacta gtacatttta cagaaaatgg gactgcagag tttcaaaata actgttgtgat aaa

120

180

240

300

360

420

480

531

PL 201 529 B1 &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (I) ... (521) &lt;223&gt; n = A, T, CG &lt;400&gt; 139 tgggtgggca ccatggctgg gatcaccacc atcgaggcgg tgaagcgcaa gatccaggtt ctgcagcagc aggcagatga tgcagaggag cgagctgagc gcctccagcg agaagttgag ggagaaaggc gggcccggga acaggcrgag gctgaggtgg cctccttgaa ccgtaggatc cagctggttg aagaagagct ggaccgtgct caggagcgcc tggccactgc cctgcaaaag ctggaagaag ctgaaaaagc tgctgatgag agtgagagag gtatgaaggt tattgaaaac cgggccttaa aagatgaaga aaagatggaa ctcacaggaagaa agacagcta aagaga agacagcta aagagaa gaagaggtgg ctcgtaagtt ggtgatcatt gaaggagact tggaaccgca cagaaggaac gagcttgagc ttggcaaaag tcccgttgcc cagagatggg atgaaccaga ttagactgat ggaccanaac c &lt;210&gt; 140.

&lt;211&gt; 571 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) - .. (571) &lt;223&gt; n = A, T, C or G &lt;400&gt; 140 ^and9gę? R^cng^cEF igtgcgtggg ccactgggtg accgacttag cctggccaga ctctcagcac ctggaagcgc cccgagagtg acagcgtgag gctgggaggg aggacttggc ttgagcttgt taaactctgc tctgagcctc cttgtcgcct gcatttagat ggctcccgca aagaagggtn gcgagaagaa aaagggccgt tctgccatca acgaagtggt aacccgagaa tacaccatca acattcacaa gcgcatccat ggagtgggct tcaagaagcg tgcacctcgg gcactcaaag agattcggaa atttgccatg aaggagatgg gaactccaga tgtgcgcatt gacaccaggc tcaacaaagc tgtctgggcc aaaggaataa ggaatgtgcc ataccgaatc cggtgtgcgg ctgtccagaa aacgtaarga ggatgaagat tcaccaaata agctatatac tttggttacc tatgraccrg ttaccacttt caaaaatcta cagacagtca atgtgaatga gaactaatcg ctgatcgtca gatcaaataa agttataaaa t

120

180

240

300

360

420

480

521

120

180

240

300

360

420

480

540

571

<td> &lt;210&gt;</td><td> 141</td>

<td> &lt;211&gt;</td><td> 531</td>

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

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

<td> &lt;400&gt;</td><td> 141</td>

tcgggagcca cacttggccc tcttcctctc caaagsgcca gaacctcctt ctctttggag aatggggagg cctcttggag acacagaggg tttcaccttg gatgacctct agagaaattg cccaagaagc ccaccttctg gtcccaacct gcagacccca cagcagtcag ttggtcaggc cctgctgtag aaggtcactt ggctccattg cctgcttcca accaatgggc aggagagaag gcctttattt ctcgcccacc cattcctcct gtaccagcac ctccgttttc agtcagtgtt gtccagcaac ggtaccgttt acacagtcac ctcagacaca ccatttcacc tcccttgcca agctgttagc cttagagtga ttgcagtgaa cactgtttac acaccgtgaa tccattccca tcagtccatt ccagttggca ccagcctgaa ccatttggta cctggtgtta actggagtcc tgtttacaag gtggagtcgg ggcttgctga cttctcttca tttgagggca c

120

180

240

300

360

420

480

531

PL 201 529 B1

<td> &lt;210&gt;</td><td> 142</td>

<td> &lt;211&gt;</td><td> 491</td>

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

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

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

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

<td> &lt;222&gt;</td><td> (1) . . . (491)</td>

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

<td> &lt;400&gt;</td><td> 142</td>

acctagacag ttgtcctgaa aactgctgac agagtggaag gtgggaagag aggcaagggc atttgttgca caggaaagtg gaagtgatt cttgtaaagt g aaggtgggtg accctactgg tgcatctgtt cgtctcaagg tgaagcccat tgtgctctct agaaaccttg agggaggact agaagtcagc aagagttaac gtcccacagt gaagaactga gcagcaggga cccggatact gatggagagc ggtaggaggc atgaggcacc agtaaagagg ggaggtccct gatgaagcaa gccccacgag agcggaaaac agagaagcct tgaggcaatt tactgagaga tagaagtgtg gagctacctc ggatggggtt tcagaagaaa tggaggcggn atgcacagtg ccttggtagt agtgcccaga tttctgaatc ccttccgtga cctgggctcc agaactaatc ggtgggggca gccgagtcca

120

180

240

300

360

420

480

491

<td> &lt;210&gt;</td><td> 143</td>

<td> &lt;211&gt;</td><td> 515</td>

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

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

<td> &lt;400&gt;</td><td> 143</td>

ttcaagcaat tttccagttg aaagccaaaa tcaccggccc cgggcgtgtg gaggtcaaga acaaaaatta gcagaagaat cactctagcc tgtaacaagt ctattttcca attatattta atctccttcc gctcatgcct gattgagacc gctgggcatg cgcttgaacc tgggcgacag atatgtagat aattgttctg tgacaagaaa tctttttcct gtaatcccag atcctggcca gtggcgcatg cgggaggcag actgagactc tagagtgagc taatgtcgtt gccatcccta aactatgcca cattttggga acatggtgaa cctgtagtct aggatgcagt tgctc aaaatcatat aaaattactt cattaatctt ttaaaactgt ggccaaggca accccgcctc cagctactcg gagccccgat acsattttca aaaaattaac acttttccac tctactgggc ggcggatcat gactaagaat ggaggctgag cgcgccactg

120

180

240

300

360

420

480

515

<td> &lt;210&gt;</td><td> 144</td>

<td> &lt;211&gt;</td><td> 340</td>

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

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

<td> &lt;400&gt;</td><td> 144</td>

tgtgccagtc tacaggccta cagcccaacc ccatgagccc ctacaaggcc ccttctccac cagccttctc gcccaggcca agcagatccc ggccacagtc cacaccacgt accccatgga tcagcagcga ccagcagcat taattctctc ccagcccccc ttccccacag acaagggcat ctccttcagc aacagatggg gtcccctgtt 60 atgctcccaa atcaggccca gtccccacac 120 tccaatcaag tgcgctctcc ccagcctgtc 180 cactccagtc cttccccaag gatgcagcct 240 acaagttccc cacatcctgg actggtagtt 300 tttgccagcc 340 &lt;210&gt; 145 &lt;211&gt; 630 &lt;212 &gt; DNA &lt;213&gt; Homo sapien

GB 201 529 B1 &lt;400&gt; 145 tgtaaaaact tgtttttaat tttgtataaa ataaaggtgg aggaaatcca agcagaccag ctggggtggg gggatgtagc tcctcaaaac gggctgagaa ggcccgtcag gggcccaggt actcccccaa cccgaggggc agactgggca gtggggagcc gccacaggct gaaggagggg cctgaggcac cgcagcctgc actaactttt tacagaataa aaggaacatg gggatgggga gggcccgagg gccccagatc ccaggagggc caggactcag agctcccaca gctcctggca caggaggccg ccacggattg tcacgccaca tttggagaac ttgtcccgac agaggtcagc cacacactgt acgaacacag atctccttgt taatgacgta gacagggcac gggaggtctc agccccactt tccatgccca ctacctcggg cccacagaga cccatcgtgc aacccccagg aaaaagcacc gatgccagca gcacaggccg tcggaggagc cacacggcgg cgggggctgt cacacggcgg cgggggctgt gggtcagc aggggtgcagcaggggggcagc agggc ggcctcagcagggggcagcagc

120

180

240

300

360

420

480

540

600

630

<td> &lt;210&gt;</td><td> 146</td>

<td> &lt;211&gt;</td><td> 521</td>

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

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

<td> &lt;400&gt;</td><td> 146</td>

atggctgcta gatttaggta gtaatagggg ctgrgggcca ccttgggtct ggagagccst gaagagggaa ggaaaagaag atgacctgat ggattgctcg accaagacac agaagtgaag acagactgga gtttttggtg ctgaatagag ccagttgcta agaaatctga ttgttgtgtg tattcaatgt gtgattttaa aaaaaccctg actggctgtt ttttccctgt attctttaca aaattattat acttcaccta aatggaagac tgctgtgttt taatttattt tattctctct cctttttatt ttgcctgcag aggcttaata tttaattgat ttgtttaata tgtatataaa taaatctgaa gcaagtcctg tctgtgtctg aaaaattggg aaataaacag actatttttt gtggaaattt aatccgttga gccttgagaa aacctaacca tgcactcccc ggtttggtga caacaacaat gaccctctga tgtaattttt gagactaata

120

180

240

300

360

420

480

521

<td> &lt;210&gt;</td><td> 147</td>

<td> &lt;211&gt;</td><td> 562</td>

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

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

<td> &lt;400&gt;</td><td> 147</td>

ggcatgcgag cgcacrcggc agacgcaagg gcggcgggga gccgggttgg gacagcgtct tcgctgctgc tggatagtcg actcaccaga aaccgaaaat gccgaaacca atcaatgtcc gagctggagt ttgcaatcca gccaaataca actggaaaac aagactatcg gcctccggga agtgtggtac tttggcctcc tttcctacct ggctgaagct ggataagaag gtgtctgccc cccctccagt tcaagttccg ggccaaagtt ctaccctgaa ccaggacatc acccagaaac ttttcttcct tcaagtgaag gatctactgc cccccttgar actgccgtgc tcttggggtc tttggggact accaccaaga ag gcacacggag tgttttcggg □ agttaccac agctttttga actatgtgga aggaggtcag gatgtggctg gaaggaatcc ctacgcttgt cactgcaggc gatcgaggat carggatgca tcaggtggta taataaagga gaaggagaat aggagctcat ttagcgatga gcatgccaag

120 180 240 300 360 420 480 540 5 62

<td> &lt;2</td><td> 10&gt;</td><td> 148</td>

<td> &lt;2</td><td> 11&gt;</td><td> 820</td>

<td> &lt;2</td><td> 12&gt;</td><td>GOUT</td>

<td> &lt;2</td><td> 13&gt;</td><td>Homo sapien</td>

<td> &lt;4</td><td> 00&gt;</td><td> 148</td>

gaaggagtcg ggatactcag cattgatgca ccccaatttc gtctctggga caatctctag ggtcactacc tggaaactcg gaaaggaaag aacacctgca gaaccggaca gaaattcacc aaagcggcat ttagggtaca ccctgtcgatc ttagggtaca ccctgtcgatca

120

180

GB 201 529 B1 ctcggtcgac cagaagtcat ggctaaagat gacgaggacg ttgtcaattc cctgggcttt tcgaagtgag tccagcagca gtctgaggta ttcgggccgg ttatgcacct ggaccaccag caccagctcc cggggggccc aggtgccagc cttatctaca ttcctcaggg tctgatcaaa gttcagctgg tacaccaggg nccggtaccg cagcgtcagg ttgtccgctc gggctggggg accgccggga ccagggaagc cgccgacacg ttggagaccc tgcggatgcc cacagccaca gaggggtggt ccccaccgcg gccgccggca ccccgcgcgg gttcggcgtc cagcaacggt ggggcgaggg cctcgttctt cctttgtcgc ccattgctgc tccagaggac gaagccgcag gcggccacca cgagcgtcag gattagcacc ttccgtttgt agatgcggaa cctcatggtc tccagggccg ggagcgcagc tacagctcga gcgtcggcgc cgccgctagg agccgcggct cggcttcgtc tccgtcctct ccattgcagga cccgcctcagc tccgtcctct ccattggga

240

300

360

420

480

540

600

660

720

780

820

<td> &lt;210&gt;</td><td> 149</td>

<td> &lt;211&gt;</td><td> 501</td>

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

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

<td> &lt;400&gt;</td><td> 149</td>

cagattttta tttgcagtcg tcactggggc cgtttcttgc tgcttatttg tctgctagcc tgctcttcca gctgcatggc caggcgcaag gccttgatga catctcgcag ggctgagaaa tgcttggctt gctgggccag agcagattcc gctttgttca caaaggtctc caggtcatag tctggctgct cggtcatctc agagagctca agccagtctg gtccttgctg tatgatctcc ttgagctctt ccatagcctt ctcctccagc tccctgatct gagtcatggc ttcgttaaag ctggacatct gggaagacag ttcctcctct tccttggata aattgcctgg aatcagcgcc ccgttagagc aggcttccat ctcttctgtt tccatttgaa tcaactgctc tccactgggc ccactgtggg ggctcagctc cttgaccctg ctgcatatct taagggtgtt taaaggatat tcacaggagc ttatgcctgg t &lt;210&gt; 150 &lt;211&gt; 511 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (511) &lt;223&gt; n = A, T, C Lfc&gt; G &lt;400&gt; 150.

ctcctcttgg tacatgaacc caagttgaaa gtggacttaa caaagtatct ggagaaccaa gcattctgct ttgactttgc atttgatgaa acagcttcga atgaagttgt ctacaggttc acagcaaggc cactggtaca gacaatcttt gaaggtggaa aagcaacttg ttttgcatat ggccagacag gaagtggcaa gacacatact atgggcggag acctctctgg gaaagcccag aatgcatcca aagggatcta tgccatggcc ttccgggacg tcttcttctg aagaatcaac cctgctaccg gaagttgggc ctggaagtct atgtgacatt cttcgagatc tacaatggga agctgtttga cctgctcaac aagaaggcca agcttgcgcg tgctggaaga cggcaagcaa caggtgcaag tggtgggggc ttgcaggaac atctggntaa ctctgcttga tgatggcant caagatgatc gacatgggca gcgcctgcag a

120

180

240

300

360

420

480

501

120

180

240

300

360

420

480

511

<td> &lt;210&gt;</td><td> 151</td>

<td> &lt;211&gt;</td><td> 566</td>

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

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

<td> &lt;400&gt;</td><td> 151</td>

GB 201 529 B1 tcccgaattc caaatctttt ttcacaatca gtagaagaga aaagagagga tgggtggcgg cacctctagg ccatgagtgg cggggcctgt gtagagggag aagcgacaaa gcgccaagat agaaatgcag ggaagagatg aagttacagc aggagcaatg aggtggtggt ttccatgata gggtggacag agaagagtac ttggawagtg ctgatgagac aaacgtaaag atgattcgtc cgaatgggct aacatgggag ggcataggtt ggaagtgaca ggtcctagag gaaggc aaatggaaga gacaggaaga aaatgcaatt aacgtgagat acatggatcc atccctatgg atgaagctaa tgcgtactga gaatggggcc cgcctatcat attaagacgc gaggcaagag ggaagaacaa acgggaaaga ttcaggaggc tcctggcgtt gcactttggg tggaactcca gaacatcagg atggaagaac gaggaacgac atgaggcgcc gacatgcgaa cagaaatttc ccaccagcaa cagggaggtg gcaggatatg

120

180

240

300

360

420

480

540

566

<td> &lt;210&gt;</td><td> 152</td>

<td> &lt;211&gt;</td><td> 518</td>

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

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

<td> &lt;400&gt;</td><td> 152</td>

ttcgtgaaga tgagaatgtc gatctttgct agagtccacc cctgactggt ggcaaagatc ccctgactgg aaggcaaaga gggaaacagc ctgcacctgg aagaccatca caagataagg gaaacagctg gaagatggac gcacttggtc ctgcgcttga tttcattgca ctttcctttc taagaccatc tccaagacaa tagaagatgg tgcrccgtct ccctcgaggt aaggcatccc gcaccctgtc gggggggtgt aataaagttg actctcgaag ggaaggcatc acgcaccctg cagaggtggg ggagcccagt tcctgatcag tgactacaac ctaagtttcc ttgcattc tggagcccga cctcctgacc tctgactaca atacaaatct gacaccatcg cagaggttga atccagaaag ccttttaagg gtgacaccat agcakaggtt acatccagaa tcgtgaagac agaatgtcaa tctttgctgg agtccactct tttcaacaaa

120

180

240

300

360

420

480

518

<td> &lt;210&gt;</td><td> 153</td>

<td> &lt;211&gt;</td><td> 542</td>

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

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

<td> &lt;400&gt;</td><td> 153</td>

gcgcgggtgc gtgggccact agcgccccga gagtgacagc tctgctctga acctccttgt aagaaaaaag gccgttctgc cacaagcgca cggaaatttg aaagctgtct agaaaacgta cctgttacca gt tccatggagt ccatgaagga gggccaaagg atgaggatga ctttcaaaaa gggtgaccga gtgaggctgg cgcctgcatt catcaacgaa gggcttcaag gatgggaact aataaggaat agattcacca tctacagaca cttagccrag gagggaagac tagatggctc gtggtaaccc aagcgtgcac ccagatgtgc gtgccatacc aataagctat gtcaatgtgg ccagactctc ttggcttgag ccgcaaagaa gagaatacac ctcgggcact gcattgacac gaatccgtgt atactttggt atgagaacta agcacctgga cttgtraaac gggrggcaag catcaacatt caaagagatt caggctcaac gcggctgtcc tacctatgta atcgctgatc

120

180

240

300

360

420

480

540

542

<td> &lt;210&gt;</td><td> 154</td>

<td> &lt;211&gt;</td><td> 411</td>

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

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

<td> &lt;400&gt;</td><td> 154</td>

aattctttat ttaaatcaac aaactcatct tcctcaagcc ctccctctcc atcccctcac cccacccctt agccacagrg gccacgaggg cccctgccag ggaaggctgc cccagatgtg gctgtggctg gggcagcagc tgccacaggc tcctccctat cagctgtggg agaagcatac ttgtagaagc aaggccagtc ccagaccatg gtaggcagcc 60 aagggaatgg aaaatgagaa 120 tggtgagcac agtcagtgca aaattaagtt cctgcagcca 180 240 300 cagcarcaga aggcagaggc

PL 201 529 B1 agcatcagtg actcccagcc atggaatgaa cggaggacac agagctcaga gacagaacag gccaggggga agaaggagag acagaatagg ccagggcatg gcggtgaggg a

360

411

<td> &lt;210&gt;</td><td> 155</td>

<td> &lt;211&gt;</td><td> 421</td>

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

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

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

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

<td> &lt;222&gt;</td><td> (1) . . . (421)</td>

<td> &lt;223&gt;</td><td>n = A_fT, CU</td>

<td> &lt;400&gt;</td><td> 155</td>

tgatgaatct actggttccc agggcaagaa tgactggcta ctcccacgaa ccccagagct ctgaagtgcc c

gggtgggctg taagaaatcc cgtgatcggg cgggatgcca tggttaatat ctcaagctcc tgctggcatc gcagtagccc aaggagaatc ttacagatgg cgccagatcc atatgtagat cttctgtcag ctctccccca gagatgatgg ctcggaactt gcaccaaccg tctgatccca atatatttta ggtggggggt tgcttactaa gctcttctct ctcggataac cggggcgtct ccccaggcct gcagtgacat tcaagcctgt tacattccct ggggatccca cagctgcaag cangcaggca tgcccctgcc tcccagagag cctgtcacct tccccatagc

120

180

240

300

360

420

421

<td> &lt;210&gt;</td><td> 156</td>

<td> &lt;211&gt;</td><td> 670</td>

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

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

<td> &lt;400&gt;</td><td> 156</td>

agcggagctc aactccagcg acacaggtgg tacctgaagg cccaccaaga ctactgagca atcctcaacc acttcgtcgg cctcctgcag atcttttccc ttcctgtacc gtttggtcta cctcccctgg actgggtaac tgggacagac acagtgagaa acaacaaggt ttgatggtga tccgcttcct atgaagagtg ggctaggcgg tccctggtgc tcctccccac tggctacaac cactgacatt aggtgtcatc ggttgtcagc gaaagtgatc ggatggcatt ggggaagctc atcctccttc attgttctgg tcattggaat agcttgcttt ccacacacgc caggtgaagg cgcaatgtca atttccagtg ctgggcgagg gtccgtatgg ctggaagcct cttccctggc atttcctttt ctgagtagag tgttgtaccg caggctcagg tgcgggacac cggggggcat agcacctgga atcgggaagc accttgatga gaagcaggca ccttggctgt gtttttcctt tctgggggag tctttcaata catcgagcag ctacctggat gtgctctatg gcctatcacc cacgggcgtc gcagctcaag gggccgatgg gacacaagat ttaggtttcc ggtccccacc aaaagaagct

120

180

240

300

360

420

480

540

600

660

670

<td> &lt;210&gt;</td><td> 157</td>

<td> &lt;211&gt;</td><td> 421</td>

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

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

<td> &lt;400&gt;</td><td> 157</td>

ggttcacagc ttagcagctc aagaatcgag atttacacgg gacaagtatg tccgtggaga aaaactcagg actgctgctt gttctccggt ttgaaatcaa ggaaggctcc ccctggagcg acgctgcaga cagtggattt gtgtgttgcc ttttagtgcc tgatgtggag aaacctcgac cttaaaggtc aattctcatc catcaactat ggccaggaat atgtttgaac cctgaagttt aaaatggctg atgtgtgagg ctggccgacc catgcttcgg tccaggctca atgaaatgga ttaaggaaat atgatttgct atgccctctg tccacagtgc atgtcttgga caaggctatc ggagagcaaa gatgtgcttc ggcagctgct cagtaacctg agatcagttg gacctcttgg

120

180

240

300

360

420

PL 201 529 B1

421

<td> &lt;210&gt;</td><td> 158</td>

<td> &lt;211&gt;</td><td> 321</td>

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

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

<td> &lt;400&gt;</td><td> 158</td>

tcgtagccat ttttctgctt ctttggagaa tgacgccaca ctgactgctc attgtcgttg 60 gttccatgcc aattggtgaa atagaacctc atccggtagt ggagccggag ggacatcttg 120 tcatcaacgg tgatggtgcg atttggagca taccagagct tggtgttctc gccatacagg 180 gcaaagaggt tgtgacaaag aggagagata cggcatgcct gtgcagccct gatgcacagt 240 tcctctgctg tgtactctcc actgcccagc cggaggggct ccctgtccga cagatagaag 300 atcacttcca cccctggctt 521 g

<td> &lt;210&gt;</td><td> 159</td>

<td> &lt;211&gt;</td><td> 596</td>

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

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

<td> &lt;400&gt;</td><td> 159</td>

tggcacactg ctcttaagaa cttttgagtg gtaatcatat gggaattcat tttcatcact cttcaagttg taaaaatgaa actgataaga ctgtttttaa aaatgagact tactgggtga tgtgtgtgtg ttgtgttgtg ttgaaattac tgkgtaaata gvctgtataa gtwctaratg cttaaaattg taaccygcct actatgawga gtgtctttat gggagtgtcc agtgacttta gtaacttaag ggaaattcat ttttgttttt tatgtytgat cmtccctggg ttttcccttt tctgagattt agatgtacat ttagtgtata aaagaaaata gacctttggg tgtttaaaga taagggaggg aatgatttgc kgttgatytt getytcmatt ttttgtgtat acctccttgc aaaaccatgc ggggatggtc tctacaagta tggtcgtgtg aatttattat tytttgvcma ccmagatatt aaagtctatt gtttttgact acaaatggag tggtatatgg caggatctcc tatgtgaaaa tgtgtgtgtg ttaccattgc ctaaaattag gatgatamcc ccmagatatt

120

180

240

300

360

420

480

540

596

<td> &lt;210&gt;</td><td> 160</td>

<td> &lt;211&gt;</td><td> 515</td>

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

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

<td> &lt;400&gt;</td><td> 160</td>

gggggtaggc tetttattag cagtgtcaga ggcccgcgtt tgggtgggtt tcttcagaaa tggaactgga aggcttcagt gagatgccca tgacgtgcca agccgcacgc etgcctetgc gtctgagtcc ggaataggag acagctccat tgagcccctg taaggggcgc ctgccagggc acggttartg cagcccaaga agccccagag cacatgctgc ggtctcccca caggaggcca caggggcagg cagtacaggy cacggccagg ctgtactaca atgtggattt gcagggacca ttccacgctt tctgacacca atcatggtag tccctgcgga gtagtgcctt agge gggtcagagt tctctcccta gtgagctcca ccaggctggg gtgaagtctg gcagcattgc gaggcacttc ggaccaagcc gcagtgtaag ttgatcacag aggttagaag cagcaaggag gtaggacagc agggtcagag tggcctgaag cacagcctga

120

180

240

300

360

420

480

515

<td> &lt;210&gt;</td><td> 161</td>

<td> &lt;211&gt;</td><td> 936</td>

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

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

<td> &lt;400&gt;</td><td> 161</td>

taatttctta gtcgtttgga atccttaagc atgcaaaagc tttgaacaga agggttcaca

GB 201 529 B1 aaggaaccag ggttgtctta tggcatccag ttaagccaga gctgggaatg atccacatca ggagcagaag cacttgactt gtcggtcctg ctgccacggt accacgccca cgtccacctc gtcctcccct gccgccacgt cctgggcggc aaaattgatc tccagctgag acgttatatc atttgctggc ttccggaaat aaccgaatct tcagcatgag cctcttcact ctttgattta tgaagaacaa ccactgccca tcagcacctt catttggttt tcggatatta aattctactt cttattttga atagccttcc actcatccaa agtcatctct tttggaccct ctcttcaact tcattctcct tattttcagt gtctgccact ggatgatgtt aggtgtttcc tcagtcacat ttgattgatc caagtcagtt aattcgtctt ccagttgtga gatccgctac ctccacgttt gtcctcgtgc ttcaggccag tccactatgc ctatcaaatt cacgtttgcc acgagaatca aatccatctc tccacgtcca cggccccctc gacctcttcc aagaccacca cgacctcgaa aataatcggt ctatcaactg aaaattcgcc tccttcaccc ttttcttcaa gaatcttcgt tcacgaggtg gtcgcctttc tggtcttcta tcaattattt ctgaagttgt tgatcaggtc ttcttccaac tcgtgc

<td> &lt;210&gt;</td><td> 162</td>

<td> &lt;211&gt;</td><td> 950</td>

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

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

<td> &lt;400&gt;</td><td> 162</td>

aagcggatgg acctgagtca gccgaatcct agccccttcc cttgggcctg cgacatcagt gacagacgga agcagcagac catcaaggct acgggaggcc gcgaagatga agtttggctg cctctccttc cggcagcctt atgctggctt ggaatcaaga ctgtggagac gcgctggcgt cctctgctga gcagccagcg atcgccgtcc acattgctca cagggactgg gaaggcgatg cctgtcggga gagagactcg ggatgactcc tgctcagatt caggccttgc tcaggaaagg ggtcgaggag tgatagcggg actcgttgac attggggaaa ctttgcaatg ttaactcccg atgaggttgt ggaactagaa aatcaagctg cactgaccaa aagtacctga ctgtgatttc aaaccccagg tggttactag agcccatacc ggcaaggatg tattccaggt agacatccca gagcacctga tccctttggg tgacaagtgt gggctcctga aaggaatgtt ccrgagaaac cagctaaatc caatttgcca tcgtgacgca gacctgtata aattaggtta aagatgaatt tggagagtcc cacccactaa gcactatgca tgtaaacagg ttcctttgct aagtaggggg tggggctttc cttgtgtgat gcctccttag gcacacaggc gtactttgac cttagggtag aaggcaaagc tgccagtaaa tgtctcagca ttttggtcct gctagtttct ggattgtaca aataaatgtg ttgtagatga cctctgggtc ttgggcgccc caaggtctcc gatggtccat atcccttctt ttgcccggtc cctcttttac cttcaccttc tgacagttcc atctatcact ctcggcccat taggtcggtc gtggcttttc tcccttcacc

120

180

240

300

360

420

480

540

600

660

720

780

Θ40

900

936 ctgtggtgct cggggcgctt tgtcttaaat gaactgtacc gctgctggtg ggaaaagttt ccccgaagac cctgaagcag taggaaagga gcatgaagtg atggcacctt tccactgctt cagatgaagg aatgtctcaa ttgtctcaa ttgtctcaa

120

180

240

300

360

420

480

540

600

660

720

780

840

900

950

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td>163 475 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> (1) .7</td><td> (475) _</td>

<td> &lt;223&gt;</td><td>n = A</td><td>fTf 6 1 (a, U</td>

<td> &lt;400&gt;</td><td> 163</td><td></td>

tcgagcggcc gcccgggcag gtgtcggagt ccagcacggg aggcgtggtc tctccggctg cccattactc tcccactcca cggcgatgtc gctgggatag ccaggcaggt caggctgacc tggttcttgg tcatctcctc ccgggatggg acacctgtgg ttctcggggc tgccctttgg ctttggagat ggttttctcg ggagggcttt gttggagacc ttgcacttgt actccttgcc attcaaccag ttgtagttgt aagcctttga ggcagggtgt atgggggctg tcctggtgca

120

180

240

300

PL 201 529 B1 ngacggtgag gacgctnacc acacggtacg ngctggtgta ctgctcctcc cgcggctttg tcttggcatt atgcacctcc acgccgtcca cgtaccaatt gaacttgacc tcagggtcttcgcggtctaccgncggtctaccgncggtctaccgncggtctc

360

420

475

<td> &lt;210&gt;</td><td> 164</td>

<td> &lt;211&gt;</td><td> 476</td>

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

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

<td> &lt;400&gt;</td><td> 164</td>

agcgtggtcg cggccgaggt ctgaggttac atgcgtggtg gtggacgtga ccctgaggtc aagttcaact ggtacgtgga cggcgtggag gtgcataatg gccgcgggag gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccaggactgg ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag ccccatcgag aaaaccatct ccaaagccaa agggcagccc cgagaaccac cctgccccca tcccgggagg agatgaccaa gaaccaggtc agcctgacct aggcttctat cccagcgaca tcgcccgtgg agtgggagag caatgggcag actacaagac cacgcctccc gtgctggact ccgacacctg ccgggcggcc gccacgaaga ccaagacaaa ccgtcctgca ccctcccagc aggtgtacac gcctggtcaa ccggagaaca gctcga

120

180

240

300

360

420

476

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td>165 256 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> (1) . .</td><td> .(256)</td>

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

<td> &lt;400&gt;</td><td> 165</td><td></td>

agcgtggttn cggccgaggt cccaaccaag gctgcancct ggatgccatc aaagtcttct 60 gcaacatgga gactggtgag acętgcgtgt accccactca gcccagtgtg gcccagaaga 120 actggtacat cagcaagaac cccaaggaca agaggcatgt ctggttcggc gagagcatga 180 ccgatggatt ccagttcgag tatggcggcc agggctccga ccctgccgat gtggacctgc 240 ccgggcggnc gctcga 256

<td> &lt;210&gt;</td><td> 166</td>

<td> &lt;211&gt;</td><td> 332</td>

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

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

<td> &lt;400&gt;</td><td> 166</td>

agcgtggtcg cggccgaggt caagaacccc gcccgcacct gccgtgacct caagatgtgc 60 cactctgact ggaagagtgg agagtactgg attgacccca accaaggctg caacctggat 120 gccatcaaag tcttctgcaa catggagact ggtgagacct gcgtgtaccc cactcagccc 180 agtgtggccc agaagaactg gtacatcagc aagaacccca aggacaagag gcatgtctgg 240 ttcggcgaga gcatgaccga cggattccag ttcgagtatg gcggccaggg ctccgaccct 300 gccgatgtgg acctgcccgg gcggccgctc branch 332

<td> &lt;210&gt;</td><td> 167</td>

<td> &lt;211&gt;</td><td> 332</td>

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

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

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

PL 201 529 B1 &lt;221&gt; misc_feature &lt;222&gt; tl) ... (332) &lt;223&gt; n = A, T, CG &lt;40Q&gt; 167 tcgagcggtc gcccggggcag gtccacatcg gcagggtcgg agccctggcc gccatactcg 60 aactgacattcgtggctccg 60 aactgacattc gtggctctcg 60 aactgacattc gtggctcatcgggctctcg 60 aactgacattcacgggctctcg 60 aactgacattcacgggctctcg 60 aactgacattcg. ctgggctgag tggggtacac gcaggtctca 180 ccantctcca tgttgcanaa ccantctcca tgttgcanaa gactttgatg gcatccaggt tgcagccttg gttggggtca 240 atccagtact ctccactctt ccaggacagag tgggcacatct tggggctcggcgggtctcgcgggtctcgcgggtctcggcgggtctcg

<td> &lt;210&gt;</td><td> 168</td>

<td> &lt;211&gt;</td><td> 276</td>

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

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

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

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

<td> &lt;222&gt;</td><td> (1)...(276)</td>

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

<td> &lt;400&gt;</td><td> 168</td>

tcgagcggcc gcccgggcag gtcctcctca gagcggtagc tgttcttatt gccccggcag 60 cctccataga tnaagttatt gcangagttc ctctccacgt caaagtacca gcgtgggaag 120 gatgcacggc aaggcccagt gactgcgttg gcggtgcagt attcttcata gttgaacata 180 tcgctggagt ggacttcaga atcctgcctt ctgggagcac ttgggacaga ggaatccgct 240 gcattcctgc tggtggacct cggccgcgac cacgct 276

<td> &lt;210&gt;</td><td> 169</td>

<td> &lt;211&gt;</td><td> 276</td>

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

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

<td> &lt;400&gt;</td><td> 169</td>

agcgtggtcg cggccgaggt ccaccagcag gaatgcagcg gattcctctg tcccaagtgc 60 tcccagaagg caggattctg aagaccactc cagcgatatg ttcaactatg aagaatactg 120 caccgccaac gcagtcactg ggccttgccg tgcatccttc ccacgctggt actttgacgt 180 ggagaggaac tcctgcaata acttcatcta tggaggctgc cggggcaata agaacagcta 240 ccgctctgag gaggacctgc ccgggcggcc gctcga 276 &lt;210&gt; 170 &lt;211&gt; 332 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (332) &lt;223&gt; n = A, T, CG &lt;400&gt; 170 tcgagcggcc gcccgggcag gtccacatcg gcagggtcgg agccctggcc gccatactcg 60 aactggaatc catcggtcat gctctcgccg aaccagacat gcctcttgtc cttggggttc 120 ttgctgatgt accagttctt ctgggccaca ctgggctgag tggggtacac gcaggtctca 180

PL 201 529 B1 ccagtctcca tgttgcagaa gactttgatg gcatccaggt tgcagccttg atccagtact ctccactctt ccagccagaa tggcacatct tgaggtcacg gcggggttct tgacctcggc cgcgacgacgt cgtc ggc cgcgttcgtg

240

300

332

<td> &lt;210&gt;</td><td> 171</td>

<td> &lt;211&gt;</td><td> 333</td>

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

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

<td> &lt;400&gt;</td><td> 171</td>

agcgtggtcg cggccgaggt caagaaaccc cgcccgcacc tgccgtgacc ccactctggc tggaagagtg gagagtactg gattgacccc aaccaaggct tgccatcaaa gtcttctgca acatggagac tggtgagacc tgcgtgtacc cagtgtggcc cagaagaact ggtacatcag caagaacccc aaggacaaga gctcggcgag agcatgaccg atggattcca gttcgagtat ggcggccagg tgccgatgtg gacctgcccg ggcggccgct ega &lt;210&gt; 172 &lt;211&gt; 527 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (527) &lt;223&gt; n = A, T, CG &lt;400&gt; 172 agcgtggtcg cggccgaggt cctgtcagag tggcacrggt agaagntcca actgtaaggg ttcttcatca gtgccaacag gatgacatga aatgatgtac cctgnaatgg ggcccatgan atggttgnct gagagagage ttcttgtcct ggtatggtct tggcctatgc cttatggggg tggccgttgn gggcggtgng aaccatgttc ctcaaagatc atttgttgcc caacactggg ttgctgacca gaagctgaat accatttcca gtgtcatacc cagggtgggt gacgaaaggg ctgtggaagg aacatccaag atcttcagatt gggttcgattgga cataaagatt gggttcgtgga cataaagatt gggttcgtgga tcactcttct cagggcaatg acataaattg tatatteggr tcccggttcc aggccag &lt;210&gt; 173 &lt;211&gt; 635 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc__feature &lt;222&gt; (1) ... (635) &lt;223&gt; n = A, T, CG &lt;400&gt; 173 tcgagcggcc gcccgggcag gtccaccaca cccaattcct tgctggtatc ccacgtgcca ggattaccgg ctacatcatc aagtatgaga agcctgggtc gaagtggtcc ctcggccccg ccctggtgtc acagaggcta ctattactgg ggaaccgaat atacaattta tgtcattgcc ctgaagaata atcagaagag attggaagga aaaagacaga cgagcttccc caactggtaa cccttccaca catggaccag agatettgga tgttccttcc acagttcaaa agaccccttt tcaagatgtg gcaacctgga ccactcagcc ggcatgtctga gctccgaccc ggcgtctga tcc ggcgtctgacc ggcgtctga naagtgccag gtcttttaaa agggttacca gaatattett atggcagccg tcctcccaga cctggaaccg cgagcccctg ccccaatctt cgtcaccaac

120

180

240

300

333

120

180

240

300

360

420

480

527

120

180

240

300

360

GB 201 529 B1 cctgggtatg acactggaaa tggtattcag cttcctggca cttctggtca gcaacccagt gttgggcaac aaatgatctt tgangaacat agntttaggc ggaccacacc ggccacaacg ggcaccccca taaggcatag gccaagaaca tacccgncga atgtaggaca agaagctctn tctcanacaa ncatctcatg ggccccattc cangacactt ctgagtacat canttcatgg catcctggtg gcactgataa aaacccttac agtta

420

480

540

600

635 &lt;210&gt; 174 &lt;211&gt; 572 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (572) &lt;223&gt; n - A, T, C ίιΛ G &lt;400&gt;

agcgtggtcg actgtaaggg cctggaatgg ggtatggtct aaccatgttc gaagctgaat ctgtggaagg gttggggaag tcagggcaat ctgtgacacc

174 cgggcgaggt ttcttcatca ggcccatgag tggcctatgc ctcaaagatc accatttcca aacatccaag ctcgtctgtc gacataaatt anggcggggc cctgtcagag grgccaacag atggttgtct cttatggggg atttgttgcc gtgtcatacc atctctggtc tttttccttc gtatattcgg cgaagganca tggcactggt gatgacatga gagagagagc gaccgttgt caacactggg cagggtgggt catgaagatt caatcanggg ntcccgggtn ct agaagttcca aatgatgtac ttcttgtcct gggcggtgtg ttgctgacca gacgaaaggg ggggtgtgga ctcgctcttc cagccaataa ggaaccctga tcagaagtgt acattcggcg gtccgcctaa gaagtgccag gtcttttgaa agggttacca tgattattct taataaccct

120

180

240

300

360

420

480

540

572

<td> &lt;210&gt;</td><td> 175</td>

<td> &lt;211&gt;</td><td> 372</td>

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

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

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

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

<td> &lt;222&gt;</td><td> (1) . . . (372)</td>

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

<td> &lt;400&gt;</td><td> 1,75</td>

agcgtggtcg ctgaaagacc aacgaaggct tatgccgttg tgcttangct ggtgtgaact gcggccgctc cggccgaggt agcagaggca tgaaccaacc gagatgagtg ttggaagtgg acaagattgg aa cctcaccaga taaggttcgg tacggatgac ggaacgaatg tcatttcaga agagaagtgg ggtaccacct gaagaggttg tcgtgctttg tctgaatcag tgtgattcat gaccgtcagg acaacatcat ttaccgtggg acccctacac gctttaaact ctagatggtg gagaaaatgg agtggaggca caactctgtc agtttcccat gttgtgccag ccatgacaat acctgcccgg

120

180

240

300

360

372

<td> &lt;210&gt;</td><td> 176</td><td></td>

<td> &lt;211&gt;</td><td> 372</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</td><td></td><td></td>

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

<td> &lt;222&gt;</td><td>(U ·</td><td> \ (372)</td>

GB 201 529 B1 &lt;223&gt; η = A, T, C IiaG G &lt;400&gt; 176 tcgagcggcc gcccgggcag gtccattttc tccctgacgg tcccacttct gtagtrcaca ccattgtcat ggcaccatct agatgaatca catctgaaat aaagcctaag cactggcaca acagtttaaa gcctgattca gacattcgtt tccaacggca taatgggaaa ctgtgtaggg gtcaaagcac gagtcatccg caagccttcg ntgacagagt tgcccacggt aacaacctct tcccgaacct ctggtctttc agtgcctcca ctatgatgtt gtaggtggta cctctggtga cgcgaccacg ct &lt;210&gt; 177 &lt;211&gt; 269 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc ^ feature &lt;222&gt; ¢ 1) ... (269) &lt;223&gt; n = A, T, C tub G &lt;400&gt; 177 agcgtggccg cggccgaggt ccattggctg gaacggcatc aacttggaag tctcagcctt ggttctccag ctaatggtga tggngctagctaggctgctgaca ctaatggtga tggngctcagctaatggtaga cttaagagca tagacactca cttcatattt ggcgnccacc atacaaccac ggaatgacct gtcaggaac ctccaatctt gaccacttcc cccactcatc taggttggtt tatgcctctg ggacctcggc ccagtgatcg gtcacacctctggtaggtctggactgtctg

120

180

240

300

360

372

120

180

240

269

<td> &lt;210&gt;</td><td> 178</td>

<td> &lt;211&gt;</td><td> 529</td>

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

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

<td> &lt;400&gt;</td><td> 178</td>

tcgagcggcc gcccgggcag gtcctcagac cgggttctga atacacagtc ccttgcacga tgatatggag agccagcccc tgattggaac ccagtccaca caccaactga cctgaagttc actcaggrca cacccacaag cćtgagcgcc cacccaatgt tcagctcact ggatatcgag tgcgggtgac ccccaaggag caatgaaaga aatcaacctt gctcctgaca gctcatccgt ggttgtatca cggccaccaa atatgaagtg agtgtctatg ctcttaagga cactttgaca ctcagggtgt tgtcaccact ctggagaatg tcagcccacc aagaagggct atgctactga gaccaccatc accattagct ggagaaccaa aactgagacg tccaagttga tgccgttcca gccaatggac ctcggccgcg accacgctt &lt;210&gt; 179 &lt;211&gt; 454 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (454) &lt;223&gt; n = A, T, C Ub G &lt;400&gt; 179 agtgtggttg gctattcctg cagtggacac aagaccggac ggacttatgg agcagaccag cgtgtgacag atcactggct

120

180

240

300

360

420

480

529

GB 201 529 B1 agcgtggtcg cggccgaggt ctggccgaac tgccagtgta cagggaagat gtacatgtta 60 tagntcttct cgaagtcccg ggccagcagc tccacggggt ggtctcctgc ctccaggcgc 120 ttctcattct catggatctt cttcacccgc agcttctgct tctcagtcag aaggttgttg 180 tcctcatccc tctcatacag ggtgaccagg acgttcttga gccagtcccg catgcgcagg 240 gggaattcgg tcagctcaga gtccaggcaa ggggggatgt atttgcaagg cccgatgtag 300 tccaagtgga gcttgtggcc cttcttggtg ccctccaagg tgcactttgt ggcaaagaag 360 tggcaggaag agtcgaaggt cttgttgtca ttgctgcaca ccttctcaaa ctcgccaatg 420 ggggctgggc agacctgccc gggcggccgc tcga 454

<td> &lt;210&gt;</td><td> 180</td>

<td> &lt;211&gt;</td><td> 454</td>

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

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

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

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

<td> &lt;222&gt;</td><td> (1) . · · (454}</td>

<td> &lt;223&gt;</td><td>η = Αχ T, C [u- (p</td>

<td> &lt;400&gt;</td><td> 180</td>

tcgagcggcc gcccgggcag gtctgcccag cccccattgg cgagtttgag aaggngtgca 60 gcaatgacaa caagaccttc gactcttcct gccacttctt tgccacaaag tgcaccctgg 120 agggcaccaa gaagggccac aagctccacc tggactacat cgggccttgc aaatacatcc 180 ccccttgcct ggactctgag ctgaccgaat tccccctgcg catgcgggac tggctcaaga 240 acgtcctggt caccctgtat gagagggatg aggacaacaa ccttctgact gagaagcana 300 agctgcgggt gaagaanatc catgagaatg anaagcgcct gnaggcanga gaccaccccg 360 tggagctgct ggcccgggac ttcgagaaga actataacat gtacatcttc cctgtacact 420 ggcagttcgg ccagacctcg gccgcgacca cgct 454

<td> &lt;210&gt;</td><td> 181</td><td></td>

<td> &lt;211&gt;</td><td> 102</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> (102)</td>

<td> &lt;223&gt;</td><td>n = A</td><td>-, T, C lUj, G</td>

<td> &lt;400&gt;</td><td> 181</td><td></td>

agcgtggntg cggacgacgc ccacaaagcc attgtatgta gttttanttc agctgcaaan 60 aataccncca gcatccacct tactaaccag catatgcaga ca 102

<td> &lt;210&gt;</td><td> 182</td>

<td> &lt;211&gt;</td><td> 337</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).7.(337)</td>

<td> &lt;223&gt;</td><td>n = A_WITHT, C lu 1 G</td>

<td> &lt;400&gt;</td><td> 182</td>

tcgagcggtc gcccgggcag gtctgggcgg atagcaccgg gcatattttg gaatggatga 60

GB 201 529 B1 ggtctggcac cctgagcagc ccagcgagga cttggtctta gttgagcaat ttggctagga 120 ggatagtatg cagcacggtt ctgagtctgt gggatagctg ccatgaagna acctgaagga 180 ggcgctggct ggtangggtt gattacaggg ctgggaacag ctcgtacact tgccattctc 240 tgcatatact ggntagtgag gcgagcctgg cgctcttctt tgcgctgagc taaagctaca 300 tacaatggct ttgnggacct cggccgcgac cacgctt 337

<td> &lt;210&gt;</td><td> 183</td>

<td> &lt;211&gt;</td><td> 374</td>

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

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

<td> &lt;400&gt;</td><td> 183</td>

tcgagcggcc gcccgggcag gtccattttc tccctgacgg tcccacttct gtagttcaca ccattgtcat gacaccatct agatgaatca catctgaaat aaagcctaag cactggcaca acagtttaaa gcctgattca gacattcgtt tccaacggca taatgggaaa ctgtgtaggg gtcaaagcac gagtcatccg caagccttcg ttgacagaag ttgcccacgg taacaacctc ttcccgaacc gctggtcttt caagtgcctc cactatgatg ttgtaggtgg cacctctggt accgcgacca CGCT ctccaatctt gaccacttcc cccactcatc taggttggtt ttatgcctct gaggacctcg

120

180

240

300

360

374 &lt;210 134 &lt;211&gt; 375 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; {1). . . (375&gt; &lt;223&gt; n = A, T, CG &lt;400 agcgtggttt actgaaagac caacgaaggc ttatgccatt gtgcttangc tggtgngaac gggcggcncg&gt; 184 gcggccgagg cagcagaggc ttgaaccaac ggagatgagt tttggaagtg tacaagattg ctcga tcctcaccan ataaggttcg ctacggatga gggaacgaat gtcatttcag gagagaagtg aggtgccacc ggaagaggtt ctcgtgcttt gtctgaatca atgtgartca gnaccgtcag tacaacatca gttaccgtgg gacccctaca ggctttaaac tctanatggt ggganaaaat tagtggagac gcaactctgt cagnttccca tgttgrgcca gtcargacaa ggacctgccc

120

180

240

300

360

375 &lt;210&gt; 185 '&lt;211&gt; 148 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) .7. (148) &lt;223&gt; n = M, C Io4 G &lt;400&gt; 185 agcgtggtcg cggccgaggt ctggcttnct gctcangtga ttatcctgaa tcgcagatgagc 60 caaataagctgaa ccgcagcta cgt ccggccagctgagcgca 148 &gt; 186

PL 201 529 B1

<td> &lt;211&gt;</td><td> 397</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> .(397)</td>

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

<td> &lt;400&gt;</td><td> 186</td><td></td>

tcgagcggcc gcccgggcag gtccaattga aacaaacagt actgattaag agtggggngg cgggtattag ggataatatt ctgggcagac ttggtgacct tgccagctcc agcagccttc acccaccgca actgtctgtc tcatatcacg aacagcaaag tgagaagctc tcaacacaca tgggcttgcc aggaaccata cagacttcaa gaatttaagg gccatcttcc agctttttac tccttcagct cagcaaactt gcatgcaatg tgagccg &lt;210&gt; 187 &lt;211&gt; 584 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1). . . (584) &lt;223&gt; n = A, T, CG &lt;400&gt; 187 tcgagcggcc gcccgggcag gtccagaggg ctgtgctgaa ccactccaat tgctggccgc ttcactcctg gaaccttcac tccgggagcc acggcttctt gtggntactg accccagggc aggcatctta tgttaaccta cctaccattg cgctgtgtaa atgtggacat tgccatccca tgcaacaaca agggagctca tggatgctgg ctcgggaagt tctgcgcatg cgtggcacca gangncatgc ctgatctgga cttctacaga gatcctgaag gctgnttgct ganaaagcaa gtgaccaagg angaaatttc ccgctcctga attcactgct actcaacctg angntgcaga gggccctctg ggcctattta agcancttcg gtcgcgaaca tctgagaccg catttagcct tggtccactg cgacccaaag tcaacaatgg cagaacggcg gtttgctgct taaccagatc tgaccaccag cacagattct ctcagngggg tttcccgtga agattgaaaa ańgggtgaaa ctggtcttga cgnt ttcttccacc tctgagcttt ctttgatgac gtggatagtc gcagcatcac atcaatcttt gccactggag caggcagcct cctctcacgg cctctgcgcr:

tttgatgtgg acacccatgg agaagaacag nggactgctc aggngnacan

120

180

240

300

360

397

120

180

240

300

360

420

480

540

584

<td> &lt;210&gt;</td><td> 188</td>

<td> &lt;211&gt;</td><td> 579</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)...(579)</td>

<td> &lt;223&gt;</td><td>n - A_f T, C IcUo</td>

<td> &lt;400&gt;</td><td> 188</td>

agcgrgngtc gcggccgagg tgctgaatag gcacagaggg agtctgcaac ctcaggctga gtagcagtga actcaggagc gaaattcctc cttggncact gccttctcag cagcagcctg caggatctct gtagaagtac agatcaggca tgacctccca cacctgtaca gggagcagtc ctcttctttt tgggtgttca ccttcagacc cattcaccct tcaatctctt cgggaaatgg

120

180

240

GB 201 529 B1 tgccacgcat gcgcagaact tcccgagcca gcatccacca catcaaaccc actgagtgag ctcccttgtt gttgcatggg atgggcaatg tccacatagc gcagaggaga atctgtgtta cacagcgcaa tggtaggtag gttaacataa gatgcctccg cgagaagctg gtggtcagcc ctggggtcaa gtaaccacaa gaagccgtgg ctcccggaag gctgcctgga tctggttagt gaaggntcca ggagtgaagc ggccaacaat tggagtggct tcagtggcaa gcagcaaact tcagcacaag ccctctggac ctgcccggcg gccgctcga &lt;210&gt; 189 &lt;211&gt; 374 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc__feature &lt;222&gt; {1) -. (374) &lt;223&gt; n = A, T, CU&gt; G &lt;400&gt; 189 tcgagcggcc gcccgggcag gtccattttc tccctgacgg ncccacttct ctccaatctt gtagttcaca ccattgtcat ggcaccatct agatgaatca catctgaaat gaccacttcc aaagcctaag cactggcaca acagtttaaa gcctgattca gacattcgtt cccactcatc tccaacggca taatgggaaa ctgtgtaggg gtcaaagcac gagtcatccg taggttggtt caagccttcg ttgacagagt tgcccacggt aacaacctcn tccccgaacc ttatgcctct gctgggcttt cagngcctcc actatgatgn tgtagggggg cacctctggn gangacctcg gccgcgacca cgct

300

360

420

480

540

579

120

180

240

300

360

374