COMPOUNDS AND METHODS USEFUL FOR DETECTION AND TREATMENT OF CANCER

Abstract

The present invention relates to compounds and methods useful for the detection and treatment of disorders associated with frameshift mutations in coding microsatellite regions. The compounds and methods are applicable in cancers, especially of DNA mismatch repair deficient (MMR) sporadic tumors and HNPCC associated tumors. The compounds are useful for detection of disorders and in therapy such as immuno-therapy. The diagnostic methods relate to diagnosis and prognostic assessment of disorders associated with frameshift polypeptides originating from frameshift mutations in coding microsatellite regions of genes based on the detection of immunological entities directed against said frameshift polypeptides in body fluids. With respect to the treatment of cancer, the invention pertains to methods which use immuno therapy with combinatorial mixtures of tumor specific frameshift peptides to elicit a cytotoxic T-cell response specifically directed against tumor cells for prevention and curative treatment of cancers and pre-cancers.

Description

[0001] This application is a continuation of U.S. application Ser. No. 13/284,660 filed Oct. 28, 2011; which is a divisional of U.S. patent application Ser. No. 10/511,698, filed Jun. 2, 2005, U.S. Pat. No. 8,053,552; which is a National Stage of International Application PCT/EP03/04083, filed Apr. 17, 2003, published Oct. 23, 2003, under PCT Article 21(2) in English; which claims the priority of EP 02008773.0, filed Apr. 18, 2002, EP 02008771.4, filed Apr. 18, 2002, and EP 02008774.8, filed Apr. 18, 2002. The contents of the above-identified applications are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to compounds and methods useful for the detection and treatment of disorders associated with frameshift mutations in coding microsatellite regions. The compounds and methods are applicable in cancers, especially of DNA mismatch repair deficient (MMR) sporadic tumors and HNPCC associated tumors. The compounds disclosed in the invention are useful for detection of disorders and in therapy such as e.g. immuno-therapy. The diagnostic methods relate to diagnosis and prognostic assessment of disorders associated with frameshift polypeptides originating from frameshift mutations in coding microsatellite regions of genes based on the detection of immunological entities directed against said frameshift polypeptides in body fluids. With respect to the treatment of cancer, especially of DNA mismatch repair deficient (MMR) sporadic tumors and HNPCC associated tumors, the invention pertains to methods which use immuno therapy with combinatorial mixtures of tumor specific frameshift peptides to elicit a cytotoxic T-cell response specifically directed against tumor cells for use in prevention as well as in curative treatment of cancers and pre-cancers.

REFERENCE TO SEQUENCE LISTING, TABLE OR COMPUTER PROGRAM

[0003] The Sequence Listing is concurrently submitted herewith with the specification as an ASCII formatted text file via EFS-Web with a file name of Sequence_Listing.txt with a creation date of Oct. 27, 2011, and a size of 264 kilobytes. The Sequence Listing filed via EFS-Web is part of the specification and is hereby incorporated in its entirety by reference herein.

BACKGROUND OF THE INVENTION

[0004] Tumor cells accumulate mutations in components of cellular pathways, that are essential for the maintenance of normal growth and differentiation. In human epithelial tumors, 2 types of genetic instability have been identified: chromosomal instability (CIN), which marks structural and numerical chromosomal aberration in aneuploid neoplastic cells, and microsatellite instability (MSI), which reflects length variations at repetitive DNA sequences in diploid tumor cells. The type and spectrum of mutated genes markedly differs among CIN and MSI tumors, suggesting distinct but not mutually exclusive pathways of carcinogenesis. MSI occurs in about 90% of hereditary nonpolyposis colorectal cancers (HNPCC) as well as in about 15% of sporadic tumors of the colon and other organs, and is caused by mutational inactivation of different DNA mismatch repair genes.

[0005] The mutations lead especially in the case of frameshift mutations in coding microsatellite regions to the expression of new peptide sequences in the affected cells, that do not occur in wild-type cells. The altered peptides may be used as detection markers for disorders associated with frameshift mutations in coding microsatellite regions such as degenerative disorders or cancers (e.g. gastrointestinal cancers).

[0006] The accumulation of genetic alterations and resulting mutant proteins represent a major obstacle for tumor cells to escape immune surveillance. The mutant proteins or peptides encoded by expressed mutant genes may elicit a specific cellular immune response and thus may be recognized by CTL. This is especially true concerning mutations resulting from chromosomal instabilities, but also pertains to more subtle genetic alterations, such as small deletions and insertions in microsatellites.

[0007] This situation can be used for prevention and therapies in cancers. The cancer cells are characterized by the expression of neo-peptides, which arouse from the genetic alterations. These proteins are not present in normal, non cancerous tissues. Thus, the neo-peptides may be used to distinguish on a molecular level between tumors and normal tissues. As tools suitable for the molecular discrimination antigen specific molecules or cells may be used. Thus it is possible to elicit an immune response against frameshift peptides, as might arise from MSI mutations, specific for tumors. Using cytotoxic T lymphocytes or FS8-specific antibodies it is thus possible to specifically attack and eliminate tumor cells in organisms and tissues.

[0008] A large number of genes containing coding microsatellites have been identified. Various of these genes show mutations within the microsatellites with certain frequencies in sporadic tumors. For few of these genes it could be shown, that they are involved in the majority of cases of particular tumors. For example the (A)₁₀ tract within the TGFβRII gene and the (G)₈ tract within the BAX gene are commonly mutated in gastrointestinal cancers such as colon cancer or gastric cancer.

[0009] The T-cell mediated immune response on the other hand provides a strong and specific selection pressure for the rapidly growing tumor cells. (Tomlinson I, et al., Nat. Med. 1999; 5: 11-2) Thus tumor evolution is forced to circumvent the immune surveillance by the cellular immune response. As a consequence of this selection pressure, mutations in genes of the antigen processing or presenting machinery arise in MMR-deficient tumor cells. In fact evasion of the immune surveillance by acquiring β2-microglobulin mutations has been observed at high frequency in MSI.sup.+ tumor cells (Bicknell D C, et al., Curr. Biol 1996; 6: 1695-7). Other targets of specific mutation or down-regulation of expression are TAP1/TAP2 or HLA alleles. Direct down-regulation of expression of immunogenic epitopes is also a possible mechanism of immune escape as has been shown for melanoma-associated antigens in vivo (Jager E, et al., Int. J. Cancer 1997; 71: 142-7). Due to this fact the relevant epitopes may not be detectable by the immune system.

[0010] As a consequence the promising therapies based on immune response directed against frameshift peptides in tumor tissues may fail in a not yet determined number of cases of tumors. So the approaches for the use of the vaccination therapy of cancer mediated by frameshift peptides might be limited by the fact, that the potential immunogenic frameshift peptides are not always detectable by the immune system due to mutations in the antigen presenting and processing properties of the cancer cells.

[0011] Even supposed, that during specific stages of tumor development cells express the aberrant proteins and thus are vulnerable to the immune surveillance, there potentially remains a population of tumor cells, that is not eliminated by the therapy. This state is quite undesirable for any therapy of cancers, for the remaining cells may continue growing and thus the tumor is not eliminated from the organism.

[0012] Similarly methods for detection of molecular markers suitable for diagnosis of disorders associated with frameshift mutations in coding microsatellite regions and for assessment of prognosis for said disorders are prone to overlook especially markers originating from small populations of affected cells as they may occur particularly in early stages of the disorder. This may in part be overcome by an elevated effort in the preparation of testing samples to raise the probability of the detection of disorders. However especially concerning disorders located in body regions, that are merely inaccessible, or accessible only under circumstances, that are quite consuming or discomfortable to patients alternative methods for reliable detection of molecular markers associated with disorders are desirable.

[0013] It is known in the art, that the mutant proteins or peptides derived from aberrantly expressed proteins may elicit a specific cellular immune response and thus may be recognized by cytotoxic T lymphocytes (CTL). This is especially true concerning mutations resulting from chromosomal instabilities, but pertains also to the more subtle genetic alterations, such as small deletions and insertions in microsatellites.

[0014] The T-cell mediated immune response on the other hand provides a strong and specific selection pressure for the rapidly growing tumor cells (Tomlinson I, et al., Nat. Med. 1999; 5: 11-2). Thus tumor evolution is forced to circumvent the immune surveillance by the cellular immune response. As a consequence of this selection pressure, mutations in genes of the antigen processing or presenting machinery arise in DNA mismatch repair (MMR)-deficient tumor cells. In fact evasion of the immune surveillance by acquiring β2-microglobulin mutations has been observed at high frequency in MSI.sup.+ tumor cells (Bicknell D C, et al., Curr. Biol 1996; 6: 1695-7). Other targets of specific mutation or down-regulation of expression are TAP1/TAP2 or HLA alleles. Direct down-regulation of expression of immunogenic epitopes is also a possible mechanism of immune escape as has been shown for melanoma-associated antigens in vivo (Jager E, et al., Int. J. Cancer 1997; 71: 142-7). Due to this fact the relevant epitopes may not be detectable by the immune system. Thus it was suspected, that components of the immune system directed against novel peptides, characteristic for e.g. tumor cells, are not suitable for the detection of the disorders especially in the case of frameshift mutation peptides. This is due to the fact, that MSI disorders are frequently associated with DNA mismatch repair deficiency and thus are especially prone to mutations. This makes the affected cells especially apt to escape mutations in response to the attack by the immune system.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIGS. 1-1 and 1-2:

[0016] ELISpot-analysis of FSP T-cell lines. Titrated amounts of T-cells were incubated overnight with 3.5×10⁴ peptide loaded T2 cells per well. The number of IFN-γ-releasing activated T-cells (spots) among the total number of cells analyzed (10⁶) is depicted for each frameshift peptide. Reactivity against peptide YLLPAIVHI from the nuclear protein P68 served as a negative control and is indicated (open bars).

[0017] FIGS. 2-1 to 2-8:

[0018] Listing of sequences of polypeptides encoded by genes with coding microsatellites; the sequences of polypeptides arising from different possible frameshift mutations are depicted. For each polypeptide the sequence expressed from the wild type open reading frames is given (wtORF); Furthermore the sequences expressed from (-1) mutations and from (-2/+1) mutation are given.

[0019] FIG. 3: Frameshift peptide specific and HLA-A2-restricted lysis of target cells. (FSP02); The antigen specificity of the FSP02 CTL line was tested in the presence of unlabeled cold targets, T2 cells pulsed with FSP02 (open squares) at an inhibitor:target ratio of 50:1. Lysis without cold targets is shown as a control (closed squares). All data are shown as the mean and standard deviation from 3 replicate wells. For experimental details see example 6.

[0020] FIG. 4: Frameshift peptide specific and HLA-A2-restricted lysis of target cells. (FSP06); The antigen specificity of the FSP06 CTL line was tested in the presence of unlabeled cold targets, T2 cells pulsed either with FSP06 (open squares) at an inhibitor:target ratio of 50:1. Lysis without cold targets is shown as a control (closed squares). All data are shown as the mean and standard deviation from 3 replicate wells. For experimental details see example 6.

DETAILED DESCRIPTION OF THE INVENTION

[0021] The inventors have now surprisingly found, that specific antibodies or antigen recognizing cells directed against a particular new frameshift peptide are in detectable levels present within the body fluids of individuals harbouring MSI associated disorders. This is especially due to the fact, that during specific stages of tumor development cells express the aberrant proteins. During these stages the peptides may be accessible to the immune surveillance, and thus an immune response may be elicited. Even though cell populations affected by respective disorders such as tumors may be eliminated from the organism, or may be mutated, such, that no further presentation of immunogenic epitopes may occur, there remains an immunological memory of the presence of the respective peptides at a certain time. Such the evolution of a cell population affected by a disorder associated with the expression of new frameshift peptides leaves immunological traces of its existence consisting e.g. of antibodies and specific T-lymphocytes directed against the particular peptides. Hence the presence of specific immune response elements directed against a particular frameshift peptide is indicative of the presence of a population of (tumor) cells, that expresses or has expressed at a certain time the respective peptide.

[0022] To further enhance the fidelity of the detection of the presence or absence of a disorder a set of peptides frequently occurring in disorders such as tumors may be applied in the detection reaction.

[0023] The present invention thus provides a method for the detection of disorders associated with frameshift peptides arising from mutations in coding microsatellite regions based on the detection of specific immunological entities directed against said frameshift peptides present in the body fluids of affected individuals directed against said frameshift peptides. The method is suited for primary detection of disorders such as tumors, for the early detection of disorders or of precursory stages of disorders, and for the assessment of prognosis in said disorders.

[0024] One further aspect of the invention is based on the inventors findings, that a mixture of frameshift peptides chosen according to combinatorial parameters minimizes the escape of particular populations of tumor cells from immunogenic elimination and may be used as a vaccine against a wide variety of DNA mismatch repair deficient tumors.

[0025] The invention is based on the fact, that the immune escape of tumor cells is directed towards single immunogenic epitopes (frameshift peptides) in a potentially restricted subpopulation of the tumor cells. In the vast majority of MSI+ tumors various mutations may be found within the genome of the affected cells. So a combinatorial vaccination approach including several antigenic peptides could overcome this obstacle.

[0026] It is one aspect of the present invention to provide nucleic acid sequences of the genes TAF1B, MACS, UVRAG, ELAVL3, TCF6L1, ABCF1, AIM2, CH D2 and HT001, that have frameshift mutations within their coding regions.

[0027] A second aspect of the present invention is to provide new frameshift peptides, that occur in a wide range of different MSI.sup.+ tumors.

[0028] A third aspect of the present invention is a method for detection of MSI.sup.+ tumors using said frameshift peptides as molecular markers.

[0029] A fourth aspect of the present invention is a method for treatment of MSI.sup.+ tumors using said frameshift peptides for therapeutic purposes.

[0030] In a fifth aspect the present invention provides sets of frameshift peptides, that occur in a wide range of different MSI.sup.+ tumors and that diminish the probability of escape of tumors to be attacked by the immuno-therapy.

[0031] A sixth aspect of the present invention is a method for vaccination against MSI.sup.+ tumors using said set of frameshift peptides.

[0032] A seventh aspect of the present invention is a method for treatment of MSI.sup.+ tumors using a set of frameshift peptides, that elicit an immune response directed against a wide range of tumors.

[0033] An eighth aspect of the invention relates to the detection of disorders associated with frameshift mutations in coding microsatellite regions comprising the detection of immunological entities directed against frameshift peptides in body fluids of individuals.

[0034] The present invention thus provides compounds and methods for the therapy and detection of disorders associated with frameshift peptides arising from mutations in coding microsatellite regions. The diagnostic and therapeutic methods are suited for application in disorders such as tumors or in precursory stages of disorders.

[0035] Within the context of the present invention disorders associated with frameshift mutations comprises for example degenerative diseases, such as neurodegenerative diseases, vascular disorders, disorders caused by stress, such as oxidative stress, chemically induced stress, irradiation induced stress, etc. and cancers including all sporadic cancers as well as HNPCC associated cancers. Cancers as used herein may comprise e.g. colorectal cancer, small cell lung cancer, liver cancer (primary and secondary), renal cancer, melanoma, cancer of the brain, head and neck cancer, gastrointestinal cancers, leukemias, lymphomas. prostate cancer, breast cancer, ovary cancer, endometrial cancer, lung cancer, bladder cancer etc.

[0036] The method according to the present invention may be applied to any eucaryotic organisms. In one aspect the eucaryotic organisms are those exhibiting an immunologic defense system. The eucaryotic organisms are for example mammalian animals and especially animals of agricultural value such as pigs, cows, sheep, etc., companion animals, such as cats, dogs, horses etc., animals employed in research purposes such as mice, rats, rabbits, hamsters etc. or humans.

[0037] Nucleic acid molecules according to the present invention may comprise polynucleotides or fragments thereof. Preferred polynucleotides may comprise at least 20 consecutive nucleotides, preferably at least 30 consecutive nucleotides and more preferably at least 45 consecutive nucleotides of the sequences. The nucleic acids according to the present invention may also be complementary or reverse complementary to any of said polynucleotides. Polynucleotides may for example include single-stranded (sense or antisense) or double-stranded molecules, and may be DNA (genomic, cDNA or synthetic) or RNA. RNA molecules comprise as well hnRNA (containing introns) as mRNA (not containing introns). According to the present invention the polynucleotides may also be linked to any other molecules, such as support materials or detection marker molecules, and may, but need not, contain additional coding or non-coding sequences.

[0038] Mutation as used in the context of the present invention may comprise insertions or deletions of one or several nucleotides (or nucleotide repeats) within the specified microsatellite sequences. In a preferred embodiment of the present invention the number of nucleotides to be inserted or deleted is not 3 or must not be divisible by 3, such that the mutation leads to a frameshift with respect to the translational reading frame of the downstream nucleic acid sequence. Thus the nucleic acid sequence downstream of the mutation point will render a polypeptide-sequence different from the native sequence encoded by the respective gene. The mutation in these cases leads to a novel peptide sequence (a neo-peptide). Commonly the new peptide sequence is short due to the fact, that novel stop codons arise from the shift in the reading frame.

[0039] Frameshift mutations in microsatellites are usually due to DNA polymerase slippage and may be characterized by the type of the repeat. Thus in mono nucleotides repeats this type of mutation renders 1 nt insertion or deletion. In dinucleotide repeats and tetranucleotide repeats mutations are insertions or deletions of 2 or 4 nt respectively. For example commonly (-1) mutations occur in mononucleotide repeats (MNRs). In these mutations one nucleotide is deleted such that the reading frame is shifted by one nucleotide toward the 5' end of the gene compared to the original reading frame. This type of mutation renders a reading frame identical to that produced by (+2) mutations, which arise from two nucleotide insertions in the respective microsatellites. The respective (-1) or (+2) polypeptides might differ by one amino acid. The other frameshift mutation variant leading to frameshift mutations differing from (-1) mutations concerning the resulting reading frame is the (+1) mutation, arising from one nucleotide insertion, thus rendering a reading frame one nucleotide toward the 3' end of the gene compared to the original reading frame. This mutation type gives a reading frame identical to that of (-2) mutations, wherein the encoded polypeptides differ by one amino acid. (-3) and (+3) mutations are irrelevant according to the present invention, for they do not give rise to frameshift polypeptides.

[0040] Frameshift polypeptides as used herein shall comprise any polypeptides or fragments thereof, that arise by a frameshift mutation within a coding microsatellite sequence of a gene. A gene may harbour one or more coding microsatellite regions, that may give rise to frameshift peptides. The coding microsatellites according to the present invention comprise mononucleotide repeats, dinucleotide repeats, trinucleotide repeats, tetranucleotide repeats and pentanucleotide repeats of any length. According to present invention coding microsatellites contain preferably at least 3 and more preferably at least 5 repeats of the respective nucleotide pattern (1-5 nucleotides, which are repeated).

[0041] The frameshift polypeptides as used according to the present invention comprise at least 1, more preferred at least 2 and even more preferred at least 3 amino acids of the mutated part of the polypeptide. Additionally, the frameshift polypeptides may comprise fragments of the originally non-mutated proteins and/or may be fused to any other polypeptide sequences suitable for the purposes of the present invention. Examples of such polypeptide sequences are linker sequences, or structural peptide sequences, such as beta barrels, loop sequences etc. that facilitate the immunogenicity of the frameshift sequences according to the present invention within the fusion polypeptide.

[0042] In certain embodiments of the invention the frameshift polypeptides suitable for the methods disclosed herein are immunogenic polypeptides. This requires, that the polypeptides may stimulate immune responses in host organisms either in the form the polypeptides adopt in their natural environment and/or especially in the form the polypeptides adopt after processing by the cellular antigen processing and presenting machinery.

[0043] According to the present invention the frameshift polypeptides may also be represented by nucleic acids coding for said polypeptides. These nucleic acids may for example be used for the in situ expression of the respective polypeptides. For the purpose of expression of nucleic acids, the particular nucleic acids may be joined with suitable other nucleic acid sequences, that enable for the cloning and expression of said nucleic acids encoding the frameshift polypeptides.

[0044] In certain embodiments of the present invention frameshift polypeptides may comprise fusion or chimeric polypeptides containing sequences disclosed herein. Fusion proteins comprise the frameshift polypeptide according to the present invention together with any second and further polypeptides, such as e.g. one more frameshift polypeptide of the same sequence or of another sequence. Heterologous polypeptides may comprise enzymes, receptor molecules, antigens, antigenic or immunogenic epitopes or fragments, antibodies or fragments thereof, signalling polypeptides or signal transducing polypeptides, labelled polypeptides etc. In one embodiment of the invention the fusion peptides may be constructed for enhanced detection or purification of the frameshift polypeptides, or of complexes of the frameshift polypeptides with the respective immunological entities according to the present invention. For the purpose of purification tags, such as e.g. his-tags, myc-tags etc. may be added to the polypeptides. For the purpose of detection antigenic portions, enzymes, chromogenic sequences etc. may be fused to the polypeptides. The fusion proteins of the present invention may (but need not) include a linker peptide between the first and second polypeptides.

[0045] A nucleic acid sequence encoding a fusion protein of the present invention is constructed using known recombinant DNA techniques to assemble separate nucleic acid sequences encoding the first and second polypeptides into an appropriate expression vector. The 3' end of a nucleic acid sequence encoding the first polypeptide is ligated, with or without a peptide linker, to the 5' end of a nucleic acid sequence encoding the second polypeptide ensuring the appropriate reading frames of the sequences to permit mRNA translation of the two nucleic acid sequences into a single fusion protein that retains the biological activity (antigenicity) of both the first and the second polypeptides.

[0046] A peptide linker sequence may be employed to separate the first and the second polypeptides by a distance sufficient to ensure, that each polypeptide folds into its secondary and tertiary structures. Such a peptide linker sequence is incorporated into the fusion protein using standard techniques well known in the art. Suitable peptide linker sequences may be chosen based on the following factors: (1) their ability to adopt a flexible extended conformation; (2) their inability to adopt a secondary structure that could interact with functional epitopes on the first and second polypeptides; and (3) the lack of hydrophobic or charged residues that might react with the polypeptide functional epitopes. Preferred peptide linker sequences contain Gly, Asn and Ser residues. Other near neutral amino acids, such as Thr and Ala may also be used in the linker sequence. Amino acid sequences which may be usefully employed as linkers include those disclosed in Maratea et al., Gene 40:39-46, 1985; Murphy et al., Proc. Natl. Acad. Sci. USA 83:8258-8262, 1986; U.S. Pat. No. 4,935,233 and U.S. Pat. No. 4,751,180. The linker sequence may be from 1 to about 50 amino acids in length. Peptide 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 interference.

[0047] In certain embodiments of the present invention, especially for the detection of specific antibodies directed against frameshift polypeptides, the frameshift polypeptides themselves may be employed. Immunogenic portions as used herein is a portion of a protein, that is recognized by a B-cell and/or T-cell surface antigen receptor. The immunogenic portions comprise at least 5 amino acid residues, more preferably at least 10 amino acid residues and most preferably at least 15 amino acid residues of the frameshift polypeptides according to the present invention.

[0048] Immunogenic portions useful for the detection of specific antibodies may be provided as oligopeptides or as part of larger proteins. This is dependent on the embodiment of the invention. Where antibodies are to be detected, the antigenic epitopes may either be primary structures of polypeptides or the epitopes may be built by complex arrangements of tertiary structures of polypeptides. Concerning cells directed against specific frameshift peptides the relevant immunogenic portions are merely short fragments of peptides with a length of about 10-20 amino acids. Thus depending on the particular detection method the immunogenic portions have to be chosen.

[0049] In one embodiment of the invention a set of frameshift polypeptides is used for the detection of antibodies. The set may be a combination of the relevant peptides in solution, in cases, where information about the presence of immunological entities in general is sought. In contrast, when information about the presence or absence of particular frameshift peptides within a set of peptides is sought, the frameshift peptides may for example be tested each as a single, simultaneously in multiple testing reactions. Such experiments may for example be carried out in form of multi-well tests or using peptide arrays etc.

[0050] In order to address a representative choice of mutations potentially characterizing a disorder a set of frameshift polypeptides used according to the method disclosed herein comprises for example 5-20, in a preferred embodiment 10-30, in another preferred embodiment 20-50, in a more preferred embodiment 50-100, in an even more preferred embodiment 100-500 and in the most preferred embodiment more than 500 different frameshift polypeptides originating from frameshift mutations in coding microsatellite regions. The frameshift polypeptides to be used as a set according to the present invention are selected with respect to a number of parameters characterizing said polypeptides. A nucleic acid sequence encoding a fusion protein of the present invention is constructed using known recombinant DNA techniques to assemble separate nucleic acid sequences encoding the first and second polypeptides into an appropriate expression vector. The 3' end of a nucleic acid sequence encoding the first polypeptide is ligated, with or without a peptide linker, to the 5' end of a nucleic acid sequence encoding the second polypeptide ensuring the appropriate reading frames of the sequences to permit mRNA translation of the two nucleic acid sequences into a single fusion protein that retains the biological activity (antigenicity) of both the first and the second polypeptides.

[0051] Generally using an immense or unlimited number of occurring frameshift peptides it would be possible to address any potential number of disorder, that is associated with frameshift mutations. Due to practical and immunological concerns the number of peptides, that are included in a vaccine must be limited. To ensure a broad range of impact for any diagnostic or therapeutic method employing a set of frameshift polypeptides, the selection of particular peptides has to be based on rationale considerations.

[0052] A set of frameshift polypeptides used according to the method disclosed herein comprises at least 3, 4, 5, 6 or even 7 and in certain embodiments 8, 9 or 10 frameshift polypeptides. Due to immunological as well as practical concerns The set of frameshift peptides used as a vaccine may not include an unlimited number of frameshift peptides. Preferably the set of frameshift peptides comprises at maximum 15, in a more preferred embodiment at maximum 20 and in the most preferred embodiment of the invention at maximum 30 frameshift polypeptides. In order to ensure a maximum range of disorders to be addressed by the selected set of frameshift polypeptides the members of the set have to be selected by reasonable considerations. The frameshift polypeptides to be used as a set according to the present invention are selected with respect to a number of parameters characterizing said polypeptides.

[0053] In one embodiment the members of the set are chosen, so that only three different peptides may be used to cover a wide range of tumors for as well therapeutic as well as diagnostic approaches. Using larger panels of frameshift peptides the stringency to the choice of individual peptides is lowered. In especially small sets all parameters influencing the efficacy of addressing a wide range of tumors need to be optimally met. In larger panels even peptides occurring with lower frequencies or allowing for efficient immune-escape may be included.

[0054] One crucial aspect influencing the selection of the frameshift peptides is the mutation frequency of the relevant microsatellite region and thus the frequency of a particular expressed frameshift polypeptide. Mutation frequency as used in the context of the present invention pertains to the percentage of samples within a defined range of total samples, which show a particular mutation. Any method suitable for the determination of the percentage of individuals in a range of samples displaying the existence of a particular genotype or phenotype (with respect to the expression of polypeptides) may be employed for the determination of the frequency according to the present invention. The frequencies may be determined e.g. as described below in example 1.

[0055] The frequency may be the frequency of frameshift mutation within a coding microsatellite region or a frequency of expression of a frameshift polypeptide. Furthermore the frequency may be e.g. a frequency over a total of different tumor entities, the frequency with respect to a particular tumor entity, a frequency over several tumors entities restricted to particular stages of tumorigenesis or a frequency with respect to a particular tumor entity restricted to particular stages of tumorigenesis.

[0056] The frequency according to the present invention has to be determined taking into account a range of samples sufficient to render significant data. For example preferably at least 50 to 100 tumors may be included in the range of samples analyzed. In case, that a smaller number of samples has been taken into account for determination of the frequency, a variation of the determined frequency may take place, if the range of samples is broadened.

[0057] Generally any frequency as determined may be used as a tool for the choice of a set of frameshift polypeptides according to the present invention. To ensure best results for the method according to the present invention a largest possible number of samples has to be taken into account. Yet if there are only rare data, a frequency may also be determined with respect to a restricted number of samples. This may especially be true, if the data for the restricted population of samples indicates a quite high frequency of a particular peptide, and thus implies a high therapeutic value for the respective peptide.

[0058] Especially in cases, where a frequency is to be determined related to a particular tumor entity or related to particular stages of the tumorigenesis, the population of samples may be restricted.

[0059] The mutation may occur at any time during the tumor evolution and may be persistent or may be eliminated from the genome. Thus the frequency may comprise the frequency of the expression of a peptide at a particular stage of tumorigenesis or the occurrence of a genetic mutation at a particular defined stage of tumorigenesis. In one embodiment of the invention the frequency for the mutation is determined taking into account the widest possible range of samples. In this embodiment the method disclosed herein may be especially useful for the preventive vaccination of tumors. In another embodiment of the present invention the frequencies of mutation are related to specified tumor entities. In this embodiment the method according to the present invention may e.g. especially be useful for immuno-therapeutic approaches in treatment of tumors or in the preventive vaccination of particular subpopultions with an elevated risk for the occurrence of particular tumors. In a third embodiment of the present invention the frequency may be related to particular stages in tumorigenesis of particular tumors. This embodiment may be e.g. especially useful for the treatment of diagnostically defined tumors or for adjuvant treatment of tumors simultaneously or following primary treatment of tumors.

[0060] Using frameshift polypeptides, that occur with a high frequency, the probability, that a particular tumor expresses the peptide and may thus be recognized by antibodies or antigen-recognizing cells, increases. By combination of multiple such polypeptides, the probability to address particular tumor cells further is raised. Preferred frameshift polypeptides according to the present invention occur in at least 25%, more preferred frameshift polypeptides in at least 30% and most preferred frameshift polypeptides in at least 33% of the cases of the particular condition to be treated by the method according to the present invention.

[0061] According to the present invention the polypeptides are chosen to be expressed with a high frequency, thus the set of polypeptides may be limited to a number of members and nonetheless may cover a range of occurring diseases as wide as possible. For example a set of 10 polypeptides, each occurring with a frequency of more than 30 percent will statistically cover a range of more than 95% of the potentially existing disorders, as far as they have been included in the studies leading to the respective frequencies. Using 7 polypeptides requires the application of polypeptides with higher frequencies in order to cover a range of about 95% of potentially existing tumors. Using a set of polypeptides derived from enormously frequent mutated microsatellite regions may also allow for the employment of a set of only five different polypeptides without lowering the range of potentially addressed tumors. Thus the set of polypeptides comprises in a preferred embodiment at least 5, in a more preferred embodiment at least 7 and in the most preferred embodiment at least 10 different frameshift polypeptides.

[0062] A second aspect influencing the choice of a suitable set of frameshift polypeptides concerns the type of mutation found in the microsatellite region. Frameshift mutations microsatellites are usually due to DNA polymerase slippage and may be characterized by the type of the repeat. Thus in mono nucleotides repeats this type of mutation renders 1 nt insertion or deletion. In dinucleotide repeats and tetranucleotide repeats mutations are insertions or deletions of 2 or 4 nt respectively. (Polypeptides encoded by genes with coding microsatellites and the respective polypeptides encoded by genes with frameshift mutations are given in FIGS. 2-1 to 2-8) For example commonly (-1) mutations occur in mononucleotide repeats (MNRs). In these mutations one nucleotide is deleted such that the reading frame is shifted by one nucleotide toward the 5' end of the gene compared to the original reading frame. This type of mutation renders a reading frame identical to that produced by (+2) mutations, which arise from two nucleotide insertions in the respective microsatellites. The respective (-1) or (+2) polypeptides might differ by one amino acid. The other frameshift mutation variant leading to frameshift mutations differing from (-1) mutations concerning the resulting reading frame is the (+1) mutation, arising from one nucleotide insertion, thus rendering a reading frame shifted one nucleotide toward the 3' end of the gene compared to the original reading frame. This mutation type gives a reading frame identical to that of (-2) mutations, wherein the encoded polypeptides differ by one amino acid. (-3) and (+3) mutations are irrelevant according to the present invention, for they do not give rise to frameshift polypeptides. According to the present invention the polypeptides included within the set shall be selected as to cover the widest possible range of tumors. Thus a set comprises for example (-1) frameshift polypeptides and additionally (+1) frameshift polypeptides. Using more than one possible novel reading frame of the particular gene broadens the spectrum of target cells and thus may prevent escape of particular cells from being eliminated according to the present invention.

[0063] A further aspect influencing the choice of the member polypeptides included in a set of frameshift polypeptides according to the present invention is the involvement of the gene encoded for by the coding sequence containing the respective microsatellite in particular biochemical pathways. The term biochemical pathway is used with a rather broad meaning herein. Biochemical pathways as used within this document shall for example include signal transduction pathways, enzymatic pathways, metabolic pathways, the apoptosis pathway, DNA repair or polymerization pathways, the pathway of meiosis etc. To broaden the spectrum of tumors to be addressed by the set of frameshift polypeptides, members of different pathways are included in the set. In a preferred embodiment at least 5 different pathways, in a more preferred embodiment at least 4 different pathways and in the most preferred embodiment at least 3 different pathways are represented by the frameshift polypeptides in a set according to the present invention. For example the TGFβRII as a member of a signal transduction pathway may be used in combination with the BAX gene as a member of the apoptosis pathway with additional other polypeptides associated with other pathways.

[0064] A final aspect influencing the choice of suitable frameshift polypeptides to be included in the set according to the present invention is the length of the novel (poly)peptide sequence arising from the mutation. The shift of the reading frame leads to novel stop codons. Thus the new peptides are not of the same length as the polypeptides naturally encoded by the particular gene. In most cases the new peptides are shorter or even significantly shorter than the original wild-type polypeptide. Frequently rather oligopeptides arise from the frameshift mutations. The fidelity of the immune system in recognizing "foreign" molecules reaches thus far, to identify even polypeptides, that differ from "own" polypeptides in only one single amino-acid mutation. The fragments, bound by the antigen presenting HLA molecules comprise about 12 amino acid residues. To enhance the fidelity of recognition of new polypeptides more than one single amino-acid difference should be present. A polypeptide comprising 3 consecutive amino acids differing from the wild-type amino acid sequence is reliably recognized as foreign by the immune system. This may be due to the increased probability of new amino acid combinations being present in different fragments produced by the antigen presenting machinery. Thus the frameshift polypeptides according to the present invention contain at least one new amino acid, not present in the wild-type polypeptide, in a more preferred embodiment at least 2 new amino acids and in the most preferred embodiment at least 3 new amino acids.

[0065] According to the named parameters a basic set of frameshift polypeptides may be tailored, that is suitable to address a large variety of tumors and minimizes the danger of escape of single tumor cells from the therapy. Thus the probability of survival of tumor cells in an organism following immuno-therapy can be minimized and the rate of recurrence of the cancer can be reduced.

[0066] A basic set of frameshift polypeptides includes frameshift polypeptides, that do occur with a high mutation frequency in associated disorders. Additionally the polypeptides within the set are chosen to be involved in different biochemical pathways. The mutation types are chosen, that polypeptides of a minimal length of 3 amino acid residues is expressed from the mutated nucleic acid sequence. Furthermore different mutation types of one single microsatellite may be included in the set if applicable.

[0067] Examples of basic sets of frameshift polypeptides for use in therapeutic as well as diagnostic methods of the present invention include:

TABLE-US-00001 Set1: HT001 U79260 MACS Set2: HT001 TAF1B MACS Set3: HT001 TGFB2R MACS Set4: HT001 U79260 TGFB2R Set5: HT001 U79260 TAF1B Set6: HT001 TGFB2R TAF1B Set7: HT001 U79260 TGFB2R MACS Set8: HT001 U79260 TGFB2R AC1 Set9: HT001 U79260 TGFB2R TAF1B Set10: HT001 TGFB2R MACS CASP5 Set11: HT001 U79260 MACS CASP5 Set12: HT001 U79260 MACS AC1 Set13: HT001 TGFB2R TAF1B CASP5 Set14: HT001 U79260 MACS OGT Set15: U79260 TGFB2R AC1 CASP5 Set16: HT001 U79260 TGFB2R MACS AC1 Set17: HT001 U79260 TGFB2R TAF1B MACS Set18: HT001 U79260 TGFB2R TAF1B AC1 Set19: HT001 U79260 TGFB2R MACS AIM2 Set20: HT001 U79260 TGFB2R TAF1B AIM2 Set21: U79260 TGFB2R TAF1B AC1 CASP5 Set1: HT001 U79260 TGFB2R AC1 CASP5 Set22: U79260 TGFB2R MACS AC1 CASP5 Set23: HT001 U79260 TAF1B MACS AC1 Set24: HT001 U79260 TAF1B MACS CASP5 Set1: HT001 U79260 MACS AC1 OGT Set25: HT001 U79260 MACS MSH3 OGT Set26: HT001 U79260 TGFB2R MACS OGT Set27: HT001 TGFB2R TAF1B AC1 CASP5 Set28: HT001 U79260 TGFB2R AC1 AIM2

[0068] Additional to the parameters given above, data concerning the particular disorder in focus are taken into account for the design of particular sets of frameshift peptides according to the present invention. Thus individual mutation frequencies, typical mutation types, relevant biochemical pathways or special immunological characteristics may contribute to the set to be used in particular cases. Furthermore in particular cases based on results of examination of particular samples of individuals vaccines may be tailored as to optimally fit the therapy of the respective disorder. In one embodiment of the present invention individual tumor vaccine compositions may be set up according to molecular profiling of individual tumors

[0069] Choosing suitable combinations of the peptides within the mixture of frameshift peptides thus enables for generation of therapeutic or diagnostic preparations with a wide range of applicability. E.g. vaccines that elicit immune response specifically for tumors of particular organs. On the other hand it is possible to design sets of frameshift polypeptides that cover a wide range of degenerative disorders or cancers in individuals. The first possibility may e.g. be especially useful for the design of curative treatment, whereas the second variant of sets may be of special interest for the design of preventive vaccines.

[0070] The compositions and methods according to the present invention may be applied to any eukaryotic organisms exhibiting an immunologic defence system. The eukaryotic organisms are for example animals of agricultural value such as pigs, cows, sheep, etc., companion animals, such as cats, dogs, horses etc., animals employed in research purposes such as mice, rats, rabbits, hamsters etc. or humans.

[0071] Therapeutic methods for use in the present invention comprise immunogenic treatment such as vaccination therapy or generally immuno-therapy. The vaccines for use in the present invention comprise for example one or more sets of frameshift polypeptides.

[0072] According to the present invention frameshift polypeptides that comprise an immunogenic portion may be used for immuno-therapy for the treatment of cancer. Immunotherapy may be broadly classified into either active or passive immunotherapy. In active immunotherapy, treatment relies on the in vivo stimulation of the endogenous host immune system to react against tumors with the administration of immune response-modifying agents (for example, tumor vaccines, bacterial adjuvants, and/or cytokines). A patient may be afflicted with disease, or may be free of detectable disease. Accordingly, the compounds disclosed herein may be used to treat cancer or to inhibit the development of cancer. The compounds are preferably administered either prior to or following primary treatment of tumors such as surgical removal of the tumors, treatment by administration of radiotherapy and/or conventional chemotherapeutic drugs or any other mode of treatment of the respective cancer or its precursors.

[0073] In passive immunotherapy, treatment involves the delivery of biologic reagents with established tumor-immune reactivity (such as effector cells or antibodies) that can directly or indirectly mediate antitumor effects and does not necessarily depend on an intact host immune system. Examples of effector cells include T lymphocytes (for example, CD8+ cytotoxic T-lymphocytes, CD4+ T-helper, tumor-infiltrating lymphocytes), killer cells (such as Natural Killer cells, lymphokine-activated killer cells), B cells, or antigen presenting cells (such as dendritic cells and macrophages) expressing the disclosed antigens. The polypeptides disclosed herein may also be used to generate antibodies or anti-idiotypic antibodies (as in U.S. Pat. No. 4,918,164), for passive immunotherapy.

[0074] The predominant method of procuring adequate numbers of T-cells for adoptive transfer immunotherapy is to grow immune T-cells in vitro. Culture conditions for expanding single antigen-specific T-cells to several billion in number with retention of antigen recognition in vivo are well known in the art. These in vitro culture conditions typically utilize intermittent stimulation with antigen, often in the presence of cytokines, such as IL-2, and non-dividing feeder cells. As noted above, the immunoreactive polypeptides described herein may be used to rapidly expand antigen-specific T-cell cultures in order to generate sufficient number of cells for immunotherapy. In particular, antigen-presenting cells, such as dendritic-, macrophage- or B-cells, may be pulsed with immunoreactive polypeptides or transfected with a nucleic acid sequence(s), using standard techniques well known in the art. For example, antigen presenting cells may be transfected with a nucleic acid sequence, wherein said sequence contains a promoter region appropriate for increasing expression, and can be expressed as part of a recombinant virus or other expression system. For cultured T-cells to be effective in therapy, the cultured T-cells must be able to grow and distribute widely and to survive long term in vivo. Studies have demonstrated that cultured T-cells can be induced to grow in vivo and to survive long term in substantial numbers by repeated stimulation with antigen supplemented with IL-2 (see, for example, Cheever, M., et al, "Therapy With Cultured T-Cells: Principles Revisited," Immunological Reviews, 157:177, 1997).

[0075] According to the present invention sets of frameshift polypeptides may be employed to generate and/or isolate tumor-reactive T-cells, which can then be administered to the patient. In one technique, antigen-specific T-cell lines may be generated by in vivo immunization with short peptides corresponding to immunogenic portions of the disclosed polypeptides. The resulting antigen specific CD8+CTL or CD4+ T-helper cells clones may be isolated from the patient, expanded using standard tissue culture techniques, and returned to the patient.

[0076] Alternatively, peptides corresponding to immunogenic portions of the polypeptides of the invention may be employed to generate tumor reactive T-cell subsets by selective in vitro stimulation and expansion of autologous T-cells to provide antigen-specific T-cells which may be subsequently transferred to the patient as described, for example, by Chang et al. (Crit. Rev. Oncol. Hematol., 22(3), 213, 1996). Cells of the immune system, such as T-cells, may be isolated from the peripheral blood of a patient, using a commercially available cell separation system, such as CellPro Incorporated's (Bothell, Wash.) CEPRATE® system (see U.S. Pat. No. 5,240,856; U.S. Pat. No. 5,215,926; WO 89/06280; WO 91/16116 and WO 92/07243). The separated cells are stimulated with one or more of the immunoreactive polypeptides contained within a delivery vehicle, such as a microsphere, to provide antigen-specific T-cells. The population of tumor antigen-specific T-cells is then expanded using standard techniques and the cells are administered back to the patient.

[0077] In another embodiment, T-cell receptors and/or antibodies specific for the polypeptides can be cloned, expanded, and transferred into other vectors or effector cells for use in adoptive immunotherapy.

[0078] In a further embodiment, syngeneic or autologous dendritic cells may be pulsed with peptides corresponding to at least an immunogenic portion of a polypeptide disclosed herein. The resulting antigen-expressing and/or presenting dendritic cells may either be transferred into a patient, or employed to stimulate T-cells to provide antigen-specific T-cells which may, in turn, be administered to a patient. The use of peptide-pulsed dendritic cells to generate antigen-specific T-cells and the subsequent use of such antigen-specific T-cells to eradicate tumors in a murine model has been demonstrated by Cheever et al, (Immunological Reviews, 157:177, 1997).

[0079] Monoclonal antibodies directed against frameshift peptides presented on cellular membranes may according to the present invention also be used as therapeutic compounds in order to diminish or eliminate tumors. The antibodies may be used on their own (for instance, to inhibit metastases) or coupled to one or more therapeutic agents. Suitable agents in this regard include radionuclides, differentiation inducers, drugs, toxins, and derivatives thereof. Preferred radionuclides include 90Y, 123I, 125I, 131I, 186Re, 188Re, 211At, and 212Bi. Preferred drugs include methotrexate, and pyrimidine and purine analogues. Preferred differentiation inducers include phorbol esters and butyric acid. Preferred toxins include ricin, abrin, diptheria toxin, cholera toxin, gelonin, Pseudomonas exotoxin, Shigella toxin, and pokeweed antiviral protein.

[0080] Pharmaceutical compositions useful in immuno-therapy according to the present invention may comprise a set of at least 3, 4, 5, 6, 7, 8, 9 or 10 frameshift polypeptides (or variants thereof). Moreover sets of frameshift polypeptides may comprise 5 to 20, 7 to 30 or even ore than 15, 20 or 30 frameshift peptides (or variants thereof). (or variants thereof), In certain embodiments the pharmaceutical compositions comprise the frameshift polypeptides and a physiologically acceptable carrier. The vaccines may additionally comprise a non-specific immune-response enhancer, wherein the non-specific immune response enhancer is capable of eliciting or enhancing an immune response to an exogenous antigen. Examples of non-specific-immune response enhancers include adjuvants, biodegradable microspheres (e.g., polylactic galactide) and liposomes (into which the polypeptide is incorporated). Pharmaceutical compositions and vaccines may also contain other epitopes of tumor antigens, either incorporated into a fusion protein or present within a separate polypeptide.

[0081] Alternatively, a pharmaceutical composition or vaccine suitable for immunotherapy according to the present invention may contain nucleic acids, that code for one or more frameshift polypeptides according to the present invention. Nucleic acids may for example include single-stranded (sense or antisense) or double-stranded molecules, and may be DNA (genomic, cDNA or synthetic) or RNA. RNA molecules comprise as well HnRNA (containing introns) as mRNA (not containing introns). According to the present invention the polynucleotides may also be linked to any other molecules, such as support materials or detection marker molecules, and may, but need not, contain additional coding or non-coding sequences. The nucleic acid may be administered in a way that allows the polypeptides to be generated in situ. Suitable expression systems are known to those skilled in the art. The expression of the polypeptides may for example be persistent or transient. In pharmaceutical compositions and/or vaccines, providing for in-situ expression of polypeptides, the nucleic acids may be present within any suitable delivery system known to those of ordinary skill in the art, including nucleic acid expression systems, bacteria and viral expression systems.

[0082] Appropriate nucleic acid expression systems comprise the necessary regulatory nucleic acid sequences for expression in the patient, such as suitable promoters, terminators etc. Bacterial delivery systems may for example employ the administration of a bacterium that expresses an epitope of a cell antigen on its cell surface. In a preferred embodiment, the nucleic acid may be introduced using a viral expression system such as e.g., vaccinia virus, retrovirus, or adenovirus, which may involve the use of a non-pathogenic, replication competent virus. Suitable systems are known to those of ordinary skill in the art and are disclosed, for example, in Fisher-Hoch et al., PNAS 86:317-321, 1989; Flexner et al., Ann. N.Y. Acad Sci. 569:86-103, 1989; Flexner et al., Vaccine 8:17-21, 1990; U.S. Pat. Nos. 4,603,112, 4,769,330, and 5,017,487; WO 89/01973; U.S. Pat. No. 4,777,127; GB 2,200,651; EP 0,345,242; WO 91/02805; Berkner, Biotechniques 6:616-627, 1988; Rosenfeld et al., Science 252:431-434, 1991; Kolls et al., PNAS 91:215-219, 1994; Kass-Eisler et al., PNAS 90:11498-11502, 1993; Guzman et al., Circulation 88:2838-2848, 1993; and Guzman et al., Cir. Res. 73:1202-1207, 1993.

[0083] In another embodiment transgenic mammalian cells may be used for delivery and/or expression of the nucleic acids. The methods for producing nucleic acid constructs suitable for in-situ expression of polypeptides are known to those of skill in the art.

[0084] Furthermore the nucleic acid may be administered as naked nucleic acids. In this case appropriate physical delivery systems, which enhance the uptake of nucleic acid may be employed, such as coating the nucleic acid onto biodegradable beads, which are efficiently transported into the cells. Administration of naked nucleic acids may for example be useful for the purpose of transient expression within a host or host cell.

[0085] The pharmaceutical compositions used for immuno-therapy according to the present invention may be administered by any suitable way known to those of skill in the art. The administration may for example comprise injection, such as e.g., intra-cutaneous, intramuscular, intravenous or subcutaneous injection, intranasal administration for example by aspiration or oral administration. A suitable dosage to ensure the pharmaceutical benefit of the treatment should be chosen according to the parameters, such as age, sex, body weight etc. of the patient, known to those of skill in the art.

[0086] The type of carrier to be employed in the pharmaceutical compositions of this invention, will vary depending on the mode of administration. For parenteral administration, such as subcutaneous injection, the carrier preferably comprises water, saline, alcohol, a lipid, a wax and/or a buffer. For oral administration, any of the above carriers or a solid carrier, such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, sucrose, and/or magnesium carbonate, may be employed. Biodegradable microspheres (e.g., polylactic glycolide) may also be employed as carriers for the pharmaceutical compositions of this invention. Suitable biodegradable microspheres are disclosed, for example, in U.S. Pat. Nos. 4,897,268 and 5,075,109. Any of a variety of immune-response enhancers may be employed in the vaccines of this invention. For example, an adjuvant may be included. Most adjuvants contain a substance designed to protect the antigen from rapid catabolism, such as aluminum hydroxide or mineral oil, and a nonspecific stimulator of immune response, such as lipid A, Bordetella pertussis or Mycobacterium tuberculosis. Such adjuvants are commercially available as, for example, Freund's Incomplete Adjuvant and Complete Adjuvant (Difco Laboratories, Detroit, Mich.) and Merck Adjuvant 65 (Merck and Company, Inc., Rahway, N.J.).

[0087] The pharmaceutical compositions or immuno-therapeutic methods according to the present invention may be used for the treatment of degenerative disorders or cancers. For example the compositions and methods may be employed in the therapy of diagnosed cancers in order to eliminate the tumor cells from the affected organism. As well primary tumors as metastases or disseminated tumor cells within an organism may be targets to the therapeutic compounds and methods disclosed herein.

[0088] Furthermore the compositions and methods of the invention may be employed in the treatment of pre-neoplastic conditions. In this case the pre-neoplastic cells or tissues may be directly addressed by the immuno-therapeutic compositions or methods, or may be hindered from evolving into neoplastic or dysplastic conditions. For example in this case the pre-neoplastic condition may be treated preventively. By the vaccination the immune response may be elicited, so that emerging neoplasms may be destroyed.

[0089] The methods and compositions according to the present invention may also be used for the prevention of degenerative disorders or cancers associated with frameshift mutations in coding microsatellites. For this purpose a vaccination of a population of organisms or of subgroups of said population may be performed. The subgroups may be built by suitable parameters such as hereditary predisposition for the emergence of degenerative disorders, exposure to factors, that increase the risk of being affected by said disorders etc.

[0090] In one embodiment of the present invention the peptides disclosed herein may be used for the diagnosis of disorders associated with frameshift mutations in coding microsatellite regions.

[0091] Diagnosis as used in the context of the present invention may comprise determining the presence or absence and/or the level of frameshift peptides or of specific immunological entities directed against particular frameshift peptides in a sample, and assessing diagnosis from said presence or absence and/or level of frameshift peptides and/or immunological entities specifically directed against said frameshift polypeptides.

[0092] Based upon the determined presence or absence and/or the levels of frameshift peptides or of immunological entities specifically directed against particular frameshift peptides in the samples individuals can be subdivided into subgroups. The subgroups may be created according to scientific or clinical data, such as e.g. survival, recurrence of disease, frequency of metastases etc., related to the presence or absence and/or levels of frameshift peptides or of particular frameshift peptides in samples of tissues affected with a particular disorder, of tissues being in question of being affected with a particular disorder or of tissues at risk of being affected with a particular disorder.

[0093] Based upon these subgroups an assessment of prognosis may be done. According to the subgroups the therapy of the individuals affected by the disorders (e.g. tumors) may be tailored.

[0094] Monitoring may comprise detecting the presence or absence or level of frameshift peptides or of immunologic entities specifically directed against frameshift polypeptides in samples taken at different points in time and determining the changes in said levels or presences or absences. According to said changes the course of the disease can be followed. E.g. the occurrence of frameshift peptides or of immunologic entities directed against frameshift peptides, that have not been present at an earlier time-point may be indicative of the progression of evolution of the affected tissue. The course of the disease may be used to select therapy strategies for the particular individual.

[0095] Another aspect of diagnosis and monitoring of the disease course according to the present invention may comprise the detection of minimal residual disease. This may comprise for example the detection of presence and/or level of frameshift peptides or of immunologic entities specifically directed against said frameshift polypeptides, that have not been present in earlier examinations in one or more body samples following initial therapy of an individual once or at several time points. According to the presence and/or level of frameshift peptides or of immunologic entities specifically directed against new frameshift polypeptides detected in the samples one may select a suitable therapy for the particular individual.

[0096] Furthermore the diagnostic method may be carried out to detect disseminated tumor cells in biological samples as MRD diagnosis of minimal residual disease. For this purpose the detection of the level of immunological entities or the presence of frameshift peptides or of immunological entities, specific for particular frameshift peptides, that have not been detected in prior examinations, may be performed.

[0097] Immunological entities as used in the context of the present invention shall comprise any components of the mammalian immune system, that are able to specifically react with an antigenic epitope. Such immunological entities may comprise for example antibodies, all immunoglobulins, such as e.g. IgG, IgM, IgA, IgE, IgD, specific CD8+ T-cells or specific T-helper cells.

[0098] A sample according to the method of the present invention may comprise any sample comprising frameshift peptides or immunological entities as defined above. Samples may comprise samples of clinical relevance, such as e.g. secretions, smears, body fluids, urine, semen, stool, bile, biopsies, cell- and tissue-samples. Biopsies as used in the context of the present invention may comprise e.g. resection samples of tumors, tissue samples prepared by endoscopic means or needle biopsies of organs.

[0099] Such samples may comprise for example intact cells, lysed cells or any liquids containing polypeptides, antibodies, immunoglobulins or cells specifically directed against frameshift peptides. Even solids, to which peptides, cells, cell fragments or antigen binding polypeptides, such as antibodies or immunoglobulins may adhere, or may be fixed to, may be samples according to the method disclosed herein. The method for detection of the level of the frameshift peptides or of the immunological entities according to the present invention is any method, which is suited to detect very small amounts of specific frameshift peptides or of specific immunological entities in biological samples. The detection reaction according to the present invention is a detection either on the level of polypeptides, nucleic acids, antibodies or on the level of cells specific for particular antigens.

[0100] For diagnostic purposes detection procedures related to one single frameshift polypeptides or to immunological entities specifically recognizing said frameshift peptides may be performed. Furthermore detection procedures may be performed that are tailored to display the presence or absence or the level of one or more sets of polypeptides or immunological entities directed against these polypeptides, wherein the sets have been put together according to rational combinatorial parameters as they are given below.

[0101] The detection may be carried out in solution or using reagents fixed to a solid phase. Solid phases may comprise beads of a variety of materials, such as e.g. agarose, dextrane polymers, polystyrene, silica, etc. or surfaces of suitable materials such as e.g. polystyrene, glass, agarose, protein, dextran etc. coated surfaces etc. The detection of one or more immunological entities, such as immunoglobulins or cells carrying specific antigen recognizing epitopes, with different antigen binding specificities may be performed in a single reaction mixture or in two or more separate reaction mixtures. Alternatively the detection reactions for several immunological entities may for example be performed simultaneously in multi-well reaction vessels.

[0102] Applicable formats for the detection reaction according to the present invention may be, (reverse) blotting techniques, such as Western-Blot. The blotting techniques are known to those of ordinary skill in the art and may be performed for example as electro-blots, semidry-blots, vacuum-blots or dot-blots. Furthermore immunological methods for detection of molecules may be applied, such as for example immunoprecipitation or immunological assays, such as ELISA, RIA, Elispot assay, lateral flow assays, immuno-cytochemical methods etc.

[0103] The immunological entities specifically recognizing particular frameshift peptides may be detected using reagents that specifically recognise these immunological entities alone or in complex with their respective antigen (e.g. antibodies), or reagents, that are specifically recognized by the immunological entities themselves (e.g. the antigen). In one embodiment the antigen may be fused to another polypeptide, so as to allow binding of the antigen by the immunological entity in question and simultaneously binding of the second part of the fusion protein by another (labelled) antibody for the detection. The detection reaction for the immunological entities may comprise one or more reactions with detecting agents either recognizing the initial entities or recognizing the prior molecules used to recognize the immunological entities.

[0104] The detection reaction further may comprise a reporter reaction indicating the presence or absence and/or the level of the immunological entities. The reporter reaction may be for example a reaction producing a coloured compound, a bioluminescence reaction, a chemiluminescent reaction, a fluorescence reaction, generally a radiation emitting reaction etc. The detection reactions may for example employ antibodies or binding reagents that are detectably labelled.

[0105] Furthermore the binding of detection molecules to the entities in question may be detected by any measurable changes in physical or physical-chemical properties, such as changes in spectroscopic properties, in magnetic resonance properties etc. Different immunological entities or immunological entities of different specificities may be recognized by different methods or agents. This may be due to difficulties in detection of several entities, or entities with particular specificities by a particular method. An advantage of the use of different detection techniques for different immunological entities or for immunological entities with different specificities may for example be, that the different reporter signals referring to different immunological entities could be distinguished.

[0106] Generally in a method according to the present invention the detection of different immunological entities such as the detection of immunoglobulins and the detection of immunocompetent cells may be performed simultaneously.

[0107] For all detection purposes optionally the original sample may be concentrated by any suitable means known to those of ordinary skill in the art. Furthermore steps may be involved to selectively extract immunological entities from the sample mixture such as affinity based purification techniques either employing specific antibodies or the respective antigen recognized by the entities in question.

[0108] In one preferred embodiment of the invention the detection of the level of immunological entities specific for frameshift peptides is carried out on the level of antibodies. This may be e.g. performed using the specific interaction between the respective frameshift peptides with the antibodies. The determination of the presence or absence and/or the level of the antibodies may for example be carried out with recombinantly produces frameshift peptides. The peptides can be used in many different detection techniques for example in western-blot, ELISA or immuno-precipitation. In one embodiment the detection of antibodies is carryout as antibody capture assay (Antibodies A laboratory Manual, Harlow, Ed. et al., Cold Spring Harbor Laboratory 1988).

[0109] In another embodiment of the invention the detection of the specific antibodies is carried out using monoclonal or polyclonal antibodies specifically recognizing the antigen binding epitope of the first antibodies. For this purpose the above mentioned immunological detection procedures may be applied. In a further embodiment chimeric antigens may be employed in the detection reaction. Such chimeric antigens may for example comprise fusion proteins combining the antigenic epitope of a frameshift polypeptide, recognized by the antibody in question, fused to another antigen, that may be recognized by a detection antibody. The particular antigens within the chimeric polypeptide may be separated by a linker or spacer region.

[0110] Any other method for determining the amount of particular antibodies or immunoglobulins in biological samples can be used according to the present invention.

[0111] Generally the detection of the antibodies according to the present invention may be performed as well in vitro as directly in situ for example in the course of an immuno-histochemical or immuno-cytochemical staining reaction.

[0112] Cells exhibiting specificity for a particular antigen may be detected by any methods suitable for that purpose known to those of ordinary skill in the art. Methods may for example comprise proliferation-assays, cytokine-ELISAs, ELISpot assays, intracellular FACS-staining, PCR-mediated identification of peptide-specific cytokine (or similar)-expressing cells, tetramer-staining, cytotoxicity assays and DTH-(delayed type hypersensitivity) reactions.

[0113] In case of proliferation-assays induction of peptide-specific T-cell proliferation may be measured by methods known to those of skill in the art. This can be achieved by simply counting of cells, by measuring incorporation of labelled nucleotides into cellular DNA or by measuring level and/or activity of cellular protein(s). Cytokine-ELISA may comprise identification of peptide-specific cytokine-secreting cells by measuring cytokine levels in supernatant. In the course of an ELISpot assay the number of peptide-specific cytokine (i.e. IFN-g)-secreting cells in a sample is determined. Similarly the Intracellular FACS-staining identifies cytokine-expressing cells on the protein level. In contrast (real-time) PCR may be used for identification of peptide-specific cytokine (or similar)-expressing cells on the transcript level. In the course of a tetramer-staining assay the label is a tetramer-molecule of recombinant MHC-class I molecules, loaded with specific peptide and coupled to a dye. The tetramer binds to the T-cell receptor. Cytotoxicity assays are a method for identification of cells, that can recognize and kill target cells in a peptide-specific manner. DTH-(delayed type hypersensitivity) reaction is based on the measuring of skin reaction of vaccinated persons after intradermal (or similar) application of peptide(s).

[0114] In a preferred embodiment of the invention the detection of the immunological entities directed against particular frameshift polypeptides is carried out on the level of antibodies. In this embodiment the binding agent may be for example a frameshift polypeptide or a fragment thereof, recognized by the respective antibody, or a fusion polypeptide comprising said frameshift polypeptide or a fragment thereof. Furthermore the binding agent may comprise an antibody or a fragment thereof specific for the antibody in question, for the complex of the antibody with the respective frameshift polypeptide or for an antigenic epitope fused to the frameshift polypeptide.

[0115] In another embodiment of the test kit the detection of the immunological entities is carried out on the level of cells specifically recognizing frameshift polypeptides. In this embodiment of the invention the reagent for the detection may be for example a frameshift polypeptide or a fragment thereof, recognized by the respective antibody or T-cell receptor, or a fusion polypeptide comprising said frameshift polypeptdie or a fragment thereof. Furthermore the binding agent may comprise an antibody or a fragment thereof specific for the antibody in question, for the complex of the antibody with the respective frameshift polypeptide or for an antigenic epitope fused to the frameshift polypeptide.

[0116] The method for detection of the level of the frameshift polypeptides according to the present invention is any method, which is suited to detect very small amounts of specific biologically active molecules in biological samples. The detection reaction according to the present invention is a detection either on the level of nucleic acids or on the level of polypeptides.

[0117] The detection may be carried out in solution or using reagents fixed to a solid phase. The detection of one or more molecular markers, such as polypeptides or nucleic acids, may be performed in a single reaction mixture or in two or separate reaction mixtures. Alternatively the detection reactions for several marker molecules may for example be performed simultaneously in multi-well reaction vessels. The markers characteristic for the frameshift polypeptides may be detected using reagents that specifically recognise these molecules. The detection reaction for the marker molecules may comprise one or more reactions with detecting agents either recognizing the initial marker molecules or recognizing the prior molecules used to recognize other molecules.

[0118] In one preferred embodiment of the invention the detection of the level of frameshift polypeptides is carried out by detection of the level of nucleic acids coding for the frameshift polypeptides or fragments thereof present in the sample. The means for detection of nucleic acid molecules are known to those skilled in the art. The procedure for the detection of nucleic acids can for example be carried out by a binding reaction of the molecule to be detected to complementary nucleic acid probes, proteins with binding specificity for the nucleic acids or any other entities specifically recognizing and binding to said nucleic acids. This method can be performed as well in vitro as directly in situ for example in the course of a detecting staining reaction. The use of this detection procedure is restricted to cases, where hybridisation properties of the respective frameshift mutations are significantly altered in comparison to the respective wild-type nucleic acids. Another way of detecting the frameshift polypeptides in a sample on the level of nucleic acids performed in the method according to the present invention may comprise an amplification reaction of nucleic acids. In these cases a subsequent reaction displaying the presence or absence of a frameshift mutation within the coding microsatellite region is necessary.

[0119] In another preferred embodiment of the invention the detection of the level of frameshift polypeptides is carried out by determining the level of expression of a protein. The determination of the frameshift polypeptides on the protein level can for example be carried out in a reaction comprising an antibody specific for the detection of the frameshift polypeptides. The antibodies can be used in many different detection techniques for example in western-blot, ELISA or immuno-precipitation. Generally antibody based detection can be carried out as well in vitro as directly in situ for example in the course of an immuno-histochemical staining reaction. Any other method for determining the amount of particular polypeptides in biological samples can be used according to the present invention.

[0120] Furthermore according to the present invention diagnosis may comprise detection of immunological entities specifically recognizing particular frameshift peptides using reagents that specifically recognise these immunological entities alone or in complex with their respective antigen (e.g. antibodies), or reagents, that are specifically recognized by the immunological entities themselves (e.g. the antigen). In one embodiment the antigen may be fused to another polypeptide, so as to allow binding of the antigen by the immunological entity in question and simultaneously binding of the second part of the fusion protein by another (labelled) antibody for the detection. The detection reaction for the immunological entities may comprise one or more reactions with detecting agents either recognizing the initial entities or recognizing the prior molecules used to recognize the immunological entities.

[0121] The detection reaction further may comprise a reporter reaction indicating the presence or absence and/or the level of the frameshift polypeptides or of the immunological entities. The reporter reaction may be for example a reaction producing a coloured compound, a bioluminescence reaction, a chemiluminescent reaction, a fluorescence reaction, generally a radiation emitting reaction etc. The detection reactions may for example employ antibodies or binding reagents that are detectably labelled.

[0122] Furthermore the binding of detection molecules to the peptides or immunological entities in question may be detected by any measurable changes in physical or physical-chemical properties, such as changes in spectroscopic properties, in magnetic resonance properties etc. Different polypeptides or immunological entities or immunological entities of different specificities may be recognized by different methods or agents. This may be due to difficulties in detection of several entities, or entities with particular specificities by a particular method. An advantage of the use of different detection techniques for different polypeptides and/or immunological entities or for immunological entities with different specificities may for example be, that the different reporter signals referring to different immunological entities could be distinguished.

[0123] Generally in a method according to the present invention the detection of different polypeptides, of different immunological entities such as the detection of immunoglobulins and the detection of immunocompetent cells may be performed simultaneously.

[0124] For all detection purposes optionally the original sample may be concentrated by any suitable means known to those of ordinary skill in the art. Furthermore steps may be involved to selectively extract polypeptides and/or immunological entities from the sample mixture such as affinity based purification techniques either employing specific antibodies or the respective antigen recognized by the entities in question.

[0125] Another aspect of the present invention is a testing kit for performing the method according to the present invention. The kit may be for example a diagnostic kit or a research kit.

[0126] A kit according to the present invention comprises at least an agent suitable for detecting the immunological entities according to the method disclosed herein. Furthermore a kit according to present invention may comprise:

a) reagents for the detection of the antibodies or cells specifically recognizing antigens. b) reagents and buffers commonly used for carrying out the detection reactions as described herein, such as buffers, detection-markers, carrier substances and others c) a sample for carrying out a positive control reaction, that may comprise an antigen or a set of antigens, to which all members of a target population of individuals have antibodies.

[0127] The reagent for the detection of the antibodies or cells specifically recognizing antigens may include any agent capable of binding to the antibodies or cells specifically recognizing antigens. Such reagents may include proteins, polypeptides, nucleic acids, peptide nucleic acids, glycoproteins, proteoglycans, polysaccharides or lipids.

[0128] The sample for carrying out a positive control may comprise for example an antigenic peptide or a set of antigenic peptides. Suitable antigens may include antigens, against which a wide percentage of the population has antibodies. Examples of such antigens may for example comprise antigens present in lysed E. coli cells, tetanus antigen, the viral capsid antigen of the Epstein-Barr virus, antigens derived from matrix proteins of Haemophilus influenzae. The antigens may for example be used as a mixture to ensure, that a particular individual actually displays a positive reaction.

[0129] The present invention provides compositions and methods for enhanced immunotherapy of disorders associated with MSI.sup.+ related occurrence of frameshift peptides. The invention provides sets for the immuno-therapy of said disorders, that address a wide range of different types of disorders in an organism and may thus be employed as a preventive vaccine against said disorders. Furthermore the invention also provides sets of polypeptides useful for the treatment of particular types of disorders. The use of sets of frameshift polypeptides for the immuno-therapy according to the present invention provides the means for a reliable treatment of degenerative disorders and cancers associated with frameshift mutations in coding microsatellites reducing the risk of escape of several tumor cells or of a population of tumor cells from being addressed by the therapy. Thus the method of the invention reduces the risk of recurrence of tumors after immuno-therapy employing CTLs, T-helper cells and possibly specific antibody producing B-cells raised against frameshift polypeptides characteristic for tumor cells. The present invention furthermore provides compositions and methods for enhanced diagnosis and therapy of disorders associated with MSI.sup.+ related occurrence of frameshift peptides. The invention provides new frameshift polypeptides for diagnosis therapy of said disorders, that may be used each alone or in combinations tailored, to address a wide range of different types of disorders in an organism and may thus be employed as a preventive vaccine against said disorders.

[0130] The following examples are given for illustration of the invention only and are not intended to limit the scope of the invention.

EXAMPLES

Example 1

Analysis of the Mutation Frequency of Genes Harbouring Repeat Tracts

[0131] Investigations were performed regarding the mutation frequencies of unpublished coding microsatellite regions. Nine novel coding microsatellites residing in genes not yet analyzed for frameshift mutations in MSI colorectal, endometrial or gastric tumors have been examined in the course of the studies leading to the present invention. They include three genes containing A11 repeats (TAF1B, MACS, HT001), five genes with A10 repeats (CHD2, UVRAG, TCF6L1, ABCF1, AIM2) and one gene harboring a G9 repeat (ELAVL3). The MSI status of these specimen was determined using the NCI ICG-HNPCC microsatellite reference marker panel (8). PCR reactions were performed as follows:

[0132] Genomic DNA was isolated from 5-8 haematoxylin and eosin stained 5 μm sections after microdissection, using the Qiamp Tissue Kit (Qiagen, Hilden, Germany). Preparation of DNA from cell lines was performed according to standard protocols. PCR primers were designed to closely flank the target sequence, yielding short amplimeres of about 100 base pairs thus allowing precise fragment sizing and robust amplification from archival tissues (Table 1). PCR reactions were performed in a total volume of 25 μl containing 50 ng genomic DNA, 2.5 μl 10× reaction buffer (Life Technologies, Karlsruhe, Germany), 1.5 mM MgCl₂, 200 μM dNTPs, 0.3 μM of each primer, and 0.5 U Taq DNA polymerase (Life Technologies) and using the following conditions: initial denaturation at 94° C. for 4 min, followed by 35 cycles of denaturation at 94° C. for 30 s, annealing at 58° C. for 45 s, and primer extension at 72° C. for 30 s. The final extension step was carried out at 72° C. for 6 min. PCR fragments were analyzed on an ALF DNA sequencing device (Amersham Pharmacia Biotech, Freiburg, Germany) using 6.6 polyacrylamide/7 M urea gels. Size, height and profile of microsatellite peaks were analyzed using the AlleleLinks software (Amersham Pharmacia Biotech). Coding microsatellite instability was scored, if smaller or larger-sized amplimeres were detected in tumor DNA compared to DNA from non-neoplastic cells. Allele intensities were determined and ratios of wild-type and novel alleles in normal and tumor tissues were calculated, defining a two-fold difference as threshold for allelic shifts. Similarly, unstable alleles in tumor cell lines were identified by comparison to 36 unmatched normal mucosae. In order to determine the predicted repeat type and length amplified coding microsatellites were subjected to Big Dye terminator cycle sequencing (Perkin Elmer, Darmstadt, Germany) and subsequent analysis on an ABI 310 sequencing device.

[0133] The frequencies of mutations in a particular microsatellite region examined herein are given in Tables 1 and 2. The mutation rates are calculated with respect to the total number of samples included in the study.

TABLE-US-00002 TABLE 1 Coding microsatellite genes investigated in MSI-H colorectal cancer. Repeat: type of nucleotide and length of repeat tract, n: number of samples investigated, mut.: number of samples mutated, %: percentage of mutated samples, repe gene acc.no. at n mut. % HPDMPK Y10936 T14 21 20 95% HT001 AF1135 A11 20 17 85% 39 TGFbIIR D50683 A10 735 602 82% U79260 U79260 T14 21 17 81% PTHL3 M2435 A11 21 17 81% 0 MACS D10522 A11 19 14 74% TAF1B L39061 A11 19 13 68% AC1 D82070 T10 21 14 67% AIM2 AF0247 A10 19 10 53% 14 BAX L22473 G8 538 235 44% SLC23A1 AF0583 C9 21 9 43% 19 ABCF1 AF0273 A10 19 8 42% 02 TCF-4 Y11306 A9 248 98 40% Caspase 5 U28015 A10 120 47 39% TCF6L1 M8507 A10 18 7 39% 9 FLT3LG U29874 C9 21 8 38% MSH3 J04810 A8 596 223 37% ELAVL3 D26158 G9 19 7 37% MAC30X L19183 A10 21 7 33% UVRAG X99050 A10 18 6 33% SLC4A3 U05596 C9 21 7 33% GRB-14 L76687 A9 57 18 32% RIZ U17838 A9 83 23 28% MBD4/MED1 AF0722 A10 83 22 27% 50 RAD50 U63139 A9 109 28 26% MSH6 U54777 C8 684 169 25% IGFIIR Y00285 G8 423 90 21% Axin2 AF2058 G7 45 9 20% 88 GART X54199 A10 21 4 19% Bcl-10 AF0822 A8 32 6 19% 83 RHAMM U29343 A9 57 9 16% PTEN U92436 A6 32 5 16% OGT U77413 T10 78 10 13% BLM U39817 A9 170 19 11% Fas X63717 T7 30 3 10% Apaf-1 AF0132 A8 43 4 9% 63 MLH3 AF1956 A9 99 9 9% 57 CBF M3719 A9 57 5 9% 7 HTP1 AB0245 A9 57 5 9% 82 RECQL L36140 A9 68 5 7% RBBP8 U72066 A9 70 5 7% MLH3 AF1956 A8 123 7 6% 57 PTEN U92436 A6 32 2 6% CHD2 AF0065 A10 19 1 5% 14 ATRmRNA U76308 A10 77 4 5% INPPL1/DRP L24444 C7 82 4 5% CHK1 AF0165 A9 21 1 5% 82 SYCP1 X95654 A10 71 3 4% RIZ U17838 A8 83 3 4% ANG2 AF0043 A9 57 2 4% 27 KKIAMRE/C U35146 A9 57 2 4% DKL2 ATM U82828 T7 39 1 3% CDX2 Y13709 G7 45 1 2% Axin2 AF2058 A6 45 1 2% 88 BRCA1 U14680 A8 92 2 2% Doc-1 U53445 A9 57 1 2% BRCA2 U43746 A8 119 2 2% RFC3 L07541 A10 76 1 1% 40 Casp8AP2/F AF1544 A9 13 0 0% LASH 15 ERCC5/XPG D16305 A9 13 0 0% HUMGPRKL L03718 A9 57 0 0% G DP2 U18422 A9 57 0 0% PMS2 U14658 A8 133 0 0% Caspase 1/l M8750 A8 42 0 0% CE 7 WRN L76937 A8 11 0 0% POLA X06745 A8 83 0 0% NSEP M8523 C8 132 0 0% 4 SHC1 U73377 G8 11 0 0% NBS1 AF0586 A7 39 0 0% 96 BRCA2 X95152 T6 31 0 0%

TABLE-US-00003 TABLE 2 Coding microsatellite genes investigated in MSI-H gastric cancer. Repeat: type of nucleotide and length of repeat tract, n: number of samples investigated, mut.: number of samples mutated, %: percentage of mutated samples repe gene acc.no. at n mut. % HPDMPK Y10936 T14 15 15 100% TAF1B L39061 A11 15 13 87% PTHL3 M2435 A11 15 11 73% 0 MACS D10522 A11 15 9 60% TGFbllR M8507 A10 227 122 54% 9 HT001 AF1135 A11 15 8 53% 39 MBD4/MED1 AF0722 A10 15 7 47% 50 RIZ U17838 A9 51 23 45% Caspase 5 U28015 A10 25 11 44% AIM2 AF0247 A10 15 6 40% 14 OGT U77413 T10 15 6 40% SLC23A1 AF0583 C9 15 6 40% 19 BAX L22473 G8 208 72 35% MSH6 U54777 C8 224 76 34% ABCF1 AF0273 A10 15 5 33% 02 FLT3LG U29874 C9 15 5 33% MSH3 J04810 A8 202 65 32% RAD50 Z75311 A9 36 10 28% PRKDC U63630 A10 30 8 27% SLC4A3 U05596 C9 15 4 27% BLM U39817 A9 36 9 25% ATRmRNA U76308 A10 18 4 22% B2M AB0212 A5 28 6 21% 88 MAC30X L19183 A10 15 3 20% RFC3 L07541 A10 15 3 20% UVRAG X99050 A10 15 3 20% AC1 D82070 T10 15 3 20% IGFllR Y00285 G8 202 36 18% Apaf-1 AF0132 A8 20 3 15% 63 TCF-4 Y11306 A9 23 3 13% SYCP1 X95654 A10 40 4 10% Bcl-10 AF0822 A8 20 2 10% 83 Fas X63717 T7 20 2 10% U79260 U79260 T14 15 1 7% CART X54199 A10 15 1 7% TCF6L1 M8507 A10 15 1 7% 9 ELAVL3 D26158 G9 15 1 7% ATM U82828 T7 36 2 6% BRCA1 U14680 A8 64 3 5% INPPL1/DRP L24444 C7 25 1 4% RIZ U17838 A8 51 1 2% CHD2 AF0065 A10 15 0 0% 14 CHK1 AF0165 A9 15 0 0% 82 BRCA2 U43746 A8 68 0 0% PMS2 U14658 A8 30 0 0% NSEP M8523 C8 50 0 0% 4 NBS1 AF0586 A7 36 0 0% 96

[0134] The results presented in Tables 1 and 2 show, that the tested microsatellite regions are frequently mutated in tumor samples.

Example 2

Detection of the Expression of Frameshift Mutated mRNA from Genes Harbouring Coding Microsatellite Regions Using PCR

[0135] Samples of colon, gastric and endometrial carcinomas are used to determine the expression of mRNA showing frameshift mutations in coding microsatellite regions using PCR and subsequent sequencing of the amplified nucleic acid products.

[0136] Tumors are collected, snap frozen, and stored at -80° C. They are verified to be composed predominantly of neoplastic cells by histopathological analysis. mRNA is isolated from tumors using Qiagen reagents (Qiagen, Hilden, Germany), and single-stranded cDNA is synthesized using Superscript II (Life Technologies, Inc.).

[0137] PCR reactions were performed in a total volume of 25 μl containing 50 ng cDNA, 2.5 μl 10× reaction buffer (Life Technologies, Karlsruhe, Germany), 1.5 mM MgCl₂, 200 μM dNTPs, 0.3 μM of each primer, and 0.5 U Taq DNA polymerase (Life Technologies) and using the following conditions: initial denaturation at 94° C. for 4 min, followed by 35 cycles of denaturation at 94° C. for 30 s, annealing at 58° C. for 45 s, and primer extension at 72° C. for 30 s. The final extension step was carried out at 72° C. for 6 min. PCR fragments were analyzed on an ALF DNA sequencing device (Amersham Pharmacia Biotech, Freiburg, Germany) using 6.6% polyacrylamide/7 M urea gels.

[0138] The experiments described show, that in the cases of the tested genes CHD2, UVRAG, ELAVL3, TCF6L1, ABCF1, AIM2, TAF1B, MACS and HT001 mutated coding microsatellite regions are transcribed into mRNA.

[0139] These results indicate, that the cells harbouring mutations in coding microsatellite regions of the nine genes tested express neo-polypeptides derived from these frameshift mutations.

Example 3

Stimulation of Cellular Immune Response by Frameshift Peptides

[0140] The present experiments were performed in order to determine, whether the frameshift peptides arising from mutations in coding microsatellite regions according to the present invention are suited to stimulate a cellular immune response. The experiments were performed as follows:

[0141] Peptides displaying HLA-A2.1-binding motifs were selected by taking advantage of specific computer programs [(Parker, Bednarek, & Coligan 1994); bimas.dcrt.nih.gov/molbio/hla_bind/ and (Rammensee et al. 1999); 134.2.96.221/scripts/MHCServerdll/home.htm].

TABLE-US-00004 TABLE 3 Frameshift Peptides analyzed for in vitro stimulation of a cellular immune response. All analyzed peptides (SEQ ID NOs: 75-106, as listed in Table 3 in order) are derived from (-1) mutations in microsatellites of the cognate proteins; the protein or nucleotide accession numbers are indicated within the table; the position of the start amino acid in the protein is indicated in the tables; the predicted binding scores to HLA-A2.1 using computer assisted analysis; Accession Theoretical Scores Protein Number Name Peptide Ken Parker SYFPEITHI TGF-betaRII (-1) AAA61164 FSP01 ¹²⁸-SLVRLSSCV 70 23 TGF-betaRII (-1) AAA61164 FSP02 ¹³¹-RLSSCVPVA 5 19 TGF-betaRII (-1) AAA61164 FSP03 ¹³⁵-CVPVALMSA 1 14 HPDMPK (-1) CAA71862 FSP04 ¹³⁶-LLHSAPTPSL 36 25 HPDMPK (-1) CAA71862 FSP05 ¹²⁹-FLSASHFLL 570 21 HPDMPK (-1) CAA71862 FSP07 ¹²⁵-RVFFFYQHL 39 15 OGT (-1) AAB63466 FSP06 ¹²⁸-SLYKFSPFPL 397 23 D070 (-1) BAA11534 FSP08 .sup. 35-KIFTFFFQL 1593 21 D070 (-1) BAA11534 FSP09 .sup. 68-ALLPAGPLT 28 21 D070 (-1) BAA11534 FSP10 .sup. 69-LLPAGPLTQT 29 20 U79260 (-1) AAB50206 FSP11 .sup. 59-TLSPGWSAV 118 25 U79260 (-1) AAB50206 FSP12 .sup. 83-ILLPQPPEWL 362 26 Sec63 (-1) AAC83375 FSP13 ⁵⁵¹-RQMESLGMKL 33 15 MAC30X (-1) AAA16188 FSP14 ¹⁹⁸-VEMPTGWLL 20 14 MAC30X (-1) AAA16188 FSP15 ¹⁹⁸-VEMPTGWLLV 14 15 FLT3L (-1) U29874 FSP16 ¹¹³-FQPPPAVFA 13 10 MSH-3 (-1) AAB47281 FSP17 ³⁸⁹-ALWECSLPQA 389 24 MSH-3 (-1) AAB47281 FSP18 ³⁸⁶-FLLALWECSL 364 25 MSH-3 (-1) AAB47281 FSP19 ³⁸⁷-LLALWECSL 36 26 MSH-3 (-1) AAB47281 FSP20 ³⁹⁴-SLPQARLCL 21 23 MSH-3 (-1) AAB47281 FSP21 ⁴⁰²-LIVSRTLLL 5 23 MSH-3 (-1) AAB47281 FSP22 ⁴⁰¹-CLIVSRTLL 21 22 MSH-3 (-1) AAB47281 FSP23 ⁴⁰³-IVSRTLLLV 24 21 MSH-3 (-1) AAB47281 FSP24 ³⁸²-KRATFLLAL 0,1 20 Caspase-5 (-1) U28015 FSP25 .sup. 61-KMFFMVFLI 1301 20 Caspase-5 (-1) U28015 FSP26 .sup. 67-FLIIWQNTM 22,85 21 TAF-1b (-1) L39061 FSP27 ¹⁰⁸-GMCVKVSSI 17 24 HT001 (-1) NP 054784 FSP30 ²⁸¹-VLRTEGEPL n.d. 21 MSH-3 (-1) AAB47281 FSP31 ⁴⁰²-LIVSRTLLLV 37 25 MSH-3 (-1) AAB47281 FSP32 ³⁹⁴-SLPQARLCLI 24 24 MSH-3 (-1) AAB47281 FSP33 ⁴⁰¹-CLIVSRTLLL 21 23 MSH-3 (-1) AAB47281 FSP34 ³⁹⁹-RLCLIVSRTL 4 22

[0142] Peptides were purchased from the peptide synthesis unit of the DKFZ. Stock solutions (10 mg/ml in DMSO) were stored at -70° C. and diluted to 1 mg/ml in PBS before use. T2 cells were pulsed with 50 μg/ml peptide and 5 μg/ml β2-microglobulin (Sigma; Deisenhofen, Germany) overnight at 37° C. The expression of HLA-A2.1 was then analyzed by flow cytometry using mAb BB7.2 followed by incubation with FITC-conjugated (ab')2 goat anti-mouse Ig (Vonderheide et al. 1999).

[0143] Peripheral blood was obtained from a healthy HLA-A2.1+ donor and collected in heparinized tubes. PBMNC were isolated by Ficoll-density gradient centrifugation. Whole CD3+ T-cells were isolated from PBMNC by magnetic depletion of non-T-cells using the MACS Pan T-cell Isolation Kit (Miltenyi; Bergisch Gladbach, Germany) according to manufacturer's instructions. Preparations contained at least 97% of CD3+ cells as assessed by immunophenotypic analysis.

[0144] HLA-A2.1-restricted peptides were FSP27 and FSP29 from a (-1) in the TAF1B-gene; FSP30 was derived from a (-1) mutation in the HT001 gene.

[0145] CD40 Bs of a HLA-A2.1+ donor were incubated with peptide (10 μg/ml) and human β2-microglobulin (3 μg/ml; Sigma) in serum-free Iscov's DMEM medium for one hour at room temperature, washed twice to remove excess of peptide, were irradiated (30Gy) and added to purified CD3+ autologous T-cells (>97% CD3+) at a ratio of 4:1 (T:CD40 Bs) in Iscov's MEM containing 10% human AB-serum, supplements (1:100) and hIL-7 (10 ng/ml, R&D). Cells were plated at a density of 2×106 T-cells/well in 1 ml of medium. After three days in culture they were fed with 1 ml complete medium. For restimulation of T-cells, this was repeated weekly. IL-2 was first given at day 21 (10 IU/ml, R&D), also at day 24 and from day 28 on only hIL-2 was used instead of hIL7.

[0146] ELISpot assays were performed as described elsewhere (Meyer et al. 1998). Briefly, nitrocellulose-96-well plates (Multiscreen; Millipore, Bedford, USA) were covered with mouse anti-human IFN-g monoclonal antibody (Mabtech, Sweden) and blocked with serum containing medium. Varying numbers of effector cells were plated in triplicates with 3.5×104 peptide-loaded T2 cells per well as targets. After incubation for 18 h, plates were washed, incubated with biotinylated rabbit anti-human IFN-g second antibody, washed again, incubated with streptavidin coupled alkaline phosphatase, followed by a final wash. Spots were detected by incubation with NBT/BCIP (Sigma) for 45 min, reaction was stopped with water, after drying spots were counted using the KS-ELISpot reader (Zeiss Kontron; Gottingen, Germany).

[0147] The analysis shows, that the used peptides are suited to raise an immune response. Peptides arising from frameshift mutations thus may be used to raise immune response for example in the course of vaccinations according to the present invention.

Example 4

Screening for Antibodies Directed Against Frameshift Peptides in Patient Samples

[0148] Serum of 25 patients with diagnosed colorectal carcinomas was tested for the presence of antibodies to a set of frameshift peptides arising from frameshift mutations in coding microsatellite regions of the following genes: CHD2, UVRAG, ELAVL3, TCF6L1, ABCF1, AIM2, TAF1B, MACS and HT001. As a control the serum of 50 normal individuals was tested.

[0149] For the test synthetic peptides representing immunogenic portions of all relevant frameshift peptides (see FIGS. 2-1 to 2-8) arising from the respective genes were spotted onto nylon membranes. The nylon membranes were subsequently incubated for one hour in phosphate-buffered saline (PBS) with 5% milk powder for blocking unspecific membrane binding. After washing the membranes 3× with PBS, the membranes were incubated with the test and control sera. The sera were diluted 1:1.000 in PBS/0.5% milk powder and incubated overnight with gentle shaking. Subsequently the sera were removed, and membranes were washed three times in PBS before they were incubated with a polyclonal alkaline phosphatase conjugated goat anit-human IgG antibody for one hour. Thereafter, the membranes were washed repeatedly with PBS/0.05% TWEEN20 before staining reaction was developed using nitroblue tetrazolium chloride and bromochoro-indoyl-phosphate (SigmaAldrich) in Tris-buffered saline (TBS). Binding of human antibodies specific for individual frameshift polypeptides thus was made visible by color-deposit on the respective membrane.

[0150] The results show, that in all samples of tumor patients antibodies directed against at least one peptide arising from frameshift mutations were present.

[0151] This illustrates, that the method according to the present invention may be used for diagnosis of diseases associated with frameshift mutations in coding regions of genes.

Example 5

In Vitro Stimulation of Cellular Immune Response by Frameshift Peptides

[0152] The present experiments were performed in order to determine, whether the frameshift peptides arising from mutations in coding microsatellite regions according to the present invention are suited to stimulate a cellular immune response. The experiments were performed as follows:

[0153] Peptides displaying HLA-A2.1-binding motifs were selected by taking advantage of specific computer programs [(Parker, Bednarek, & Coligan 1994); bimas.dcrt.nih.gov/molbio/hla_bind/ and (Rammensee et al. 1999); 134.2.96.221/scripts/MHCServerdll/home.htm]. Peptides were purchased from the peptide synthesis unit of the DKFZ. Stock solutions (10 mg/mi in DMSO) were stored at -70° C. and diluted to 1 mg/ml in PBS before use. T2 cells were pulsed with 50 μg/ml peptide and 5 μg/ml β2-microglobulin (Sigma; Deisenhofen, Germany) overnight at 37° C. The expression of HLA-A2.1 was then analyzed by flow cytometry using mAb BB7.2 followed by incubation with FITC-conjugated (ab')2 goat anti-mouse Ig (Vonderheide et al. 1999).

[0154] Peripheral blood was obtained from a healthy HLA-A2.1+ donor and collected in heparinized tubes. PBMNC were isolated by Ficoll-density gradient centrifugation. Whole CD3+ T-cells were isolated from PBMNC by magnetic depletion of non-T-cells using the MACS Pan T-Cell Isolation Kit (Miltenyi; Bergisch Gladbach, Germany) according to manufacturer's instructions. Preparations contained at least 97% of CD3+ cells as assessed by immunophenotypic analysis.

[0155] CD40 Bs of a HLA-A2.1+ donor were incubated with peptide (10 μg/ml) and human β2-microglobulin (3 μg/ml; Sigma) in serum-free Iscov's DMEM medium for one hour at room temperature, washed twice to remove excess of peptide, were irradiated (30Gy) and added to purified CD3+ autologous T-cells (>97% CD3+) at a ratio of 4:1 (T:CD40 Bs) in Iscov's MEM containing 10% human AB-serum, supplements (1:100) and hIL-7 (10 ng/ml, R&D). Cells were plated at a density of 2×10⁶ T-cells/well in 1 ml of medium. After three days in culture they were fed with 1 ml complete medium. For restimulation of T-cells, this was repeated weekly. IL-2 was first given at day 21 (10 IU/ml, R&D), also at day 24 and from day 28 on only hIL-2 was used instead of hIL7.

[0156] ELISpot assays were performed as described elsewhere (Meyer et al. 1998). Briefly, nitrocellulose-96-well plates (Multiscreen; Millipore, Bedford, USA) were covered with mouse anti-human IFN-g monoclonal antibody (Mabtech, Sweden) and blocked with serum containing medium. Varying numbers of effector cells were plated in triplicates with 3.5×10⁴ peptide-loaded T2 cells per well as targets. After incubation for 18 h, plates were washed, incubated with biotinylated rabbit anti-human IFN-g second antibody, washed again, incubated with streptavidin coupled alkaline phosphatase, followed by a final wash. Spots were detected by incubation with NBT/BCIP (Sigma) for 45 min, reaction was stopped with water, after drying spots were counted using the KS-ELISpot reader (Zeiss Kontron; Gottingen, Germany).

[0157] These procedures were performed for peptides derived from mutations in the coding regions of the following genes: TGFβRII, OGT, U79260, CASP 5, MSH 3, HPDMPK, HT001, TAF1B, D070, MAC30X, FLT3L and SEC63. Peptides are listed in FIGS. 2-1 to 2-8. Results for ELlspot analysis is shown in FIGS. 1-1 to 1-2.

[0158] The analysis shows, that the used peptides are suited to raise an immune response. Peptides arising from frameshift mutations thus may be used to raise immune response for example in the course of vaccinations according to the present invention.

Example 6

Cytotoxicity Assay Directed Against Cells Displaying Frameshift Peptides

[0159] CTL bulk cultures and/or CTL clones obtained according to the method described in Example 1 were tested for their cytotoxicity as follows:

[0160] Due to the limited amount of cell material clones were in some experiments pooled for the determination of the cytotoxicity.

[0161] To obtain cells presenting frameshift peptides on the one hand different MSI+ cell lines endogenously expressing mutated mRNA of the respective frameshift peptides of TGFβRII, OGT, U79260, CASP 5, MSH 3, HPDMPK, HT001, TAF1B, D070, MAC30X, FLT3L and SEC63 either expressed HLA-A2.1 endogenously or were stably transfected with HLA-A2.1 on the other hand several MSI- cell lines expressing HLA-A2.1 were transfected with the mutated full-length cDNA of the respective frameshift peptides (of TGFβRII, OGT, U79260, CASP 5, MSH 3, HPDMPK, HT001, TAF1B, D070, MAC30X, FLT3L and SEC63). After selection and expansion of the transfected cell lines for each respective frameshift peptide at least two stably transfected sub-cell lines were available. These cell lines were used in cytotoxicity assays, wherein negative controls were the respective untransfected MSI+ HLA-A2.1 negative and/or the MSI-, HLA-A2.1 positive cell lines.

[0162] It could be shown, that the transfected cell lines were lysed by the bulk cultures and/or pooled clones of CTLs. The reactivity was tested at different target cell to effector cell ratios. In average around 20%-30% of the target cells were lysed in the assays. The control cells were always lysed at a significantly lower percentage.

[0163] In FIGS. 3 and 4 results for the frameshift peptides FSP02 (TGFβRII(-1)) and FSP06 (OGT(-1)) respectively are shown. These results shall be representative for the results related to the other frameshift peptides, which rendered similar rates of lysis.

[0164] The experiments show, that frameshift peptides may generate immune response. The frameshift peptides may furthermore be applied for the detection of the presence of cytotoxic T-cells directed against a particular frameshift peptide.

Example 7

Screening for Antibodies Directed Against Frameshift Peptides in Patient Samples

[0165] Serum of 25 patients with diagnosed colorectal carcinomas was tested for the presence of antibodies to a set of frameshift peptides arising from frameshift mutations in coding microsatellite regions of the following genes: TGWU, U79260, CASP 5, HT001, PTHL3, MACS, TCF4, TAF1B, AC1, AIM2, SLC23A1, ABCF1, HSPC259, BAX, TCF6L1, FTL3L, OGT, ELAVL3, MAC30X, MAC30X, SLC4A3, PRKDC, UVRAG, MSH3 and SEC63. As a control the serum of 50 normal individuals was tested.

[0166] For the test synthetic peptides (20 to 40 mers, partly overlapping) representing immunogenic portions of all relevant frameshift peptides (see FIGS. 2-1 to 2-8) arising from the respective genes were spotted onto nylon membranes. The nylon membranes were subsequently incubated for one hour in phosphate-buffered saline (PBS) with 5% milk powder for blocking unspecific membrane binding. After washing the membranes 3× with PBS, the membranes were incubated with the test and control sera. The sera were diluted 1:1.000 in PBS/0.5% milk powder and incubated overnight with gentle shaking. Subsequently the sera were removed, and membranes were washed three times in PBS before they were incubated with a polyclonal alkaline phosphatase conjugated goat anti-human IgG antibody for one hour. Thereafter, the membranes were washed repeatedly with PBS/0.05% TWEEN20 before staining reaction was developed using nitroblue tetrazolium chloride and bromochloro-indoyl-phosphate (SigmaAldrich) in Tris-buffered saline (TBS). Binding of human antibodies specific for individual frameshift polypeptides thus was made visible by color-deposit on the respective membrane.

[0167] The results show, that in all samples of tumor patients antibodies directed against at least one peptide arising from frameshift mutations were present.

[0168] This illustrates, that the method according to the present invention may be used for diagnosis of diseases associated with frameshift mutations in coding regions of genes.

Sequence CWU 1

1

1201320PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 1Met Gln Arg Pro Asn Ala His Arg Ile Ser Gln Pro Ile Arg Gln Ile 1 5 10 15 Ile Tyr Gly Leu Leu Leu Asn Ala Ser Pro His Leu Asp Lys Thr Ser 20 25 30 Trp Asn Ala Leu Pro Pro Gln Pro Leu Ala Phe Ser Glu Val Glu Arg 35 40 45 Ile Asn Lys Asn Ile Arg Thr Ser Ile Ile Asp Ala Val Glu Leu Ala 50 55 60 Lys Asp His Ser Asp Leu Ser Arg Leu Thr Glu Leu Ser Leu Arg Arg 65 70 75 80Arg Gln Met Leu Leu Leu Glu Thr Leu Lys Val Lys Gln Thr Ile Leu 85 90 95 Glu Pro Ile Pro Thr Ser Leu Lys Leu Pro Ile Ala Val Ser Cys Tyr 100 105 110 Trp Leu Gln His Thr Glu Thr Lys Ala Lys Leu His His Leu Gln Ser 115 120 125 Leu Leu Leu Thr Met Leu Val Gly Pro Leu Ile Ala Ile Ile Asn Ser 130 135 140 Pro Gly Lys Glu Glu Leu Gln Glu Asp Gly Ala Lys Met Leu Tyr Ala 145 150 155 160Glu Phe Gln Arg Val Lys Ala Gln Thr Arg Leu Gly Thr Arg Leu Asp 165 170 175 Leu Asp Thr Ala His Ile Phe Cys Gln Trp Gln Ser Cys Leu Gln Met 180 185 190 Gly Met Tyr Leu Asn Gln Leu Leu Ser Thr Pro Leu Pro Glu Pro Asp 195 200 205 Leu Thr Arg Leu Tyr Ser Gly Ser Leu Val His Gly Leu Cys Gln Gln 210 215 220 Leu Leu Ala Ser Thr Ser Val Glu Ser Leu Leu Ser Ile Cys Pro Glu 225 230 235 240Ala Lys Gln Leu Tyr Glu Tyr Leu Phe Asn Ala Thr Arg Ser Tyr Ala 245 250 255 Pro Ala Glu Ile Phe Leu Pro Lys Gly Arg Ser Asn Ser Lys Lys Lys 260 265 270 Arg Gln Lys Lys Gln Asn Thr Ser Cys Ser Lys Asn Arg Gly Arg Thr 275 280 285 Thr Ala His Thr Lys Cys Trp Tyr Glu Gly Asn Asn Arg Phe Gly Leu 290 295 300 Leu Met Val Glu Asn Leu Glu Glu His Ser Glu Ala Ser Asn Ile Glu 305 310 315 3202304PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 2Met Gln Arg Pro Asn Ala His Arg Ile Ser Gln Pro Ile Arg Gln Ile 1 5 10 15 Ile Tyr Gly Leu Leu Leu Asn Ala Ser Pro His Leu Asp Lys Thr Ser 20 25 30 Trp Asn Ala Leu Pro Pro Gln Pro Leu Ala Phe Ser Glu Val Glu Arg 35 40 45 Ile Asn Lys Asn Ile Arg Thr Ser Ile Ile Asp Ala Val Glu Leu Ala 50 55 60 Lys Asp His Ser Asp Leu Ser Arg Leu Thr Glu Leu Ser Leu Arg Arg 65 70 75 80Arg Gln Met Leu Leu Leu Glu Thr Leu Lys Val Lys Gln Thr Ile Leu 85 90 95 Glu Pro Ile Pro Thr Ser Leu Lys Leu Pro Ile Ala Val Ser Cys Tyr 100 105 110 Trp Leu Gln His Thr Glu Thr Lys Ala Lys Leu His His Leu Gln Ser 115 120 125 Leu Leu Leu Thr Met Leu Val Gly Pro Leu Ile Ala Ile Ile Asn Ser 130 135 140 Pro Gly Lys Glu Glu Leu Gln Glu Asp Gly Ala Lys Met Leu Tyr Ala 145 150 155 160Glu Phe Gln Arg Val Lys Ala Gln Thr Arg Leu Gly Thr Arg Leu Asp 165 170 175 Leu Asp Thr Ala His Ile Phe Cys Gln Trp Gln Ser Cys Leu Gln Met 180 185 190 Gly Met Tyr Leu Asn Gln Leu Leu Ser Thr Pro Leu Pro Glu Pro Asp 195 200 205 Leu Thr Arg Leu Tyr Ser Gly Ser Leu Val His Gly Leu Cys Gln Gln 210 215 220 Leu Leu Ala Ser Thr Ser Val Glu Ser Leu Leu Ser Ile Cys Pro Glu 225 230 235 240Ala Lys Gln Leu Tyr Glu Tyr Leu Phe Asn Ala Thr Arg Ser Tyr Ala 245 250 255 Pro Ala Glu Ile Phe Leu Pro Lys Gly Arg Ser Asn Ser Lys Lys Lys 260 265 270 Gly Arg Arg Asn Arg Ile Pro Ala Val Leu Arg Thr Glu Gly Glu Pro 275 280 285 Leu His Thr Pro Ser Val Gly Met Arg Glu Thr Thr Gly Leu Gly Cys 290 295 300 3282PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 3Met Gln Arg Pro Asn Ala His Arg Ile Ser Gln Pro Ile Arg Gln Ile 1 5 10 15 Ile Tyr Gly Leu Leu Leu Asn Ala Ser Pro His Leu Asp Lys Thr Ser 20 25 30 Trp Asn Ala Leu Pro Pro Gln Pro Leu Ala Phe Ser Glu Val Glu Arg 35 40 45 Ile Asn Lys Asn Ile Arg Thr Ser Ile Ile Asp Ala Val Glu Leu Ala 50 55 60 Lys Asp His Ser Asp Leu Ser Arg Leu Thr Glu Leu Ser Leu Arg Arg 65 70 75 80Arg Gln Met Leu Leu Leu Glu Thr Leu Lys Val Lys Gln Thr Ile Leu 85 90 95 Glu Pro Ile Pro Thr Ser Leu Lys Leu Pro Ile Ala Val Ser Cys Tyr 100 105 110 Trp Leu Gln His Thr Glu Thr Lys Ala Lys Leu His His Leu Gln Ser 115 120 125 Leu Leu Leu Thr Met Leu Val Gly Pro Leu Ile Ala Ile Ile Asn Ser 130 135 140 Pro Gly Lys Glu Glu Leu Gln Glu Asp Gly Ala Lys Met Leu Tyr Ala 145 150 155 160Glu Phe Gln Arg Val Lys Ala Gln Thr Arg Leu Gly Thr Arg Leu Asp 165 170 175 Leu Asp Thr Ala His Ile Phe Cys Gln Trp Gln Ser Cys Leu Gln Met 180 185 190 Gly Met Tyr Leu Asn Gln Leu Leu Ser Thr Pro Leu Pro Glu Pro Asp 195 200 205 Leu Thr Arg Leu Tyr Ser Gly Ser Leu Val His Gly Leu Cys Gln Gln 210 215 220 Leu Leu Ala Ser Thr Ser Val Glu Ser Leu Leu Ser Ile Cys Pro Glu 225 230 235 240Ala Lys Gln Leu Tyr Glu Tyr Leu Phe Asn Ala Thr Arg Ser Tyr Ala 245 250 255 Pro Ala Glu Ile Phe Leu Pro Lys Gly Arg Ser Asn Ser Lys Lys Lys 260 265 270 Lys Ala Glu Glu Thr Glu Tyr Gln Leu Phe 275 280 4139PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 4Met Gly His Pro Arg Ala Ile Gln Pro Ser Val Phe Phe Ser Pro Tyr 1 5 10 15 Asp Val His Phe Leu Leu Tyr Pro Ile Arg Cys Pro Tyr Leu Lys Ile 20 25 30 Gly Arg Phe His Ile Lys Leu Lys Gly Leu His Phe Leu Phe Ser Phe 35 40 45 Leu Phe Phe Phe Phe Glu Thr Gln Ser His Ser Val Thr Arg Leu Glu 50 55 60 Cys Ser Gly Thr Ile Ser Ala His Cys Asn Leu Cys Leu Pro Gly Ser 65 70 75 80Ser Asn Ser Pro Ala Ser Ala Ser Arg Val Ala Gly Thr Ala Gly Thr 85 90 95 Cys Arg Arg Ala Gln Leu Ile Phe Val Phe Leu Ala Glu Met Gly Phe 100 105 110 His His Val Gly Arg Asp Gly Leu Asp Leu Asn Leu Val Ile His Pro 115 120 125 Pro Arg Ser Pro Lys Ala Leu Gly Leu Gln Ala 130 135 5101PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 5Met Gly His Pro Arg Ala Ile Gln Pro Ser Val Phe Phe Ser Pro Tyr 1 5 10 15 Asp Val His Phe Leu Leu Tyr Pro Ile Arg Cys Pro Tyr Leu Lys Ile 20 25 30 Gly Arg Phe His Ile Lys Leu Lys Gly Leu His Phe Leu Phe Ser Phe 35 40 45 Leu Phe Phe Phe Leu Arg His Ser Leu Thr Leu Ser Pro Gly Trp Ser 50 55 60 Ala Val Ala Arg Ser Arg Leu Thr Ala Thr Ser Ala Ser Gln Val Gln 65 70 75 80Val Ile Leu Leu Pro Gln Pro Pro Glu Trp Leu Gly Leu Gln Ala Arg 85 90 95 Ala Ala Ala Pro Ser 100 653PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 6Met Gly His Pro Arg Ala Ile Gln Pro Ser Val Phe Phe Ser Pro Tyr 1 5 10 15 Asp Val His Phe Leu Leu Tyr Pro Ile Arg Cys Pro Tyr Leu Lys Ile 20 25 30 Gly Arg Phe His Ile Lys Leu Lys Gly Leu His Phe Leu Phe Ser Phe 35 40 45 Leu Phe Phe Phe Phe 50 7209PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 7Met Gln Arg Arg Leu Val Gln Gln Trp Ser Val Ala Val Phe Leu Leu 1 5 10 15 Ser Tyr Ala Val Pro Ser Cys Gly Arg Ser Val Glu Gly Leu Ser Arg 20 25 30 Arg Leu Lys Arg Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly 35 40 45 Lys Ser Ile Gln Asp Leu Arg Arg Arg Phe Phe Leu His His Leu Ile 50 55 60 Ala Glu Ile His Thr Ala Glu Ile Arg Ala Thr Ser Glu Val Ser Pro 65 70 75 80Asn Ser Lys Pro Ser Pro Asn Thr Lys Asn His Pro Val Arg Phe Gly 85 90 95 Ser Asp Asp Glu Gly Arg Tyr Leu Thr Gln Glu Thr Asn Lys Val Glu 100 105 110 Thr Tyr Lys Glu Gln Pro Leu Lys Thr Pro Gly Lys Lys Lys Lys Gly 115 120 125 Lys Pro Gly Lys Arg Lys Glu Gln Glu Lys Lys Lys Arg Arg Thr Arg 130 135 140 Ser Ala Trp Leu Asp Ser Gly Val Thr Gly Ser Gly Leu Glu Gly Asp 145 150 155 160His Leu Ser Asp Thr Ser Thr Thr Ser Leu Glu Leu Asp Ser Arg Thr 165 170 175 Ala Leu Leu Trp Gly Leu Lys Lys Lys Lys Glu Asn Asn Arg Arg Thr 180 185 190 His His Met Gln Leu Met Ile Ser Leu Phe Lys Ser Pro Leu Leu Leu 195 200 205 Leu 8196PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 8Met Gln Arg Arg Leu Val Gln Gln Trp Ser Val Ala Val Phe Leu Leu 1 5 10 15 Ser Tyr Ala Val Pro Ser Cys Gly Arg Ser Val Glu Gly Leu Ser Arg 20 25 30 Arg Leu Lys Arg Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly 35 40 45 Lys Ser Ile Gln Asp Leu Arg Arg Arg Phe Phe Leu His His Leu Ile 50 55 60 Ala Glu Ile His Thr Ala Glu Ile Arg Ala Thr Ser Glu Val Ser Pro 65 70 75 80Asn Ser Lys Pro Ser Pro Asn Thr Lys Asn His Pro Val Arg Phe Gly 85 90 95 Ser Asp Asp Glu Gly Arg Tyr Leu Thr Gln Glu Thr Asn Lys Val Glu 100 105 110 Thr Tyr Lys Glu Gln Pro Leu Lys Thr Pro Gly Lys Lys Lys Lys Gly 115 120 125 Lys Pro Gly Lys Arg Lys Glu Gln Glu Lys Lys Lys Arg Arg Thr Arg 130 135 140 Ser Ala Trp Leu Asp Ser Gly Val Thr Gly Ser Gly Leu Glu Gly Asp 145 150 155 160His Leu Ser Asp Thr Ser Thr Thr Ser Leu Glu Leu Asp Ser Arg Thr 165 170 175 Ala Leu Leu Trp Gly Leu Lys Lys Lys Arg Lys Thr Thr Glu Glu His 180 185 190 Ile Ile Cys Asn 195 9202PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 9Met Gln Arg Arg Leu Val Gln Gln Trp Ser Val Ala Val Phe Leu Leu 1 5 10 15 Ser Tyr Ala Val Pro Ser Cys Gly Arg Ser Val Glu Gly Leu Ser Arg 20 25 30 Arg Leu Lys Arg Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly 35 40 45 Lys Ser Ile Gln Asp Leu Arg Arg Arg Phe Phe Leu His His Leu Ile 50 55 60 Ala Glu Ile His Thr Ala Glu Ile Arg Ala Thr Ser Glu Val Ser Pro 65 70 75 80Asn Ser Lys Pro Ser Pro Asn Thr Lys Asn His Pro Val Arg Phe Gly 85 90 95 Ser Asp Asp Glu Gly Arg Tyr Leu Thr Gln Glu Thr Asn Lys Val Glu 100 105 110 Thr Tyr Lys Glu Gln Pro Leu Lys Thr Pro Gly Lys Lys Lys Lys Gly 115 120 125 Lys Pro Gly Lys Arg Lys Glu Gln Glu Lys Lys Lys Arg Arg Thr Arg 130 135 140 Ser Ala Trp Leu Asp Ser Gly Val Thr Gly Ser Gly Leu Glu Gly Asp 145 150 155 160His Leu Ser Asp Thr Ser Thr Thr Ser Leu Glu Leu Asp Ser Arg Thr 165 170 175 Ala Leu Leu Trp Gly Leu Lys Lys Lys Lys Gly Lys Gln Gln Lys Asn 180 185 190 Thr Ser Tyr Ala Thr Asn Asp Leu Ile Ile 195 200 10567PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 10Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu 1 5 10 15 Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val 20 25 30 Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro 35 40 45 Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln 50 55 60 Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro 65 70 75 80Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr 85 90 95 Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile 100 105 110 Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys 115 120 125 Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn 130 135 140 Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu 145 150 155 160Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu 165 170 175 Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn 180 185 190 Arg Gln Gln Lys Leu Ser Ser Thr Trp Glu Thr Gly Lys Thr Arg Lys 195 200 205 Leu Met Glu Phe Ser Glu His Cys Ala Ile Ile Leu Glu Asp Asp Arg 210 215 220 Ser Asp Ile Ser Ser Thr Cys Ala Asn Asn Ile Asn His Asn Thr Glu 225 230 235 240Leu Leu Pro Ile Glu Leu Asp Thr Leu Val Gly Lys Gly Arg Phe Ala 245 250 255 Glu Val Tyr Lys Ala Lys Leu Lys Gln Asn Thr Ser Glu Gln Phe Glu 260 265 270 Thr Val Ala Val Lys Ile Phe Pro Tyr Glu Glu Tyr Ala Ser Trp Lys 275 280 285 Thr Glu Lys Asp Ile Phe Ser

Asp Ile Asn Leu Lys His Glu Asn Ile 290 295 300 Leu Gln Phe Leu Thr Ala Glu Glu Arg Lys Thr Glu Leu Gly Lys Gln 305 310 315 320Tyr Trp Leu Ile Thr Ala Phe His Ala Lys Gly Asn Leu Gln Glu Tyr 325 330 335 Leu Thr Arg His Val Ile Ser Trp Glu Asp Leu Arg Lys Leu Gly Ser 340 345 350 Ser Leu Ala Arg Gly Ile Ala His Leu His Ser Asp His Thr Pro Cys 355 360 365 Gly Arg Pro Lys Met Pro Ile Val His Arg Asp Leu Asn Ser Ser Asn 370 375 380 Ile Leu Val Lys Asn Asp Leu Thr Cys Cys Leu Cys Asp Phe Gly Leu 385 390 395 400Ser Leu Arg Leu Asp Pro Thr Leu Ser Val Asp Asp Leu Ala Asn Ser 405 410 415 Gly Gln Val Gly Thr Ala Arg Tyr Met Ala Pro Glu Val Leu Glu Ser 420 425 430 Arg Met Asn Leu Glu Asn Ala Glu Ser Phe Lys Gln Thr Asp Val Tyr 435 440 445 Ser Met Ala Leu Val Leu Trp Glu Met Thr Ser Arg Cys Asn Ala Val 450 455 460 Gly Glu Val Lys Asp Tyr Glu Pro Pro Phe Gly Ser Lys Val Arg Glu 465 470 475 480His Pro Cys Val Glu Ser Met Lys Asp Asn Val Leu Arg Asp Arg Gly 485 490 495 Arg Pro Glu Ile Pro Ser Phe Trp Leu Asn His Gln Gly Ile Gln Met 500 505 510 Val Cys Glu Thr Leu Thr Glu Cys Trp Asp His Asp Pro Glu Ala Arg 515 520 525 Leu Thr Ala Gln Cys Val Ala Glu Arg Phe Ser Glu Leu Glu His Leu 530 535 540 Asp Arg Leu Ser Gly Arg Ser Cys Ser Glu Glu Lys Ile Pro Glu Asp 545 550 555 560Gly Ser Leu Asn Thr Thr Lys 565 11161PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 11Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu 1 5 10 15 Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val 20 25 30 Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro 35 40 45 Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln 50 55 60 Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro 65 70 75 80Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr 85 90 95 Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile 100 105 110 Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Ser 115 120 125 Leu Val Arg Leu Ser Ser Cys Val Pro Val Ala Leu Met Ser Ala Met 130 135 140 Thr Thr Ser Ser Ser Gln Lys Asn Ile Thr Pro Ala Ile Leu Thr Cys 145 150 155 160Cys 12130PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 12Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu 1 5 10 15 Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val 20 25 30 Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro 35 40 45 Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln 50 55 60 Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro 65 70 75 80Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr 85 90 95 Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile 100 105 110 Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys 115 120 125 Ala Trp 13013332PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 13Met Gly Ala Gln Phe Ser Lys Thr Ala Ala Lys Gly Glu Ala Ala Ala 1 5 10 15 Glu Arg Pro Gly Glu Ala Ala Val Ala Ser Ser Pro Ser Lys Ala Asn 20 25 30 Gly Gln Glu Asn Gly His Val Lys Val Asn Gly Asp Ala Ser Pro Ala 35 40 45 Ala Ala Glu Ser Gly Ala Lys Glu Glu Leu Gln Ala Asn Gly Ser Ala 50 55 60 Pro Ala Ala Asp Lys Glu Glu Pro Ala Ala Ala Gly Ser Gly Ala Ala 65 70 75 80Ser Pro Ser Ser Ala Glu Lys Gly Glu Pro Ala Ala Ala Ala Ala Pro 85 90 95 Glu Ala Gly Ala Ser Pro Val Glu Lys Glu Ala Pro Ala Glu Gly Glu 100 105 110 Ala Ala Glu Pro Gly Ser Ala Thr Ala Ala Glu Gly Glu Ala Ala Ser 115 120 125 Ala Ala Ser Ser Thr Ser Ser Pro Lys Ala Glu Asp Gly Ala Thr Pro 130 135 140 Ser Pro Ser Asn Glu Thr Pro Lys Lys Lys Lys Lys Arg Phe Ser Phe 145 150 155 160Lys Lys Ser Phe Lys Leu Ser Gly Phe Ser Phe Lys Lys Asn Lys Lys 165 170 175 Glu Ala Gly Glu Gly Gly Glu Ala Glu Ala Pro Ala Ala Glu Gly Gly 180 185 190 Lys Asp Glu Ala Ala Gly Gly Ala Ala Ala Ala Ala Ala Glu Ala Gly 195 200 205 Ala Ala Ser Gly Glu Gln Ala Ala Ala Pro Gly Glu Glu Ala Ala Ala 210 215 220 Gly Glu Glu Gly Ala Ala Gly Gly Asp Pro Gln Glu Ala Lys Pro Gln 225 230 235 240Glu Ala Ala Val Ala Pro Glu Lys Pro Pro Ala Ser Asp Glu Thr Lys 245 250 255 Ala Ala Glu Glu Pro Ser Lys Val Glu Glu Lys Lys Ala Glu Glu Ala 260 265 270 Gly Ala Ser Ala Ala Ala Cys Glu Ala Pro Ser Ala Ala Gly Pro Gly 275 280 285 Ala Pro Pro Glu Gln Glu Ala Ala Pro Ala Glu Glu Pro Ala Ala Ala 290 295 300 Ala Ala Ser Ser Ala Cys Ala Ala Pro Ser Gln Glu Ala Gln Pro Glu 305 310 315 320Cys Ser Pro Glu Ala Pro Pro Ala Glu Ala Ala Glu 325 330 14165PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 14Met Gly Ala Gln Phe Ser Lys Thr Ala Ala Lys Gly Glu Ala Ala Ala 1 5 10 15 Glu Arg Pro Gly Glu Ala Ala Val Ala Ser Ser Pro Ser Lys Ala Asn 20 25 30 Gly Gln Glu Asn Gly His Val Lys Val Asn Gly Asp Ala Ser Pro Ala 35 40 45 Ala Ala Glu Ser Gly Ala Lys Glu Glu Leu Gln Ala Asn Gly Ser Ala 50 55 60 Pro Ala Ala Asp Lys Glu Glu Pro Ala Ala Ala Gly Ser Gly Ala Ala 65 70 75 80Ser Pro Ser Ser Ala Glu Lys Gly Glu Pro Ala Ala Ala Ala Ala Pro 85 90 95 Glu Ala Gly Ala Ser Pro Val Glu Lys Glu Ala Pro Ala Glu Gly Glu 100 105 110 Ala Ala Glu Pro Gly Ser Ala Thr Ala Ala Glu Gly Glu Ala Ala Ser 115 120 125 Ala Ala Ser Ser Thr Ser Ser Pro Lys Ala Glu Asp Gly Ala Thr Pro 130 135 140 Ser Pro Ser Asn Glu Thr Pro Lys Lys Lys Arg Ser Ala Phe Pro Ser 145 150 155 160Arg Ser Leu Ser Ser 16515182PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 15Met Gly Ala Gln Phe Ser Lys Thr Ala Ala Lys Gly Glu Ala Ala Ala 1 5 10 15 Glu Arg Pro Gly Glu Ala Ala Val Ala Ser Ser Pro Ser Lys Ala Asn 20 25 30 Gly Gln Glu Asn Gly His Val Lys Val Asn Gly Asp Ala Ser Pro Ala 35 40 45 Ala Ala Glu Ser Gly Ala Lys Glu Glu Leu Gln Ala Asn Gly Ser Ala 50 55 60 Pro Ala Ala Asp Lys Glu Glu Pro Ala Ala Ala Gly Ser Gly Ala Ala 65 70 75 80Ser Pro Ser Ser Ala Glu Lys Gly Glu Pro Ala Ala Ala Ala Ala Pro 85 90 95 Glu Ala Gly Ala Ser Pro Val Glu Lys Glu Ala Pro Ala Glu Gly Glu 100 105 110 Ala Ala Glu Pro Gly Ser Ala Thr Ala Ala Glu Gly Glu Ala Ala Ser 115 120 125 Ala Ala Ser Ser Thr Ser Ser Pro Lys Ala Glu Asp Gly Ala Thr Pro 130 135 140 Ser Pro Ser Asn Glu Thr Pro Lys Lys Lys Lys Glu Ala Leu Phe Leu 145 150 155 160Gln Glu Val Phe Gln Ala Glu Arg Leu Leu Leu Gln Glu Glu Gln Glu 165 170 175 Gly Gly Trp Arg Arg Arg 180 16596PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 16Met Pro Gln Leu Asn Gly Gly Gly Gly Asp Asp Leu Gly Ala Asn Asp 1 5 10 15 Glu Leu Ile Ser Phe Lys Asp Glu Gly Glu Gln Glu Glu Lys Ser Ser 20 25 30 Glu Asn Ser Ser Ala Glu Arg Asp Leu Ala Asp Val Lys Ser Ser Leu 35 40 45 Val Asn Glu Ser Glu Thr Asn Gln Asn Ser Ser Ser Asp Ser Glu Ala 50 55 60 Glu Arg Arg Pro Pro Pro Arg Ser Glu Ser Phe Arg Asp Lys Ser Arg 65 70 75 80Glu Ser Leu Glu Glu Ala Ala Lys Arg Gln Asp Gly Gly Leu Phe Lys 85 90 95 Gly Pro Pro Tyr Pro Gly Tyr Pro Phe Ile Met Ile Pro Asp Leu Thr 100 105 110 Ser Pro Tyr Leu Pro Asn Gly Ser Leu Ser Pro Thr Ala Arg Thr Tyr 115 120 125 Leu Gln Met Lys Trp Pro Leu Leu Asp Val Gln Ala Gly Ser Leu Gln 130 135 140 Ser Arg Gln Ala Leu Lys Asp Ala Arg Ser Pro Ser Pro Ala His Ile 145 150 155 160Val Ser Asn Lys Val Pro Val Val Gln His Pro His His Val His Pro 165 170 175 Leu Thr Pro Leu Ile Thr Tyr Ser Asn Glu His Phe Thr Pro Gly Asn 180 185 190 Pro Pro Pro His Leu Pro Ala Asp Val Asp Pro Lys Thr Gly Ile Pro 195 200 205 Arg Pro Pro His Pro Pro Asp Ile Ser Pro Tyr Tyr Pro Leu Ser Pro 210 215 220 Gly Thr Val Gly Gln Ile Pro His Pro Leu Gly Trp Leu Val Pro Gln 225 230 235 240Gln Gly Gln Pro Val Tyr Pro Ile Thr Thr Gly Gly Phe Arg His Pro 245 250 255 Tyr Pro Thr Ala Leu Thr Val Asn Ala Ser Val Ser Arg Phe Pro Pro 260 265 270 His Met Val Pro Pro His His Thr Leu His Thr Thr Gly Ile Pro His 275 280 285 Pro Ala Ile Val Thr Pro Thr Val Lys Gln Glu Ser Ser Gln Ser Asp 290 295 300 Val Gly Ser Leu His Ser Ser Lys His Gln Asp Ser Lys Lys Glu Glu 305 310 315 320Glu Lys Lys Lys Pro His Ile Lys Lys Pro Leu Asn Ala Phe Met Leu 325 330 335 Tyr Met Lys Glu Met Arg Ala Lys Val Val Ala Glu Cys Thr Leu Lys 340 345 350 Glu Ser Ala Ala Ile Asn Gln Ile Leu Gly Arg Arg Trp His Ala Leu 355 360 365 Ser Arg Glu Glu Gln Ala Lys Tyr Tyr Glu Leu Ala Arg Lys Glu Arg 370 375 380 Gln Leu His Met Gln Leu Tyr Pro Gly Trp Ser Ala Arg Asp Asn Tyr 385 390 395 400Gly Lys Lys Lys Lys Arg Lys Arg Asp Lys Gln Pro Gly Glu Thr Asn 405 410 415 Glu His Ser Glu Cys Phe Leu Asn Pro Cys Leu Ser Leu Pro Pro Ile 420 425 430 Thr Asp Leu Ser Ala Pro Lys Lys Cys Arg Ala Arg Phe Gly Leu Asp 435 440 445 Gln Gln Asn Asn Trp Cys Gly Pro Cys Arg Arg Lys Lys Lys Cys Val 450 455 460 Arg Tyr Ile Gln Gly Glu Gly Ser Cys Leu Ser Pro Pro Ser Ser Asp 465 470 475 480Gly Ser Leu Leu Asp Ser Pro Pro Pro Ser Pro Asn Leu Leu Gly Ser 485 490 495 Pro Pro Arg Asp Ala Lys Ser Gln Thr Glu Gln Thr Gln Pro Leu Ser 500 505 510 Leu Ser Leu Lys Pro Asp Pro Leu Ala His Leu Ser Met Met Pro Pro 515 520 525 Pro Pro Ala Leu Leu Leu Ala Glu Ala Thr His Lys Ala Ser Ala Leu 530 535 540 Cys Pro Asn Gly Ala Leu Asp Leu Pro Pro Ala Ala Leu Gln Pro Ala 545 550 555 560Ala Pro Ser Ser Ser Ile Ala Gln Pro Ser Thr Ser Trp Leu His Ser 565 570 575 His Ser Ser Leu Ala Gly Thr Gln Pro Gln Pro Leu Ser Leu Val Thr 580 585 590 Lys Ser Leu Glu 595 17483PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 17Met Pro Gln Leu Asn Gly Gly Gly Gly Asp Asp Leu Gly Ala Asn Asp 1 5 10 15 Glu Leu Ile Ser Phe Lys Asp Glu Gly Glu Gln Glu Glu Lys Ser Ser 20 25 30 Glu Asn Ser Ser Ala Glu Arg Asp Leu Ala Asp Val Lys Ser Ser Leu 35 40 45 Val Asn Glu Ser Glu Thr Asn Gln Asn Ser Ser Ser Asp Ser Glu Ala 50 55 60 Glu Arg Arg Pro Pro Pro Arg Ser Glu Ser Phe Arg Asp Lys Ser Arg 65 70 75 80Glu Ser Leu Glu Glu Ala Ala Lys Arg Gln Asp Gly Gly Leu Phe Lys 85 90 95 Gly Pro Pro Tyr Pro Gly Tyr Pro Phe Ile Met Ile Pro Asp Leu Thr 100 105 110 Ser Pro Tyr Leu Pro Asn Gly Ser Leu Ser Pro Thr Ala Arg Thr Tyr 115 120 125 Leu Gln Met Lys Trp Pro Leu Leu Asp Val Gln Ala Gly Ser Leu Gln 130 135 140 Ser Arg Gln Ala Leu Lys Asp Ala Arg Ser Pro Ser Pro Ala His Ile 145 150 155 160Val Ser Asn Lys Val Pro Val Val Gln His Pro His His Val His Pro 165 170 175 Leu Thr Pro Leu Ile Thr Tyr Ser Asn Glu His Phe Thr Pro Gly Asn 180 185 190 Pro Pro Pro His Leu Pro Ala Asp Val Asp Pro Lys Thr Gly Ile Pro 195 200 205 Arg Pro Pro His Pro Pro Asp Ile Ser Pro Tyr Tyr Pro Leu Ser Pro 210 215 220 Gly Thr Val Gly Gln Ile Pro His Pro Leu Gly Trp Leu Val Pro Gln 225 230 235 240Gln Gly Gln Pro Val Tyr Pro Ile Thr Thr Gly Gly Phe Arg His Pro 245 250 255 Tyr Pro Thr Ala Leu Thr Val Asn Ala Ser Val Ser Arg Phe Pro Pro 260 265 270 His Met Val Pro Pro His His Thr Leu His Thr Thr Gly Ile Pro His 275 280 285 Pro Ala Ile Val Thr Pro Thr Val Lys Gln Glu Ser Ser Gln Ser Asp 290 295 300

Val Gly Ser Leu His Ser Ser Lys His Gln Asp Ser Lys Lys Glu Glu 305 310 315 320Glu Lys Lys Lys Pro His Ile Lys Lys Pro Leu Asn Ala Phe Met Leu 325 330 335 Tyr Met Lys Glu Met Arg Ala Lys Val Val Ala Glu Cys Thr Leu Lys 340 345 350 Glu Ser Ala Ala Ile Asn Gln Ile Leu Gly Arg Arg Trp His Ala Leu 355 360 365 Ser Arg Glu Glu Gln Ala Lys Tyr Tyr Glu Leu Ala Arg Lys Glu Arg 370 375 380 Gln Leu His Met Gln Leu Tyr Pro Gly Trp Ser Ala Arg Asp Asn Tyr 385 390 395 400Gly Lys Lys Lys Lys Arg Lys Arg Asp Lys Gln Pro Gly Glu Thr Asn 405 410 415 Glu His Ser Glu Cys Phe Leu Asn Pro Cys Leu Ser Leu Pro Pro Ile 420 425 430 Thr Asp Leu Ser Ala Pro Lys Lys Cys Arg Ala Arg Phe Gly Leu Asp 435 440 445 Gln Gln Asn Asn Trp Cys Gly Pro Cys Arg Arg Lys Lys Ser Ala Phe 450 455 460 Ala Thr Tyr Lys Val Lys Ala Ala Ala Ser Ala His Pro Leu Gln Met 465 470 475 480Glu Ala Tyr 18469PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 18Met Pro Gln Leu Asn Gly Gly Gly Gly Asp Asp Leu Gly Ala Asn Asp 1 5 10 15 Glu Leu Ile Ser Phe Lys Asp Glu Gly Glu Gln Glu Glu Lys Ser Ser 20 25 30 Glu Asn Ser Ser Ala Glu Arg Asp Leu Ala Asp Val Lys Ser Ser Leu 35 40 45 Val Asn Glu Ser Glu Thr Asn Gln Asn Ser Ser Ser Asp Ser Glu Ala 50 55 60 Glu Arg Arg Pro Pro Pro Arg Ser Glu Ser Phe Arg Asp Lys Ser Arg 65 70 75 80Glu Ser Leu Glu Glu Ala Ala Lys Arg Gln Asp Gly Gly Leu Phe Lys 85 90 95 Gly Pro Pro Tyr Pro Gly Tyr Pro Phe Ile Met Ile Pro Asp Leu Thr 100 105 110 Ser Pro Tyr Leu Pro Asn Gly Ser Leu Ser Pro Thr Ala Arg Thr Tyr 115 120 125 Leu Gln Met Lys Trp Pro Leu Leu Asp Val Gln Ala Gly Ser Leu Gln 130 135 140 Ser Arg Gln Ala Leu Lys Asp Ala Arg Ser Pro Ser Pro Ala His Ile 145 150 155 160Val Ser Asn Lys Val Pro Val Val Gln His Pro His His Val His Pro 165 170 175 Leu Thr Pro Leu Ile Thr Tyr Ser Asn Glu His Phe Thr Pro Gly Asn 180 185 190 Pro Pro Pro His Leu Pro Ala Asp Val Asp Pro Lys Thr Gly Ile Pro 195 200 205 Arg Pro Pro His Pro Pro Asp Ile Ser Pro Tyr Tyr Pro Leu Ser Pro 210 215 220 Gly Thr Val Gly Gln Ile Pro His Pro Leu Gly Trp Leu Val Pro Gln 225 230 235 240Gln Gly Gln Pro Val Tyr Pro Ile Thr Thr Gly Gly Phe Arg His Pro 245 250 255 Tyr Pro Thr Ala Leu Thr Val Asn Ala Ser Val Ser Arg Phe Pro Pro 260 265 270 His Met Val Pro Pro His His Thr Leu His Thr Thr Gly Ile Pro His 275 280 285 Pro Ala Ile Val Thr Pro Thr Val Lys Gln Glu Ser Ser Gln Ser Asp 290 295 300 Val Gly Ser Leu His Ser Ser Lys His Gln Asp Ser Lys Lys Glu Glu 305 310 315 320Glu Lys Lys Lys Pro His Ile Lys Lys Pro Leu Asn Ala Phe Met Leu 325 330 335 Tyr Met Lys Glu Met Arg Ala Lys Val Val Ala Glu Cys Thr Leu Lys 340 345 350 Glu Ser Ala Ala Ile Asn Gln Ile Leu Gly Arg Arg Trp His Ala Leu 355 360 365 Ser Arg Glu Glu Gln Ala Lys Tyr Tyr Glu Leu Ala Arg Lys Glu Arg 370 375 380 Gln Leu His Met Gln Leu Tyr Pro Gly Trp Ser Ala Arg Asp Asn Tyr 385 390 395 400Gly Lys Lys Lys Lys Arg Lys Arg Asp Lys Gln Pro Gly Glu Thr Asn 405 410 415 Glu His Ser Glu Cys Phe Leu Asn Pro Cys Leu Ser Leu Pro Pro Ile 420 425 430 Thr Asp Leu Ser Ala Pro Lys Lys Cys Arg Ala Arg Phe Gly Leu Asp 435 440 445 Gln Gln Asn Asn Trp Cys Gly Pro Cys Arg Arg Lys Lys Lys Val Arg 450 455 460 Ser Leu His Thr Arg 465 19556PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 19Ile Pro Ala Phe Pro Ala Gly Thr Val Leu Gln Pro Phe Pro Glu Ala 1 5 10 15 Ala Leu Ala Thr Arg Val Thr Val Pro Ala Val Glu Ala Pro Ala Ala 20 25 30 Pro Arg Leu Asp Leu Glu Glu Ser Glu Glu Phe Lys Glu Arg Cys Thr 35 40 45 Gln Cys Ala Ala Val Ser Trp Gly Leu Thr Asp Glu Gly Lys Tyr Tyr 50 55 60 Cys Thr Ser Cys His Asn Val Thr Glu Arg Tyr Gln Glu Val Thr Asn 65 70 75 80Thr Asp Leu Ile Pro Asn Thr Gln Ile Lys Ala Leu Asn Arg Gly Leu 85 90 95 Lys Lys Lys Asn Asn Thr Glu Lys Gly Trp Asp Trp Tyr Val Cys Glu 100 105 110 Gly Phe Gln Tyr Ile Leu Tyr Gln Gln Ala Glu Ala Leu Lys Asn Leu 115 120 125 Gly Val Gly Pro Glu Leu Lys Asn Asp Val Leu His Asn Phe Trp Lys 130 135 140 Arg Tyr Leu Gln Lys Ser Lys Gln Ala Tyr Cys Lys Asn Pro Val Tyr 145 150 155 160Thr Thr Gly Arg Lys Pro Thr Val Leu Glu Asp Asn Leu Ser His Ser 165 170 175 Asp Trp Ala Ser Glu Pro Glu Leu Leu Ser Asp Val Ser Cys Pro Pro 180 185 190 Phe Leu Glu Ser Gly Ala Glu Ser Gln Ser Asp Ile His Thr Arg Lys 195 200 205 Pro Phe Pro Val Ser Lys Ala Ser Gln Ser Glu Thr Ser Val Cys Ser 210 215 220 Gly Ser Leu Asp Gly Val Glu Tyr Ser Gln Arg Lys Glu Lys Gly Ile 225 230 235 240Val Lys Met Thr Met Pro Gln Thr Leu Ala Phe Cys Tyr Leu Ser Leu 245 250 255 Leu Trp Gln Arg Glu Ala Ile Thr Leu Ser Asp Leu Leu Arg Phe Val 260 265 270 Glu Glu Asp His Ile Pro Tyr Ile Asn Ala Phe Gln His Phe Pro Glu 275 280 285 Gln Met Lys Leu Tyr Gly Arg Asp Arg Gly Ile Phe Gly Ile Glu Ser 290 295 300 Trp Pro Asp Tyr Glu Asp Ile Tyr Lys Lys Thr Ile Glu Val Gly Thr 305 310 315 320Phe Leu Asp Leu Pro Arg Phe Pro Asp Ile Thr Glu Asp Cys Tyr Leu 325 330 335 His Pro Asn Ile Leu Cys Met Lys Tyr Leu Met Glu Val Asn Leu Pro 340 345 350 Asp Glu Met His Ser Leu Thr Cys His Val Val Lys Met Thr Gly Met 355 360 365 Gly Glu Val Asp Phe Leu Thr Phe Asp Pro Ile Ala Lys Met Ala Lys 370 375 380 Ala Val Lys Tyr Asp Val Gln Ala Val Ala Ile Ile Val Val Val Leu 385 390 395 400Lys Leu Leu Phe Leu Met Asp Asp Ser Phe Glu Trp Ser Leu Ser Asn 405 410 415 Leu Ala Glu Lys His Asn Glu Lys Asn Lys Lys Asp Lys Pro Trp Phe 420 425 430 Asp Phe Arg Lys Trp Tyr Gln Ile Met Lys Lys Ala Phe Asp Glu Lys 435 440 445 Lys Gln Lys Trp Glu Glu Ala Arg Ala Lys Tyr Leu Trp Lys Ser Glu 450 455 460 Lys Pro Leu Tyr Tyr Ser Phe Val Asp Lys Pro Val Ala Tyr Lys Lys 465 470 475 480Arg Glu Met Val Val Asn Leu Gln Lys Gln Phe Ser Thr Leu Val Asp 485 490 495 Ser Thr Ala Thr Ala Gly Lys Lys Ser Pro Ser Ser Phe Gln Phe Asn 500 505 510 Trp Thr Glu Glu Asp Thr Asp Arg Thr Cys Phe His Gly His Ser Leu 515 520 525 Gln Gly Val Leu Lys Glu Lys Gly Gln Ser Leu Leu Thr Lys Asn Ser 530 535 540 Leu Tyr Trp Leu Ser Thr Gln Lys Phe Cys Arg Trp 545 550 555 20124PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 20Ile Pro Ala Phe Pro Ala Gly Thr Val Leu Gln Pro Phe Pro Glu Ala 1 5 10 15 Ala Leu Ala Thr Arg Val Thr Val Pro Ala Val Glu Ala Pro Ala Ala 20 25 30 Pro Arg Leu Asp Leu Glu Glu Ser Glu Glu Phe Lys Glu Arg Cys Thr 35 40 45 Gln Cys Ala Ala Val Ser Trp Gly Leu Thr Asp Glu Gly Lys Tyr Tyr 50 55 60 Cys Thr Ser Cys His Asn Val Thr Glu Arg Tyr Gln Glu Val Thr Asn 65 70 75 80Thr Asp Leu Ile Pro Asn Thr Gln Ile Lys Ala Leu Asn Arg Gly Leu 85 90 95 Lys Lys Lys Thr Ile Leu Lys Lys Ala Gly Ile Gly Met Cys Val Lys 100 105 110 Val Ser Ser Ile Phe Phe Ile Asn Lys Gln Lys Pro 115 120 21102PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 21Ile Pro Ala Phe Pro Ala Gly Thr Val Leu Gln Pro Phe Pro Glu Ala 1 5 10 15 Ala Leu Ala Thr Arg Val Thr Val Pro Ala Val Glu Ala Pro Ala Ala 20 25 30 Pro Arg Leu Asp Leu Glu Glu Ser Glu Glu Phe Lys Glu Arg Cys Thr 35 40 45 Gln Cys Ala Ala Val Ser Trp Gly Leu Thr Asp Glu Gly Lys Tyr Tyr 50 55 60 Cys Thr Ser Cys His Asn Val Thr Glu Arg Tyr Gln Glu Val Thr Asn 65 70 75 80Thr Asp Leu Ile Pro Asn Thr Gln Ile Lys Ala Leu Asn Arg Gly Leu 85 90 95 Lys Lys Lys Lys Gln Tyr 100 2293PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 22Met Asp Thr Gln Lys Gln Ile His Lys Thr His Asn Ser Lys Asn Gln 1 5 10 15 Phe Phe Thr Ile Phe Phe Phe Leu Ser Val Glu Phe Gly Lys Glu Gly 20 25 30 Thr Arg Lys Asn Phe Tyr Leu Leu Leu Ser Ile Gly His Tyr Gly Arg 35 40 45 Lys Ser Arg Arg Ala Asp Leu Gly Thr Ala Asp Thr Ala Asp Lys Thr 50 55 60 Glu Pro Glu Cys Phe Ala Ala Ser Trp Thr Phe Asp Pro Asn Pro Ser 65 70 75 80Val Thr Val Ser Gly Ala His Ser Thr Ala Val His Gln 85 90 2380PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 23Met Asp Thr Gln Lys Gln Ile His Lys Thr His Asn Ser Lys Asn Gln 1 5 10 15 Phe Phe Thr Ile Phe Phe Ser Cys Gln Leu Asn Leu Gly Arg Lys Glu 20 25 30 His Ala Lys Ile Phe Thr Phe Phe Phe Gln Leu Asp Thr Met Asp Gly 35 40 45 Asn Pro Gly Glu Leu Thr Leu Glu Leu Gln Thr Leu Gln Ile Lys Gln 50 55 60 Ser Gln Asn Ala Leu Leu Pro Ala Gly Pro Leu Thr Gln Thr Pro Val 65 70 75 802426PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 24Met Asp Thr Gln Lys Gln Ile His Lys Thr His Asn Ser Lys Asn Gln 1 5 10 15 Phe Phe Thr Ile Phe Phe Phe Pro Val Ser 20 25 25760PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 25Met Ala Gly Gln Gln Phe Gln Tyr Asp Asp Ser Gly Asn Thr Phe Phe 1 5 10 15 Tyr Phe Leu Thr Ser Phe Val Gly Leu Ile Val Ile Pro Ala Thr Tyr 20 25 30 Tyr Leu Trp Pro Arg Asp Gln Asn Ala Glu Gln Ile Arg Leu Lys Asn 35 40 45 Ile Arg Lys Val Tyr Gly Arg Cys Met Trp Tyr Arg Leu Arg Leu Leu 50 55 60 Lys Pro Gln Pro Asn Ile Ile Pro Thr Val Lys Lys Ile Val Leu Leu 65 70 75 80Ala Gly Trp Ala Leu Phe Leu Phe Leu Ala Tyr Lys Val Ser Lys Thr 85 90 95 Asp Arg Glu Tyr Gln Glu Tyr Asn Pro Tyr Glu Val Leu Asn Leu Asp 100 105 110 Pro Gly Ala Thr Val Ala Glu Ile Lys Lys Gln Tyr Arg Leu Leu Ser 115 120 125 Leu Lys Tyr His Pro Asp Lys Gly Gly Asp Glu Val Met Phe Met Arg 130 135 140 Ile Ala Lys Ala Tyr Ala Ala Leu Thr Asp Glu Glu Ser Arg Lys Asn 145 150 155 160Trp Glu Glu Phe Gly Asn Pro Asp Gly Pro Gln Ala Thr Ser Phe Gly 165 170 175 Ile Ala Leu Pro Ala Trp Ile Val Asp Gln Lys Asn Ser Ile Leu Val 180 185 190 Leu Leu Val Tyr Gly Leu Ala Phe Met Val Ile Leu Pro Val Val Val 195 200 205 Gly Ser Trp Trp Tyr Arg Ser Ile Arg Tyr Ser Gly Asp Gln Ile Leu 210 215 220 Ile Arg Thr Thr Gln Ile Tyr Thr Tyr Phe Val Tyr Lys Thr Arg Asn 225 230 235 240Met Asp Met Lys Arg Leu Ile Met Val Leu Ala Gly Ala Ser Glu Phe 245 250 255 Asp Pro Gln Tyr Asn Lys Asp Ala Thr Ser Arg Pro Thr Asp Asn Ile 260 265 270 Leu Ile Pro Gln Leu Ile Arg Glu Ile Gly Ser Ile Asn Leu Lys Lys 275 280 285 Asn Glu Pro Pro Leu Thr Cys Pro Tyr Ser Leu Lys Ala Arg Val Leu 290 295 300 Leu Leu Ser His Leu Ala Arg Met Lys Ile Pro Glu Thr Leu Glu Glu 305 310 315 320Asp Gln Gln Phe Met Leu Lys Lys Cys Pro Ala Leu Leu Gln Glu Met 325 330 335 Val Asn Val Ile Cys Gln Leu Ile Val Met Ala Arg Asn Arg Glu Glu 340 345 350 Arg Glu Phe Arg Ala Pro Thr Leu Ala Ser Leu Glu Asn Cys Met Lys 355 360 365 Leu Ser Gln Met Ala Val Gln Gly Leu Gln Gln Phe Lys Ser Pro Leu 370 375 380 Leu Gln Leu Pro His Ile Glu Glu Asp Asn Leu Arg Arg Val Ser Asn 385 390 395 400His Lys Lys Tyr Lys Ile Lys Thr Ile Gln Asp Leu Val Ser Leu Lys 405 410 415 Glu Ser Asp Arg His Thr Leu Leu His Phe Leu Glu Asp Glu Lys Tyr 420 425 430 Glu Glu Val Met Ala Val Leu Gly Ser Phe Pro Tyr Val Thr Met Asp 435 440 445 Ile Lys Ser Gln Val Leu Asp Asp Glu Asp Ser Asn Asn Ile Thr Val 450 455 460 Gly Ser Leu Val Thr Val Leu Val Lys Leu Thr Arg Gln Thr Met Ala 465 470 475 480Glu Val Phe Glu Lys Glu Gln Ser Ile Cys Ala Ala Glu Glu Gln Pro 485 490 495 Ala Glu Asp Gly Gln Gly Glu Thr Asn Lys Asn Arg Thr Lys Gly Gly 500 505 510 Trp Gln Gln Lys Ser Lys Gly Pro

Lys Lys Thr Ala Lys Ser Lys Lys 515 520 525 Lys Lys Pro Leu Lys Lys Lys Pro Thr Pro Val Leu Leu Pro Gln Ser 530 535 540 Lys Gln Gln Lys Gln Lys Gln Ala Asn Gly Val Val Gly Asn Glu Ala 545 550 555 560Ala Val Lys Glu Asp Glu Glu Glu Val Ser Asp Lys Gly Ser Asp Ser 565 570 575 Glu Glu Glu Glu Thr Asn Arg Asp Ser Gln Ser Glu Lys Asp Asp Gly 580 585 590 Ser Asp Arg Asp Ser Asp Arg Glu Gln Asp Glu Lys Gln Asn Lys Asp 595 600 605 Asp Glu Ala Glu Trp Gln Glu Leu Gln Gln Ser Ile Gln Arg Lys Glu 610 615 620 Arg Ala Leu Leu Glu Thr Lys Ser Lys Ile Thr His Pro Val Tyr Ser 625 630 635 640Leu Tyr Phe Pro Glu Glu Lys Gln Glu Trp Trp Trp Leu Tyr Ile Ala 645 650 655 Asp Arg Lys Glu Gln Thr Leu Ile Ser Met Pro Tyr His Val Cys Thr 660 665 670 Leu Lys Asp Thr Glu Glu Val Glu Leu Lys Phe Pro Ala Pro Gly Lys 675 680 685 Pro Gly Asn Tyr Gln Tyr Thr Val Phe Leu Arg Ser Asp Ser Tyr Met 690 695 700 Gly Leu Asp Gln Ile Lys Pro Leu Lys Leu Glu Val His Glu Ala Lys 705 710 715 720Pro Val Pro Glu Asn His Pro Gln Trp Asp Thr Ala Ile Glu Gly Asp 725 730 735 Glu Asp Gln Glu Asp Ser Glu Gly Phe Glu Asp Ser Phe Glu Glu Glu 740 745 750 Glu Glu Glu Glu Glu Asp Asp Asp 755 76026531PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 26Met Ala Gly Gln Gln Phe Gln Tyr Asp Asp Ser Gly Asn Thr Phe Phe 1 5 10 15 Tyr Phe Leu Thr Ser Phe Val Gly Leu Ile Val Ile Pro Ala Thr Tyr 20 25 30 Tyr Leu Trp Pro Arg Asp Gln Asn Ala Glu Gln Ile Arg Leu Lys Asn 35 40 45 Ile Arg Lys Val Tyr Gly Arg Cys Met Trp Tyr Arg Leu Arg Leu Leu 50 55 60 Lys Pro Gln Pro Asn Ile Ile Pro Thr Val Lys Lys Ile Val Leu Leu 65 70 75 80Ala Gly Trp Ala Leu Phe Leu Phe Leu Ala Tyr Lys Val Ser Lys Thr 85 90 95 Asp Arg Glu Tyr Gln Glu Tyr Asn Pro Tyr Glu Val Leu Asn Leu Asp 100 105 110 Pro Gly Ala Thr Val Ala Glu Ile Lys Lys Gln Tyr Arg Leu Leu Ser 115 120 125 Leu Lys Tyr His Pro Asp Lys Gly Gly Asp Glu Val Met Phe Met Arg 130 135 140 Ile Ala Lys Ala Tyr Ala Ala Leu Thr Asp Glu Glu Ser Arg Lys Asn 145 150 155 160Trp Glu Glu Phe Gly Asn Pro Asp Gly Pro Gln Ala Thr Ser Phe Gly 165 170 175 Ile Ala Leu Pro Ala Trp Ile Val Asp Gln Lys Asn Ser Ile Leu Val 180 185 190 Leu Leu Val Tyr Gly Leu Ala Phe Met Val Ile Leu Pro Val Val Val 195 200 205 Gly Ser Trp Trp Tyr Arg Ser Ile Arg Tyr Ser Gly Asp Gln Ile Leu 210 215 220 Ile Arg Thr Thr Gln Ile Tyr Thr Tyr Phe Val Tyr Lys Thr Arg Asn 225 230 235 240Met Asp Met Lys Arg Leu Ile Met Val Leu Ala Gly Ala Ser Glu Phe 245 250 255 Asp Pro Gln Tyr Asn Lys Asp Ala Thr Ser Arg Pro Thr Asp Asn Ile 260 265 270 Leu Ile Pro Gln Leu Ile Arg Glu Ile Gly Ser Ile Asn Leu Lys Lys 275 280 285 Asn Glu Pro Pro Leu Thr Cys Pro Tyr Ser Leu Lys Ala Arg Val Leu 290 295 300 Leu Leu Ser His Leu Ala Arg Met Lys Ile Pro Glu Thr Leu Glu Glu 305 310 315 320Asp Gln Gln Phe Met Leu Lys Lys Cys Pro Ala Leu Leu Gln Glu Met 325 330 335 Val Asn Val Ile Cys Gln Leu Ile Val Met Ala Arg Asn Arg Glu Glu 340 345 350 Arg Glu Phe Arg Ala Pro Thr Leu Ala Ser Leu Glu Asn Cys Met Lys 355 360 365 Leu Ser Gln Met Ala Val Gln Gly Leu Gln Gln Phe Lys Ser Pro Leu 370 375 380 Leu Gln Leu Pro His Ile Glu Glu Asp Asn Leu Arg Arg Val Ser Asn 385 390 395 400His Lys Lys Tyr Lys Ile Lys Thr Ile Gln Asp Leu Val Ser Leu Lys 405 410 415 Glu Ser Asp Arg His Thr Leu Leu His Phe Leu Glu Asp Glu Lys Tyr 420 425 430 Glu Glu Val Met Ala Val Leu Gly Ser Phe Pro Tyr Val Thr Met Asp 435 440 445 Ile Lys Ser Gln Val Leu Asp Asp Glu Asp Ser Asn Asn Ile Thr Val 450 455 460 Gly Ser Leu Val Thr Val Leu Val Lys Leu Thr Arg Gln Thr Met Ala 465 470 475 480Glu Val Phe Glu Lys Glu Gln Ser Ile Cys Ala Ala Glu Glu Gln Pro 485 490 495 Ala Glu Asp Gly Gln Gly Glu Thr Asn Lys Asn Arg Thr Lys Gly Gly 500 505 510 Trp Gln Gln Lys Ser Lys Gly Pro Lys Lys Thr Ala Lys Ser Lys Lys 515 520 525 Arg Asn Leu 530 27558PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 27Met Ala Gly Gln Gln Phe Gln Tyr Asp Asp Ser Gly Asn Thr Phe Phe 1 5 10 15 Tyr Phe Leu Thr Ser Phe Val Gly Leu Ile Val Ile Pro Ala Thr Tyr 20 25 30 Tyr Leu Trp Pro Arg Asp Gln Asn Ala Glu Gln Ile Arg Leu Lys Asn 35 40 45 Ile Arg Lys Val Tyr Gly Arg Cys Met Trp Tyr Arg Leu Arg Leu Leu 50 55 60 Lys Pro Gln Pro Asn Ile Ile Pro Thr Val Lys Lys Ile Val Leu Leu 65 70 75 80Ala Gly Trp Ala Leu Phe Leu Phe Leu Ala Tyr Lys Val Ser Lys Thr 85 90 95 Asp Arg Glu Tyr Gln Glu Tyr Asn Pro Tyr Glu Val Leu Asn Leu Asp 100 105 110 Pro Gly Ala Thr Val Ala Glu Ile Lys Lys Gln Tyr Arg Leu Leu Ser 115 120 125 Leu Lys Tyr His Pro Asp Lys Gly Gly Asp Glu Val Met Phe Met Arg 130 135 140 Ile Ala Lys Ala Tyr Ala Ala Leu Thr Asp Glu Glu Ser Arg Lys Asn 145 150 155 160Trp Glu Glu Phe Gly Asn Pro Asp Gly Pro Gln Ala Thr Ser Phe Gly 165 170 175 Ile Ala Leu Pro Ala Trp Ile Val Asp Gln Lys Asn Ser Ile Leu Val 180 185 190 Leu Leu Val Tyr Gly Leu Ala Phe Met Val Ile Leu Pro Val Val Val 195 200 205 Gly Ser Trp Trp Tyr Arg Ser Ile Arg Tyr Ser Gly Asp Gln Ile Leu 210 215 220 Ile Arg Thr Thr Gln Ile Tyr Thr Tyr Phe Val Tyr Lys Thr Arg Asn 225 230 235 240Met Asp Met Lys Arg Leu Ile Met Val Leu Ala Gly Ala Ser Glu Phe 245 250 255 Asp Pro Gln Tyr Asn Lys Asp Ala Thr Ser Arg Pro Thr Asp Asn Ile 260 265 270 Leu Ile Pro Gln Leu Ile Arg Glu Ile Gly Ser Ile Asn Leu Lys Lys 275 280 285 Asn Glu Pro Pro Leu Thr Cys Pro Tyr Ser Leu Lys Ala Arg Val Leu 290 295 300 Leu Leu Ser His Leu Ala Arg Met Lys Ile Pro Glu Thr Leu Glu Glu 305 310 315 320Asp Gln Gln Phe Met Leu Lys Lys Cys Pro Ala Leu Leu Gln Glu Met 325 330 335 Val Asn Val Ile Cys Gln Leu Ile Val Met Ala Arg Asn Arg Glu Glu 340 345 350 Arg Glu Phe Arg Ala Pro Thr Leu Ala Ser Leu Glu Asn Cys Met Lys 355 360 365 Leu Ser Gln Met Ala Val Gln Gly Leu Gln Gln Phe Lys Ser Pro Leu 370 375 380 Leu Gln Leu Pro His Ile Glu Glu Asp Asn Leu Arg Arg Val Ser Asn 385 390 395 400His Lys Lys Tyr Lys Ile Lys Thr Ile Gln Asp Leu Val Ser Leu Lys 405 410 415 Glu Ser Asp Arg His Thr Leu Leu His Phe Leu Glu Asp Glu Lys Tyr 420 425 430 Glu Glu Val Met Ala Val Leu Gly Ser Phe Pro Tyr Val Thr Met Asp 435 440 445 Ile Lys Ser Gln Val Leu Asp Asp Glu Asp Ser Asn Asn Ile Thr Val 450 455 460 Gly Ser Leu Val Thr Val Leu Val Lys Leu Thr Arg Gln Thr Met Ala 465 470 475 480Glu Val Phe Glu Lys Glu Gln Ser Ile Cys Ala Ala Glu Glu Gln Pro 485 490 495 Ala Glu Asp Gly Gln Gly Glu Thr Asn Lys Asn Arg Thr Lys Gly Gly 500 505 510 Trp Gln Gln Lys Ser Lys Gly Pro Lys Lys Thr Ala Lys Ser Lys Lys 515 520 525 Lys Glu Thr Phe Lys Lys Lys Thr Tyr Thr Cys Ala Ile Thr Thr Val 530 535 540 Lys Ala Thr Glu Thr Lys Ala Gly Lys Trp Ser Arg Trp Glu 545 550 555 28561PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 28Met Ala Gly Gln Gln Phe Gln Tyr Asp Asp Ser Gly Asn Thr Phe Phe 1 5 10 15 Tyr Phe Leu Thr Ser Phe Val Gly Leu Ile Val Ile Pro Ala Thr Tyr 20 25 30 Tyr Leu Trp Pro Arg Asp Gln Asn Ala Glu Gln Ile Arg Leu Lys Asn 35 40 45 Ile Arg Lys Val Tyr Gly Arg Cys Met Trp Tyr Arg Leu Arg Leu Leu 50 55 60 Lys Pro Gln Pro Asn Ile Ile Pro Thr Val Lys Lys Ile Val Leu Leu 65 70 75 80Ala Gly Trp Ala Leu Phe Leu Phe Leu Ala Tyr Lys Val Ser Lys Thr 85 90 95 Asp Arg Glu Tyr Gln Glu Tyr Asn Pro Tyr Glu Val Leu Asn Leu Asp 100 105 110 Pro Gly Ala Thr Val Ala Glu Ile Lys Lys Gln Tyr Arg Leu Leu Ser 115 120 125 Leu Lys Tyr His Pro Asp Lys Gly Gly Asp Glu Val Met Phe Met Arg 130 135 140 Ile Ala Lys Ala Tyr Ala Ala Leu Thr Asp Glu Glu Ser Arg Lys Asn 145 150 155 160Trp Glu Glu Phe Gly Asn Pro Asp Gly Pro Gln Ala Thr Ser Phe Gly 165 170 175 Ile Ala Leu Pro Ala Trp Ile Val Asp Gln Lys Asn Ser Ile Leu Val 180 185 190 Leu Leu Val Tyr Gly Leu Ala Phe Met Val Ile Leu Pro Val Val Val 195 200 205 Gly Ser Trp Trp Tyr Arg Ser Ile Arg Tyr Ser Gly Asp Gln Ile Leu 210 215 220 Ile Arg Thr Thr Gln Ile Tyr Thr Tyr Phe Val Tyr Lys Thr Arg Asn 225 230 235 240Met Asp Met Lys Arg Leu Ile Met Val Leu Ala Gly Ala Ser Glu Phe 245 250 255 Asp Pro Gln Tyr Asn Lys Asp Ala Thr Ser Arg Pro Thr Asp Asn Ile 260 265 270 Leu Ile Pro Gln Leu Ile Arg Glu Ile Gly Ser Ile Asn Leu Lys Lys 275 280 285 Asn Glu Pro Pro Leu Thr Cys Pro Tyr Ser Leu Lys Ala Arg Val Leu 290 295 300 Leu Leu Ser His Leu Ala Arg Met Lys Ile Pro Glu Thr Leu Glu Glu 305 310 315 320Asp Gln Gln Phe Met Leu Lys Lys Cys Pro Ala Leu Leu Gln Glu Met 325 330 335 Val Asn Val Ile Cys Gln Leu Ile Val Met Ala Arg Asn Arg Glu Glu 340 345 350 Arg Glu Phe Arg Ala Pro Thr Leu Ala Ser Leu Glu Asn Cys Met Lys 355 360 365 Leu Ser Gln Met Ala Val Gln Gly Leu Gln Gln Phe Lys Ser Pro Leu 370 375 380 Leu Gln Leu Pro His Ile Glu Glu Asp Asn Leu Arg Arg Val Ser Asn 385 390 395 400His Lys Lys Tyr Lys Ile Lys Thr Ile Gln Asp Leu Val Ser Leu Lys 405 410 415 Glu Ser Asp Arg His Thr Leu Leu His Phe Leu Glu Asp Glu Lys Tyr 420 425 430 Glu Glu Val Met Ala Val Leu Gly Ser Phe Pro Tyr Val Thr Met Asp 435 440 445 Ile Lys Ser Gln Val Leu Asp Asp Glu Asp Ser Asn Asn Ile Thr Val 450 455 460 Gly Ser Leu Val Thr Val Leu Val Lys Leu Thr Arg Gln Thr Met Ala 465 470 475 480Glu Val Phe Glu Lys Glu Gln Ser Ile Cys Ala Ala Glu Glu Gln Pro 485 490 495 Ala Glu Asp Gly Gln Gly Glu Thr Asn Lys Asn Arg Thr Lys Gly Gly 500 505 510 Trp Gln Gln Lys Ser Lys Gly Pro Lys Lys Thr Ala Lys Ser Lys Lys 515 520 525 Lys Lys Pro Leu Lys Lys Asn Leu His Leu Cys Tyr Tyr His Ser Gln 530 535 540 Ser Asn Arg Asn Lys Ser Arg Gln Met Glu Ser Leu Gly Met Lys Leu 545 550 555 560Gln 29558PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 29Met Ala Gly Gln Gln Phe Gln Tyr Asp Asp Ser Gly Asn Thr Phe Phe 1 5 10 15 Tyr Phe Leu Thr Ser Phe Val Gly Leu Ile Val Ile Pro Ala Thr Tyr 20 25 30 Tyr Leu Trp Pro Arg Asp Gln Asn Ala Glu Gln Ile Arg Leu Lys Asn 35 40 45 Ile Arg Lys Val Tyr Gly Arg Cys Met Trp Tyr Arg Leu Arg Leu Leu 50 55 60 Lys Pro Gln Pro Asn Ile Ile Pro Thr Val Lys Lys Ile Val Leu Leu 65 70 75 80Ala Gly Trp Ala Leu Phe Leu Phe Leu Ala Tyr Lys Val Ser Lys Thr 85 90 95 Asp Arg Glu Tyr Gln Glu Tyr Asn Pro Tyr Glu Val Leu Asn Leu Asp 100 105 110 Pro Gly Ala Thr Val Ala Glu Ile Lys Lys Gln Tyr Arg Leu Leu Ser 115 120 125 Leu Lys Tyr His Pro Asp Lys Gly Gly Asp Glu Val Met Phe Met Arg 130 135 140 Ile Ala Lys Ala Tyr Ala Ala Leu Thr Asp Glu Glu Ser Arg Lys Asn 145 150 155 160Trp Glu Glu Phe Gly Asn Pro Asp Gly Pro Gln Ala Thr Ser Phe Gly 165 170 175 Ile Ala Leu Pro Ala Trp Ile Val Asp Gln Lys Asn Ser Ile Leu Val 180 185 190 Leu Leu Val Tyr Gly Leu Ala Phe Met Val Ile Leu Pro Val Val Val 195 200 205 Gly Ser Trp Trp Tyr Arg Ser Ile Arg Tyr Ser Gly Asp Gln Ile Leu 210 215 220 Ile Arg Thr Thr Gln Ile Tyr Thr Tyr Phe Val Tyr Lys Thr Arg Asn 225 230 235 240Met Asp Met Lys Arg Leu Ile Met Val Leu Ala Gly Ala Ser Glu Phe 245 250 255 Asp Pro Gln Tyr Asn Lys Asp Ala Thr Ser Arg Pro Thr Asp Asn Ile 260 265 270 Leu Ile Pro Gln Leu Ile Arg Glu Ile Gly Ser Ile Asn Leu Lys Lys 275 280 285 Asn Glu Pro Pro Leu Thr Cys Pro Tyr Ser Leu Lys Ala Arg Val Leu 290 295 300 Leu Leu Ser His Leu Ala Arg Met Lys Ile Pro Glu Thr Leu Glu Glu 305 310 315 320Asp Gln Gln Phe Met Leu Lys Lys Cys Pro Ala

Leu Leu Gln Glu Met 325 330 335 Val Asn Val Ile Cys Gln Leu Ile Val Met Ala Arg Asn Arg Glu Glu 340 345 350 Arg Glu Phe Arg Ala Pro Thr Leu Ala Ser Leu Glu Asn Cys Met Lys 355 360 365 Leu Ser Gln Met Ala Val Gln Gly Leu Gln Gln Phe Lys Ser Pro Leu 370 375 380 Leu Gln Leu Pro His Ile Glu Glu Asp Asn Leu Arg Arg Val Ser Asn 385 390 395 400His Lys Lys Tyr Lys Ile Lys Thr Ile Gln Asp Leu Val Ser Leu Lys 405 410 415 Glu Ser Asp Arg His Thr Leu Leu His Phe Leu Glu Asp Glu Lys Tyr 420 425 430 Glu Glu Val Met Ala Val Leu Gly Ser Phe Pro Tyr Val Thr Met Asp 435 440 445 Ile Lys Ser Gln Val Leu Asp Asp Glu Asp Ser Asn Asn Ile Thr Val 450 455 460 Gly Ser Leu Val Thr Val Leu Val Lys Leu Thr Arg Gln Thr Met Ala 465 470 475 480Glu Val Phe Glu Lys Glu Gln Ser Ile Cys Ala Ala Glu Glu Gln Pro 485 490 495 Ala Glu Asp Gly Gln Gly Glu Thr Asn Lys Asn Arg Thr Lys Gly Gly 500 505 510 Trp Gln Gln Lys Ser Lys Gly Pro Lys Lys Thr Ala Lys Ser Lys Lys 515 520 525 Lys Lys Pro Leu Lys Lys Lys Thr Tyr Thr Cys Ala Ile Thr Thr Val 530 535 540 Lys Ala Thr Glu Thr Lys Ala Gly Lys Trp Ser Arg Trp Glu 545 550 555 30418PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 30Met Phe Lys Gly Ile Leu Gln Ser Gly Leu Asp Asn Phe Val Ile Asn 1 5 10 15 His Met Leu Lys Asn Asn Val Ala Gly Gln Thr Ser Ile Gln Thr Leu 20 25 30 Val Pro Asn Thr Asp Gln Lys Ser Thr Ser Val Lys Lys Asp Asn His 35 40 45 Lys Lys Lys Thr Val Lys Met Leu Glu Tyr Leu Gly Lys Asp Val Leu 50 55 60 His Gly Val Phe Asn Tyr Leu Ala Lys His Asp Val Leu Thr Leu Lys 65 70 75 80Glu Glu Glu Lys Lys Lys Tyr Tyr Asp Ala Lys Ile Glu Asp Lys Ala 85 90 95 Leu Ile Leu Val Asp Ser Leu Arg Lys Asn Arg Val Ala His Gln Met 100 105 110 Phe Thr Gln Thr Leu Leu Asn Met Asp Gln Lys Ile Thr Ser Val Lys 115 120 125 Pro Leu Leu Gln Ile Glu Ala Gly Pro Pro Glu Ser Ala Glu Ser Thr 130 135 140 Asn Ile Leu Lys Leu Cys Pro Arg Glu Glu Phe Leu Arg Leu Cys Lys 145 150 155 160Lys Asn His Asp Glu Ile Tyr Pro Ile Lys Lys Arg Glu Asp Arg Arg 165 170 175 Arg Leu Ala Leu Ile Ile Cys Asn Thr Lys Phe Asp His Leu Pro Ala 180 185 190 Arg Asn Gly Ala His Tyr Asp Ile Val Gly Met Lys Arg Leu Leu Gln 195 200 205 Gly Leu Gly Tyr Thr Val Val Asp Glu Lys Asn Leu Thr Ala Arg Asp 210 215 220 Met Glu Ser Val Leu Arg Ala Phe Ala Ala Arg Pro Glu His Lys Ser 225 230 235 240Ser Asp Ser Thr Phe Leu Val Leu Met Ser His Gly Ile Leu Glu Gly 245 250 255 Ile Cys Gly Thr Ala His Lys Lys Lys Lys Pro Asp Val Leu Leu Tyr 260 265 270 Asp Thr Ile Phe Gln Ile Phe Asn Asn Arg Asn Cys Leu Ser Leu Lys 275 280 285 Asp Lys Pro Lys Val Ile Ile Val Gln Ala Cys Arg Gly Glu Lys His 290 295 300 Gly Glu Leu Trp Val Arg Asp Ser Pro Ala Ser Leu Ala Val Ile Ser 305 310 315 320Ser Gln Ser Ser Glu Asn Leu Glu Ala Asp Ser Val Cys Lys Ile His 325 330 335 Glu Glu Lys Asp Phe Ile Ala Phe Cys Ser Ser Thr Pro His Asn Val 340 345 350 Ser Trp Arg Asp Arg Thr Arg Gly Ser Ile Phe Ile Thr Glu Leu Ile 355 360 365 Thr Cys Phe Gln Lys Tyr Ser Cys Cys Cys His Leu Met Glu Ile Phe 370 375 380 Arg Lys Val Gln Lys Ser Phe Glu Val Pro Gln Ala Lys Ala Gln Met 385 390 395 400Pro Thr Ile Glu Arg Ala Thr Leu Thr Arg Asp Phe Tyr Leu Phe Pro 405 410 415 Gly Asn 3176PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 31Met Phe Lys Gly Ile Leu Gln Ser Gly Leu Asp Asn Phe Val Ile Asn 1 5 10 15 His Met Leu Lys Asn Asn Val Ala Gly Gln Thr Ser Ile Gln Thr Leu 20 25 30 Val Pro Asn Thr Asp Gln Lys Ser Thr Ser Val Lys Lys Asp Asn His 35 40 45 Lys Lys Lys Gln Leu Arg Cys Trp Asn Thr Trp Ala Lys Met Phe Phe 50 55 60 Met Val Phe Leu Ile Ile Trp Gln Asn Thr Met Phe 65 70 75 3253PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 32Met Phe Lys Gly Ile Leu Gln Ser Gly Leu Asp Asn Phe Val Ile Asn 1 5 10 15 His Met Leu Lys Asn Asn Val Ala Gly Gln Thr Ser Ile Gln Thr Leu 20 25 30 Val Pro Asn Thr Asp Gln Lys Ser Thr Ser Val Lys Lys Asp Asn His 35 40 45 Lys Lys Lys Asn Ser 50 33343PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 33Met Glu Ser Lys Tyr Lys Glu Ile Leu Leu Leu Thr Gly Leu Asp Asn 1 5 10 15 Ile Thr Asp Glu Glu Leu Asp Arg Phe Lys Phe Phe Leu Ser Asp Glu 20 25 30 Phe Asn Ile Ala Thr Gly Lys Leu His Thr Ala Asn Arg Ile Gln Val 35 40 45 Ala Thr Leu Met Ile Gln Asn Ala Gly Ala Val Ser Ala Val Met Lys 50 55 60 Thr Ile Arg Ile Phe Gln Lys Leu Asn Tyr Met Leu Leu Ala Lys Arg 65 70 75 80Leu Gln Glu Glu Lys Glu Lys Val Asp Lys Gln Tyr Lys Ser Val Thr 85 90 95 Lys Pro Lys Pro Leu Ser Gln Ala Glu Met Ser Pro Ala Ala Ser Ala 100 105 110 Ala Ile Arg Asn Asp Val Ala Lys Gln Arg Ala Ala Pro Lys Val Ser 115 120 125 Pro His Val Lys Pro Glu Gln Lys Gln Met Val Ala Gln Gln Glu Ser 130 135 140 Ile Arg Glu Gly Phe Gln Lys Arg Cys Leu Pro Val Met Val Leu Lys 145 150 155 160Ala Lys Lys Pro Phe Thr Phe Glu Thr Gln Glu Gly Lys Gln Glu Met 165 170 175 Phe His Ala Thr Val Ala Thr Glu Lys Glu Phe Phe Phe Val Lys Val 180 185 190 Phe Asn Thr Leu Leu Lys Asp Lys Phe Ile Pro Lys Arg Ile Ile Ile 195 200 205 Ile Ala Arg Tyr Tyr Arg His Ser Gly Phe Leu Glu Val Asn Ser Ala 210 215 220 Ser Arg Val Leu Asp Ala Glu Ser Asp Gln Lys Val Asn Val Pro Leu 225 230 235 240Asn Ile Ile Arg Lys Ala Gly Glu Thr Pro Lys Ile Asn Thr Leu Gln 245 250 255 Thr Gln Pro Leu Gly Thr Ile Val Asn Gly Leu Phe Val Val Gln Lys 260 265 270 Val Thr Glu Lys Lys Lys Asn Ile Leu Phe Asp Leu Ser Asp Asn Thr 275 280 285 Gly Lys Met Glu Val Leu Gly Val Arg Asn Glu Asp Thr Met Lys Cys 290 295 300 Lys Glu Gly Asp Lys Val Arg Leu Thr Phe Phe Thr Leu Ser Lys Asn 305 310 315 320Gly Glu Lys Leu Gln Leu Thr Ser Gly Val His Ser Thr Ile Lys Val 325 330 335 Ile Lys Ala Lys Lys Lys Thr 340 34355PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 34Met Glu Ser Lys Tyr Lys Glu Ile Leu Leu Leu Thr Gly Leu Asp Asn 1 5 10 15 Ile Thr Asp Glu Glu Leu Asp Arg Phe Lys Phe Phe Leu Ser Asp Glu 20 25 30 Phe Asn Ile Ala Thr Gly Lys Leu His Thr Ala Asn Arg Ile Gln Val 35 40 45 Ala Thr Leu Met Ile Gln Asn Ala Gly Ala Val Ser Ala Val Met Lys 50 55 60 Thr Ile Arg Ile Phe Gln Lys Leu Asn Tyr Met Leu Leu Ala Lys Arg 65 70 75 80Leu Gln Glu Glu Lys Glu Lys Val Asp Lys Gln Tyr Lys Ser Val Thr 85 90 95 Lys Pro Lys Pro Leu Ser Gln Ala Glu Met Ser Pro Ala Ala Ser Ala 100 105 110 Ala Ile Arg Asn Asp Val Ala Lys Gln Arg Ala Ala Pro Lys Val Ser 115 120 125 Pro His Val Lys Pro Glu Gln Lys Gln Met Val Ala Gln Gln Glu Ser 130 135 140 Ile Arg Glu Gly Phe Gln Lys Arg Cys Leu Pro Val Met Val Leu Lys 145 150 155 160Ala Lys Lys Pro Phe Thr Phe Glu Thr Gln Glu Gly Lys Gln Glu Met 165 170 175 Phe His Ala Thr Val Ala Thr Glu Lys Glu Phe Phe Phe Val Lys Val 180 185 190 Phe Asn Thr Leu Leu Lys Asp Lys Phe Ile Pro Lys Arg Ile Ile Ile 195 200 205 Ile Ala Arg Tyr Tyr Arg His Ser Gly Phe Leu Glu Val Asn Ser Ala 210 215 220 Ser Arg Val Leu Asp Ala Glu Ser Asp Gln Lys Val Asn Val Pro Leu 225 230 235 240Asn Ile Ile Arg Lys Ala Gly Glu Thr Pro Lys Ile Asn Thr Leu Gln 245 250 255 Thr Gln Pro Leu Gly Thr Ile Val Asn Gly Leu Phe Val Val Gln Lys 260 265 270 Val Thr Glu Lys Lys Lys Asn Ile Leu Phe Asp Leu Ser Asp Asn Thr 275 280 285 Gly Lys Met Glu Val Leu Gly Val Arg Asn Glu Asp Thr Met Lys Cys 290 295 300 Lys Glu Gly Asp Lys Val Arg Leu Thr Phe Phe Thr Leu Ser Lys Asn 305 310 315 320Gly Glu Lys Leu Gln Leu Thr Ser Gly Val His Ser Thr Ile Lys Val 325 330 335 Ile Lys Ala Lys Lys Lys His Arg Glu Val Lys Arg Thr Asn Ser Ser 340 345 350 Gln Leu Val 35535346PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 35Met Glu Ser Lys Tyr Lys Glu Ile Leu Leu Leu Thr Gly Leu Asp Asn 1 5 10 15 Ile Thr Asp Glu Glu Leu Asp Arg Phe Lys Phe Phe Leu Ser Asp Glu 20 25 30 Phe Asn Ile Ala Thr Gly Lys Leu His Thr Ala Asn Arg Ile Gln Val 35 40 45 Ala Thr Leu Met Ile Gln Asn Ala Gly Ala Val Ser Ala Val Met Lys 50 55 60 Thr Ile Arg Ile Phe Gln Lys Leu Asn Tyr Met Leu Leu Ala Lys Arg 65 70 75 80Leu Gln Glu Glu Lys Glu Lys Val Asp Lys Gln Tyr Lys Ser Val Thr 85 90 95 Lys Pro Lys Pro Leu Ser Gln Ala Glu Met Ser Pro Ala Ala Ser Ala 100 105 110 Ala Ile Arg Asn Asp Val Ala Lys Gln Arg Ala Ala Pro Lys Val Ser 115 120 125 Pro His Val Lys Pro Glu Gln Lys Gln Met Val Ala Gln Gln Glu Ser 130 135 140 Ile Arg Glu Gly Phe Gln Lys Arg Cys Leu Pro Val Met Val Leu Lys 145 150 155 160Ala Lys Lys Pro Phe Thr Phe Glu Thr Gln Glu Gly Lys Gln Glu Met 165 170 175 Phe His Ala Thr Val Ala Thr Glu Lys Glu Phe Phe Phe Val Lys Val 180 185 190 Phe Asn Thr Leu Leu Lys Asp Lys Phe Ile Pro Lys Arg Ile Ile Ile 195 200 205 Ile Ala Arg Tyr Tyr Arg His Ser Gly Phe Leu Glu Val Asn Ser Ala 210 215 220 Ser Arg Val Leu Asp Ala Glu Ser Asp Gln Lys Val Asn Val Pro Leu 225 230 235 240Asn Ile Ile Arg Lys Ala Gly Glu Thr Pro Lys Ile Asn Thr Leu Gln 245 250 255 Thr Gln Pro Leu Gly Thr Ile Val Asn Gly Leu Phe Val Val Gln Lys 260 265 270 Val Thr Glu Lys Lys Lys Asn Ile Leu Phe Asp Leu Ser Asp Asn Thr 275 280 285 Gly Lys Met Glu Val Leu Gly Val Arg Asn Glu Asp Thr Met Lys Cys 290 295 300 Lys Glu Gly Asp Lys Val Arg Leu Thr Phe Phe Thr Leu Ser Lys Asn 305 310 315 320Gly Glu Lys Leu Gln Leu Thr Ser Gly Val His Ser Thr Ile Lys Val 325 330 335 Ile Lys Ala Lys Lys Lys Asn Ile Glu Lys 340 345 36650PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 36Met Met Gly Ile Gly Lys Asn Thr Thr Ser Lys Ser Met Glu Ala Gly 1 5 10 15 Ser Ser Thr Glu Gly Lys Tyr Glu Asp Glu Ala Lys His Pro Ala Phe 20 25 30 Phe Thr Leu Pro Val Val Ile Asn Gly Gly Ala Thr Ser Ser Gly Glu 35 40 45 Gln Asp Asn Glu Asp Thr Glu Leu Met Ala Ile Tyr Thr Thr Glu Asn 50 55 60 Gly Ile Ala Glu Lys Ser Ser Leu Ala Glu Thr Leu Asp Ser Thr Gly 65 70 75 80Ser Leu Asp Pro Gln Arg Ser Asp Met Ile Tyr Thr Ile Glu Asp Val 85 90 95 Pro Pro Trp Tyr Leu Cys Ile Phe Leu Gly Leu Gln His Tyr Leu Thr 100 105 110 Cys Phe Ser Gly Thr Ile Ala Val Pro Phe Leu Leu Ala Asp Ala Met 115 120 125 Cys Val Gly Tyr Asp Gln Trp Ala Thr Ser Gln Leu Ile Gly Thr Ile 130 135 140 Phe Phe Cys Val Gly Ile Thr Thr Leu Leu Gln Thr Thr Phe Gly Cys 145 150 155 160Arg Leu Pro Leu Phe Gln Thr Ser Ala Phe Ala Phe Leu Ala Pro Ala 165 170 175 Arg Ala Ile Leu Ser Leu Asp Lys Trp Lys Cys Asn Thr Thr Asp Val 180 185 190 Ser Val Ala Asn Gly Thr Ala Glu Leu Leu His Thr Glu His Ile Trp 195 200 205 Tyr Pro Arg Ile Arg Glu Ile Gln Gly Ala Ile Ile Met Ser Ser Leu 210 215 220 Ile Glu Val Val Ile Gly Leu Leu Gly Leu Pro Gly Ala Leu Leu Lys 225 230 235 240Tyr Ile Gly Pro Leu Thr Ile Thr Pro Thr Val Ala Leu Ile Gly Leu 245 250 255 Ser Gly Phe Gln Ala Ala Gly Glu Arg Ala Gly Lys His Trp Gly Ile 260 265 270 Ala Met Leu Thr Ile Phe Leu Val Leu Leu Phe Ser Gln Tyr Ala Arg 275 280 285 Asn Val Lys Phe Pro Leu Pro Ile Tyr Lys Ser Lys Lys Gly Trp Thr 290 295 300 Ala Tyr Lys Leu Gln Leu Phe Lys Met Phe Pro Ile Ile Leu Ala Ile 305 310 315 320Leu Val Ser Trp Leu Leu Cys Phe Ile Phe Thr Val Thr Asp Val Phe 325

330 335 Pro Pro Asp Ser Thr Lys Tyr Gly Phe Tyr Ala Arg Thr Asp Ala Arg 340 345 350 Gln Gly Val Leu Leu Val Ala Pro Trp Phe Lys Val Pro Tyr Pro Phe 355 360 365 Gln Trp Gly Leu Pro Thr Val Ser Ala Ala Gly Val Ile Gly Met Leu 370 375 380 Ser Ala Val Val Ala Ser Ile Ile Glu Ser Ile Gly Asp Tyr Tyr Ala 385 390 395 400Cys Ala Arg Leu Ser Cys Ala Pro Pro Pro Pro Ile His Ala Ile Asn 405 410 415 Arg Gly Ile Phe Val Glu Gly Leu Ser Cys Val Leu Asp Gly Ile Phe 420 425 430 Gly Thr Gly Asn Gly Ser Thr Ser Ser Ser Pro Asn Ile Gly Val Leu 435 440 445 Gly Ile Thr Lys Val Gly Ser Arg Arg Val Ile Gln Cys Gly Ala Ala 450 455 460 Leu Met Leu Ala Leu Gly Met Ile Gly Lys Phe Ser Ala Leu Phe Ala 465 470 475 480Ser Leu Pro Asp Pro Val Leu Gly Ala Leu Phe Cys Thr Leu Phe Gly 485 490 495 Met Ile Thr Ala Val Gly Leu Ser Asn Leu Gln Phe Ile Asp Leu Asn 500 505 510 Ser Ser Arg Asn Leu Phe Val Leu Gly Phe Ser Ile Phe Phe Gly Leu 515 520 525 Val Leu Pro Ser Tyr Leu Arg Gln Asn Pro Leu Val Thr Gly Ile Thr 530 535 540 Gly Ile Asp Gln Val Leu Asn Val Leu Leu Thr Thr Ala Met Phe Val 545 550 555 560Gly Gly Cys Val Ala Phe Ile Leu Asp Asn Thr Ile Pro Gly Thr Pro 565 570 575 Glu Glu Arg Gly Ile Arg Lys Trp Lys Lys Gly Val Gly Lys Gly Asn 580 585 590 Lys Ser Leu Asp Gly Met Glu Ser Tyr Asn Leu Pro Phe Gly Met Asn 595 600 605 Ile Ile Lys Lys Tyr Arg Cys Phe Ser Tyr Leu Pro Ile Ser Pro Thr 610 615 620 Phe Val Gly Tyr Thr Trp Lys Gly Leu Arg Lys Ser Asp Asn Ser Arg 625 630 635 640Ser Ser Asp Glu Asp Ser Gln Ala Thr Gly 645 65037414PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 37Met Met Gly Ile Gly Lys Asn Thr Thr Ser Lys Ser Met Glu Ala Gly 1 5 10 15 Ser Ser Thr Glu Gly Lys Tyr Glu Asp Glu Ala Lys His Pro Ala Phe 20 25 30 Phe Thr Leu Pro Val Val Ile Asn Gly Gly Ala Thr Ser Ser Gly Glu 35 40 45 Gln Asp Asn Glu Asp Thr Glu Leu Met Ala Ile Tyr Thr Thr Glu Asn 50 55 60 Gly Ile Ala Glu Lys Ser Ser Leu Ala Glu Thr Leu Asp Ser Thr Gly 65 70 75 80Ser Leu Asp Pro Gln Arg Ser Asp Met Ile Tyr Thr Ile Glu Asp Val 85 90 95 Pro Pro Trp Tyr Leu Cys Ile Phe Leu Gly Leu Gln His Tyr Leu Thr 100 105 110 Cys Phe Ser Gly Thr Ile Ala Val Pro Phe Leu Leu Ala Asp Ala Met 115 120 125 Cys Val Gly Tyr Asp Gln Trp Ala Thr Ser Gln Leu Ile Gly Thr Ile 130 135 140 Phe Phe Cys Val Gly Ile Thr Thr Leu Leu Gln Thr Thr Phe Gly Cys 145 150 155 160Arg Leu Pro Leu Phe Gln Thr Ser Ala Phe Ala Phe Leu Ala Pro Ala 165 170 175 Arg Ala Ile Leu Ser Leu Asp Lys Trp Lys Cys Asn Thr Thr Asp Val 180 185 190 Ser Val Ala Asn Gly Thr Ala Glu Leu Leu His Thr Glu His Ile Trp 195 200 205 Tyr Pro Arg Ile Arg Glu Ile Gln Gly Ala Ile Ile Met Ser Ser Leu 210 215 220 Ile Glu Val Val Ile Gly Leu Leu Gly Leu Pro Gly Ala Leu Leu Lys 225 230 235 240Tyr Ile Gly Pro Leu Thr Ile Thr Pro Thr Val Ala Leu Ile Gly Leu 245 250 255 Ser Gly Phe Gln Ala Ala Gly Glu Arg Ala Gly Lys His Trp Gly Ile 260 265 270 Ala Met Leu Thr Ile Phe Leu Val Leu Leu Phe Ser Gln Tyr Ala Arg 275 280 285 Asn Val Lys Phe Pro Leu Pro Ile Tyr Lys Ser Lys Lys Gly Trp Thr 290 295 300 Ala Tyr Lys Leu Gln Leu Phe Lys Met Phe Pro Ile Ile Leu Ala Ile 305 310 315 320Leu Val Ser Trp Leu Leu Cys Phe Ile Phe Thr Val Thr Asp Val Phe 325 330 335 Pro Pro Asp Ser Thr Lys Tyr Gly Phe Tyr Ala Arg Thr Asp Ala Arg 340 345 350 Gln Gly Val Leu Leu Val Ala Pro Trp Phe Lys Val Pro Tyr Pro Phe 355 360 365 Gln Trp Gly Leu Pro Thr Val Ser Ala Ala Gly Val Ile Gly Met Leu 370 375 380 Ser Ala Val Val Ala Ser Ile Ile Glu Ser Ile Gly Asp Tyr Tyr Ala 385 390 395 400Cys Ala Arg Leu Ser Cys Ala Pro Pro Pro Pro Ser Thr Gln 405 410 38428PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 38Met Met Gly Ile Gly Lys Asn Thr Thr Ser Lys Ser Met Glu Ala Gly 1 5 10 15 Ser Ser Thr Glu Gly Lys Tyr Glu Asp Glu Ala Lys His Pro Ala Phe 20 25 30 Phe Thr Leu Pro Val Val Ile Asn Gly Gly Ala Thr Ser Ser Gly Glu 35 40 45 Gln Asp Asn Glu Asp Thr Glu Leu Met Ala Ile Tyr Thr Thr Glu Asn 50 55 60 Gly Ile Ala Glu Lys Ser Ser Leu Ala Glu Thr Leu Asp Ser Thr Gly 65 70 75 80Ser Leu Asp Pro Gln Arg Ser Asp Met Ile Tyr Thr Ile Glu Asp Val 85 90 95 Pro Pro Trp Tyr Leu Cys Ile Phe Leu Gly Leu Gln His Tyr Leu Thr 100 105 110 Cys Phe Ser Gly Thr Ile Ala Val Pro Phe Leu Leu Ala Asp Ala Met 115 120 125 Cys Val Gly Tyr Asp Gln Trp Ala Thr Ser Gln Leu Ile Gly Thr Ile 130 135 140 Phe Phe Cys Val Gly Ile Thr Thr Leu Leu Gln Thr Thr Phe Gly Cys 145 150 155 160Arg Leu Pro Leu Phe Gln Thr Ser Ala Phe Ala Phe Leu Ala Pro Ala 165 170 175 Arg Ala Ile Leu Ser Leu Asp Lys Trp Lys Cys Asn Thr Thr Asp Val 180 185 190 Ser Val Ala Asn Gly Thr Ala Glu Leu Leu His Thr Glu His Ile Trp 195 200 205 Tyr Pro Arg Ile Arg Glu Ile Gln Gly Ala Ile Ile Met Ser Ser Leu 210 215 220 Ile Glu Val Val Ile Gly Leu Leu Gly Leu Pro Gly Ala Leu Leu Lys 225 230 235 240Tyr Ile Gly Pro Leu Thr Ile Thr Pro Thr Val Ala Leu Ile Gly Leu 245 250 255 Ser Gly Phe Gln Ala Ala Gly Glu Arg Ala Gly Lys His Trp Gly Ile 260 265 270 Ala Met Leu Thr Ile Phe Leu Val Leu Leu Phe Ser Gln Tyr Ala Arg 275 280 285 Asn Val Lys Phe Pro Leu Pro Ile Tyr Lys Ser Lys Lys Gly Trp Thr 290 295 300 Ala Tyr Lys Leu Gln Leu Phe Lys Met Phe Pro Ile Ile Leu Ala Ile 305 310 315 320Leu Val Ser Trp Leu Leu Cys Phe Ile Phe Thr Val Thr Asp Val Phe 325 330 335 Pro Pro Asp Ser Thr Lys Tyr Gly Phe Tyr Ala Arg Thr Asp Ala Arg 340 345 350 Gln Gly Val Leu Leu Val Ala Pro Trp Phe Lys Val Pro Tyr Pro Phe 355 360 365 Gln Trp Gly Leu Pro Thr Val Ser Ala Ala Gly Val Ile Gly Met Leu 370 375 380 Ser Ala Val Val Ala Ser Ile Ile Glu Ser Ile Gly Asp Tyr Tyr Ala 385 390 395 400Cys Ala Arg Leu Ser Cys Ala Pro Pro Pro Pro His Pro Arg Asn Lys 405 410 415 Gln Gly Asn Phe Arg Gly Arg Pro Leu Leu Cys Ser 420 425 39807PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 39Met Pro Lys Ala Pro Lys Gln Gln Pro Pro Glu Pro Glu Trp Ile Gly 1 5 10 15 Asp Gly Glu Ser Thr Ser Pro Ser Asp Lys Val Val Lys Lys Gly Lys 20 25 30 Lys Asp Lys Lys Ile Lys Lys Thr Phe Phe Glu Glu Leu Ala Val Glu 35 40 45 Asp Lys Gln Ala Gly Glu Glu Glu Lys Val Leu Lys Glu Lys Glu Gln 50 55 60 Gln Gln Gln Gln Gln Gln Gln Gln Gln Lys Lys Lys Arg Asp Thr Arg 65 70 75 80Lys Gly Arg Arg Lys Lys Asp Val Asp Asp Asp Gly Glu Glu Lys Glu 85 90 95 Leu Met Glu Arg Leu Lys Lys Leu Ser Val Pro Thr Ser Asp Glu Glu 100 105 110 Asp Glu Val Pro Ala Pro Lys Pro Arg Gly Gly Lys Lys Thr Lys Gly 115 120 125 Gly Asn Val Phe Ala Ala Leu Ile Gln Asp Gln Ser Glu Glu Glu Glu 130 135 140 Glu Glu Glu Lys His Pro Pro Lys Pro Ala Lys Pro Glu Lys Asn Arg 145 150 155 160Ile Asn Lys Ala Val Ser Glu Glu Gln Gln Pro Ala Leu Lys Gly Lys 165 170 175 Lys Gly Lys Glu Glu Lys Ser Lys Gly Lys Ala Lys Pro Gln Asn Lys 180 185 190 Phe Ala Ala Leu Asp Asn Glu Glu Glu Asp Lys Glu Glu Glu Ile Ile 195 200 205 Lys Glu Lys Glu Pro Pro Lys Gln Gly Lys Glu Lys Ala Lys Lys Ala 210 215 220 Glu Gln Met Glu Tyr Glu Arg Gln Val Ala Ser Leu Lys Ala Ala Asn 225 230 235 240Ala Ala Glu Asn Asp Phe Ser Val Ser Gln Ala Glu Met Ser Ser Arg 245 250 255 Gln Ala Met Leu Glu Asn Ala Ser Asp Ile Lys Leu Glu Lys Phe Ser 260 265 270 Ile Ser Ala His Gly Lys Glu Leu Phe Val Asn Ala Asp Leu Tyr Ile 275 280 285 Val Ala Gly Arg Arg Tyr Gly Leu Val Gly Pro Asn Gly Lys Gly Lys 290 295 300 Thr Thr Leu Leu Lys His Ile Ala Asn Arg Ala Leu Ser Ile Pro Pro 305 310 315 320Asn Ile Asp Val Leu Leu Cys Glu Gln Glu Val Val Ala Asp Glu Thr 325 330 335 Pro Ala Val Gln Ala Val Leu Arg Ala Asp Thr Lys Arg Leu Lys Leu 340 345 350 Leu Glu Glu Glu Arg Arg Leu Gln Gly Gln Leu Glu Gln Gly Asp Asp 355 360 365 Thr Ala Ala Glu Arg Leu Glu Lys Val Tyr Glu Glu Leu Arg Ala Thr 370 375 380 Gly Ala Ala Ala Ala Glu Ala Lys Ala Arg Arg Ile Leu Ala Gly Leu 385 390 395 400Gly Phe Asp Pro Glu Met Gln Asn Arg Pro Thr Gln Lys Phe Ser Gly 405 410 415 Gly Trp Arg Met Arg Val Ser Leu Ala Arg Ala Leu Phe Met Glu Pro 420 425 430 Thr Leu Leu Met Leu Asp Glu Pro Thr Asn His Leu Asp Leu Asn Ala 435 440 445 Val Ile Trp Leu Asn Asn Tyr Leu Gln Gly Trp Arg Lys Thr Leu Leu 450 455 460 Ile Val Ser His Asp Gln Gly Phe Leu Asp Asp Val Cys Thr Asp Ile 465 470 475 480Ile His Leu Asp Ala Gln Arg Leu His Tyr Tyr Arg Gly Asn Tyr Met 485 490 495 Thr Phe Lys Lys Met Tyr Gln Gln Lys Gln Lys Glu Leu Leu Lys Gln 500 505 510 Tyr Glu Lys Gln Glu Lys Lys Leu Lys Glu Leu Lys Ala Gly Gly Lys 515 520 525 Ser Thr Lys Gln Ala Glu Lys Gln Thr Lys Glu Ala Leu Thr Arg Lys 530 535 540 Gln Gln Lys Cys Arg Arg Lys Asn Gln Asp Glu Glu Ser Gln Glu Ala 545 550 555 560Pro Glu Leu Leu Lys Arg Pro Lys Glu Tyr Thr Val Arg Phe Thr Phe 565 570 575 Pro Asp Pro Pro Pro Leu Ser Pro Pro Val Leu Gly Leu His Gly Val 580 585 590 Thr Phe Gly Tyr Gln Gly Gln Lys Pro Leu Phe Lys Asn Leu Asp Phe 595 600 605 Gly Ile Asp Met Asp Ser Arg Ile Cys Ile Val Gly Pro Asn Gly Val 610 615 620 Gly Lys Ser Thr Leu Leu Leu Leu Leu Thr Gly Lys Leu Thr Pro Thr 625 630 635 640His Gly Glu Met Arg Lys Asn His Arg Leu Lys Ile Gly Phe Phe Asn 645 650 655 Gln Gln Tyr Ala Glu Gln Leu Arg Met Glu Glu Thr Pro Thr Glu Tyr 660 665 670 Leu Gln Arg Gly Phe Asn Leu Pro Tyr Gln Asp Ala Arg Lys Cys Leu 675 680 685 Gly Arg Phe Gly Leu Glu Ser His Ala His Thr Ile Gln Ile Cys Lys 690 695 700 Leu Ser Gly Gly Gln Lys Ala Arg Val Val Phe Ala Glu Leu Ala Cys 705 710 715 720Arg Glu Pro Asp Val Leu Ile Leu Asp Glu Pro Thr Asn Asn Leu Asp 725 730 735 Ile Glu Ser Ile Asp Ala Leu Gly Glu Ala Ile Asn Glu Tyr Lys Gly 740 745 750 Ala Val Ile Val Val Ser His Asp Ala Arg Leu Ile Thr Glu Thr Asn 755 760 765 Cys Gln Leu Trp Val Val Glu Glu Gln Ser Val Ser Gln Ile Asp Gly 770 775 780 Asp Phe Glu Asp Tyr Lys Arg Glu Val Leu Glu Ala Leu Gly Glu Val 785 790 795 800Met Val Ser Arg Pro Arg Glu 805 40134PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 40Met Pro Lys Ala Pro Lys Gln Gln Pro Pro Glu Pro Glu Trp Ile Gly 1 5 10 15 Asp Gly Glu Ser Thr Ser Pro Ser Asp Lys Val Val Lys Lys Gly Lys 20 25 30 Lys Asp Lys Lys Ile Lys Lys Thr Phe Phe Glu Glu Leu Ala Val Glu 35 40 45 Asp Lys Gln Ala Gly Glu Glu Glu Lys Val Leu Lys Glu Lys Glu Gln 50 55 60 Gln Gln Gln Gln Gln Gln Gln Gln Gln Lys Lys Ser Glu Ile Pro Glu 65 70 75 80Lys Ala Gly Gly Arg Arg Met Trp Met Met Met Glu Lys Arg Lys Ser 85 90 95 Ser Trp Ser Val Leu Arg Ser Ser Gln Cys Gln Pro Val Met Arg Arg 100 105 110 Met Lys Tyr Pro Pro Gln Asn Pro Ala Glu Gly Arg Lys Pro Arg Val 115 120 125 Val Met Phe Leu Gln Pro 130 4189PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 41Met Pro Lys Ala Pro Lys Gln Gln Pro Pro Glu Pro Glu Trp Ile Gly 1 5 10 15 Asp Gly Glu Ser Thr Ser Pro Ser Asp Lys Val Val Lys Lys Gly Lys 20 25 30 Lys Asp Lys Lys Ile Lys Lys Thr Phe Phe Glu Glu Leu Ala Val Glu 35 40 45 Asp Lys Gln Ala Gly Glu Glu Glu Lys Val Leu Lys Glu Lys Glu Gln 50 55 60 Gln Gln Gln Gln Gln Gln Gln Gln Gln Lys Lys Lys Ala Arg Tyr Pro 65 70 75 80Lys Arg Gln Ala Glu Glu Gly Cys Gly 85 42286PRTArtificial SequenceDescription of Artificial Sequence

polypeptides encoded by genes with coding microsatellites 42Ser Pro Asp Tyr Phe Pro Gln Ile Ser Ser Gln Phe Gly Thr Val Glu 1 5 10 15 Lys Met Glu Lys Ile Phe Ile Ser Ser Ser Thr Lys Ala Glu Gly Lys 20 25 30 Gly Ile Ser Pro Phe Glu Ala Pro Ile Asn Thr Gln Ala Pro Pro Glu 35 40 45 Lys Gly Lys Glu Ala Val Val Gln Glu Pro Glu Arg Ser Trp Phe Gln 50 55 60 Thr Lys Glu Glu Arg Lys Lys Glu Lys Ile Ala Lys Ala Leu Gln Glu 65 70 75 80Phe Asp Leu Ala Leu Arg Gly Lys Lys Lys Arg Lys Lys Phe Met Lys 85 90 95 Asp Ala Lys Lys Lys Gly Glu Met Thr Ala Glu Glu Arg Ser Gln Phe 100 105 110 Glu Ile Leu Lys Ala Gln Met Phe Ala Glu Arg Leu Ala Lys Arg Asn 115 120 125 Arg Arg Ala Lys Arg Ala Arg Ala Met Pro Glu Glu Glu Pro Val Arg 130 135 140 Gly Pro Ala Lys Lys Gln Lys Gln Gly Lys Lys Ser Val Phe Asp Glu 145 150 155 160Glu Leu Thr Asn Thr Ser Lys Lys Ala Leu Lys Gln Tyr Arg Ala Gly 165 170 175 Pro Ser Phe Glu Glu Arg Lys Gln Leu Gly Leu Pro His Gln Arg Arg 180 185 190 Gly Gly Asn Phe Lys Ser Asn Pro Asp Thr Arg Gly Gly Ser Ser Cys 195 200 205 Arg Gly Leu Lys Lys Phe Met Gly Ala Ala Leu Lys Ser Leu Pro Cys 210 215 220 Gly Lys Ser Ser Trp Leu Val Cys Leu Phe Ser Ile Cys Leu Lys Lys 225 230 235 240Lys Gln Lys Gln Lys Thr Thr Leu Trp Cys Gly Gly Met Val Arg Ser 245 250 255 Tyr Phe Pro Lys His Val Cys Gln Ser Pro Phe Leu Leu Ile Ser Phe 260 265 270 His Met Thr Ile Leu Asn Gly Ser Ile Phe Gly Lys Arg Glu 275 280 285 43251PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 43Met Glu Lys Ile Phe Ile Ser Ser Ser Thr Lys Ala Glu Gly Lys Gly 1 5 10 15 Ile Ser Pro Phe Glu Ala Pro Ile Asn Thr Gln Ala Pro Pro Glu Lys 20 25 30 Gly Lys Glu Ala Val Val Gln Glu Pro Glu Arg Ser Trp Phe Gln Thr 35 40 45 Lys Glu Glu Arg Lys Lys Glu Lys Ile Ala Lys Ala Leu Gln Glu Phe 50 55 60 Asp Leu Ala Leu Arg Gly Lys Lys Lys Arg Lys Lys Phe Met Lys Asp 65 70 75 80Ala Lys Lys Lys Gly Glu Met Thr Ala Glu Glu Arg Ser Gln Phe Glu 85 90 95 Ile Leu Lys Ala Gln Met Phe Ala Glu Arg Leu Ala Lys Arg Asn Arg 100 105 110 Arg Ala Lys Arg Ala Arg Ala Met Pro Glu Glu Glu Pro Val Arg Gly 115 120 125 Pro Ala Lys Lys Gln Lys Gln Gly Lys Lys Ser Val Phe Asp Glu Glu 130 135 140 Leu Thr Asn Thr Ser Lys Lys Ala Leu Lys Gln Tyr Arg Ala Gly Pro 145 150 155 160Ser Phe Glu Glu Arg Lys Gln Leu Gly Leu Pro His Gln Arg Arg Gly 165 170 175 Gly Asn Phe Lys Ser Asn Pro Asp Thr Arg Gly Gly Ser Ser Cys Arg 180 185 190 Gly Leu Lys Lys Phe Met Gly Ala Ala Leu Lys Ser Leu Pro Cys Gly 195 200 205 Lys Ser Ser Trp Leu Val Cys Leu Phe Ser Ile Cys Leu Lys Lys Asn 210 215 220 Lys Asn Lys Lys Gln His Phe Gly Val Val Val Trp Tyr Val Ala Ile 225 230 235 240Phe Leu Ser Met Ser Val Asn Leu Pro Ser Cys 245 250 44238PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 44Met Glu Lys Ile Phe Ile Ser Ser Ser Thr Lys Ala Glu Gly Lys Gly 1 5 10 15 Ile Ser Pro Phe Glu Ala Pro Ile Asn Thr Gln Ala Pro Pro Glu Lys 20 25 30 Gly Lys Glu Ala Val Val Gln Glu Pro Glu Arg Ser Trp Phe Gln Thr 35 40 45 Lys Glu Glu Arg Lys Lys Glu Lys Ile Ala Lys Ala Leu Gln Glu Phe 50 55 60 Asp Leu Ala Leu Arg Gly Lys Lys Lys Arg Lys Lys Phe Met Lys Asp 65 70 75 80Ala Lys Lys Lys Gly Glu Met Thr Ala Glu Glu Arg Ser Gln Phe Glu 85 90 95 Ile Leu Lys Ala Gln Met Phe Ala Glu Arg Leu Ala Lys Arg Asn Arg 100 105 110 Arg Ala Lys Arg Ala Arg Ala Met Pro Glu Glu Glu Pro Val Arg Gly 115 120 125 Pro Ala Lys Lys Gln Lys Gln Gly Lys Lys Ser Val Phe Asp Glu Glu 130 135 140 Leu Thr Asn Thr Ser Lys Lys Ala Leu Lys Gln Tyr Arg Ala Gly Pro 145 150 155 160Ser Phe Glu Glu Arg Lys Gln Leu Gly Leu Pro His Gln Arg Arg Gly 165 170 175 Gly Asn Phe Lys Ser Asn Pro Asp Thr Arg Gly Gly Ser Ser Cys Arg 180 185 190 Gly Leu Lys Lys Phe Met Gly Ala Ala Leu Lys Ser Leu Pro Cys Gly 195 200 205 Lys Ser Ser Trp Leu Val Cys Leu Phe Ser Ile Cys Leu Lys Lys Lys 210 215 220 Thr Lys Thr Lys Asn Asn Thr Leu Val Trp Trp Tyr Gly Thr 225 230 235 45192PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 45Met Asp Gly Ser Gly Glu Gln Pro Arg Gly Gly Gly Pro Thr Ser Ser 1 5 10 15 Glu Gln Ile Met Lys Thr Gly Ala Leu Leu Leu Gln Gly Phe Ile Gln 20 25 30 Asp Arg Ala Gly Arg Met Gly Gly Glu Ala Pro Glu Leu Ala Leu Asp 35 40 45 Pro Val Pro Gln Asp Ala Ser Thr Lys Lys Leu Ser Glu Cys Leu Lys 50 55 60 Arg Ile Gly Asp Glu Leu Asp Ser Asn Met Glu Leu Gln Arg Met Ile 65 70 75 80Ala Ala Val Asp Thr Asp Ser Pro Arg Glu Val Phe Phe Arg Val Ala 85 90 95 Ala Asp Met Phe Ser Asp Gly Asn Phe Asn Trp Gly Arg Val Val Ala 100 105 110 Leu Phe Tyr Phe Ala Ser Lys Leu Val Leu Lys Ala Leu Cys Thr Lys 115 120 125 Val Pro Glu Leu Ile Arg Thr Ile Met Gly Trp Thr Leu Asp Phe Leu 130 135 140 Arg Glu Arg Leu Leu Gly Trp Ile Gln Asp Gln Gly Gly Trp Asp Gly 145 150 155 160Leu Leu Ser Tyr Phe Gly Thr Pro Thr Trp Gln Thr Val Thr Ile Phe 165 170 175 Val Ala Gly Val Leu Thr Ala Ser Leu Thr Ile Trp Lys Lys Met Gly 180 185 190 4658PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 46Met Asp Gly Ser Gly Glu Gln Pro Arg Gly Gly Gly Pro Thr Ser Ser 1 5 10 15 Glu Gln Ile Met Lys Thr Gly Ala Leu Leu Leu Gln Gly Phe Ile Gln 20 25 30 Asp Arg Ala Gly Arg Met Gly Gly Arg His Pro Ser Trp Pro Trp Thr 35 40 45 Arg Cys Leu Arg Met Arg Pro Pro Arg Ser 50 55 4772PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 47Met Asp Gly Ser Gly Glu Gln Pro Arg Gly Gly Gly Pro Thr Ser Ser 1 5 10 15 Glu Gln Ile Met Lys Thr Gly Ala Leu Leu Leu Gln Gly Phe Ile Gln 20 25 30 Asp Arg Ala Gly Arg Met Gly Gly Gly Gly Thr Arg Ala Gly Pro Gly 35 40 45 Pro Gly Ala Ser Gly Cys Val His Gln Glu Ala Glu Arg Val Ser Gln 50 55 60 Ala His Arg Gly Arg Thr Gly Gln 65 70 48246PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 48Met Ala Phe Leu Arg Ser Met Trp Gly Val Leu Ser Ala Leu Gly Arg 1 5 10 15 Ser Gly Ala Glu Leu Cys Thr Gly Cys Gly Ser Arg Leu Arg Ser Pro 20 25 30 Phe Ser Phe Val Tyr Leu Pro Arg Trp Phe Ser Ser Val Leu Ala Ser 35 40 45 Cys Pro Lys Lys Pro Val Ser Ser Tyr Leu Arg Phe Ser Lys Glu Gln 50 55 60 Leu Pro Ile Phe Lys Ala Gln Asn Pro Asp Ala Lys Thr Thr Glu Leu 65 70 75 80Ile Arg Arg Ile Ala Gln Arg Trp Arg Glu Leu Pro Asp Ser Lys Lys 85 90 95 Lys Ile Tyr Gln Asp Ala Tyr Arg Ala Glu Trp Gln Val Tyr Lys Glu 100 105 110 Glu Ile Ser Arg Phe Lys Glu Gln Leu Thr Pro Ser Gln Ile Met Ser 115 120 125 Leu Glu Lys Glu Ile Met Asp Lys His Leu Lys Arg Lys Ala Met Thr 130 135 140 Lys Lys Lys Glu Leu Thr Leu Leu Gly Lys Pro Lys Arg Pro Arg Ser 145 150 155 160Ala Tyr Asn Val Tyr Val Ala Glu Arg Phe Gln Glu Ala Lys Gly Asp 165 170 175 Ser Pro Gln Glu Lys Leu Lys Thr Val Lys Glu Asn Trp Lys Asn Leu 180 185 190 Ser Asp Ser Glu Lys Glu Leu Tyr Ile Gln His Ala Lys Glu Asp Glu 195 200 205 Thr Arg Tyr His Asn Glu Met Lys Ser Trp Glu Glu Gln Met Ile Glu 210 215 220 Val Gly Arg Lys Asp Leu Leu Arg Arg Thr Ile Lys Lys Gln Arg Lys 225 230 235 240Tyr Gly Ala Glu Glu Cys 245 49148PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 49Met Ala Phe Leu Arg Ser Met Trp Gly Val Leu Ser Ala Leu Gly Arg 1 5 10 15 Ser Gly Ala Glu Leu Cys Thr Gly Cys Gly Ser Arg Leu Arg Ser Pro 20 25 30 Phe Ser Phe Val Tyr Leu Pro Arg Trp Phe Ser Ser Val Leu Ala Ser 35 40 45 Cys Pro Lys Lys Pro Val Ser Ser Tyr Leu Arg Phe Ser Lys Glu Gln 50 55 60 Leu Pro Ile Phe Lys Ala Gln Asn Pro Asp Ala Lys Thr Thr Glu Leu 65 70 75 80Ile Arg Arg Ile Ala Gln Arg Trp Arg Glu Leu Pro Asp Ser Lys Lys 85 90 95 Lys Ile Tyr Gln Asp Ala Tyr Arg Ala Glu Trp Gln Val Tyr Lys Glu 100 105 110 Glu Ile Ser Arg Phe Lys Glu Gln Leu Thr Pro Ser Gln Ile Met Ser 115 120 125 Leu Glu Lys Glu Ile Met Asp Lys His Leu Lys Arg Lys Ala Met Thr 130 135 140 Lys Lys Lys Ser 145 50162PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 50Met Ala Phe Leu Arg Ser Met Trp Gly Val Leu Ser Ala Leu Gly Arg 1 5 10 15 Ser Gly Ala Glu Leu Cys Thr Gly Cys Gly Ser Arg Leu Arg Ser Pro 20 25 30 Phe Ser Phe Val Tyr Leu Pro Arg Trp Phe Ser Ser Val Leu Ala Ser 35 40 45 Cys Pro Lys Lys Pro Val Ser Ser Tyr Leu Arg Phe Ser Lys Glu Gln 50 55 60 Leu Pro Ile Phe Lys Ala Gln Asn Pro Asp Ala Lys Thr Thr Glu Leu 65 70 75 80Ile Arg Arg Ile Ala Gln Arg Trp Arg Glu Leu Pro Asp Ser Lys Lys 85 90 95 Lys Ile Tyr Gln Asp Ala Tyr Arg Ala Glu Trp Gln Val Tyr Lys Glu 100 105 110 Glu Ile Ser Arg Phe Lys Glu Gln Leu Thr Pro Ser Gln Ile Met Ser 115 120 125 Leu Glu Lys Glu Ile Met Asp Lys His Leu Lys Arg Lys Ala Met Thr 130 135 140 Lys Lys Lys Arg Val Asn Thr Ala Trp Lys Thr Lys Lys Thr Ser Phe 145 150 155 160Ser Leu 51235PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 51Met Thr Val Leu Ala Pro Ala Trp Ser Pro Thr Thr Tyr Leu Leu Leu 1 5 10 15 Leu Leu Leu Leu Ser Ser Gly Leu Ser Gly Thr Gln Asp Cys Ser Phe 20 25 30 Gln His Ser Pro Ile Ser Ser Asp Phe Ala Val Lys Ile Arg Glu Leu 35 40 45 Ser Asp Tyr Leu Leu Gln Asp Tyr Pro Val Thr Val Ala Ser Asn Leu 50 55 60 Gln Asp Glu Glu Leu Cys Gly Gly Leu Trp Arg Leu Val Leu Ala Gln 65 70 75 80Arg Trp Met Glu Arg Leu Lys Thr Val Ala Gly Ser Lys Met Gln Gly 85 90 95 Leu Leu Glu Arg Val Asn Thr Glu Ile His Phe Val Thr Lys Cys Ala 100 105 110 Phe Gln Pro Pro Pro Ser Cys Leu Arg Phe Val Gln Thr Asn Ile Ser 115 120 125 Arg Leu Leu Gln Glu Thr Ser Glu Gln Leu Val Ala Leu Lys Pro Trp 130 135 140 Ile Thr Arg Gln Asn Phe Ser Arg Cys Leu Glu Leu Gln Cys Gln Pro 145 150 155 160Asp Ser Ser Thr Leu Pro Pro Pro Trp Ser Pro Arg Pro Leu Glu Ala 165 170 175 Thr Ala Pro Thr Ala Pro Gln Pro Pro Leu Leu Leu Leu Leu Leu Leu 180 185 190 Pro Val Gly Leu Leu Leu Leu Ala Ala Ala Trp Cys Leu His Trp Gln 195 200 205 Arg Thr Arg Arg Arg Thr Pro Arg Pro Gly Glu Gln Val Pro Pro Val 210 215 220 Pro Ser Pro Gln Asp Leu Leu Leu Val Glu His 225 230 23552140PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 52Met Thr Val Leu Ala Pro Ala Trp Ser Pro Thr Thr Tyr Leu Leu Leu 1 5 10 15 Leu Leu Leu Leu Ser Ser Gly Leu Ser Gly Thr Gln Asp Cys Ser Phe 20 25 30 Gln His Ser Pro Ile Ser Ser Asp Phe Ala Val Lys Ile Arg Glu Leu 35 40 45 Ser Asp Tyr Leu Leu Gln Asp Tyr Pro Val Thr Val Ala Ser Asn Leu 50 55 60 Gln Asp Glu Glu Leu Cys Gly Gly Leu Trp Arg Leu Val Leu Ala Gln 65 70 75 80Arg Trp Met Glu Arg Leu Lys Thr Val Ala Gly Ser Lys Met Gln Gly 85 90 95 Leu Leu Glu Arg Val Asn Thr Glu Ile His Phe Val Thr Lys Cys Ala 100 105 110 Phe Gln Pro Pro Pro Ala Val Phe Ala Ser Ser Arg Pro Thr Ser Pro 115 120 125 Ala Ser Cys Arg Arg Pro Pro Ser Ser Trp Trp Arg 130 135 14053161PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 53Met Thr Val Leu Ala Pro Ala Trp Ser Pro Thr Thr Tyr Leu Leu Leu 1 5 10 15 Leu Leu Leu Leu Ser Ser Gly Leu Ser Gly Thr Gln Asp Cys Ser Phe 20 25 30 Gln His Ser Pro Ile Ser Ser Asp Phe Ala Val Lys Ile Arg Glu Leu 35

40 45 Ser Asp Tyr Leu Leu Gln Asp Tyr Pro Val Thr Val Ala Ser Asn Leu 50 55 60 Gln Asp Glu Glu Leu Cys Gly Gly Leu Trp Arg Leu Val Leu Ala Gln 65 70 75 80Arg Trp Met Glu Arg Leu Lys Thr Val Ala Gly Ser Lys Met Gln Gly 85 90 95 Leu Leu Glu Arg Val Asn Thr Glu Ile His Phe Val Thr Lys Cys Ala 100 105 110 Phe Gln Pro Pro Pro Gln Leu Ser Ser Leu Arg Pro Asp Gln His Leu 115 120 125 Pro Pro Pro Ala Gly Asp Leu Arg Ala Ala Gly Gly Ala Glu Ala Leu 130 135 140 Asp His Ser Pro Glu Leu Leu Pro Val Pro Gly Ala Ala Val Ser Ala 145 150 155 160Arg 54920PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 54Met Leu Gln Gly His Phe Trp Leu Val Arg Glu Gly Ile Met Ile Ser 1 5 10 15 Pro Ser Ser Pro Pro Pro Pro Asn Leu Phe Phe Phe Pro Leu Gln Ile 20 25 30 Phe Pro Phe Pro Phe Thr Ser Phe Pro Ser His Leu Leu Ser Leu Thr 35 40 45 Pro Pro Lys Ala Cys Tyr Leu Lys Ala Ile Glu Thr Gln Pro Asn Phe 50 55 60 Ala Val Ala Trp Ser Asn Leu Gly Cys Val Phe Asn Ala Gln Gly Glu 65 70 75 80Ile Trp Leu Ala Ile His His Phe Glu Lys Ala Val Thr Leu Asp Pro 85 90 95 Asn Phe Leu Asp Ala Tyr Ile Asn Leu Gly Asn Val Leu Lys Glu Ala 100 105 110 Arg Ile Phe Asp Arg Ala Val Ala Ala Tyr Leu Arg Ala Leu Ser Leu 115 120 125 Ser Pro Asn His Ala Val Val His Gly Asn Leu Ala Cys Val Tyr Tyr 130 135 140 Glu Gln Gly Leu Ile Asp Leu Ala Ile Asp Thr Tyr Arg Arg Ala Ile 145 150 155 160Glu Leu Gln Pro His Phe Pro Asp Ala Tyr Cys Asn Leu Ala Asn Ala 165 170 175 Leu Lys Glu Lys Gly Ser Val Ala Glu Ala Glu Asp Cys Tyr Asn Thr 180 185 190 Ala Leu Arg Leu Cys Pro Thr His Ala Asp Ser Leu Asn Asn Leu Ala 195 200 205 Asn Ile Lys Arg Glu Gln Gly Asn Ile Glu Glu Ala Val Arg Leu Tyr 210 215 220 Arg Lys Ala Leu Glu Val Phe Pro Glu Phe Ala Ala Ala His Ser Asn 225 230 235 240Leu Ala Ser Val Leu Gln Gln Gln Gly Lys Leu Gln Glu Ala Leu Met 245 250 255 His Tyr Lys Glu Ala Ile Arg Ile Ser Pro Thr Phe Ala Asp Ala Tyr 260 265 270 Ser Asn Met Gly Asn Thr Leu Lys Glu Met Gln Asp Val Gln Gly Ala 275 280 285 Leu Gln Cys Tyr Thr Arg Ala Ile Gln Ile Asn Pro Ala Phe Ala Asp 290 295 300 Ala His Ser Asn Leu Ala Ser Ile His Lys Asp Ser Gly Asn Ile Pro 305 310 315 320Glu Ala Ile Ala Ser Tyr Arg Thr Ala Leu Lys Leu Lys Pro Asp Phe 325 330 335 Pro Asp Ala Tyr Cys Asn Leu Ala His Cys Leu Gln Ile Val Cys Asp 340 345 350 Trp Thr Asp Tyr Asp Glu Arg Met Lys Lys Leu Val Ser Ile Val Ala 355 360 365 Asp Gln Leu Glu Lys Asn Arg Leu Pro Ser Val His Pro His His Ser 370 375 380 Met Leu Tyr Pro Leu Ser His Gly Phe Arg Lys Ala Ile Ala Glu Arg 385 390 395 400His Gly Asn Leu Cys Leu Asp Lys Ile Asn Val Leu His Lys Pro Pro 405 410 415 Tyr Glu His Pro Lys Asp Leu Lys Leu Ser Asp Gly Arg Leu Arg Val 420 425 430 Gly Tyr Val Ser Ser Asp Phe Gly Asn His Pro Thr Ser His Leu Met 435 440 445 Gln Ser Ile Pro Gly Met His Asn Pro Asp Lys Phe Glu Val Phe Cys 450 455 460 Tyr Ala Leu Ser Pro Asp Asp Gly Thr Asn Phe Arg Val Lys Val Met 465 470 475 480Ala Glu Ala Asn His Phe Ile Asp Leu Ser Gln Ile Pro Cys Asn Gly 485 490 495 Lys Ala Ala Asp Arg Ile His Gln Asp Gly Ile His Ile Leu Val Asn 500 505 510 Met Asn Gly Tyr Thr Lys Gly Ala Arg Asn Glu Leu Phe Ala Leu Arg 515 520 525 Pro Ala Pro Ile Gln Ala Met Trp Leu Gly Tyr Pro Gly Thr Ser Gly 530 535 540 Ala Leu Phe Met Asp Tyr Ile Ile Thr Asp Gln Glu Thr Ser Pro Ala 545 550 555 560Glu Val Ala Glu Gln Tyr Ser Glu Lys Leu Ala Tyr Met Pro His Thr 565 570 575 Phe Phe Ile Gly Asp His Ala Asn Met Phe Pro His Leu Lys Lys Lys 580 585 590 Ala Val Ile Asp Phe Lys Ser Asn Gly His Ile Tyr Asp Asn Arg Ile 595 600 605 Val Leu Asn Gly Ile Asp Leu Lys Ala Phe Leu Asp Ser Leu Pro Asp 610 615 620 Val Lys Ile Val Lys Met Lys Cys Pro Asp Gly Gly Asp Asn Ala Asp 625 630 635 640Ser Ser Asn Thr Ala Leu Asn Met Pro Val Ile Pro Met Asn Thr Ile 645 650 655 Ala Glu Ala Val Ile Glu Met Ile Asn Arg Gly Gln Ile Gln Ile Thr 660 665 670 Ile Asn Gly Phe Ser Ile Ser Asn Gly Leu Ala Thr Thr Gln Ile Asn 675 680 685 Asn Lys Ala Ala Thr Gly Glu Glu Val Pro Arg Thr Ile Ile Val Thr 690 695 700 Thr Arg Ser Gln Tyr Gly Leu Pro Glu Asp Ala Ile Val Tyr Cys Asn 705 710 715 720Phe Asn Gln Leu Tyr Lys Ile Asp Pro Ser Thr Leu Gln Met Trp Ala 725 730 735 Asn Ile Leu Lys Arg Val Pro Asn Ser Val Leu Trp Leu Leu Arg Phe 740 745 750 Pro Ala Val Gly Glu Pro Asn Ile Gln Gln Tyr Ala Gln Asn Met Gly 755 760 765 Leu Pro Gln Asn Arg Ile Ile Phe Ser Pro Val Ala Pro Lys Glu Glu 770 775 780 His Val Arg Arg Gly Gln Leu Ala Asp Val Cys Leu Asp Thr Pro Leu 785 790 795 800Cys Asn Gly His Thr Thr Gly Met Asp Val Leu Trp Ala Gly Thr Pro 805 810 815 Met Val Thr Met Pro Gly Glu Thr Leu Ala Ser Arg Val Ala Ala Ser 820 825 830 Gln Leu Thr Cys Leu Gly Cys Leu Glu Leu Ile Ala Lys Asn Arg Gln 835 840 845 Glu Tyr Glu Asp Ile Ala Val Lys Leu Gly Thr Asp Leu Glu Tyr Leu 850 855 860 Lys Lys Val Arg Gly Lys Val Trp Lys Gln Arg Ile Ser Ser Pro Leu 865 870 875 880Phe Asn Thr Lys Gln Tyr Thr Met Glu Leu Glu Arg Leu Tyr Leu Gln 885 890 895 Met Trp Glu His Tyr Ala Ala Gly Asn Lys Pro Asp His Met Ile Lys 900 905 910 Pro Val Glu Val Thr Glu Ser Ala 915 9205546PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 55Met Leu Gln Gly His Phe Trp Leu Val Arg Glu Gly Ile Met Ile Ser 1 5 10 15 Pro Ser Ser Pro Pro Pro Pro Asn Leu Phe Phe Ser Leu Tyr Lys Phe 20 25 30 Ser Pro Phe Pro Leu Pro Pro Phe Pro Pro Ile Phe Phe His 35 40 45 5650PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 56Met Leu Gln Gly His Phe Trp Leu Val Arg Glu Gly Ile Met Ile Ser 1 5 10 15 Pro Ser Ser Pro Pro Pro Pro Asn Leu Phe Phe Phe Pro Phe Thr Asn 20 25 30 Phe Pro Leu Ser Leu Tyr Leu Leu Ser Leu Pro Ser Ser Phe Ile Asn 35 40 45 Pro Ser 5057350PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 57Met Glu Ser Gln Val Gly Gly Gly Pro Ala Gly Arg Pro Ala Gln Arg 1 5 10 15 Pro Leu Leu Gly Thr Asn Gly Ala Thr Asp Asp Ser Lys Thr Asn Leu 20 25 30 Ile Val Asn Tyr Leu Pro Gln Asn Met Thr Gln Asp Glu Phe Lys Ser 35 40 45 Leu Phe Gly Ser Ile Gly Asp Ile Glu Ser Cys Lys Leu Val Arg Asp 50 55 60 Lys Ile Thr Gly Gln Ser Leu Gly Tyr Gly Phe Val Asn Tyr Ser Asp 65 70 75 80Pro Asn Asp Ala Asp Lys Ala Ile Asn Thr Leu Asn Gly Leu Lys Leu 85 90 95 Gln Thr Lys Thr Ile Lys Val Ser Tyr Ala Arg Pro Ser Ser Ala Ser 100 105 110 Ile Arg Asp Ala Asn Leu Tyr Val Ser Gly Leu Pro Lys Thr Met Ser 115 120 125 Gln Lys Glu Met Glu Gln Leu Phe Ser Gln Tyr Gly Arg Ile Ile Thr 130 135 140 Ser Arg Ile Leu Val Asp Gln Val Thr Gly Val Ser Arg Gly Val Gly 145 150 155 160Phe Ile Arg Phe Asp Lys Arg Ile Glu Ala Glu Glu Ala Ile Lys Gly 165 170 175 Leu Asn Gly Gln Lys Pro Leu Gly Ala Arg Glu Pro Ile Thr Val Lys 180 185 190 Phe Ala Asn Asn Pro Ser Gln Lys Thr Gly Gln Ala Leu Leu Thr His 195 200 205 Leu Tyr Gln Ser Ser Ala Arg Arg Tyr Ala Gly Pro Leu His His Gln 210 215 220 Thr Gln Arg Phe Arg Leu Asp Asn Leu Leu Asn Met Ala Tyr Ala Val 225 230 235 240Lys Arg Phe Ser Pro Ile Ala Ile Asp Gly Met Ser Gly Leu Ala Gly 245 250 255 Val Gly Leu Ser Gly Gly Ala Ala Gly Gly Trp Cys Ile Phe Val Tyr 260 265 270 Asn Leu Ser Pro Glu Pro Asp Gln Ser Val Leu Trp Gln Leu Phe Gly 275 280 285 Pro Phe Gly Ala Val Thr Asn Val Lys Val Ile Arg Asp Phe Thr Thr 290 295 300 Asn Lys Cys Lys Gly Phe Gly Phe Met Thr Met Thr Asn Tyr Asp Glu 305 310 315 320Ala Ala Met Ala Ile Ala Ser Leu Asn Gly Tyr Arg Leu Gly Gln Arg 325 330 335 Val Leu Gln Val Ser Phe Lys Thr Ser Lys Gln His Lys Ala 340 345 3505840PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 58Met Glu Ser Gln Val Gly Gly Ala Arg Pro Ala Gly Leu Pro Asn Gly 1 5 10 15 His Ser Leu Val Gln Met Glu Pro Leu Thr Thr Ala Arg Pro Thr Ser 20 25 30 Ser Ser Thr Thr Cys Pro Arg Thr 35 405925PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 59Met Glu Ser Gln Val Gly Gly Gly Pro Gly Arg Pro Ala Cys Pro Thr 1 5 10 15 Ala Thr Pro Trp Tyr Lys Trp Ser His 20 2560189PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 60Leu Phe Ser His Gln Arg Val Gln Ala Gln Pro Thr Asp Tyr Gly Gly 1 5 10 15 Ser Phe Thr Arg Arg Cys Val Glu Trp Leu Leu Gly Leu Tyr Phe Leu 20 25 30 Ser His Ile Pro Ile Thr Leu Phe Met Asp Leu Gln Ala Val Val Pro 35 40 45 Arg Glu Leu Tyr Pro Val Glu Phe Arg Asn Leu Leu Lys Trp Tyr Ala 50 55 60 Lys Glu Phe Lys Asp Pro Leu Leu Gln Glu Pro Pro Ala Trp Phe Lys 65 70 75 80Ser Phe Leu Phe Cys Glu Leu Val Phe Gln Leu Pro Phe Phe Pro Ile 85 90 95 Ala Thr Tyr Ala Phe Leu Lys Gly Ser Cys Lys Trp Ile Arg Thr Pro 100 105 110 Ala Ile Ile Tyr Ser Val His Thr Met Thr Thr Leu Ile Leu Ile Leu 115 120 125 Ser Thr Phe Leu Phe Glu Asp Phe Ser Lys Ala Ser Gly Phe Lys Gly 130 135 140 Gln Arg Pro Glu Thr Leu His Glu Arg Leu Thr Leu Val Ser Val Tyr 145 150 155 160Ala Pro Tyr Leu Leu Ile Pro Phe Ile Leu Leu Ile Phe Met Leu Arg 165 170 175 Ser Pro Tyr Tyr Lys Tyr Glu Glu Lys Arg Lys Lys Lys 180 185 61251PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 61Leu Phe Ser His Gln Arg Val Gln Ala Gln Pro Thr Asp Tyr Gly Gly 1 5 10 15 Ser Phe Thr Arg Arg Cys Val Glu Trp Leu Leu Gly Leu Tyr Phe Leu 20 25 30 Ser His Ile Pro Ile Thr Leu Phe Met Asp Leu Gln Ala Val Val Pro 35 40 45 Arg Glu Leu Tyr Pro Val Glu Phe Arg Asn Leu Leu Lys Trp Tyr Ala 50 55 60 Lys Glu Phe Lys Asp Pro Leu Leu Gln Glu Pro Pro Ala Trp Phe Lys 65 70 75 80Ser Phe Leu Phe Cys Glu Leu Val Phe Gln Leu Pro Phe Phe Pro Ile 85 90 95 Ala Thr Tyr Ala Phe Leu Lys Gly Ser Cys Lys Trp Ile Arg Thr Pro 100 105 110 Ala Ile Ile Tyr Ser Val His Thr Met Thr Thr Leu Ile Leu Ile Leu 115 120 125 Ser Thr Phe Leu Phe Glu Asp Phe Ser Lys Ala Ser Gly Phe Lys Gly 130 135 140 Gln Arg Pro Glu Thr Leu His Glu Arg Leu Thr Leu Val Ser Val Tyr 145 150 155 160Ala Pro Tyr Leu Leu Ile Pro Phe Ile Leu Leu Ile Phe Met Leu Arg 165 170 175 Ser Pro Tyr Tyr Lys Tyr Glu Glu Lys Arg Lys Lys Asn Glu Gly Asn 180 185 190 Asn His Trp Pro Arg Val Glu Met Pro Thr Gly Trp Leu Leu Val Gly 195 200 205 Tyr Ile Gln Glu His Cys Ser Glu Pro Thr Ser Ser Ala Ala Phe Glu 210 215 220 Thr Leu Ala Ala Met His Lys Ser Lys Met Val Ser Gly Thr Met Ser 225 230 235 240Asn Pro His Leu Leu Pro Phe Phe Phe Phe Phe 245 250 62198PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 62Leu Phe Ser His Gln Arg Val Gln Ala Gln Pro Thr Asp Tyr Gly Gly 1 5 10 15 Ser Phe Thr Arg Arg Cys Val Glu Trp Leu Leu Gly Leu Tyr Phe Leu 20 25 30 Ser His Ile Pro Ile Thr Leu Phe Met Asp Leu Gln Ala Val Val Pro 35 40 45 Arg Glu Leu Tyr Pro Val Glu Phe Arg Asn Leu Leu Lys Trp Tyr Ala 50 55 60 Lys Glu Phe Lys Asp Pro Leu Leu Gln Glu Pro Pro Ala Trp Phe Lys 65 70 75 80Ser Phe Leu Phe Cys Glu Leu Val Phe Gln Leu Pro Phe Phe Pro Ile 85 90 95 Ala Thr Tyr Ala Phe Leu Lys Gly Ser Cys Lys Trp Ile Arg Thr Pro 100 105 110 Ala Ile Ile Tyr Ser Val His Thr Met Thr Thr Leu Ile Leu Ile Leu 115 120

125 Ser Thr Phe Leu Phe Glu Asp Phe Ser Lys Ala Ser Gly Phe Lys Gly 130 135 140 Gln Arg Pro Glu Thr Leu His Glu Arg Leu Thr Leu Val Ser Val Tyr 145 150 155 160Ala Pro Tyr Leu Leu Ile Pro Phe Ile Leu Leu Ile Phe Met Leu Arg 165 170 175 Ser Pro Tyr Tyr Lys Tyr Glu Glu Lys Arg Lys Lys Lys Met Lys Glu 180 185 190 Thr Thr Thr Gly Pro Gly 195 631232PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 63Met Ala Asn Gly Val Ile Pro Pro Pro Gly Gly Ala Ser Pro Leu Pro 1 5 10 15 Gln Val Arg Val Pro Leu Glu Glu Pro Pro Leu Ser Pro Asp Val Glu 20 25 30 Glu Glu Asp Asp Asp Leu Gly Lys Thr Leu Ala Val Ser Arg Phe Gly 35 40 45 Asp Leu Ile Ser Lys Pro Pro Ala Trp Asp Pro Glu Lys Pro Ser Arg 50 55 60 Ser Tyr Ser Glu Arg Asp Phe Glu Phe His Arg His Thr Ser His His 65 70 75 80Thr His His Pro Leu Ser Ala Arg Leu Pro Pro Pro His Lys Leu Arg 85 90 95 Arg Leu Pro Pro Thr Ser Ala Arg His Thr Arg Arg Lys Arg Lys Lys 100 105 110 Glu Lys Thr Ser Ala Pro Pro Ser Glu Gly Thr Pro Pro Ile Gln Glu 115 120 125 Glu Gly Gly Ala Gly Val Asp Glu Glu Glu Glu Glu Glu Glu Glu Glu 130 135 140 Glu Gly Glu Ser Glu Ala Glu Pro Val Glu Pro Pro Pro Ser Gly Thr 145 150 155 160Pro Gln Lys Ala Lys Phe Ser Ile Gly Ser Asp Glu Asp Asp Ser Pro 165 170 175 Gly Leu Pro Gly Arg Ala Ala Val Thr Lys Pro Leu Pro Ser Val Gly 180 185 190 Pro His Thr Asp Lys Ser Pro Gln His Ser Ser Ser Ser Pro Ser Pro 195 200 205 Arg Ala Arg Ala Ser Arg Leu Ala Gly Glu Lys Ser Arg Pro Trp Ser 210 215 220 Pro Ser Ala Ser Tyr Asp Leu Arg Glu Arg Leu Cys Pro Gly Ser Ala 225 230 235 240Leu Gly Asn Pro Gly Gly Pro Glu Gln Gln Val Pro Thr Asp Glu Ala 245 250 255 Glu Ala Gln Met Leu Gly Ser Ala Asp Leu Asp Asp Met Lys Ser His 260 265 270 Arg Leu Glu Asp Asn Pro Gly Val Arg Arg His Leu Val Lys Lys Pro 275 280 285 Ser Arg Thr Gln Gly Gly Arg Gly Ser Pro Ser Gly Leu Ala Pro Ile 290 295 300 Leu Arg Arg Lys Lys Lys Lys Lys Lys Leu Asp Arg Arg Pro His Glu 305 310 315 320Val Phe Val Glu Leu Asn Glu Leu Met Leu Asp Arg Ser Gln Glu Pro 325 330 335 His Trp Arg Glu Thr Ala Arg Trp Ile Lys Phe Glu Glu Asp Val Glu 340 345 350 Glu Glu Thr Glu Arg Trp Gly Lys Pro His Val Ala Ser Leu Ser Phe 355 360 365 Arg Ser Leu Leu Glu Leu Arg Arg Thr Ile Ala His Gly Ala Ala Leu 370 375 380 Leu Asp Leu Glu Gln Thr Thr Leu Pro Gly Ile Ala His Leu Val Val 385 390 395 400Glu Thr Met Ile Val Ser Asp Gln Ile Arg Pro Glu Asp Arg Ala Ser 405 410 415 Val Leu Arg Thr Leu Leu Leu Lys His Ser His Pro Asn Asp Asp Lys 420 425 430 Asp Ser Gly Phe Phe Pro Arg Asn Pro Ser Ser Ser Ser Met Asn Ser 435 440 445 Val Leu Gly Asn His His Pro Thr Pro Ser His Gly Pro Asp Gly Ala 450 455 460 Val Pro Thr Met Ala Asp Asp Leu Gly Glu Pro Ala Pro Leu Trp Pro 465 470 475 480His Asp Pro Asp Ala Lys Glu Lys Pro Leu His Met Pro Gly Gly Asp 485 490 495 Gly His Arg Gly Lys Ser Leu Lys Leu Leu Glu Lys Ile Pro Glu Asp 500 505 510 Ala Glu Ala Thr Val Val Leu Val Gly Cys Val Pro Phe Leu Glu Gln 515 520 525 Pro Ala Ala Ala Phe Val Arg Leu Asn Glu Ala Val Leu Leu Glu Ser 530 535 540 Val Leu Glu Val Pro Val Pro Val Arg Phe Leu Phe Val Met Leu Gly 545 550 555 560Pro Ser His Thr Ser Thr Asp Tyr His Glu Leu Gly Arg Ser Ile Ala 565 570 575 Thr Leu Met Ser Asp Lys Leu Phe His Glu Ala Ala Tyr Gln Ala Asp 580 585 590 Asp Arg Gln Asp Leu Leu Ser Ala Ile Ser Glu Phe Leu Asp Gly Ser 595 600 605 Ile Val Ile Pro Pro Ser Glu Val Glu Gly Arg Asp Leu Leu Arg Ser 610 615 620 Val Ala Ala Phe Gln Arg Glu Leu Leu Arg Lys Arg Arg Glu Arg Glu 625 630 635 640Gln Thr Lys Val Glu Met Thr Thr Arg Gly Gly Tyr Thr Ala Pro Gly 645 650 655 Lys Glu Leu Ser Leu Glu Leu Gly Gly Ser Glu Ala Thr Pro Glu Asp 660 665 670 Asp Pro Leu Leu Arg Thr Gly Ser Val Phe Gly Gly Leu Val Arg Asp 675 680 685 Val Arg Arg Arg Tyr Pro His Tyr Pro Ser Asp Leu Arg Asp Ala Leu 690 695 700 His Ser Gln Cys Val Ala Ala Val Leu Phe Ile Tyr Phe Ala Ala Leu 705 710 715 720Ser Pro Ala Ile Thr Phe Gly Gly Leu Leu Gly Glu Lys Thr Glu Gly 725 730 735 Leu Met Gly Val Ser Glu Leu Ile Val Ser Thr Ala Val Leu Gly Val 740 745 750 Leu Phe Ser Leu Leu Gly Ala Gln Pro Leu Leu Val Val Gly Phe Ser 755 760 765 Gly Pro Leu Leu Val Phe Glu Glu Ala Phe Phe Lys Phe Cys Arg Ala 770 775 780 Gln Asp Leu Glu Tyr Leu Thr Gly Arg Val Trp Val Gly Leu Trp Leu 785 790 795 800Val Val Phe Val Leu Ala Leu Val Ala Ala Glu Gly Ser Phe Leu Val 805 810 815 Arg Tyr Ile Ser Pro Phe Thr Gln Glu Ile Phe Ala Phe Leu Ile Ser 820 825 830 Leu Ile Phe Ile Tyr Glu Thr Phe Tyr Lys Leu Tyr Lys Val Phe Thr 835 840 845 Glu His Pro Leu Leu Pro Phe Tyr Pro Pro Glu Gly Ala Leu Glu Gly 850 855 860 Ser Leu Ala Ala Gly Leu Glu Pro Asn Gly Ser Ala Leu Pro Pro Thr 865 870 875 880Glu Gly Pro Pro Ser Pro Arg Asn Gln Pro Asn Thr Ala Leu Leu Ser 885 890 895 Leu Ile Leu Met Leu Gly Thr Phe Phe Ile Ala Phe Phe Leu Arg Lys 900 905 910 Phe Arg Asn Ser Arg Phe Leu Gly Gly Lys Ala Arg Arg Ile Ile Gly 915 920 925 Asp Phe Gly Ile Pro Ile Ser Ile Leu Val Met Val Leu Val Asp Tyr 930 935 940 Ser Ile Thr Asp Thr Tyr Thr Gln Lys Leu Thr Val Pro Thr Gly Leu 945 950 955 960Ser Val Thr Ser Pro Asp Lys Arg Ser Trp Phe Ile Pro Pro Leu Gly 965 970 975 Ser Ala Arg Pro Phe Pro Pro Trp Met Met Val Ala Ala Ala Val Pro 980 985 990 Ala Leu Leu Val Leu Ile Leu Ile Phe Met Glu Thr Gln Ile Thr Ala 995 1000 1005 Leu Ile Val Ser Gln Lys Ala Arg Arg Leu Leu Lys Gly Ser Gly Phe 1010 1015 1020 His Leu Asp Leu Leu Leu Ile Gly Ser Leu Gly Gly Leu Cys Gly Leu 1025 1030 1035 1040Phe Gly Leu Pro Trp Leu Thr Ala Ala Thr Val Arg Ser Val Thr His 1045 1050 1055 Val Asn Ala Leu Thr Val Met Arg Thr Ala Ile Ala Pro Gly Asp Lys 1060 1065 1070 Pro Gln Ile Gln Glu Val Arg Glu Gln Arg Val Thr Gly Val Leu Ile 1075 1080 1085 Ala Ser Leu Val Gly Leu Ser Ile Val Met Gly Ala Val Leu Arg Arg 1090 1095 1100 Ile Pro Leu Ala Val Leu Phe Gly Ile Phe Leu Tyr Met Gly Val Thr 1105 1110 1115 1120Ser Leu Ser Gly Ile Gln Leu Ser Gln Arg Leu Leu Leu Ile Leu Met 1125 1130 1135 Pro Ala Lys His His Pro Glu Gln Pro Tyr Val Thr Lys Val Lys Thr 1140 1145 1150 Trp Arg Met His Leu Phe Thr Cys Ile Gln Leu Gly Cys Ile Ala Leu 1155 1160 1165 Leu Trp Val Val Lys Ser Thr Ala Ala Ser Leu Ala Phe Pro Phe Leu 1170 1175 1180 Leu Leu Leu Thr Val Pro Leu Arg His Cys Leu Leu Pro Arg Leu Phe 1185 1190 1195 1200Gln Asp Arg Glu Leu Gln Ala Leu Asp Ser Glu Asp Ala Glu Pro Asn 1205 1210 1215 Phe Asp Glu Asp Gly Gln Asp Glu Tyr Asn Glu Leu His Met Pro Val 1220 1225 1230 64268PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 64Met Ala Asn Gly Val Ile Pro Pro Pro Gly Gly Ala Ser Pro Leu Pro 1 5 10 15 Gln Val Arg Val Pro Leu Glu Glu Pro Pro Leu Ser Pro Asp Val Glu 20 25 30 Glu Glu Asp Asp Asp Leu Gly Lys Thr Leu Ala Val Ser Arg Phe Gly 35 40 45 Asp Leu Ile Ser Lys Pro Pro Ala Trp Asp Pro Glu Lys Pro Ser Arg 50 55 60 Ser Tyr Ser Glu Arg Asp Phe Glu Phe His Arg His Thr Ser His His 65 70 75 80Thr His His Pro Leu Ser Ala Arg Leu Pro Pro Pro His Lys Leu Arg 85 90 95 Arg Leu Pro Pro Thr Ser Ala Arg His Thr Arg Arg Lys Arg Lys Lys 100 105 110 Glu Lys Thr Ser Ala Pro Pro Ser Glu Gly Thr Pro Pro Ile Gln Glu 115 120 125 Glu Gly Gly Ala Gly Val Asp Glu Glu Glu Glu Glu Glu Glu Glu Glu 130 135 140 Glu Gly Glu Ser Glu Ala Glu Pro Val Glu Pro Pro Pro Gln Gly Pro 145 150 155 160His Arg Arg Gln Ser Ser Pro Leu Glu Val Thr Arg Met Thr Val Gln 165 170 175 Ala Ser Leu Gly Gly Leu Leu Ser Pro Ser Pro Cys Pro Arg Trp Ala 180 185 190 His Thr Leu Thr Arg Ala Pro Ser Thr Pro Ala Ala Pro Pro Ala Pro 195 200 205 Gly Pro Gly Pro Pro Asp Ser Leu Gly Arg Lys Ala Gly Pro Gly Ala 210 215 220 His Arg Pro Val Met Thr Cys Gly Ser Asp Cys Ala Gln Ala Val Pro 225 230 235 240Trp Ala Thr Gln Val Val Gln Ser Ser Arg Cys Pro Gln Met Arg Arg 245 250 255 Arg Pro Arg Cys Trp Val Leu Gln Thr Trp Thr Thr 260 265 65170PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 65Met Ala Asn Gly Val Ile Pro Pro Pro Gly Gly Ala Ser Pro Leu Pro 1 5 10 15 Gln Val Arg Val Pro Leu Glu Glu Pro Pro Leu Ser Pro Asp Val Glu 20 25 30 Glu Glu Asp Asp Asp Leu Gly Lys Thr Leu Ala Val Ser Arg Phe Gly 35 40 45 Asp Leu Ile Ser Lys Pro Pro Ala Trp Asp Pro Glu Lys Pro Ser Arg 50 55 60 Ser Tyr Ser Glu Arg Asp Phe Glu Phe His Arg His Thr Ser His His 65 70 75 80Thr His His Pro Leu Ser Ala Arg Leu Pro Pro Pro His Lys Leu Arg 85 90 95 Arg Leu Pro Pro Thr Ser Ala Arg His Thr Arg Arg Lys Arg Lys Lys 100 105 110 Glu Lys Thr Ser Ala Pro Pro Ser Glu Gly Thr Pro Pro Ile Gln Glu 115 120 125 Glu Gly Gly Ala Gly Val Asp Glu Glu Glu Glu Glu Glu Glu Glu Glu 130 135 140 Glu Gly Glu Ser Glu Ala Glu Pro Val Glu Pro Pro Pro Leu Arg Asp 145 150 155 160Pro Thr Glu Gly Lys Val Leu His Trp Lys 165 17066686PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 66Met Ala Gly Ser Gly Ala Gly Val Arg Cys Ser Leu Leu Arg Leu Gln 1 5 10 15 Glu Thr Leu Ser Ala Ala Asp Arg Cys Gly Ala Ala Leu Ala Gly His 20 25 30 Gln Leu Ile Arg Gly Leu Gly Gln Glu Cys Val Leu Ser Ser Ser Pro 35 40 45 Ala Val Leu Ala Leu Gln Thr Ser Leu Val Phe Ser Arg Asp Phe Gly 50 55 60 Leu Leu Val Phe Val Arg Lys Ser Leu Asn Ser Ile Glu Phe Arg Glu 65 70 75 80Cys Arg Glu Glu Ile Leu Lys Phe Leu Cys Ile Phe Leu Glu Lys Met 85 90 95 Gly Gln Lys Ile Ala Pro Tyr Ser Val Glu Ile Lys Asn Thr Cys Thr 100 105 110 Ser Val Tyr Thr Lys Asp Arg Ala Ala Lys Cys Lys Ile Pro Ala Leu 115 120 125 Asp Leu Leu Ile Lys Leu Leu Gln Thr Phe Arg Ser Ser Arg Leu Met 130 135 140 Asp Glu Phe Lys Ile Gly Glu Leu Phe Ser Lys Phe Tyr Gly Glu Leu 145 150 155 160Ala Leu Lys Lys Lys Ile Pro Asp Thr Val Leu Glu Lys Val Tyr Glu 165 170 175 Leu Leu Gly Leu Leu Gly Glu Val His Pro Ser Glu Met Ile Asn Asn 180 185 190 Ala Glu Asn Leu Phe Arg Ala Phe Leu Gly Glu Leu Lys Thr Gln Met 195 200 205 Thr Ser Ala Val Arg Glu Pro Lys Leu Pro Val Leu Ala Gly Cys Leu 210 215 220 Lys Gly Leu Ser Ser Leu Leu Cys Asn Phe Thr Lys Ser Met Glu Glu 225 230 235 240Asp Pro Gln Thr Ser Arg Glu Ile Phe Asn Phe Val Leu Lys Ala Ile 245 250 255 Arg Pro Gln Ile Asp Leu Lys Arg Tyr Ala Val Pro Ser Ala Gly Leu 260 265 270 Arg Leu Phe Ala Leu His Ala Ser Gln Phe Ser Thr Cys Leu Leu Asp 275 280 285 Asn Tyr Val Ser Leu Phe Glu Val Leu Leu Lys Trp Cys Ala His Thr 290 295 300 Asn Val Glu Leu Lys Lys Ala Ala Leu Ser Ala Leu Glu Ser Phe Leu 305 310 315 320Lys Gln Val Ser Asn Met Val Ala Lys Asn Ala Glu Met His Lys Asn 325 330 335 Lys Leu Gln Tyr Phe Met Glu Gln Phe Tyr Gly Ile Ile Arg Asn Val 340 345 350 Asp Ser Asn Asn Lys Glu Leu Ser Ile Ala Ile Arg Gly Tyr Gly Leu 355 360 365 Phe Ala Gly Pro Cys Lys Val Ile Asn Ala Lys Asp Val Asp Phe Met 370 375 380 Tyr Val Glu Leu Ile Gln Arg Cys Lys Gln Met Phe Leu Thr Gln Thr 385 390 395 400Asp Thr Gly Asp Asp Arg Val Tyr Gln Met Pro Ser Phe Leu Gln Ser 405 410 415 Val Ala Ser Val Leu Leu Tyr Leu Asp Thr Val Pro Glu Val Tyr Thr 420 425 430 Pro Val Leu Glu His Leu Val Val Met Gln Ile Asp Ser Phe Pro Gln 435 440 445 Tyr Ser Pro Lys Met Gln Leu Val Cys Cys Arg Ala Ile Val Lys Val 450 455 460 Phe Leu Ala Leu Ala Ala Lys Gly Pro Val Leu Arg Asn Cys Ile Ser 465 470 475 480Thr Val Val His

Gln Gly Leu Ile Arg Ile Cys Ser Lys Pro Val Val 485 490 495 Leu Pro Lys Gly Pro Glu Ser Glu Ser Glu Asp His Arg Ala Ser Gly 500 505 510 Glu Val Arg Thr Gly Lys Trp Lys Val Pro Thr Tyr Lys Asp Tyr Val 515 520 525 Asp Leu Phe Arg His Leu Leu Ser Ser Asp Gln Met Met Asp Ser Ile 530 535 540 Leu Ala Asp Glu Ala Phe Phe Ser Val Asn Ser Ser Ser Glu Ser Leu 545 550 555 560Asn His Leu Leu Tyr Asp Glu Phe Val Lys Ser Val Leu Lys Ile Val 565 570 575 Glu Lys Leu Asp Leu Thr Leu Glu Ile Gln Thr Val Gly Glu Gln Glu 580 585 590 Asn Gly Asp Glu Ala Pro Gly Val Trp Met Ile Pro Thr Ser Asp Pro 595 600 605 Ala Ala Asn Leu His Pro Ala Lys Pro Lys Asp Phe Ser Ala Phe Ile 610 615 620 Asn Leu Val Glu Phe Cys Arg Glu Ile Leu Pro Glu Lys Gln Ala Glu 625 630 635 640Phe Phe Glu Pro Trp Val Tyr Ser Phe Ser Tyr Glu Leu Ile Leu Gln 645 650 655 Ser Thr Arg Leu Pro Leu Ile Ser Gly Phe Tyr Lys Leu Leu Ser Ile 660 665 670 Thr Val Arg Asn Ala Lys Lys Ile Lys Tyr Phe Glu Gly Ser 675 680 685 67170PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 67Met Ala Gly Ser Gly Ala Gly Val Arg Cys Ser Leu Leu Arg Leu Gln 1 5 10 15 Glu Thr Leu Ser Ala Ala Asp Arg Cys Gly Ala Ala Leu Ala Gly His 20 25 30 Gln Leu Ile Arg Gly Leu Gly Gln Glu Cys Val Leu Ser Ser Ser Pro 35 40 45 Ala Val Leu Ala Leu Gln Thr Ser Leu Val Phe Ser Arg Asp Phe Gly 50 55 60 Leu Leu Val Phe Val Arg Lys Ser Leu Asn Ser Ile Glu Phe Arg Glu 65 70 75 80Cys Arg Glu Glu Ile Leu Lys Phe Leu Cys Ile Phe Leu Glu Lys Met 85 90 95 Gly Gln Lys Ile Ala Pro Tyr Ser Val Glu Ile Lys Asn Thr Cys Thr 100 105 110 Ser Val Tyr Thr Lys Asp Arg Ala Ala Lys Cys Lys Ile Pro Ala Leu 115 120 125 Asp Leu Leu Ile Lys Leu Leu Gln Thr Phe Arg Ser Ser Arg Leu Met 130 135 140 Asp Glu Phe Lys Ile Gly Glu Leu Phe Ser Lys Phe Tyr Gly Glu Leu 145 150 155 160Ala Leu Lys Lys Lys Tyr Gln Ile Gln Phe 165 17068175PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 68Met Ala Gly Ser Gly Ala Gly Val Arg Cys Ser Leu Leu Arg Leu Gln 1 5 10 15 Glu Thr Leu Ser Ala Ala Asp Arg Cys Gly Ala Ala Leu Ala Gly His 20 25 30 Gln Leu Ile Arg Gly Leu Gly Gln Glu Cys Val Leu Ser Ser Ser Pro 35 40 45 Ala Val Leu Ala Leu Gln Thr Ser Leu Val Phe Ser Arg Asp Phe Gly 50 55 60 Leu Leu Val Phe Val Arg Lys Ser Leu Asn Ser Ile Glu Phe Arg Glu 65 70 75 80Cys Arg Glu Glu Ile Leu Lys Phe Leu Cys Ile Phe Leu Glu Lys Met 85 90 95 Gly Gln Lys Ile Ala Pro Tyr Ser Val Glu Ile Lys Asn Thr Cys Thr 100 105 110 Ser Val Tyr Thr Lys Asp Arg Ala Ala Lys Cys Lys Ile Pro Ala Leu 115 120 125 Asp Leu Leu Ile Lys Leu Leu Gln Thr Phe Arg Ser Ser Arg Leu Met 130 135 140 Asp Glu Phe Lys Ile Gly Glu Leu Phe Ser Lys Phe Tyr Gly Glu Leu 145 150 155 160Ala Leu Lys Lys Lys Asn Thr Arg Tyr Ser Phe Arg Lys Ser Ile 165 170 17569648PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 69Met Ser Ala Ser Ala Ser Val Gly Gly Pro Val Pro Gln Pro Pro Pro 1 5 10 15 Gly Pro Ala Ala Ala Leu Pro Pro Gly Ser Ala Ala Arg Ala Leu His 20 25 30 Val Glu Leu Pro Ser Gln Gln Arg Arg Leu Arg His Leu Arg Asn Ile 35 40 45 Ala Ala Arg Asn Ile Val Asn Arg Asn Gly His Gln Leu Leu Asp Thr 50 55 60 Tyr Phe Thr Leu His Leu Cys Ser Thr Glu Lys Ile Tyr Lys Glu Phe 65 70 75 80Tyr Arg Ser Glu Val Ile Lys Asn Ser Leu Asn Pro Thr Trp Arg Ser 85 90 95 Leu Asp Phe Gly Ile Met Pro Asp Arg Leu Asp Thr Ser Val Ser Cys 100 105 110 Phe Val Val Lys Ile Trp Gly Gly Lys Glu Asn Ile Tyr Gln Leu Leu 115 120 125 Ile Glu Trp Lys Val Cys Leu Asp Gly Leu Lys Tyr Leu Gly Gln Gln 130 135 140 Ile His Ala Arg Asn Gln Asn Glu Ile Ile Phe Gly Leu Asn Asp Gly 145 150 155 160Tyr Tyr Gly Ala Pro Phe Glu His Lys Gly Tyr Ser Asn Ala Gln Lys 165 170 175 Thr Ile Leu Leu Gln Val Asp Gln Asn Cys Val Arg Asn Ser Tyr Asp 180 185 190 Val Phe Ser Leu Leu Arg Leu His Arg Ala Gln Cys Ala Ile Lys Gln 195 200 205 Thr Gln Val Thr Val Gln Lys Ile Gly Lys Glu Ile Glu Glu Lys Leu 210 215 220 Arg Leu Thr Ser Thr Ser Asn Glu Leu Lys Lys Lys Ser Glu Cys Leu 225 230 235 240Gln Leu Lys Ile Leu Val Leu Gln Asn Glu Leu Glu Arg Gln Lys Lys 245 250 255 Ala Leu Gly Arg Glu Val Ala Leu Leu His Lys Gln Gln Ile Ala Leu 260 265 270 Gln Asp Lys Gly Ser Ala Phe Ser Ala Glu His Leu Lys Leu Gln Leu 275 280 285 Gln Lys Glu Ser Leu Asn Glu Leu Arg Lys Glu Cys Thr Ala Lys Arg 290 295 300 Glu Leu Phe Leu Lys Thr Asn Ala Gln Leu Thr Ile Arg Cys Arg Gln 305 310 315 320Leu Leu Ser Glu Leu Ser Tyr Ile Tyr Pro Ile Asp Leu Asn Glu His 325 330 335 Lys Asp Tyr Phe Val Cys Gly Val Lys Leu Pro Asn Ser Glu Asp Phe 340 345 350 Gln Ala Lys Asp Asp Gly Ser Ile Ala Val Ala Leu Gly Tyr Thr Ala 355 360 365 His Leu Val Ser Met Ile Ser Phe Phe Leu Gln Val Pro Leu Arg Tyr 370 375 380 Pro Ile Ile His Lys Gly Ser Arg Ser Thr Ile Lys Asp Asn Ile Asn 385 390 395 400Asp Lys Leu Thr Glu Lys Glu Arg Glu Phe Pro Leu Tyr Pro Lys Gly 405 410 415 Gly Glu Lys Leu Gln Phe Asp Tyr Gly Val Tyr Leu Leu Asn Lys Asn 420 425 430 Ile Ala Gln Leu Arg Tyr Gln His Gly Leu Gly Thr Pro Asp Leu Arg 435 440 445 Gln Thr Leu Pro Asn Leu Lys Asn Phe Met Glu His Gly Leu Met Val 450 455 460 Arg Cys Asp Arg His His Thr Ser Ser Ala Ile Pro Val Pro Lys Arg 465 470 475 480Gln Ser Ser Ile Phe Gly Gly Ala Asp Val Gly Phe Ser Gly Gly Ile 485 490 495 Pro Ser Pro Asp Lys Gly His Arg Lys Arg Ala Ser Ser Glu Asn Glu 500 505 510 Arg Leu Gln Tyr Lys Thr Pro Pro Pro Ser Tyr Asn Ser Ala Leu Ala 515 520 525 Gln Pro Val Thr Thr Val Pro Ser Met Gly Glu Thr Glu Arg Lys Ile 530 535 540 Thr Ser Leu Ser Ser Ser Leu Asp Thr Ser Leu Asp Phe Ser Lys Glu 545 550 555 560Asn Lys Lys Lys Gly Glu Asp Leu Val Gly Ser Leu Asn Gly Gly His 565 570 575 Ala Asn Val His Pro Ser Gln Glu Gln Gly Glu Ala Leu Ser Gly His 580 585 590 Arg Ala Thr Val Asn Gly Thr Leu Leu Pro Ser Glu Gln Ala Gly Ser 595 600 605 Ala Ser Val Gln Leu Pro Gly Glu Phe His Pro Val Ser Glu Ala Glu 610 615 620 Leu Cys Cys Thr Val Glu Gln Ala Glu Glu Ile Ile Gly Leu Glu Ala 625 630 635 640Gln Val Ser Pro Gln Val Ile Ser 645 70241PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 70Met Ser Ala Ser Ala Ser Val Gly Gly Pro Val Pro Gln Pro Pro Pro 1 5 10 15 Gly Pro Ala Ala Ala Leu Pro Pro Gly Ser Ala Ala Arg Ala Leu His 20 25 30 Val Glu Leu Pro Ser Gln Gln Arg Arg Leu Arg His Leu Arg Asn Ile 35 40 45 Ala Ala Arg Asn Ile Val Asn Arg Asn Gly His Gln Leu Leu Asp Thr 50 55 60 Tyr Phe Thr Leu His Leu Cys Ser Thr Glu Lys Ile Tyr Lys Glu Phe 65 70 75 80Tyr Arg Ser Glu Val Ile Lys Asn Ser Leu Asn Pro Thr Trp Arg Ser 85 90 95 Leu Asp Phe Gly Ile Met Pro Asp Arg Leu Asp Thr Ser Val Ser Cys 100 105 110 Phe Val Val Lys Ile Trp Gly Gly Lys Glu Asn Ile Tyr Gln Leu Leu 115 120 125 Ile Glu Trp Lys Val Cys Leu Asp Gly Leu Lys Tyr Leu Gly Gln Gln 130 135 140 Ile His Ala Arg Asn Gln Asn Glu Ile Ile Phe Gly Leu Asn Asp Gly 145 150 155 160Tyr Tyr Gly Ala Pro Phe Glu His Lys Gly Tyr Ser Asn Ala Gln Lys 165 170 175 Thr Ile Leu Leu Gln Val Asp Gln Asn Cys Val Arg Asn Ser Tyr Asp 180 185 190 Val Phe Ser Leu Leu Arg Leu His Arg Ala Gln Cys Ala Ile Lys Gln 195 200 205 Thr Gln Val Thr Val Gln Lys Ile Gly Lys Glu Ile Glu Glu Lys Leu 210 215 220 Arg Leu Thr Ser Thr Ser Asn Glu Leu Lys Lys Lys Val Asn Ala Cys 225 230 235 240Ser 71237PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 71Met Ser Ala Ser Ala Ser Val Gly Gly Pro Val Pro Gln Pro Pro Pro 1 5 10 15 Gly Pro Ala Ala Ala Leu Pro Pro Gly Ser Ala Ala Arg Ala Leu His 20 25 30 Val Glu Leu Pro Ser Gln Gln Arg Arg Leu Arg His Leu Arg Asn Ile 35 40 45 Ala Ala Arg Asn Ile Val Asn Arg Asn Gly His Gln Leu Leu Asp Thr 50 55 60 Tyr Phe Thr Leu His Leu Cys Ser Thr Glu Lys Ile Tyr Lys Glu Phe 65 70 75 80Tyr Arg Ser Glu Val Ile Lys Asn Ser Leu Asn Pro Thr Trp Arg Ser 85 90 95 Leu Asp Phe Gly Ile Met Pro Asp Arg Leu Asp Thr Ser Val Ser Cys 100 105 110 Phe Val Val Lys Ile Trp Gly Gly Lys Glu Asn Ile Tyr Gln Leu Leu 115 120 125 Ile Glu Trp Lys Val Cys Leu Asp Gly Leu Lys Tyr Leu Gly Gln Gln 130 135 140 Ile His Ala Arg Asn Gln Asn Glu Ile Ile Phe Gly Leu Asn Asp Gly 145 150 155 160Tyr Tyr Gly Ala Pro Phe Glu His Lys Gly Tyr Ser Asn Ala Gln Lys 165 170 175 Thr Ile Leu Leu Gln Val Asp Gln Asn Cys Val Arg Asn Ser Tyr Asp 180 185 190 Val Phe Ser Leu Leu Arg Leu His Arg Ala Gln Cys Ala Ile Lys Gln 195 200 205 Thr Gln Val Thr Val Gln Lys Ile Gly Lys Glu Ile Glu Glu Lys Leu 210 215 220 Arg Leu Thr Ser Thr Ser Asn Glu Leu Lys Lys Lys Lys 225 230 235 721137PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 72Met Ser Arg Arg Lys Pro Ala Ser Gly Gly Leu Ala Ala Ser Ser Ser 1 5 10 15 Ala Pro Ala Arg Gln Ala Val Leu Ser Arg Phe Phe Gln Ser Thr Gly 20 25 30 Ser Leu Lys Ser Thr Ser Ser Ser Thr Gly Ala Ala Asp Gln Val Asp 35 40 45 Pro Gly Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Pro Pro 50 55 60 Ala Pro Pro Ala Pro Ala Phe Pro Pro Gln Leu Pro Pro His Val Ala 65 70 75 80Thr Glu Ile Asp Arg Arg Lys Lys Arg Pro Leu Glu Asn Asp Gly Pro 85 90 95 Val Lys Lys Lys Val Lys Lys Val Gln Gln Lys Glu Gly Gly Ser Asp 100 105 110 Leu Gly Met Ser Gly Asn Ser Glu Pro Lys Lys Cys Leu Arg Thr Arg 115 120 125 Asn Val Ser Lys Ser Leu Glu Lys Leu Lys Glu Phe Cys Cys Asp Ser 130 135 140 Ala Leu Pro Gln Ser Arg Val Gln Thr Glu Ser Leu Gln Glu Arg Phe 145 150 155 160Ala Val Leu Pro Lys Cys Thr Asp Phe Asp Asp Ile Ser Leu Leu His 165 170 175 Ala Lys Asn Ala Val Ser Ser Glu Asp Ser Lys Arg Gln Ile Asn Gln 180 185 190 Lys Asp Thr Thr Leu Phe Asp Leu Ser Gln Phe Gly Ser Ser Asn Thr 195 200 205 Ser His Glu Asn Leu Gln Lys Thr Ala Ser Lys Ser Ala Asn Lys Arg 210 215 220 Ser Lys Ser Ile Tyr Thr Pro Leu Glu Leu Gln Tyr Ile Glu Met Lys 225 230 235 240Gln Gln His Lys Asp Ala Val Leu Cys Val Glu Cys Gly Tyr Lys Tyr 245 250 255 Arg Phe Phe Gly Glu Asp Ala Glu Ile Ala Ala Arg Glu Leu Asn Ile 260 265 270 Tyr Cys His Leu Asp His Asn Phe Met Thr Ala Ser Ile Pro Thr His 275 280 285 Arg Leu Phe Val His Val Arg Arg Leu Val Ala Lys Gly Tyr Lys Val 290 295 300 Gly Val Val Lys Gln Thr Glu Thr Ala Ala Leu Lys Ala Ile Gly Asp 305 310 315 320Asn Arg Ser Ser Leu Phe Ser Arg Lys Leu Thr Ala Leu Tyr Thr Lys 325 330 335 Ser Thr Leu Ile Gly Glu Asp Val Asn Pro Leu Ile Lys Leu Asp Asp 340 345 350 Ala Val Asn Val Asp Glu Ile Met Thr Asp Thr Ser Thr Ser Tyr Leu 355 360 365 Leu Cys Ile Ser Glu Asn Lys Glu Asn Val Arg Asp Lys Lys Lys Gly 370 375 380 Asn Ile Phe Ile Gly Ile Val Gly Val Gln Pro Ala Thr Gly Glu Val 385 390 395 400Val Phe Asp Ser Phe Gln Asp Ser Ala Ser Arg Ser Glu Leu Glu Thr 405 410 415 Arg Met Ser Ser Leu Gln Pro Val Glu Leu Leu Leu Pro Ser Ala Leu 420 425 430 Ser Glu Gln Thr Glu Ala Leu Ile His Arg Ala Thr Ser Val Ser Val 435 440 445 Gln Asp Asp Arg Ile Arg Val Glu Arg Met Asp Asn Ile Tyr Phe Glu 450 455 460 Tyr Ser His Ala Phe Gln Ala Val Thr Glu Phe Tyr Ala Lys Asp Thr 465 470 475 480Val Asp Ile Lys Gly Ser Gln Ile Ile Ser Gly Ile Val Asn Leu Glu 485 490 495 Lys Pro Val Ile Cys Ser Leu Ala Ala Ile Ile Lys Tyr Leu Lys Glu 500

505 510 Phe Asn Leu Glu Lys Met Leu Ser Lys Pro Glu Asn Phe Lys Gln Leu 515 520 525 Ser Ser Lys Met Glu Phe Met Thr Ile Asn Gly Thr Thr Leu Arg Asn 530 535 540 Leu Glu Ile Leu Gln Asn Gln Thr Asp Met Lys Thr Lys Gly Ser Leu 545 550 555 560Leu Trp Val Leu Asp His Thr Lys Thr Ser Phe Gly Arg Arg Lys Leu 565 570 575 Lys Lys Trp Val Thr Gln Pro Leu Leu Lys Leu Arg Glu Ile Asn Ala 580 585 590 Arg Leu Asp Ala Val Ser Glu Val Leu His Ser Glu Ser Ser Val Phe 595 600 605 Gly Gln Ile Glu Asn His Leu Arg Lys Leu Pro Asp Ile Gly Arg Gly 610 615 620 Leu Cys Ser Ile Tyr His Lys Lys Cys Ser Thr Gln Glu Phe Phe Leu 625 630 635 640Ile Val Lys Thr Leu Tyr His Leu Lys Ser Glu Phe Gln Ala Ile Ile 645 650 655 Pro Ala Val Asn Ser His Ile Gln Ser Asp Leu Leu Arg Thr Val Ile 660 665 670 Leu Glu Ile Pro Glu Leu Leu Ser Pro Val Glu His Tyr Leu Lys Ile 675 680 685 Leu Asn Glu Gln Ala Ala Lys Val Gly Asp Lys Thr Glu Leu Phe Lys 690 695 700 Asp Leu Ser Asp Phe Pro Leu Ile Lys Lys Arg Lys Asp Glu Ile Gln 705 710 715 720Gly Val Ile Asp Glu Ile Arg Met His Leu Gln Glu Ile Arg Lys Ile 725 730 735 Leu Lys Asn Pro Ser Ala Gln Tyr Val Thr Val Ser Gly Gln Glu Phe 740 745 750 Met Ile Glu Ile Lys Asn Ser Ala Val Ser Cys Ile Pro Thr Asp Trp 755 760 765 Val Lys Val Gly Ser Thr Lys Ala Val Ser Arg Phe His Ser Pro Phe 770 775 780 Ile Val Glu Asn Tyr Arg His Leu Asn Gln Leu Arg Glu Gln Leu Val 785 790 795 800Leu Asp Cys Ser Ala Glu Trp Leu Asp Phe Leu Glu Lys Phe Ser Glu 805 810 815 His Tyr His Ser Leu Cys Lys Ala Val His His Leu Ala Thr Val Asp 820 825 830 Cys Ile Phe Ser Leu Ala Lys Val Ala Lys Gln Gly Asp Tyr Cys Arg 835 840 845 Pro Thr Val Gln Glu Glu Arg Lys Ile Val Ile Lys Asn Gly Arg His 850 855 860 Pro Val Ile Asp Val Leu Leu Gly Glu Gln Asp Gln Tyr Val Pro Asn 865 870 875 880Asn Thr Asp Leu Ser Glu Asp Ser Glu Arg Val Met Ile Ile Thr Gly 885 890 895 Pro Asn Met Gly Gly Lys Ser Ser Tyr Ile Lys Gln Val Ala Leu Ile 900 905 910 Thr Ile Met Ala Gln Ile Gly Ser Tyr Val Pro Ala Glu Glu Ala Thr 915 920 925 Ile Gly Ile Val Asp Gly Ile Phe Thr Arg Met Gly Ala Ala Asp Asn 930 935 940 Ile Tyr Lys Gly Arg Ser Thr Phe Met Glu Glu Leu Thr Asp Thr Ala 945 950 955 960Glu Ile Ile Arg Lys Ala Thr Ser Gln Ser Leu Val Ile Leu Asp Glu 965 970 975 Leu Gly Arg Gly Thr Ser Thr His Asp Gly Ile Ala Ile Ala Tyr Ala 980 985 990 Thr Leu Glu Tyr Phe Ile Arg Asp Val Lys Ser Leu Thr Leu Phe Val 995 1000 1005 Thr His Tyr Pro Pro Val Cys Glu Leu Glu Lys Asn Tyr Ser His Gln 1010 1015 1020 Val Gly Asn Tyr His Met Gly Phe Leu Val Ser Glu Asp Glu Ser Lys 1025 1030 1035 1040Leu Asp Pro Gly Thr Ala Glu Gln Val Pro Asp Phe Val Thr Phe Leu 1045 1050 1055 Tyr Gln Ile Thr Arg Gly Ile Ala Ala Arg Ser Tyr Gly Leu Asn Val 1060 1065 1070 Ala Lys Leu Ala Asp Val Pro Gly Glu Ile Leu Lys Lys Ala Ala His 1075 1080 1085 Lys Ser Lys Glu Leu Glu Gly Leu Ile Asn Thr Lys Arg Lys Arg Leu 1090 1095 1100 Lys Tyr Phe Ala Lys Leu Trp Thr Met His Asn Ala Gln Asp Leu Gln 1105 1110 1115 1120Lys Trp Thr Glu Glu Phe Asn Met Glu Glu Thr Gln Thr Ser Leu Leu 1125 1130 1135 His 73413PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 73Met Ser Arg Arg Lys Pro Ala Ser Gly Gly Leu Ala Ala Ser Ser Ser 1 5 10 15 Ala Pro Ala Arg Gln Ala Val Leu Ser Arg Phe Phe Gln Ser Thr Gly 20 25 30 Ser Leu Lys Ser Thr Ser Ser Ser Thr Gly Ala Ala Asp Gln Val Asp 35 40 45 Pro Gly Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Pro Pro 50 55 60 Ala Pro Pro Ala Pro Ala Phe Pro Pro Gln Leu Pro Pro His Val Ala 65 70 75 80Thr Glu Ile Asp Arg Arg Lys Lys Arg Pro Leu Glu Asn Asp Gly Pro 85 90 95 Val Lys Lys Lys Val Lys Lys Val Gln Gln Lys Glu Gly Gly Ser Asp 100 105 110 Leu Gly Met Ser Gly Asn Ser Glu Pro Lys Lys Cys Leu Arg Thr Arg 115 120 125 Asn Val Ser Lys Ser Leu Glu Lys Leu Lys Glu Phe Cys Cys Asp Ser 130 135 140 Ala Leu Pro Gln Ser Arg Val Gln Thr Glu Ser Leu Gln Glu Arg Phe 145 150 155 160Ala Val Leu Pro Lys Cys Thr Asp Phe Asp Asp Ile Ser Leu Leu His 165 170 175 Ala Lys Asn Ala Val Ser Ser Glu Asp Ser Lys Arg Gln Ile Asn Gln 180 185 190 Lys Asp Thr Thr Leu Phe Asp Leu Ser Gln Phe Gly Ser Ser Asn Thr 195 200 205 Ser His Glu Asn Leu Gln Lys Thr Ala Ser Lys Ser Ala Asn Lys Arg 210 215 220 Ser Lys Ser Ile Tyr Thr Pro Leu Glu Leu Gln Tyr Ile Glu Met Lys 225 230 235 240Gln Gln His Lys Asp Ala Val Leu Cys Val Glu Cys Gly Tyr Lys Tyr 245 250 255 Arg Phe Phe Gly Glu Asp Ala Glu Ile Ala Ala Arg Glu Leu Asn Ile 260 265 270 Tyr Cys His Leu Asp His Asn Phe Met Thr Ala Ser Ile Pro Thr His 275 280 285 Arg Leu Phe Val His Val Arg Arg Leu Val Ala Lys Gly Tyr Lys Val 290 295 300 Gly Val Val Lys Gln Thr Glu Thr Ala Ala Leu Lys Ala Ile Gly Asp 305 310 315 320Asn Arg Ser Ser Leu Phe Ser Arg Lys Leu Thr Ala Leu Tyr Thr Lys 325 330 335 Ser Thr Leu Ile Gly Glu Asp Val Asn Pro Leu Ile Lys Leu Asp Asp 340 345 350 Ala Val Asn Val Asp Glu Ile Met Thr Asp Thr Ser Thr Ser Tyr Leu 355 360 365 Leu Cys Ile Ser Glu Asn Lys Glu Asn Val Arg Asp Lys Lys Arg Ala 370 375 380 Thr Phe Leu Leu Ala Leu Trp Glu Cys Ser Leu Pro Gln Ala Arg Leu 385 390 395 400Cys Leu Ile Val Ser Arg Thr Leu Leu Leu Val Gln Ser 405 410 74402PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 74Met Ser Arg Arg Lys Pro Ala Ser Gly Gly Leu Ala Ala Ser Ser Ser 1 5 10 15 Ala Pro Ala Arg Gln Ala Val Leu Ser Arg Phe Phe Gln Ser Thr Gly 20 25 30 Ser Leu Lys Ser Thr Ser Ser Ser Thr Gly Ala Ala Asp Gln Val Asp 35 40 45 Pro Gly Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Pro Pro 50 55 60 Ala Pro Pro Ala Pro Ala Phe Pro Pro Gln Leu Pro Pro His Val Ala 65 70 75 80Thr Glu Ile Asp Arg Arg Lys Lys Arg Pro Leu Glu Asn Asp Gly Pro 85 90 95 Val Lys Lys Lys Val Lys Lys Val Gln Gln Lys Glu Gly Gly Ser Asp 100 105 110 Leu Gly Met Ser Gly Asn Ser Glu Pro Lys Lys Cys Leu Arg Thr Arg 115 120 125 Asn Val Ser Lys Ser Leu Glu Lys Leu Lys Glu Phe Cys Cys Asp Ser 130 135 140 Ala Leu Pro Gln Ser Arg Val Gln Thr Glu Ser Leu Gln Glu Arg Phe 145 150 155 160Ala Val Leu Pro Lys Cys Thr Asp Phe Asp Asp Ile Ser Leu Leu His 165 170 175 Ala Lys Asn Ala Val Ser Ser Glu Asp Ser Lys Arg Gln Ile Asn Gln 180 185 190 Lys Asp Thr Thr Leu Phe Asp Leu Ser Gln Phe Gly Ser Ser Asn Thr 195 200 205 Ser His Glu Asn Leu Gln Lys Thr Ala Ser Lys Ser Ala Asn Lys Arg 210 215 220 Ser Lys Ser Ile Tyr Thr Pro Leu Glu Leu Gln Tyr Ile Glu Met Lys 225 230 235 240Gln Gln His Lys Asp Ala Val Leu Cys Val Glu Cys Gly Tyr Lys Tyr 245 250 255 Arg Phe Phe Gly Glu Asp Ala Glu Ile Ala Ala Arg Glu Leu Asn Ile 260 265 270 Tyr Cys His Leu Asp His Asn Phe Met Thr Ala Ser Ile Pro Thr His 275 280 285 Arg Leu Phe Val His Val Arg Arg Leu Val Ala Lys Gly Tyr Lys Val 290 295 300 Gly Val Val Lys Gln Thr Glu Thr Ala Ala Leu Lys Ala Ile Gly Asp 305 310 315 320Asn Arg Ser Ser Leu Phe Ser Arg Lys Leu Thr Ala Leu Tyr Thr Lys 325 330 335 Ser Thr Leu Ile Gly Glu Asp Val Asn Pro Leu Ile Lys Leu Asp Asp 340 345 350 Ala Val Asn Val Asp Glu Ile Met Thr Asp Thr Ser Thr Ser Tyr Leu 355 360 365 Leu Cys Ile Ser Glu Asn Lys Glu Asn Val Arg Asp Lys Lys Lys Gly 370 375 380 Gln His Phe Tyr Trp His Cys Gly Ser Ala Ala Cys His Arg Arg Gly 385 390 395 400Cys Val 759PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 75Ser Leu Val Arg Leu Ser Ser Cys Val 1 5 769PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 76Arg Leu Ser Ser Cys Val Pro Val Ala 1 5 779PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 77Cys Val Pro Val Ala Leu Met Ser Ala 1 5 7810PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 78Leu Leu His Ser Ala Pro Thr Pro Ser Leu 1 5 10799PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 79Phe Leu Ser Ala Ser His Phe Leu Leu 1 5 809PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 80Arg Val Phe Phe Phe Tyr Gln His Leu 1 5 8110PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 81Ser Leu Tyr Lys Phe Ser Pro Phe Pro Leu 1 5 10829PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 82Lys Ile Phe Thr Phe Phe Phe Gln Leu 1 5 839PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 83Ala Leu Leu Pro Ala Gly Pro Leu Thr 1 5 8410PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 84Leu Leu Pro Ala Gly Pro Leu Thr Gln Thr 1 5 10859PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 85Thr Leu Ser Pro Gly Trp Ser Ala Val 1 5 8610PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 86Ile Leu Leu Pro Gln Pro Pro Glu Trp Leu 1 5 108710PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 87Arg Gln Met Glu Ser Leu Gly Met Lys Leu 1 5 10889PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 88Val Glu Met Pro Thr Gly Trp Leu Leu 1 5 8910PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 89Val Glu Met Pro Thr Gly Trp Leu Leu Val 1 5 10909PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 90Phe Gln Pro Pro Pro Ala Val Phe Ala 1 5 9110PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 91Ala Leu Trp Glu Cys Ser Leu Pro Gln Ala 1 5 109210PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 92Phe Leu Leu Ala Leu Trp Glu Cys Ser Leu 1 5 10939PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 93Leu Leu Ala Leu Trp Glu Cys Ser Leu 1 5 949PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 94Ser Leu Pro Gln Ala Arg Leu Cys Leu 1 5 959PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 95Leu Ile Val Ser Arg Thr Leu Leu Leu 1 5 969PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 96Cys Leu Ile Val Ser Arg Thr Leu Leu 1 5 979PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 97Ile Val Ser Arg Thr Leu Leu Leu Val 1 5 989PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 98Lys Arg Ala Thr Phe Leu Leu Ala Leu 1 5 999PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 99Lys Met Phe Phe Met Val Phe Leu Ile 1 5 1009PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 100Phe Leu Ile Ile Trp Gln Asn Thr Met 1 5 1019PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 101Gly Met Cys Val Lys Val Ser Ser Ile 1 5 1029PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 102Val Leu Arg Thr Glu Gly Glu Pro Leu 1 5 10310PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 103Leu Ile Val Ser Arg Thr Leu Leu Leu Val 1 5 1010410PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 104Ser Leu Pro Gln Ala Arg Leu Cys Leu Ile 1 5 1010510PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 105Cys Leu Ile Val Ser Arg Thr Leu Leu Leu 1 5 1010610PRTArtificial SequenceDescription of Artificial Sequence Frameshift Peptide 106Arg Leu Cys Leu Ile Val Ser Arg Thr Leu 1 5 10107513PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 107Met Gly Ala Ala Ala Lys Leu Ala Phe Ala Val Phe Leu Ile Ser Cys 1 5 10 15 Ser Ser Gly Ala Ile Leu Gly

Arg Ser Glu Thr Gln Glu Cys Leu Phe 20 25 30 Phe Asn Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu 35 40 45 Pro Cys Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp 50 55 60 Lys Asn Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu 65 70 75 80 Asp Asp Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp 85 90 95 Ser Pro Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu 100 105 110 Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Asn 115 120 125 Pro Val Thr Pro Lys Pro Pro Tyr Tyr Asn Ile Leu Leu Tyr Ser Leu 130 135 140 Val Pro Leu Met Leu Ile Ala Gly Ile Val Ile Cys Ala Phe Trp Val 145 150 155 160 Tyr Arg His His Lys Met Ala Tyr Pro Pro Val Leu Val Pro Thr Gln 165 170 175 Asp Pro Gly Pro Pro Pro Pro Ser Pro Leu Leu Gly Leu Lys Pro Leu 180 185 190 Gln Leu Leu Glu Val Lys Ala Arg Gly Arg Phe Gly Cys Val Trp Lys 195 200 205 Ala Gln Leu Leu Asn Glu Tyr Val Ala Val Lys Ile Phe Pro Ile Gln 210 215 220 Asp Lys Gln Ser Trp Gln Asn Glu Tyr Glu Val Tyr Ser Leu Pro Gly 225 230 235 240 Met Lys His Glu Asn Ile Leu Gln Phe Ile Gly Ala Glu Lys Arg Gly 245 250 255 Thr Ser Val Asp Val Asp Leu Trp Leu Ile Thr Ala Phe His Glu Lys 260 265 270 Gly Ser Leu Ser Asp Phe Leu Lys Ala Asn Val Val Ser Trp Asn Glu 275 280 285 Leu Cys His Ile Ala Glu Thr Met Ala Arg Gly Leu Ala Tyr Leu His 290 295 300 Glu Asp Ile Pro Gly Leu Lys Asp Gly His Lys Pro Ala Ile Ser His 305 310 315 320 Arg Asp Ile Lys Ser Lys Asn Val Leu Leu Lys Asn Asn Leu Thr Ala 325 330 335 Cys Ile Ala Asp Phe Gly Leu Ala Leu Lys Phe Glu Ala Gly Lys Ser 340 345 350 Ala Gly Asp Thr His Gly Gln Val Gly Thr Arg Arg Tyr Met Ala Pro 355 360 365 Glu Val Leu Glu Gly Ala Ile Asn Phe Gln Arg Asp Ala Phe Leu Arg 370 375 380 Ile Asp Met Tyr Ala Met Gly Leu Val Leu Trp Glu Leu Ala Ser Arg 385 390 395 400 Cys Thr Ala Ala Asp Gly Pro Val Asp Glu Tyr Met Leu Pro Phe Glu 405 410 415 Glu Glu Ile Gly Gln His Pro Ser Leu Glu Asp Met Gln Glu Val Val 420 425 430 Val His Lys Lys Lys Arg Pro Val Leu Arg Asp Tyr Trp Gln Lys His 435 440 445 Ala Gly Met Ala Met Leu Cys Glu Thr Ile Glu Glu Cys Trp Asp His 450 455 460 Asp Ala Glu Ala Arg Leu Ser Ala Gly Cys Val Gly Glu Arg Ile Thr 465 470 475 480 Gln Met Gln Arg Leu Thr Asn Ile Ile Thr Thr Glu Asp Ile Val Thr 485 490 495 Val Val Thr Met Val Thr Asn Val Asp Phe Pro Pro Lys Glu Ser Ser 500 505 510 Leu 108148PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 108Met Gly Ala Ala Ala Lys Leu Ala Phe Ala Val Phe Leu Ile Ser Cys 1 5 10 15 Ser Ser Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe 20 25 30 Phe Asn Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu 35 40 45 Pro Cys Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp 50 55 60 Lys Asn Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu 65 70 75 80 Asp Asp Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Thr 85 90 95 Ala Leu Lys Tyr Ile Phe Val Ala Val Arg Ala Ile Cys Val Met Lys 100 105 110 Ser Phe Leu Ile Phe Arg Arg Trp Lys Ser His Ser Pro Leu Gln Ile 115 120 125 Gln Leu His Leu Ser His Pro Ile Thr Thr Ser Cys Ser Ile Pro Trp 130 135 140 Cys His Leu Cys 145 109440PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 109Met Gly Ala Ala Ala Lys Leu Ala Phe Ala Val Phe Leu Ile Ser Cys 1 5 10 15 Ser Ser Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe 20 25 30 Phe Asn Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu 35 40 45 Pro Cys Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp 50 55 60 Lys Asn Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu 65 70 75 80 Asp Asp Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp 85 90 95 Ser Pro Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu 100 105 110 Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Asn 115 120 125 Pro Val Thr Pro Lys Pro Pro Tyr Tyr Asn Ile Leu Leu Tyr Ser Leu 130 135 140 Val Pro Leu Met Leu Ile Ala Gly Ile Val Ile Cys Ala Phe Trp Val 145 150 155 160 Tyr Arg His His Lys Met Ala Tyr Pro Pro Val Leu Val Pro Thr Gln 165 170 175 Asp Pro Gly Pro Pro Pro Pro Ser Pro Leu Leu Gly Leu Lys Pro Leu 180 185 190 Gln Leu Leu Glu Val Lys Ala Arg Gly Arg Phe Gly Cys Val Trp Lys 195 200 205 Ala Gln Leu Leu Asn Glu Tyr Val Ala Val Lys Ile Phe Pro Ile Gln 210 215 220 Asp Lys Gln Ser Trp Gln Asn Glu Tyr Glu Val Tyr Ser Leu Pro Gly 225 230 235 240 Met Lys His Glu Asn Ile Leu Gln Phe Ile Gly Ala Glu Lys Arg Gly 245 250 255 Thr Ser Val Asp Val Asp Leu Trp Leu Ile Thr Ala Phe His Glu Lys 260 265 270 Gly Ser Leu Ser Asp Phe Leu Lys Ala Asn Val Val Ser Trp Asn Glu 275 280 285 Leu Cys His Ile Ala Glu Thr Met Ala Arg Gly Leu Ala Tyr Leu His 290 295 300 Glu Asp Ile Pro Gly Leu Lys Asp Gly His Lys Pro Ala Ile Ser His 305 310 315 320 Arg Asp Ile Lys Ser Lys Asn Val Leu Leu Lys Asn Asn Leu Thr Ala 325 330 335 Cys Ile Ala Asp Phe Gly Leu Ala Leu Lys Phe Glu Ala Gly Lys Ser 340 345 350 Ala Gly Asp Thr His Gly Gln Val Gly Thr Arg Arg Tyr Met Ala Pro 355 360 365 Glu Val Leu Glu Gly Ala Ile Asn Phe Gln Arg Asp Ala Phe Leu Arg 370 375 380 Ile Asp Met Tyr Ala Met Gly Leu Val Leu Trp Glu Leu Ala Ser Arg 385 390 395 400 Cys Thr Ala Ala Asp Gly Pro Val Asp Glu Tyr Met Leu Pro Phe Glu 405 410 415 Glu Glu Ile Gly Gln His Pro Ser Leu Glu Asp Met Gln Glu Val Val 420 425 430 Val His Lys Lys Arg Gly Leu Phe 435 440 110630PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 110Met Val Leu Arg Lys Leu Ser Lys Lys Asp Val Thr Thr Lys Leu Lys 1 5 10 15 Ala Met Gln Glu Phe Gly Thr Met Cys Thr Glu Arg Asp Thr Glu Thr 20 25 30 Val Lys Gly Val Leu Pro Tyr Trp Pro Arg Ile Phe Cys Lys Ile Ser 35 40 45 Leu Asp His Asp Arg Arg Val Arg Glu Ala Thr Gln Gln Ala Phe Glu 50 55 60 Lys Leu Thr Leu Lys Val Lys Lys Gln Leu Ala Pro Tyr Leu Lys Ser 65 70 75 80 Leu Met Gly Tyr Trp Leu Met Ala Gln Cys Asp Thr Tyr Thr Pro Ala 85 90 95 Ala Phe Ala Ala Lys Asp Ala Phe Glu Ala Ala Phe Pro Pro Ser Lys 100 105 110 Gln Pro Glu Ala Ile Ala Phe Cys Lys Asp Glu Ile Thr Ser Val Leu 115 120 125 Gln Asp His Leu Ile Lys Glu Thr Pro Asp Thr Leu Ser Asp Pro Gln 130 135 140 Thr Val Pro Glu Glu Glu Arg Glu Ala Lys Phe Tyr Arg Val Val Thr 145 150 155 160 Cys Ser Leu Leu Ala Leu Lys Arg Leu Leu Cys Leu Leu Pro Asp Asn 165 170 175 Glu Leu Asp Ser Leu Glu Glu Lys Phe Lys Ser Leu Leu Ser Gln Asn 180 185 190 Lys Phe Trp Lys Tyr Gly Lys His Ser Val Pro Gln Ile Arg Ser Ala 195 200 205 Tyr Phe Glu Leu Val Ser Ala Leu Cys Gln Arg Ile Pro Gln Leu Met 210 215 220 Lys Glu Glu Ala Ser Lys Val Ser Pro Ser Val Leu Leu Ser Ile Asp 225 230 235 240 Asp Ser Asp Pro Ile Val Cys Pro Ala Leu Trp Glu Ala Val Leu Tyr 245 250 255 Thr Leu Thr Thr Ile Glu Asp Cys Trp Leu His Val Asn Ala Lys Lys 260 265 270 Ser Val Phe Pro Lys Leu Ser Thr Val Ile Arg Glu Gly Gly Arg Gly 275 280 285 Leu Ala Thr Val Ile Tyr Pro Tyr Leu Leu Pro Phe Ile Ser Lys Leu 290 295 300 Pro His Ser Ile Thr Asn Pro Lys Leu Asp Phe Phe Lys Asn Phe Leu 305 310 315 320 Thr Ser Leu Val Ala Gly Leu Ser Thr Glu Arg Thr Lys Thr Ser Ser 325 330 335 Ser Glu Ser Ser Ala Val Ile Ser Ala Phe Tyr Glu Cys Leu Arg Phe 340 345 350 Ile Met Gln Gln Asn Leu Gly Glu Glu Glu Ile Glu Gln Met Leu Val 355 360 365 Asn Asp Gln Leu Ile Pro Phe Ile Asp Ala Val Leu Lys Asp Pro Gly 370 375 380 Leu Gln His Gly Gln Leu Phe Asn His Leu Ala Glu Thr Leu Ser Ser 385 390 395 400 Trp Glu Ala Lys Ala Asp Thr Glu Lys Asp Glu Lys Thr Ala His Asn 405 410 415 Leu Glu Asn Val Leu Ile His Phe Trp Glu Arg Leu Ser Glu Ile Cys 420 425 430 Val Ala Lys Ile Ser Glu Pro Glu Ala Asp Val Glu Ser Val Leu Gly 435 440 445 Val Ser Asn Leu Leu Gln Val Leu Gln Lys Pro Lys Ser Ser Leu Lys 450 455 460 Ser Ser Lys Lys Lys Asn Gly Lys Val Arg Phe Ala Asp Glu Ile Leu 465 470 475 480 Glu Ser Asn Lys Glu Asn Glu Lys Cys Val Ser Ser Glu Gly Glu Lys 485 490 495 Ile Glu Gly Trp Glu Leu Thr Thr Glu Pro Ser Leu Thr His Asn Ser 500 505 510 Ser Gly Leu Leu Ser Pro Leu Arg Lys Lys Pro Leu Glu Asp Leu Val 515 520 525 Cys Lys Leu Ala Asp Ile Ser Ile Asn Tyr Val Asn Glu Arg Lys Ser 530 535 540 Glu Gln His Leu Arg Phe Leu Ser Thr Leu Leu Asp Ser Phe Ser Ser 545 550 555 560 Ser Arg Val Phe Lys Met Leu Leu Gly Asp Glu Lys Gln Ser Ile Val 565 570 575 Gln Ala Lys Pro Leu Glu Ile Ala Lys Leu Val Gln Lys Asn Pro Ala 580 585 590 Val Gln Phe Leu Tyr Gln Lys Leu Ile Gly Trp Leu Asn Glu Asp Gln 595 600 605 Arg Lys Asp Phe Gly Phe Leu Val Asp Ile Leu Tyr Ser Ala Leu Arg 610 615 620 Cys Cys Asp Asn Asp Met 625 630 111501PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 111Met Val Leu Arg Lys Leu Ser Lys Lys Asp Val Thr Thr Lys Leu Lys 1 5 10 15 Ala Met Gln Glu Phe Gly Thr Met Cys Thr Glu Arg Asp Thr Glu Thr 20 25 30 Val Lys Gly Val Leu Pro Tyr Trp Pro Arg Ile Phe Cys Lys Ile Ser 35 40 45 Leu Asp His Asp Arg Arg Val Arg Glu Ala Thr Gln Gln Ala Phe Glu 50 55 60 Lys Leu Thr Leu Lys Val Lys Lys Gln Leu Ala Pro Tyr Leu Lys Ser 65 70 75 80 Leu Met Gly Tyr Trp Leu Met Ala Gln Cys Asp Thr Tyr Thr Pro Ala 85 90 95 Ala Phe Ala Ala Lys Asp Ala Phe Glu Ala Ala Phe Pro Pro Ser Lys 100 105 110 Gln Pro Glu Ala Ile Ala Phe Cys Lys Asp Glu Ile Thr Ser Val Leu 115 120 125 Gln Asp His Leu Ile Lys Glu Thr Pro Asp Thr Leu Ser Asp Pro Gln 130 135 140 Thr Val Pro Glu Glu Glu Arg Glu Ala Lys Phe Tyr Arg Val Val Thr 145 150 155 160 Cys Ser Leu Leu Ala Leu Lys Arg Leu Leu Cys Leu Leu Pro Asp Asn 165 170 175 Glu Leu Asp Ser Leu Glu Glu Lys Phe Lys Ser Leu Leu Ser Gln Asn 180 185 190 Lys Phe Trp Lys Tyr Gly Lys His Ser Val Pro Gln Ile Arg Ser Ala 195 200 205 Tyr Phe Glu Leu Val Ser Ala Leu Cys Gln Arg Ile Pro Gln Leu Met 210 215 220 Lys Glu Glu Ala Ser Lys Val Ser Pro Ser Val Leu Leu Ser Ile Asp 225 230 235 240 Asp Ser Asp Pro Ile Val Cys Pro Ala Leu Trp Glu Ala Val Leu Tyr 245 250 255 Thr Leu Thr Thr Ile Glu Asp Cys Trp Leu His Val Asn Ala Lys Lys 260 265 270 Ser Val Phe Pro Lys Leu Ser Thr Val Ile Arg Glu Gly Gly Arg Gly 275 280 285 Leu Ala Thr Val Ile Tyr Pro Tyr Leu Leu Pro Phe Ile Ser Lys Leu 290 295 300 Pro His Ser Ile Thr Asn Pro Lys Leu Asp Phe Phe Lys Asn Phe Leu 305 310 315 320 Thr Ser Leu Val Ala Gly Leu Ser Thr Glu Arg Thr Lys Thr Ser Ser 325 330 335 Ser Glu Ser Ser Ala Val Ile Ser Ala Phe Tyr Glu Cys Leu Arg Phe 340 345 350 Ile Met Gln Gln Asn Leu Gly Glu Glu Glu Ile Glu Gln Met Leu Val 355 360 365 Asn Asp Gln Leu Ile Pro Phe Ile Asp Ala Val Leu Lys Asp Pro Gly 370 375 380 Leu Gln His Gly Gln Leu Phe Asn His Leu Ala Glu Thr Leu Ser Ser 385 390 395 400 Trp Glu Ala Lys Ala Asp Thr Glu Lys Asp Glu Lys Thr Ala His Asn 405 410 415 Leu Glu Asn Val Leu Ile His Phe Trp Glu Arg Leu Ser Glu Ile Cys 420 425 430 Val Ala Lys Ile Ser Glu Pro Glu Ala Asp Val Glu Ser Val Leu Gly 435 440 445 Val Ser Asn Leu Leu Gln Val Leu Gln Lys Pro Lys Ser Ser Leu Lys 450 455 460 Ser Ser Lys Lys Lys Met Val Arg Leu Asp Leu Leu Met Arg Tyr Leu 465 470 475 480 Lys Ala Ile Lys Arg Met Lys Asn Val Tyr Leu Gln Lys Glu Arg Arg 485 490 495 Leu Lys Ala Gly Asn 500 112470PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 112Met Val Leu Arg Lys Leu Ser Lys

Lys Asp Val Thr Thr Lys Leu Lys 1 5 10 15 Ala Met Gln Glu Phe Gly Thr Met Cys Thr Glu Arg Asp Thr Glu Thr 20 25 30 Val Lys Gly Val Leu Pro Tyr Trp Pro Arg Ile Phe Cys Lys Ile Ser 35 40 45 Leu Asp His Asp Arg Arg Val Arg Glu Ala Thr Gln Gln Ala Phe Glu 50 55 60 Lys Leu Thr Leu Lys Val Lys Lys Gln Leu Ala Pro Tyr Leu Lys Ser 65 70 75 80 Leu Met Gly Tyr Trp Leu Met Ala Gln Cys Asp Thr Tyr Thr Pro Ala 85 90 95 Ala Phe Ala Ala Lys Asp Ala Phe Glu Ala Ala Phe Pro Pro Ser Lys 100 105 110 Gln Pro Glu Ala Ile Ala Phe Cys Lys Asp Glu Ile Thr Ser Val Leu 115 120 125 Gln Asp His Leu Ile Lys Glu Thr Pro Asp Thr Leu Ser Asp Pro Gln 130 135 140 Thr Val Pro Glu Glu Glu Arg Glu Ala Lys Phe Tyr Arg Val Val Thr 145 150 155 160 Cys Ser Leu Leu Ala Leu Lys Arg Leu Leu Cys Leu Leu Pro Asp Asn 165 170 175 Glu Leu Asp Ser Leu Glu Glu Lys Phe Lys Ser Leu Leu Ser Gln Asn 180 185 190 Lys Phe Trp Lys Tyr Gly Lys His Ser Val Pro Gln Ile Arg Ser Ala 195 200 205 Tyr Phe Glu Leu Val Ser Ala Leu Cys Gln Arg Ile Pro Gln Leu Met 210 215 220 Lys Glu Glu Ala Ser Lys Val Ser Pro Ser Val Leu Leu Ser Ile Asp 225 230 235 240 Asp Ser Asp Pro Ile Val Cys Pro Ala Leu Trp Glu Ala Val Leu Tyr 245 250 255 Thr Leu Thr Thr Ile Glu Asp Cys Trp Leu His Val Asn Ala Lys Lys 260 265 270 Ser Val Phe Pro Lys Leu Ser Thr Val Ile Arg Glu Gly Gly Arg Gly 275 280 285 Leu Ala Thr Val Ile Tyr Pro Tyr Leu Leu Pro Phe Ile Ser Lys Leu 290 295 300 Pro His Ser Ile Thr Asn Pro Lys Leu Asp Phe Phe Lys Asn Phe Leu 305 310 315 320 Thr Ser Leu Val Ala Gly Leu Ser Thr Glu Arg Thr Lys Thr Ser Ser 325 330 335 Ser Glu Ser Ser Ala Val Ile Ser Ala Phe Tyr Glu Cys Leu Arg Phe 340 345 350 Ile Met Gln Gln Asn Leu Gly Glu Glu Glu Ile Glu Gln Met Leu Val 355 360 365 Asn Asp Gln Leu Ile Pro Phe Ile Asp Ala Val Leu Lys Asp Pro Gly 370 375 380 Leu Gln His Gly Gln Leu Phe Asn His Leu Ala Glu Thr Leu Ser Ser 385 390 395 400 Trp Glu Ala Lys Ala Asp Thr Glu Lys Asp Glu Lys Thr Ala His Asn 405 410 415 Leu Glu Asn Val Leu Ile His Phe Trp Glu Arg Leu Ser Glu Ile Cys 420 425 430 Val Ala Lys Ile Ser Glu Pro Glu Ala Asp Val Glu Ser Val Leu Gly 435 440 445 Val Ser Asn Leu Leu Gln Val Leu Gln Lys Pro Lys Ser Ser Leu Lys 450 455 460 Ser Ser Lys Lys Lys Trp 465 470 113471PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 113Met Val Leu Arg Lys Leu Ser Lys Lys Asp Val Thr Thr Lys Leu Lys 1 5 10 15 Ala Met Gln Glu Phe Gly Thr Met Cys Thr Glu Arg Asp Thr Glu Thr 20 25 30 Val Lys Gly Val Leu Pro Tyr Trp Pro Arg Ile Phe Cys Lys Ile Ser 35 40 45 Leu Asp His Asp Arg Arg Val Arg Glu Ala Thr Gln Gln Ala Phe Glu 50 55 60 Lys Leu Thr Leu Lys Val Lys Lys Gln Leu Ala Pro Tyr Leu Lys Ser 65 70 75 80 Leu Met Gly Tyr Trp Leu Met Ala Gln Cys Asp Thr Tyr Thr Pro Ala 85 90 95 Ala Phe Ala Ala Lys Asp Ala Phe Glu Ala Ala Phe Pro Pro Ser Lys 100 105 110 Gln Pro Glu Ala Ile Ala Phe Cys Lys Asp Glu Ile Thr Ser Val Leu 115 120 125 Gln Asp His Leu Ile Lys Glu Thr Pro Asp Thr Leu Ser Asp Pro Gln 130 135 140 Thr Val Pro Glu Glu Glu Arg Glu Ala Lys Phe Tyr Arg Val Val Thr 145 150 155 160 Cys Ser Leu Leu Ala Leu Lys Arg Leu Leu Cys Leu Leu Pro Asp Asn 165 170 175 Glu Leu Asp Ser Leu Glu Glu Lys Phe Lys Ser Leu Leu Ser Gln Asn 180 185 190 Lys Phe Trp Lys Tyr Gly Lys His Ser Val Pro Gln Ile Arg Ser Ala 195 200 205 Tyr Phe Glu Leu Val Ser Ala Leu Cys Gln Arg Ile Pro Gln Leu Met 210 215 220 Lys Glu Glu Ala Ser Lys Val Ser Pro Ser Val Leu Leu Ser Ile Asp 225 230 235 240 Asp Ser Asp Pro Ile Val Cys Pro Ala Leu Trp Glu Ala Val Leu Tyr 245 250 255 Thr Leu Thr Thr Ile Glu Asp Cys Trp Leu His Val Asn Ala Lys Lys 260 265 270 Ser Val Phe Pro Lys Leu Ser Thr Val Ile Arg Glu Gly Gly Arg Gly 275 280 285 Leu Ala Thr Val Ile Tyr Pro Tyr Leu Leu Pro Phe Ile Ser Lys Leu 290 295 300 Pro His Ser Ile Thr Asn Pro Lys Leu Asp Phe Phe Lys Asn Phe Leu 305 310 315 320 Thr Ser Leu Val Ala Gly Leu Ser Thr Glu Arg Thr Lys Thr Ser Ser 325 330 335 Ser Glu Ser Ser Ala Val Ile Ser Ala Phe Tyr Glu Cys Leu Arg Phe 340 345 350 Ile Met Gln Gln Asn Leu Gly Glu Glu Glu Ile Glu Gln Met Leu Val 355 360 365 Asn Asp Gln Leu Ile Pro Phe Ile Asp Ala Val Leu Lys Asp Pro Gly 370 375 380 Leu Gln His Gly Gln Leu Phe Asn His Leu Ala Glu Thr Leu Ser Ser 385 390 395 400 Trp Glu Ala Lys Ala Asp Thr Glu Lys Asp Glu Lys Thr Ala His Asn 405 410 415 Leu Glu Asn Val Leu Ile His Phe Trp Glu Arg Leu Ser Glu Ile Cys 420 425 430 Val Ala Lys Ile Ser Glu Pro Glu Ala Asp Val Glu Ser Val Leu Gly 435 440 445 Val Ser Asn Leu Leu Gln Val Leu Gln Lys Pro Lys Ser Ser Leu Lys 450 455 460 Ser Ser Lys Lys Lys Lys Trp 465 470 1141455PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 114Met Ala Gly Arg Pro Leu Arg Ile Gly Asp Gln Leu Val Leu Glu Glu 1 5 10 15 Asp Tyr Asp Glu Thr Tyr Ile Pro Ser Glu Gln Glu Ile Leu Glu Phe 20 25 30 Ala Arg Glu Ile Gly Ile Asp Pro Ile Lys Glu Pro Glu Leu Met Trp 35 40 45 Leu Ala Arg Glu Gly Ile Val Ala Pro Leu Pro Gly Glu Trp Lys Pro 50 55 60 Cys Gln Asp Ile Thr Gly Asp Ile Tyr Tyr Phe Asn Phe Ala Asn Gly 65 70 75 80 Gln Ser Met Trp Asp His Pro Cys Asp Glu His Tyr Arg Ser Leu Val 85 90 95 Ile Gln Glu Arg Ala Lys Leu Ser Thr Ser Gly Ala Ile Lys Lys Lys 100 105 110 Lys Lys Lys Lys Glu Lys Lys Asp Lys Lys Asp Arg Asp Pro Pro Lys 115 120 125 Ser Ser Leu Ala Leu Gly Ser Ser Leu Ala Pro Val His Val Pro Leu 130 135 140 Gly Gly Leu Ala Pro Leu Arg Gly Leu Val Asp Thr Pro Pro Ser Ala 145 150 155 160 Leu Arg Gly Ser Gln Ser Val Ser Leu Gly Ser Ser Val Glu Ser Gly 165 170 175 Arg Gln Leu Gly Glu Leu Met Leu Pro Ser Gln Gly Leu Lys Thr Ser 180 185 190 Ala Tyr Thr Lys Gly Leu Leu Gly Ser Ile Tyr Glu Asp Lys Thr Ala 195 200 205 Leu Ser Leu Leu Gly Leu Gly Glu Glu Thr Asn Glu Glu Asp Glu Glu 210 215 220 Glu Ser Asp Asn Gln Ser Val His Ser Ser Ser Glu Pro Leu Arg Asn 225 230 235 240 Leu His Leu Asp Ile Gly Ala Leu Gly Gly Asp Phe Glu Tyr Glu Glu 245 250 255 Ser Leu Arg Thr Ser Gln Pro Glu Glu Lys Lys Asp Val Ser Leu Asp 260 265 270 Ser Asp Ala Ala Gly Pro Pro Thr Pro Cys Lys Pro Ser Ser Pro Gly 275 280 285 Ala Asp Ser Ser Leu Ser Ser Ala Val Gly Lys Gly Arg Gln Gly Ser 290 295 300 Gly Ala Arg Pro Gly Leu Pro Glu Lys Glu Glu Asn Glu Lys Ser Glu 305 310 315 320 Pro Lys Ile Cys Arg Asn Leu Val Thr Pro Lys Ala Asp Pro Thr Gly 325 330 335 Ser Glu Pro Ala Lys Ala Ser Glu Lys Glu Ala Pro Glu Asp Thr Val 340 345 350 Asp Ala Gly Glu Glu Gly Ser Arg Arg Glu Glu Ala Ala Lys Glu Pro 355 360 365 Lys Lys Lys Ala Ser Ala Leu Glu Glu Gly Ser Ser Asp Ala Ser Gln 370 375 380 Glu Leu Glu Ile Ser Glu His Met Lys Glu Pro Gln Leu Ser Asp Ser 385 390 395 400 Ile Ala Ser Asp Pro Lys Ser Phe His Gly Leu Asp Phe Gly Phe Arg 405 410 415 Ser Arg Ile Ser Glu His Leu Leu Asp Val Asp Val Leu Ser Pro Val 420 425 430 Leu Gly Gly Ala Cys Arg Gln Ala Gln Gln Pro Leu Gly Ile Glu Asp 435 440 445 Lys Asp Asp Ser Gln Ser Ser Gln Asp Glu Leu Gln Ser Lys Gln Ser 450 455 460 Lys Gly Leu Glu Glu Arg Tyr His Arg Leu Ser Pro Pro Leu Pro His 465 470 475 480 Glu Glu Arg Ala Gln Ser Pro Pro Arg Ser Leu Ala Thr Glu Glu Glu 485 490 495 Pro Pro Gln Gly Pro Glu Gly Gln Pro Glu Trp Lys Glu Ala Glu Glu 500 505 510 Leu Gly Glu Asp Ser Ala Ala Ser Leu Ser Leu Gln Leu Ser Leu Gln 515 520 525 Arg Glu Gln Ala Pro Ser Pro Pro Ala Ala Cys Glu Lys Gly Lys Glu 530 535 540 Gln His Ser Gln Ala Glu Glu Leu Gly Pro Gly Gln Glu Glu Ala Glu 545 550 555 560 Asp Pro Glu Glu Lys Val Ala Val Ser Pro Thr Pro Pro Val Ser Pro 565 570 575 Glu Val Arg Ser Thr Glu Pro Val Ala Pro Pro Glu Gln Leu Ser Glu 580 585 590 Ala Ala Leu Lys Ala Met Glu Glu Ala Val Ala Gln Val Leu Glu Gln 595 600 605 Asp Gln Arg His Leu Leu Glu Ser Lys Gln Glu Lys Met Gln Gln Leu 610 615 620 Arg Glu Lys Leu Cys Gln Glu Glu Glu Glu Glu Ile Leu Arg Leu His 625 630 635 640 Gln Gln Lys Glu Gln Ser Leu Ser Ser Leu Arg Glu Arg Leu Gln Lys 645 650 655 Ala Ile Glu Glu Glu Glu Ala Arg Met Arg Glu Glu Glu Ser Gln Arg 660 665 670 Leu Ser Trp Leu Arg Ala Gln Val Gln Ser Ser Thr Gln Ala Asp Glu 675 680 685 Asp Gln Ile Arg Ala Glu Gln Glu Ala Ser Leu Gln Lys Leu Arg Glu 690 695 700 Glu Leu Glu Ser Gln Gln Lys Ala Glu Arg Ala Ser Leu Glu Gln Lys 705 710 715 720 Asn Arg Gln Met Leu Glu Gln Leu Lys Glu Glu Ile Glu Ala Ser Glu 725 730 735 Lys Ser Glu Gln Ala Ala Leu Asn Ala Ala Lys Glu Lys Ala Leu Gln 740 745 750 Gln Leu Arg Glu Gln Leu Glu Gly Glu Arg Lys Glu Ala Val Ala Thr 755 760 765 Leu Glu Lys Glu His Ser Ala Glu Leu Glu Arg Leu Cys Ser Ser Leu 770 775 780 Glu Ala Lys His Arg Glu Val Val Ser Ser Leu Gln Lys Lys Ile Gln 785 790 795 800 Glu Ala Gln Gln Lys Glu Glu Ala Gln Leu Gln Lys Cys Leu Gly Gln 805 810 815 Val Glu His Arg Val His Gln Lys Ser Tyr His Val Ala Gly Tyr Glu 820 825 830 His Glu Leu Ser Ser Leu Leu Arg Glu Lys Arg Gln Glu Val Glu Gly 835 840 845 Glu His Glu Arg Arg Leu Asp Lys Met Lys Glu Glu His Gln Gln Val 850 855 860 Met Ala Lys Ala Arg Glu Gln Tyr Glu Ala Glu Glu Arg Lys Gln Arg 865 870 875 880 Ala Glu Leu Leu Gly His Leu Thr Gly Glu Leu Glu Arg Leu Gln Arg 885 890 895 Ala His Glu Arg Glu Leu Glu Thr Val Arg Gln Glu Gln His Lys Arg 900 905 910 Leu Glu Asp Leu Arg Arg Arg His Arg Glu Gln Glu Arg Lys Leu Gln 915 920 925 Asp Leu Glu Leu Asp Leu Glu Thr Arg Ala Lys Asp Val Lys Ala Arg 930 935 940 Leu Ala Leu Leu Glu Val Gln Glu Glu Thr Ala Arg Arg Glu Lys Gln 945 950 955 960 Gln Leu Leu Asp Val Gln Arg Gln Val Ala Leu Lys Ser Glu Glu Ala 965 970 975 Thr Ala Thr His Gln Gln Leu Glu Glu Ala Gln Lys Glu His Thr His 980 985 990 Leu Leu Gln Ser Asn Gln Gln Leu Arg Glu Ile Leu Asp Glu Leu Gln 995 1000 1005 Ala Arg Lys Leu Lys Leu Glu Ser Gln Val Asp Leu Leu Gln Ala 1010 1015 1020 Gln Ser Gln Gln Leu Gln Lys His Phe Ser Ser Leu Glu Ala Glu 1025 1030 1035 Ala Gln Lys Lys Gln His Leu Leu Arg Glu Val Thr Val Glu Glu 1040 1045 1050 Asn Asn Ala Ser Pro His Phe Glu Pro Asp Leu His Ile Glu Asp 1055 1060 1065 Leu Arg Lys Ser Leu Gly Thr Asn Gln Thr Lys Glu Val Ser Ser 1070 1075 1080 Ser Leu Ser Gln Ser Lys Glu Asp Leu Tyr Leu Asp Ser Leu Ser 1085 1090 1095 Ser His Asn Val Trp His Leu Leu Ser Ala Glu Gly Val Ala Leu 1100 1105 1110 Arg Ser Ala Lys Glu Phe Leu Val Gln Gln Thr Arg Ser Met Arg 1115 1120 1125 Arg Arg Gln Thr Ala Leu Lys Ala Ala Gln Gln His Trp Arg His 1130 1135 1140 Glu Leu Ala Ser Ala Gln Glu Val Ala Lys Asp Pro Pro Gly Ile 1145 1150 1155 Lys Ala Leu Glu Asp Met Arg Lys Asn Leu Glu Lys Glu Thr Arg 1160 1165 1170 His Leu Asp Glu Met Lys Ser Ala Met Arg Lys Gly His Asn Leu 1175 1180 1185 Leu Lys Lys Lys Glu Glu Lys Leu Asn Gln Leu Glu Ser Ser Leu 1190 1195 1200 Trp Glu Glu Ala Ser Asp Glu Gly Thr Leu Gly Gly Ser Pro Thr 1205 1210 1215 Lys Lys Ala Val Thr Phe Asp Leu Ser Asp Met Asp Ser Leu Ser 1220 1225 1230 Ser Glu Ser Ser Glu Ser Phe Ser Pro Pro His Leu Asp Ser Thr 1235 1240 1245 Pro Ser Leu Thr Ser Arg Lys Ile His Gly Leu Ser His Ser Leu 1250 1255 1260 Arg Gln Ile Ser Ser Gln Leu Ser Ser Val Leu Ser Ile Leu Asp 1265 1270 1275 Ser Leu Asn Pro Gln Ser Pro Pro Pro Leu Leu Ala Ser Met Pro 1280 1285 1290 Ala Gln Leu Pro Pro Arg Asp Pro Lys Ser Thr Pro Thr Pro Thr 1295 1300 1305 Tyr Tyr Gly Ser Leu Ala Arg Phe Ser Ala Leu Ser Ser Ala Thr 1310

1315 1320 Pro Thr Ser Thr Gln Trp Ala Trp Asp Ser Gly Gln Gly Pro Arg 1325 1330 1335 Leu Pro Ser Ser Val Ala Gln Thr Val Asp Asp Phe Leu Leu Glu 1340 1345 1350 Lys Trp Arg Lys Tyr Phe Pro Ser Gly Ile Pro Leu Leu Ser Asn 1355 1360 1365 Ser Pro Thr Pro Leu Glu Ser Arg Leu Gly Tyr Met Ser Ala Ser 1370 1375 1380 Glu Gln Leu Arg Leu Leu Gln His Ser His Ser Gln Val Pro Glu 1385 1390 1395 Ala Gly Ser Thr Thr Phe Gln Gly Ile Ile Glu Ala Asn Arg Arg 1400 1405 1410 Trp Leu Glu Arg Val Lys Asn Asp Pro Arg Leu Pro Leu Phe Ser 1415 1420 1425 Ser Thr Pro Lys Pro Lys Ala Thr Leu Ser Leu Leu Gln Leu Gly 1430 1435 1440 Leu Asp Glu His Asn Arg Val Lys Val Tyr Arg Phe 1445 1450 1455 115136PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 115Met Ala Gly Arg Pro Leu Arg Ile Gly Asp Gln Leu Val Leu Glu Glu 1 5 10 15 Asp Tyr Asp Glu Thr Tyr Ile Pro Ser Glu Gln Glu Ile Leu Glu Phe 20 25 30 Ala Arg Glu Ile Gly Ile Asp Pro Ile Lys Glu Pro Glu Leu Met Trp 35 40 45 Leu Ala Arg Glu Gly Ile Val Ala Pro Leu Pro Gly Glu Trp Lys Pro 50 55 60 Cys Gln Asp Ile Thr Gly Asp Ile Tyr Tyr Phe Asn Phe Ala Asn Gly 65 70 75 80 Gln Ser Met Trp Asp His Pro Cys Asp Glu His Tyr Arg Ser Leu Val 85 90 95 Ile Gln Glu Arg Ala Lys Leu Ser Thr Ser Gly Ala Ile Lys Lys Lys 100 105 110 Lys Lys Lys Arg Lys Arg Lys Thr Arg Arg Thr Glu Thr Pro Pro Lys 115 120 125 Val Arg Trp Pro Trp Val Pro His 130 135 116202PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 116Met Ala Gly Arg Pro Leu Arg Ile Gly Asp Gln Leu Val Leu Glu Glu 1 5 10 15 Asp Tyr Asp Glu Thr Tyr Ile Pro Ser Glu Gln Glu Ile Leu Glu Phe 20 25 30 Ala Arg Glu Ile Gly Ile Asp Pro Ile Lys Glu Pro Glu Leu Met Trp 35 40 45 Leu Ala Arg Glu Gly Ile Val Ala Pro Leu Pro Gly Glu Trp Lys Pro 50 55 60 Cys Gln Asp Ile Thr Gly Asp Ile Tyr Tyr Phe Asn Phe Ala Asn Gly 65 70 75 80 Gln Ser Met Trp Asp His Pro Cys Asp Glu His Tyr Arg Ser Leu Val 85 90 95 Ile Gln Glu Arg Ala Lys Leu Ser Thr Ser Gly Ala Ile Lys Lys Lys 100 105 110 Lys Lys Lys Gly Lys Glu Arg Gln Glu Gly Gln Arg Pro Pro Gln Lys 115 120 125 Phe Ala Gly Leu Gly Phe Leu Ile Ser Pro Ser Ser Cys Ser Ser Trp 130 135 140 Gly Pro Gly Ser Phe Thr Arg Ser Cys Gly Tyr Pro Thr Leu Cys Ser 145 150 155 160 Ser Trp Ile Ser Lys Arg Glu Pro Gly Glu Leu Ser Gly Val Trp Thr 165 170 175 Ser Ala Trp Arg Thr His Ala Ala Phe Thr Gly Ser Gln Asp Leu Cys 180 185 190 Leu Tyr Lys Gly Ser Leu Gly Leu His Ile 195 200 117203PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 117Met Ala Gly Arg Pro Leu Arg Ile Gly Asp Gln Leu Val Leu Glu Glu 1 5 10 15 Asp Tyr Asp Glu Thr Tyr Ile Pro Ser Glu Gln Glu Ile Leu Glu Phe 20 25 30 Ala Arg Glu Ile Gly Ile Asp Pro Ile Lys Glu Pro Glu Leu Met Trp 35 40 45 Leu Ala Arg Glu Gly Ile Val Ala Pro Leu Pro Gly Glu Trp Lys Pro 50 55 60 Cys Gln Asp Ile Thr Gly Asp Ile Tyr Tyr Phe Asn Phe Ala Asn Gly 65 70 75 80 Gln Ser Met Trp Asp His Pro Cys Asp Glu His Tyr Arg Ser Leu Val 85 90 95 Ile Gln Glu Arg Ala Lys Leu Ser Thr Ser Gly Ala Ile Lys Lys Lys 100 105 110 Lys Lys Lys Lys Gly Lys Glu Arg Gln Glu Gly Gln Arg Pro Pro Gln 115 120 125 Lys Phe Ala Gly Leu Gly Phe Leu Ile Ser Pro Ser Ser Cys Ser Ser 130 135 140 Trp Gly Pro Gly Ser Phe Thr Arg Ser Cys Gly Tyr Pro Thr Leu Cys 145 150 155 160 Ser Ser Trp Ile Ser Lys Arg Glu Pro Gly Glu Leu Ser Gly Val Trp 165 170 175 Thr Ser Ala Trp Arg Thr His Ala Ala Phe Thr Gly Ser Gln Asp Leu 180 185 190 Cys Leu Tyr Lys Gly Ser Leu Gly Leu His Ile 195 200 118281PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 118Met Gln Arg Pro Asn Ala His Arg Ile Ser Gln Pro Ile Arg Gln Ile 1 5 10 15 Ile Tyr Gly Leu Leu Leu Asn Ala Ser Pro His Leu Asp Lys Thr Ser 20 25 30 Trp Asn Ala Leu Pro Pro Gln Pro Leu Ala Phe Ser Glu Val Glu Arg 35 40 45 Ile Asn Lys Asn Ile Arg Thr Ser Ile Ile Asp Ala Val Glu Leu Ala 50 55 60 Lys Asp His Ser Asp Leu Ser Arg Leu Thr Glu Leu Ser Leu Arg Arg 65 70 75 80 Arg Gln Met Leu Leu Leu Glu Thr Leu Lys Val Lys Gln Thr Ile Leu 85 90 95 Glu Pro Ile Pro Thr Ser Leu Lys Leu Pro Ile Ala Val Ser Cys Tyr 100 105 110 Trp Leu Gln His Thr Glu Thr Lys Ala Lys Leu His His Leu Gln Ser 115 120 125 Leu Leu Leu Thr Met Leu Val Gly Pro Leu Ile Ala Ile Ile Asn Ser 130 135 140 Pro Gly Lys Glu Glu Leu Gln Glu Asp Gly Ala Lys Met Leu Tyr Ala 145 150 155 160 Glu Phe Gln Arg Val Lys Ala Gln Thr Arg Leu Gly Thr Arg Leu Asp 165 170 175 Leu Asp Thr Ala His Ile Phe Cys Gln Trp Gln Ser Cys Leu Gln Met 180 185 190 Gly Met Tyr Leu Asn Gln Leu Leu Ser Thr Pro Leu Pro Glu Pro Asp 195 200 205 Leu Thr Arg Leu Tyr Ser Gly Ser Leu Val His Gly Leu Cys Gln Gln 210 215 220 Leu Leu Ala Ser Thr Ser Val Glu Ser Leu Leu Ser Ile Cys Pro Glu 225 230 235 240 Ala Lys Gln Leu Tyr Glu Tyr Leu Phe Asn Ala Thr Arg Ser Tyr Ala 245 250 255 Pro Ala Glu Ile Phe Leu Pro Lys Gly Arg Ser Asn Ser Lys Lys Lys 260 265 270 Ala Glu Glu Thr Glu Tyr Gln Leu Phe 275 280 119129PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 119Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu 1 5 10 15 Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val 20 25 30 Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro 35 40 45 Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln 50 55 60 Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro 65 70 75 80 Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr 85 90 95 Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile 100 105 110 Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Ala 115 120 125 Trp 120101PRTArtificial SequenceDescription of Artificial Sequence polypeptides encoded by genes with coding microsatellites 120Ile Pro Ala Phe Pro Ala Gly Thr Val Leu Gln Pro Phe Pro Glu Ala 1 5 10 15 Ala Leu Ala Thr Arg Val Thr Val Pro Ala Val Glu Ala Pro Ala Ala 20 25 30 Pro Arg Leu Asp Leu Glu Glu Ser Glu Glu Phe Lys Glu Arg Cys Thr 35 40 45 Gln Cys Ala Ala Val Ser Trp Gly Leu Thr Asp Glu Gly Lys Tyr Tyr 50 55 60 Cys Thr Ser Cys His Asn Val Thr Glu Arg Tyr Gln Glu Val Thr Asn 65 70 75 80 Thr Asp Leu Ile Pro Asn Thr Gln Ile Lys Ala Leu Asn Arg Gly Leu 85 90 95 Lys Lys Lys Gln Tyr 100

Claims

1. A method for selecting a subgroup in a colorectal cancer patient population having cancer cells associated with frameshift mutations in coding microsatellite regions, comprising: detecting the presence or absence of antibodies or antigen-recognizing cells directed against one or more frameshift polypeptides in biological samples from colorectal cancer patients, wherein the frameshift polypeptide is derived from a frameshift mutation in the A11 repeats in a coding microsatellite region of a gene selected from the group consisting of TAF1B, MACS, and HT001, and selecting a subgroup of the colorectal cancer patients that have the antibodies or the antigen-recognizing cells present in their samples.

2. The method of claim 1, wherein the frameshift polypeptide is derived from the A11 repeat of the TAF1B gene.

3. The method of claim 1, wherein the frameshift polypeptide is derived from the A11 repeat of the HT001 gene.

4. The method of claim 1, wherein the frameshift polypeptide is derived from the A11 repeat of the MACS gene.

5. The method of claim 1, which measures the presence or absence of the antibodies.

6. The method of claim 1, which measures the presence or absence of the antigen-recognizing cells.

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