JP2003111595A - Tumor antigen - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a molecule (a tumor antigen) capable of being recognized by a tumor-specific cytotoxic T cell in a manner of being restricted by a human leucocyte antigen B46 (HLA-B46). SOLUTION: A peptide recognized by the HLA-B46-restricted tumor-specific cytotoxic T cell and having an epitope of the tumor antigen is found by using the HLA-B46-restricted tumor-specific cytotoxic T cell which recognizes a HLA-B46 molecule and a tumor antigen peptide so as to be activated, and then identifying the tumor antigen capable of activating the tumor-specific cytotoxic T cell from a cDNA library of human colon cancer cell strain SW 620 through a gene expression cloning method.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a tumor antigen, and more specifically, to a peptide or polypeptide recognized by a tumor-specific cytotoxic T cell, a polynucleotide encoding the peptide or polypeptide or a complementary chain thereof, A recombinant vector containing the polynucleotide,
Transformant containing the recombinant vector, antibody against the peptide or the polypeptide, compound having an interaction with the peptide or the polypeptide or the polynucleotide, cytotoxic T consisting of the peptide and / or the polypeptide Cell-inducing agent, pharmaceutical composition comprising one or more of these, and method for producing the peptide or the polypeptide, method for screening a compound that interacts with the peptide or the polypeptide or the polynucleotide, the peptide Alternatively, the present invention relates to a method for inducing cytotoxic T cells using the polypeptide, a method for measuring the peptide or the polypeptide or a polynucleotide encoding the polypeptide, and a screening method or a reagent kit used for the measuring method. .

[0002]

2. Description of the Related Art In order to eliminate cancer in a living body, the immune system, especially cytotoxic T cells (Cytotoxi) involved in cell-mediated immunity
ct Lymphocyte) plays an important role. Invasion of cytotoxic T cells showing cytotoxicity against tumor cells has been observed in the tumor site of cancer patients [A
rch. Surg. (1990) 126: 200-20
5]. This tumor-specific cytotoxic T cell target molecule (tumor antigen) was first discovered in melanoma. Tumor antigens produced in tumor cells are decomposed intracellularly to peptides (tumor antigen peptides) consisting of 8 to 11 amino acids, and the major histocompatibility antigens (MH
C), which is a human leukocyte antigen (HLA) molecule and is presented on the surface of tumor cells. This cytotoxic T cell is this H
It recognizes the complex of LA molecule and tumor antigen peptide and damages tumor cells. That is, cytotoxic T cells are HLA
Recognize tumor cells in a restricted manner.

HLA is a cell membrane antigen and is expressed on almost all nucleated cells. HLA is roughly classified into class I antigen and class II antigen, and HLA recognized together with an antigen peptide by cytotoxic T cells is a class I antigen. HLA class I antigens further include HLA-A, B,
In humans, nucleated cells have different amounts of HLA-A, B, and C antigens. In addition, it has been reported that the gene is rich in polymorphism. For example, HL
AA includes HLA-B, such as A1, A2, and A24.
There are polymorphisms such as B8, B27, and B46 in HLA-C and Cw3 and Cw6 in HLA-C. Therefore, the type of HLA that each individual has is not necessarily the same.
Moreover, since the peptides that can be bound differ depending on the type of HLA, it is necessary to select peptides that can bind to each type of HLA in order to induce and / or activate cytotoxic T cells.

In recent years, molecules involved in specific immunity such as tumor rejection antigen gene and T cell receptor have been identified in melanoma, esophageal cancer, and other cancers, and advanced cancer or metastasis. Specific immunotherapy with peptides has been studied in sexually transmitted cancers [Science (1991) 254: 1643-1.
647; Exp. Med. (1996) 183: 1
185-1192; Immunol. (1999)
163: 4994-5004; Proc. Natl. A
cad. Sci. USA (1995) 92: 432-4.
36; Science (1995) 269: 1281-.
1284; Exp. Med. (1997) 186:
785-793].

[0005] Currently, in Europe and the United States, a cancer vaccine therapy for activating cytotoxic T cells in the body of a cancer patient by administering a tumor antigen is being developed, and the results of clinical tests for melanoma-specific tumor antigens have been reported. . For example, by subcutaneously administering the melanoma antigen gp100 peptide to melanoma patients and intravenously administering interleukin-2, tumor shrinkage is observed in 42% of patients [Nature Medicine (1998)].
4: 321]. Thus, when a tumor antigen is used as a cancer vaccine, an effective cancer therapeutic effect can be expected.

However, many of the identified tumor antigen genes are HLA-A-restricted ones, and HLA-B and HLA
There are few reports of LA-C-restricted tumor antigen genes. As described above, due to the presence of polymorphisms in the HLA gene, it is considered that the HLA type is different in each individual, and therefore the type of tumor antigen peptide that can function in each individual is different. From this, it is important to identify tumor antigen peptides capable of inducing and / or activating specific cytotoxic T cells for each type of HLA.

Further, considering the diversity of cancers, it cannot be considered that the same tumor antigen is expressed to the same extent in all cancer cells. The type and expression level of the expressed tumor antigen differ depending on the type of cancer cell and the tissue. Of course, a cancer vaccine therapy in which a cytotoxic T cell is activated by using a single tumor antigen can also provide a therapeutic effect on a cancer having the tumor antigen. However, in order to induce antigen-specific cytotoxic T cells in the treatment of cancer and to obtain a high therapeutic effect in response to the diversity of cancer, many HLA-restricted and cancer-dependent It is necessary to discover and utilize new tumor antigens.

[0008]

The problem to be solved by the present invention is to find and provide a novel tumor antigen. Specifically, it is to provide a tumor antigen recognized by cytotoxic T cells at least HLA-B46-restricted. More specifically, a peptide or polypeptide recognized by cytotoxic T cells in a HLA-B46-restricted manner, a polynucleotide encoding the peptide or the polypeptide or a complementary strand thereof, a recombinant vector containing the polynucleotide, Transformant containing recombinant vector, antibody against said peptide or said polypeptide, compound interacting with said peptide or said polypeptide or said polynucleotide, cytotoxic T cell comprising said peptide and / or said polypeptide Inducing agent, pharmaceutical composition comprising one or more of these, and method for producing the peptide or the polypeptide, screening method for a compound that interacts with the peptide or the polypeptide or the polynucleotide, the peptide or The polypeptide How induction of cytotoxic T cells to be used, it is to provide the peptide or the method of measuring the polypeptide or the polynucleotide, and a reagent kit for use in the screening method or the measuring method.

[0009]

DISCLOSURE OF THE INVENTION The present inventors have identified HLA-B46-restricted tumor-specific cells that are activated by recognizing HLA-B46 and tumor antigen peptides from tumor-infiltrating lymphocytes derived from patients with colorectal cancer. The cytotoxic T cell OK-CTL-d55 was established, and OK-CTL-d55 was HLA-B46-restricted.
Was isolated and identified from a cDNA library of human colorectal cancer cell line SW620 by gene expression cloning, and further recognized by HLA-B46-restricted cytotoxic T cells. The present invention has been completed by finding a polypeptide or peptide having an epitope of a tumor antigen.

That is, the present invention relates to (1) a peptide comprising the amino acid sequence set forth in any one of SEQ ID NOS: 1 to 50 in the sequence listing, or (2) set forth in any one of SEQ ID NOS: 51 to 99 in the sequence listing. Consisting of an amino acid sequence, HLA-B4
A polypeptide which induces 6-restricted cytotoxic T cells and / or is recognized by HLA-B46-restricted cytotoxic T cells, (3) SEQ ID NOS: 1 to 50 in the sequence listing
One or more kinds of peptides selected from the peptides consisting of the amino acid sequence of any one of SEQ ID NOs: 1 and / or consisting of the amino acid sequence of any one of SEQ ID NOs: 51 to 99, and HLA-B46-restricted cytotoxicity A medicament comprising one or more polypeptides selected from polypeptides that induce T cells and / or are recognized by cytotoxic T cells in a HLA-B46-restricted manner, (4) SEQ ID NOs: 1 to 50 in the sequence listing One or more kinds of peptides selected from the peptides consisting of the amino acid sequence of any one of SEQ ID NOs: 1 and / or consisting of the amino acid sequence of any one of SEQ ID NOs: 51 to 99, and HLA-B46-restricted cytotoxicity One selected from polypeptides that induce T cells and / or are recognized by cytotoxic T cells in a HLA-B46 restricted manner Above polypeptides, cancer vaccine containing, (5) colorectal cancer, oral cancer, lung cancer, prostate cancer or the fourth cancer vaccine for use in the treatment of gynecological cancers, and (6)
A HLA-B46-restricted cell comprising one or more peptides selected from the peptides consisting of the amino acid sequences set forth in any one of SEQ ID NOS: 1 to 6 of the Sequence Listing and / or the amino acid sequence set forth in SEQ ID NO: 100 A cancer vaccine comprising a polypeptide that induces cytotoxic T cells and / or is recognized by cytotoxic T cells in a HLA-B46-restricted manner, carrying HLA-B46 and p5.
3. Cancer vaccine used for treatment of cancer in which mutation of tumor suppressor gene is recognized, (7) one or more peptides selected from peptides consisting of amino acid sequences set forth in any one of SEQ ID NOS: 1 to 50 of Sequence Listing, / Or SEQ ID NO: 51
H consisting of the amino acid sequence of any one of 1 to 99
Cytotoxicity containing one or more polypeptides selected from polypeptides recognized by LA-B46-restricted cytotoxic T cells and / or recognized by HLA-B46-restricted cytotoxic T cells An inducer of T cells,
(8) One or more peptides selected from the peptides consisting of the amino acid sequences set forth in any one of SEQ ID NOS: 1 to 50 in the sequence listing, and / or the amino acid sequence set forth in any one of SEQ ID NOS: 51 to 99 Consisting of HLA-B4
6. One or more polypeptides selected from polypeptides that induce 6-restricted cytotoxic T cells and / or are recognized by HLA-B46-restricted cytotoxic T cells. Method for inducing cytotoxic T cell, (9) HLA consisting of peptide consisting of amino acid sequence set forth in any one of SEQ ID NOS: 1 to 50 or amino acid sequence set forth in any one of SEQ ID NOS: 51 to 99 of Sequence Listing A polynucleotide encoding a polypeptide that induces cytotoxic T cells in a B46-restricted manner and / or is recognized by a cytotoxic T cell in a HLA-B46-restricted manner, or a complementary chain thereof, (10) A polynucleotide comprising the nucleotide sequence set forth in any one of SEQ ID NOs: 100 to 141, the polynucleotide encoded by the polynucleotide. Peptide to induce cytotoxic T cells HLA-B46-restricted and / or HLA-B
46. Polynucleotide which is restrictedly recognized by cytotoxic T cell or its complementary chain, (11) Hybridization with the polynucleotide of (9) or (10) or its complementary chain under stringent conditions (12) A recombinant vector containing the polynucleotide according to any one of (9) to (11) or a complementary strand thereof, (13) the recombinant vector being an expression recombinant vector. The recombinant vector, (14) the transformant transformed with the recombinant vector of (12) or (13) above, and (15) the transformant transformed with the recombinant vector of (13) above are cultured. A method for producing the peptide according to (1) or the polypeptide according to (2) above, which comprises the steps of: (16) the peptide according to (1) above; Antibody recognizes a polypeptide immunologically said (2), polypeptides and / or HL (17) peptide or the said (1) (2)
A-B46 molecule interacts with at least HLA-B4
A compound that enhances the recognition of the peptide or the polypeptide by 6-restricted cytotoxic T cells, and / or interacts with the polynucleotide of any one of the above (9) to (11) or its complementary strand A method for screening a compound that enhances expression, the method comprising:
Peptide, the polypeptide of (2), the polynucleotide of any of (9) to (11) or its complementary strand, the recombinant vector of (12) or (13), and the transformation of (14). Or a screening method characterized by using at least one of the antibodies of (16) above, (18) a compound obtained by the screening method of (17) above, (19) above (1)
HLA-B46-restricted cytotoxic T against at least one of the peptides according to claim 1 or the polypeptide according to (2) above.
A compound that enhances cell recognition, or a compound that interacts with the polynucleotide of any one of (9) to (11) above or its complementary strand to enhance its expression, (2
0) The peptide according to (1), the polypeptide according to (2), the polynucleotide according to any one of (9) to (11) or a complementary strand thereof, (12) or (1)
3) the recombinant vector, (14) the transformant, (16) the antibody, or (18) or (1)
A pharmaceutical composition for treating cancer, comprising at least one of the compounds of 9), (21) the peptide of (1) or the polypeptide of (2), or the poly of (9) or (10). A method of quantitatively or qualitatively measuring nucleotides, (22) a reagent kit used in the screening method of (17) or the method of (21), comprising the peptide of (1) and the reagent of (2) A polypeptide, the polynucleotide of any one of the above (9) to (11) or a complementary strand thereof, or the above (16)
A reagent kit comprising at least one of the antibodies of.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION (Identification of Tumor Antigen Gene) The present inventors first of all, HLA-B46-restricted tumor-specific cytotoxic T that is activated by recognizing HLA-B46 and a tumor antigen peptide. The cells OK-CTL-d55 were previously reported [J.
Immunol. (1999) 163: 4994-50
04], colorectal cancer patients (HLA-A
0207/3101, HLA-B46 / 51, HLA-
Cw1) tumor infiltrating lymphocytes (Tumour-Info)
lighting Lymphocyto (hereinafter T)
(Sometimes abbreviated as IL). OK-CT
80% or more of the cell surface marker of L-d55 is CD3
⁺ CD4 ^- CD8 ⁺ .

The obtained tumor antigen recognized by OK-CTL-d55 was used as the cDNA of human colon cancer cell line SW620.
It was isolated and identified from the library using the gene expression cloning method. That is, human colon cancer cell line SW62
0 cDNA and HLA-B4601 cDNA were co-transfected into monkey kidney cell line COS-7, and interferon-γ (hereinafter, IFN-γ) from OK-CTL-d55 was expressed among cells expressing the transgene. HLA-B46 by selecting those that promote production.
A gene encoding a tumor antigen recognized by restricted cytotoxic T cells (hereinafter sometimes abbreviated as CTL) was identified. As a result, 5 cDNA clones were obtained.
A specific method will be shown in Examples described later. In addition, CT with HLA-A2 restriction, which was previously isolated and identified by the same method, was used.
Regarding the gene encoding the tumor antigen recognized by L, it was examined whether or not it was recognized by CTL in a HLA-B46-restricted manner. As a result, CTL was restricted to HLA-A2.
Among the genes encoding the tumor antigens recognized by S. cerevisiae, 37 cDNA clones expressing the gene product recognized by HLA-B46 restricted by OK-CTL-d55 were obtained.

The nucleotide sequences of these cDNA clones were determined by the dideoxynucleotide sequencing method, and the nucleotide sequences are shown in SEQ ID NOs: 100 to 141 of the sequence listing. It has not been reported until now that the cDNA comprising the nucleotide sequence described in any one of SEQ ID NOs: 100 to 104 in the sequence listing encodes a tumor antigen. The cDNA comprising the nucleotide sequence set forth in any one of SEQ ID NOs: 105 to 141 in the sequence listing is recognized by CTL with HLA-A2 restriction and / or HLA-A2.
It has already been disclosed by the present inventors to encode a tumor antigen that induces CTL in a restricted manner. But,
It was revealed for the first time in the present invention that these cDNAs encode tumor antigens that are recognized by CTL in an HLA-B46-restricted manner and / or induce CTLs in an HLA-B46-restricted manner.

The gene obtained in the present invention is HLA-
It is a gene encoding a tumor antigen recognized by B46-restricted tumor-specific CTL, and when expressed in cells as described above, it is recognized by HLA-B46-restricted CTL and induces and / or activates CTL. obtain. The amino acid sequences encoded by these genes are shown in SEQ ID NOs: 51 to 99 of the sequence listing (see Tables 1 to 3).

The nucleotide sequence of the above cDNA clone was subjected to homology search using an existing database such as GenBank, and among 42 genes, 39 clones were found to have highly homologous human-derived genes. It was However, none of clone 11A and clone 58 had high homology. Regarding clone 30, there was a gene with a high homology in the mouse-derived gene, but there was no gene with a high homology in the human-derived gene. The results are shown in Tables 1 to 3 below. In the table, when a gene with high homology was not found, it was indicated by "-". Although the nucleotide sequences and deduced amino acid sequences of the highly homologous genes have been disclosed, there is no report that they encode tumor antigens or that they are recognized by CTL and / or induce CTL.
NCBI (Nationa viewed on November 7, 2001)
l Center for Biotechnology
It was not disclosed in the yInformation public database.

Clone 86 and clone 100
Amino acid sequence encoded by: (SEQ ID NOS: 97 and 98)
Is the SEREX database (http: // www-
ludwig. unil. ch / SEREX. htm
Known genes ID163 and ID1 published under l)
It was found that each of them was identical to the one coded by 16. The nucleotide sequences of clone 82 and clone 86 (SEQ ID NOS: 136 and 139) are ID1197 and I, respectively.
It was the same as that of D163. In addition, clone 32, clone 41, and clone 74 were found to have partial homology with ID1072, ID1233, and ID979, respectively. The SEREX database is SEREX (Serological an
alysis of recombinant cDN
This is a database in which genes detected by the A expression libraries) method are registered. S
EREX method [Sahin, U .; et al. , Pro
c. Natl. Acad. Sci. USA (1995)
92: 11810-11813], an antigen is detected using an antibody that appears in the serum of a patient. In this way,
Antigens that induce humoral immunity are often detected. The method has already identified more than 1,500 tumor antigens.

The SEREX method is a method that can be used for the detection of tumor antigens. As a tumor antigen capable of inducing both cell-mediated immunity and humoral immunity among the over 1,500 kinds of tumor antigens detected by the method. What has been identified so far is MA
GE-1, tyrosinase, and NY-ESO-1 only. Even those identified as tumor antigens by the SEREX method do not always induce and / or activate CTLs involved in cell-mediated immunity. It is not disclosed in the database that the gene whose base sequence and amino acid sequence is published in the SEREX database encodes a tumor antigen that induces and / or activates CTL.

[0018]

[Table 1]

[0019]

[Table 2]

[0020]

[Table 3]

[0021] In the present specification, the tumor antigen means a protein or peptide possessed by a tumor cell, which is recognized by a tumor-specific cytotoxic T cell and / or can induce a cytotoxic T cell. To do. The tumor antigen peptide is a peptide generated by the decomposition of the tumor antigen in tumor cells and is recognized by tumor-specific cytotoxic T cells by being bound to HLA molecules and presented on the cell surface. And / or a peptide capable of inducing cytotoxic T cells. Furthermore, a site of an amino acid sequence that can induce and / or activate tumor-specific cytotoxic T cells possessed by a tumor antigen is referred to as a tumor antigen epitope (tumor antigen determinant).

Here, "recognize (recognize
By "e)" is meant that the recognizer recognizes the recognized object as distinct from the others and, for example, binds to the recognized object. In particular, herein, cytotoxic T
That cells recognize tumor cells or tumor antigen peptides means that cytotoxic T cells bind to tumor antigen peptides presented by HLA molecules via T cell antigen receptors (hereinafter sometimes abbreviated as TCR). Means that.
“Activate” means to further enhance or activate something or a state having an activity or action. In particular, in the present specification, activation of a cytotoxic T cell means that the cytotoxic T cell recognizes an antigen presented by an HLA molecule, for example, IF
It means producing N-γ or exhibiting cytotoxic activity against target cells recognized by cytotoxic T cells. “Induce” means to cause an activity or an action from a substance or a state having little activity or action. In particular, in this specification, inducing an antigen-specific cytotoxic T cell means differentiating and / or proliferating a cytotoxic T cell that specifically recognizes an antigen in vitro or in vivo. . The term "cytotoxic T cell inducer" used herein means a cell that recognizes an antigen from the state in which CD8 positive T cells that specifically recognize the antigen do not exist or are present at a very low ratio. It means a drug that has an effect of changing into a state in which a very large proportion of damaging T cells are present.

(Preparation of tumor antigen peptide and CTL activity)
In order to obtain tumor antigen peptides from the above-mentioned genes encoding tumor antigens, these genes have been reported previously [J. Exp. Med. (1996) 184: 735-
740] and a 9-mer peptide was designed and synthesized. COS- expressing HLA-B4601
After pulsing each peptide synthesized in 7 cells, OK-C
The cells were cultured with TL-d55, and IFN-γ produced from OK-CTL-d55 was measured. A peptide recognized by HLA-B46-restricted CTL was selected using the amount of IFN-γ produced as an index. Of the synthesized peptides,
50 peptides (SEQ ID NOS: 1-50 in the sequence listing)
Recognized by K-CTL-d55, OK-CTL-d
IFN-γ production from 55 was promoted in a peptide dose-dependent manner. Thus, 50 tumor antigen peptides that were recognized by HLA-B46-restricted CTLs and could activate the CTLs were obtained. Of these peptides, HLA-A
2 HLA-B46-restricted CT selected from genes encoding tumor antigens that can activate CTL in a restricted manner
Those derived from a gene that also encodes a tumor antigen capable of activating L were peptides encoded in regions completely different from the HLA-A2 restricted tumor antigen peptide derived from the gene. Hereinafter, when an amino acid sequence is represented, it may be represented by one letter or three letters.

(CTL Induction by Peptides in Peripheral Blood Mononuclear Cells Derived from Cancer Patients) Among the genes of the present invention, clone 7F is a gene highly homologous to the p53 tumor suppressor gene. Since a mutation in the p53 gene was found in about 50% of human cancers, and OK-CTL-d55 was established from T lymphocytes infiltrating colon cancer having a p53 mutation, it was derived from clone 7F. Focusing on peptides,
Peripheral blood mononuclear cells derived from cancer patients (Peripheral)
Blood Mononuclear Cells)
The CTL induction by the peptide in (hereinafter, sometimes abbreviated as PBMC) was examined.

PBMC derived from a cancer patient (prostate cancer, lung cancer, vulvar cancer, or colorectal cancer) pre-stimulated with peptide 7F.P2 (SEQ ID NO: 2) or 7F.P6 (SEQ ID NO: 3)
Recognized COS-7 cells pulsed with the same peptide used for stimulation by introducing the HLA-B46 gene, and produced a significant level of IFN-γ. In addition, 7
PBMCs (derived from prostate cancer cases or colon cancer cases) stimulated with F / P2 were OSC cells (oral cancer cells: HLA-B46 ⁺
It had a mutation of p53, and accumulation of p53 mutant was observed in the nucleus), and showed cytotoxic activity. However, it did not react with tumor cells that were HLA-B46 ⁺ but lacked the p53 mutation, or PHA blast T cells. Further, when 7F · P2 was pre-pulsed to the OSC cells, the cytotoxic activity of the PBMC on the OSC cells was enhanced.

From these results, it was revealed that the peptide derived from clone 7F and the polypeptide encoded by clone 7F can induce and / or activate HLA-B46-restricted tumor-specific CTL in these patients. Therefore, the peptide derived from clone 7F and the polypeptide encoded by clone 7F are used for the treatment of cancer, for example, mutation of p53 tumor suppressor gene and HLA-
It is considered effective in the treatment of B46-carrying cancers.

Furthermore, the tumor antigens of the present invention other than clone 7F and peptides derived from them can also induce and / or activate HLA-B46-restricted tumor-specific CTLs in PBMCs of cancer patients. It is speculated that this is possible, and thus it is considered suitable for use in specific immunotherapy of HLA-B46 ⁺ cancer patients.

(Polypeptide and Peptide) In the present specification, a long-chain peptide among arbitrary peptides containing two or more amino acids linked to each other by a peptide bond or a modified peptide bond is referred to as a polypeptide. For example, proteins are also included herein as polypeptides. In addition, short-chain peptides, which are also called oligopeptides and oligomers, are simply referred to as peptides.

The polypeptide according to the present invention is a polypeptide encoded by the above gene obtained from human colorectal cancer cell line SW620. Preferably SEQ ID NO: 51 in the sequence listing
~ 99 is a polypeptide consisting of the amino acid sequence of any one of. The polypeptide according to the present invention has a CT
It can be used as a tumor antigen which is recognized by L, eg HLA-B46 restricted CTL and / or induces HLA-B46 restricted CTL. Further, the polypeptide can also be used as a material for identifying a tumor antigen epitope to obtain a tumor antigen peptide.

The tumor antigen peptide according to the present invention can be obtained by selecting a peptide that is recognized by and / or induces CTL from the peptides designed based on the amino acid sequence of the above polypeptide. As the selection method, as in Examples described later, for example, peptide-pulsed antigen-presenting cells and HLA-B46-restricted CTLs such as OK-CTL-d55 are co-cultured to activate the cells. IFN produced from the produced CTL
An example is a method of measuring -γ and selecting this as an index. The tumor antigen peptide may be one that binds to HLA-B46 and is presented on the cell surface and has a property as a tumor antigen epitope recognized by CTL, and at least about 5 or more, preferably about 7 It is a peptide consisting of one or more, more preferably 9 to 10 amino acid residues. Preferably SEQ ID NO: 1 in the sequence listing
Is a peptide consisting of the amino acid sequence described in any one of 50 to 50. These peptides are recognized by the HLA-B46-restricted tumor-specific CTLs, and thus the C
It can be used as a tumor antigen peptide that induces and / or activates TL.

The above-mentioned polypeptide or peptide is CT
It may be used alone or in combination of two or more to induce and / or activate L. Since CTL is a cell population consisting of a plurality of types of peptide-specific CTL, it is recommended to use two or more of them in combination.

Further, based on the polypeptide or peptide thus identified, at least HLA-B46
Restrictive CTL recognition and / or HLA-B4
There is also provided a peptide or polypeptide having a mutation such as deletion, substitution, addition, and / or insertion of one to several amino acids, using the induction of 6-restricted CTL as an index. The peptide or polypeptide having a mutation may be a naturally-occurring peptide or a mutation-introduced peptide or polypeptide. Means for introducing mutations such as deletions, substitutions, additions and insertions are known per se, and for example, the technique of Ulmer [S
science (1983) 219: 666]. In introducing such a mutation, from the viewpoint of not changing the basic properties (physical properties, activity, immunological activity, etc.) of the peptide, for example, a cognate amino acid (polar amino acid, nonpolar amino acid, hydrophobic amino acid, Mutual substitutions between hydrophilic amino acids, positively charged amino acids, negatively charged amino acids, aromatic amino acids, etc.) are readily envisioned.
Furthermore, these available peptides can be modified to such an extent that they do not cause a significant change in function, such as modification of the constituent amino group or carboxyl group.

(Polynucleotide) The polynucleotide according to the present invention is the above gene obtained from human colorectal cancer cell line SW620, preferably SEQ ID NO: 10 in the sequence listing.
A polynucleotide comprising the nucleotide sequence according to any one of 0 to 141 or a complementary strand thereof. The polynucleotide is any one of SEQ ID NOS: 1 to 50 in the sequence listing.
It may be a peptide comprising the amino acid sequence described in 1. or a polypeptide comprising the amino acid sequence described in any one of SEQ ID NOs: 51 to 99, or a complementary chain thereof. Further, the above-mentioned polynucleotide is a polynucleotide consisting of at least about 15 or more, preferably about 21 to 30 or more consecutive nucleotides corresponding to the region encoding the tumor antigen epitope in the amino acid sequence of the polypeptide of the present invention. It may be a nucleotide or its complementary strand. The selection of this useful polynucleotide and the determination of its nucleotide sequence can be performed, for example, by confirming the CTL inducing ability and / or the CTL activating ability of the expressed peptide or polypeptide using a known protein expression system. is there.

Further, a polynucleotide which hybridizes to the above-mentioned polynucleotide under stringent conditions is also included in the scope of the present invention. Preferably, the encoding polypeptide or peptide is HLA-B46 restricted and is recognized by CTL and / or HLA-B.
It is a polynucleotide that induces CTL in a 46-restricted manner. Taking a DNA molecule as a typical example of a polynucleotide molecule, “a DNA molecule that hybridizes to a DNA molecule under stringent conditions” means, for example, Mo molecule.
regular Cloning: A Laborat
ory Manual (Edited by Sambrook et al., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 198)
9 years) and the like. Here, “hybridize under stringent conditions” means, for example, after heating at 42 ° C. in a solution of 6 × SSC, 0.5% SDS and 50% formamide,
It shows that a positive hybridization signal is still observed even under the condition of washing at 68 ° C. in a solution of 0.1 × SSC and 0.5% SDS. A polynucleotide which hybridizes to the above-mentioned polynucleotide under stringent conditions and which encodes a polypeptide or a peptide which is recognized by CTL in an HLA-B46-restricted manner and / or induces CTL in an HLA-B46-restricted manner. The nucleotides can be selected, for example, by recognizing the polypeptide or peptide expressed by a known protein expression system by CTL and / or confirming the CTL inducibility. As described in Examples below, for example, peptide-pulsed antigen-presenting cells are treated with HLA-B46-restricted CTL, for example, OK-CTLd.
-55 etc. were cultured together with and the activated CTL
The method of measuring IFN-γ produced from the enzyme and selecting it as an index can be exemplified.

The above-mentioned polynucleotide is HLA-B46.
When expressed in cells having HLA-B46, it is recognized by HLA-B46-restricted by CTL, and thus can induce and / or activate CTL.

Although the polynucleotide has a poly (A) structure at its 3'end, the number of poly (A) does not affect the coding site of the amino acid acting as a tumor antigen, The number of poly (A) contained in the polynucleotide is not particularly limited.

Each of the above-mentioned polynucleotides provides genetic information useful for producing the polypeptide or peptide according to the present invention, or can be used as a reagent or standard product as a nucleic acid.

(Recombinant Vector) A recombinant vector can be obtained by incorporating the above-mentioned polynucleotide into an appropriate vector DNA. The vector DNA used is appropriately selected depending on the type of host and the purpose of use. Vector D
The NA may be one obtained by extracting a naturally occurring one, or may be one in which a part of DNA other than the part necessary for growth is partially deleted. For example, vectors derived from chromosomes, episomes and viruses, such as bacterial plasmids, bacteriophages, transposons, yeast episomes, insertion elements, yeast chromosome elements, such as baculovirus, papovavirus, SV.
40, vectors derived from viruses such as vaccinia virus, adenovirus, fowlpox virus, pseudorabies virus and retrovirus, and vectors combining them, such as plasmids and vectors derived from genetic elements of bacteriophage, such as cosmids and phagemids. Etc. can be illustrated. Moreover, an expression vector, a cloning vector, or the like can be used depending on the purpose.

The recombinant vector comprises, as constituent elements, a gene sequence of interest and a gene sequence carrying information relating to replication and control, such as a promoter, a ribosome binding site, a terminator, a signal sequence, an enhancer, etc., and these are known per se. It is produced by combining the methods. As a method for incorporating the polynucleotide of the present invention into the vector DNA, a method known per se can be applied.
For example, a method is used in which an appropriate restriction enzyme is selected and treated to cut the DNA at a specific site, which is then mixed with DNA similarly used as a vector and religated with ligase. Alternatively, the desired recombinant vector can also be obtained by ligating an appropriate linker to the polynucleotide of interest and inserting this into the multi-cloning site of the vector suitable for the purpose.

(Transformant) By transforming a known host such as Escherichia coli, yeast, Bacillus subtilis, insect cell, or animal cell with the vector DNA incorporating the above-mentioned polynucleotide by a known method. A transformant is obtained. In the case of carrying out transformation, a more preferable system is the method of integrating into the chromosome if the stability of the gene is taken into consideration, but an autonomous replication system utilizing an extranuclear gene can be simply used. Vector D
Introduction of NA into host cells can be carried out, for example, by Molecular
r Cloning: A Laboratory Ma
It can be carried out by a standard method described in "Nual" (edited by Sambrook et al., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989). Specifically, calcium phosphate transfection, DEAE
-Dextran mediated transfection, microinjection, cationic lipid mediated transfection, electroporation, transduction, scrape loading, ballistic transduction.
n) and infection etc. can be illustrated.

The vector DN to be introduced into the transformant
When an expression vector is used as A, the polypeptide or peptide according to the present invention can be provided. The transformant introduced with the expression vector DNA incorporating the above-mentioned polynucleotide is cultivated by selecting the optimum conditions for culturing conditions of each host known per se. The culturing is carried out for the action of the polypeptide or peptide of the present invention expressed by the transformant, for example, the action of inducing and / or activating at least CTL, or the amount of the peptide or peptide produced in or outside the host. Although it may be used as an index, subculture or batch culture may be performed using the amount of transformant in the medium as an index.

(Chemical Synthesis) The polypeptide or peptide according to the present invention can be produced by the genetic engineering technique as described above using the above vector or transformant. It can also be produced by a method known in ordinary peptide chemistry. For example, peptide synthesis (Maruzen) 1975
Year and Peptide Synthesis, Inter
The method described in the textbooks such as Science, New York, 1996 and the like are exemplified, but of course, known methods can be widely used.

(Purification and Recovery of Polypeptide or Peptide) Purification and recovery of the polypeptide or peptide according to the present invention is carried out by the physical property or physiological activity of the polypeptide or the peptide, for example, CTL inducing ability and / or CTL activity. It can also be purified and recovered by a combination of gel filtration, ion column chromatography, affinity chromatography and the like using the chemical ability as an index, or by fractionating means such as ammonium sulfate and alcohol based on the difference in solubility. More preferably, a method is used in which an antibody against the amino acid sequence is prepared based on the information of these amino acid sequences, and the obtained polyclonal antibody or monoclonal antibody is used for specific adsorption and recovery.

(Antibody) The antibody according to the present invention is produced by using the above-mentioned polypeptide or peptide as an antigen. The antigen may be the polypeptide or peptide itself or a fragment thereof and is composed of at least 5, and more preferably at least 8-10 amino acids. In order to produce an antibody specific to the above-mentioned polypeptide or peptide, it is preferable to use a region consisting of an amino acid sequence unique to the polypeptide or peptide. This amino acid sequence does not necessarily have to be homologous to the amino acid sequence of the polypeptide or peptide, and an externally exposed site on the three-dimensional structure of the polypeptide or peptide is preferable. Even if it is discontinuous, it may be a continuous amino acid sequence for the exposed site. The antibody is not particularly limited as long as it immunologically binds or recognizes the polypeptide or peptide. The presence or absence of this binding or recognition is determined by a known antigen-antibody binding reaction.

In order to produce the antibody, a method known per se for producing an antibody can be used. For example, the polypeptide or peptide of the present invention is administered to an animal in the presence or absence of an adjuvant alone or in combination with a carrier to induce immunity such as humoral response and / or cellular response. It is obtained by The carrier is not particularly limited as long as it has no harmful effect on the host and enhances antigenicity, and examples thereof include cellulose, polymerized amino acids, albumin, and keyhole limpet hemocyanin (KLH). To be done. As the adjuvant, Freund's complete adjuvant (FCA), Freund's incomplete adjuvant (FIA), Ribi (MPL), Ri
bi (TDM), Ribi (MPL + TDM), pertussis vaccine (Bordetella pertussis)
vaccine), muramyl dipeptide (MDP),
Aluminum adjuvants (ALUM), and combinations thereof are exemplified. As the animal to be immunized, mouse, rat, rabbit, goat, horse, etc. are preferably used.

The polyclonal antibody is obtained from the serum of the animal immunized as described above by a method known per se for antibody recovery. As a preferable means, it is obtained by an immunoaffinity chromatography method.

To produce a monoclonal antibody,
Antibody-producing cells (for example, lymphocytes derived from the spleen or lymph nodes) are collected from the animal to which the above-mentioned immunization means has been applied, and perpetual proliferating cells known per se (for example, P3 / X63-Ag).
8 strains such as myeloma strain). For example, an antibody-producing cell and a permanently proliferating cell are fused by a method known per se to prepare a hybridoma, which is then cloned, and a hybridoma which produces an antibody specifically recognizing the above-mentioned polypeptide or peptide is selected, The antibody is recovered from the culture medium of the hybridoma.

The thus obtained polyclonal antibody or monoclonal antibody capable of recognizing and binding to the above-mentioned polypeptide or peptide can be used as an antibody for purification of the polypeptide or peptide, a reagent, a labeling marker or the like.

(Screening) Transformation was carried out based on the above-mentioned polypeptide or peptide, a polynucleotide encoding the polypeptide or peptide or a complementary strand thereof, a vector containing the polynucleotide, information on the amino acid sequence and base sequence of these. Cells, or antibodies that immunologically recognize these cells, are used alone or in combination to provide an effective means for screening a substance capable of enhancing the recognition of the polypeptide or the peptide by CTL. The screening method can be constructed using a drug screening system known per se. For example, as shown in the examples, the test substance is added to the test substance by using an experimental system in which the activation of CTL by antigen-presenting cells pulsed with a tumor antigen peptide is measured by the amount of IFN-γ produced from CTL. A substance that induces and / or activates CTL,
In addition, substances that enhance induction and / or activation can be selected. This experimental system describes one of the screening methods, and the screening method according to the present invention is not limited to this.

The compounds obtained by the above screening method are included in the scope of the present invention. The compound may be a compound that interacts with the polypeptide or peptide of the present invention and / or the HLA-B46 molecule to enhance the recognition of the polypeptide or peptide by the HLA-B46-restricted CTL. Or HLA-B4
It may be a compound or the like that interacts with the above-mentioned polypeptide or a polynucleotide encoding the peptide that is 6-restrictedly recognized by CTL to enhance its expression. The compound thus selected can be prepared as a pharmaceutical composition by selecting in consideration of the balance between biological utility and toxicity.

(Pharmaceutical Composition) The polypeptide or peptide provided in the present invention induces tumor-specific CTL as a tumor antigen or tumor antigen peptide and / or
Or it can be used to activate. That is, a drug comprising one or more selected from the above polypeptides and peptides, a method for inducing CTL characterized by using one or more selected from the above polypeptides and peptides, and the above polypeptides and peptides An inducer of CTL containing at least one selected is also included in the scope of the present invention.

Further, the above-mentioned polypeptide or peptide,
A polynucleotide encoding the polypeptide or the peptide or a complementary strand thereof, a recombinant vector prepared based on the information of the amino acid sequence and the nucleotide sequence of these, cells transformed with the recombinant vector, immunization with the polypeptide or peptide Singly or in combination of a biologically recognizing antibody, a compound that interacts with the polypeptide or peptide to enhance recognition by CTL, or a compound that interacts with the polynucleotide to enhance its expression By doing so, a pharmaceutical composition comprising at least one of these can be provided.

Specifically, for example, a pharmaceutical composition comprising one or more selected from the above-mentioned polypeptides and peptides, and a pharmaceutical composition containing one or more selected from the above-mentioned polypeptides and peptides is used as a so-called cancer vaccine. Can be used. The cancer vaccine as used herein means a drug capable of selectively injuring a cancer cell by inducing and / or enhancing a specific immune response against the cancer cell. The dose can be determined by appropriately changing it depending on the degree of recognition of the polypeptide or the peptide by CTL.
Generally 0.01 mg to 100 mg / active body
Day / adult human, preferably 0.1 mg to 10 mg / day /
An adult human. The administration method may be carried out according to the known administration method of medical peptides, preferably subcutaneously, intravenously,
Alternatively, it is performed by intramuscular administration. Upon administration, the polypeptides and / or peptides according to the invention may be used alone or in combination with a carrier, in the presence or absence of a suitable adjuvant, in order to induce and / or enhance an immune response. . The carrier is not particularly limited as long as it does not have a harmful effect on the human body and enhances the antigenicity, and examples thereof include cellulose, polymerized amino acids, albumin and the like. Any adjuvant may be used as long as it is used for ordinary peptide vaccination, and Freund's incomplete adjuvant (FIA), aluminum adjuvant (ALUM), pertussis vaccine (B
ordetella pertussis vacci
ne), mineral oil and the like. Further, the dosage form can be appropriately selected by applying a means for formulating a peptide known per se.

Alternatively, by using the above-mentioned polypeptide or peptide to induce and / or activate CTLs in a mononuclear cell fraction collected from the peripheral blood of a patient, the fraction is returned to the blood of the patient. Also, an effective cancer vaccine effect can be obtained. Culture conditions such as mononuclear cell concentration, concentration of the polypeptide or peptide according to the present invention,
The culture time and the like can be determined by a simple experiment. During culture,
A substance having lymphocyte proliferation ability such as interleukin-2 (IL-2) may be added.

When the above-mentioned polypeptide or peptide is used as a cancer vaccine, only one kind of polypeptide or peptide is effective as a cancer vaccine, but it is also possible to use a plurality of kinds of the above-mentioned polypeptides or peptides in combination. Recently, immunotherapy based on multiple peptides (multi-peptide based im
Munotherapy) is effective [Miyagi, Y. et al. , Clin.
Cancer Res. (2001) 7: 3950-3
962; Lee, P .; et al. J. Clin. O
ncol. (2001) 19: 3836-3847; N.
estr. O. et al. , Nat. Med.
(1998) 4: 328-332]. Since CTLs of cancer patients are cell populations composed of multiple types of peptide-specific CTLs, it is more effective to use a combination of multiple types of single polypeptide or peptide as a cancer vaccine as a cancer vaccine. Is sometimes obtained.

A polynucleotide encoding the above-mentioned polypeptide or peptide, preferably a peptide, or its complementary strand can be used for cancer gene therapy. There is a method of carrying these polynucleotides on a vector and directly introducing them into the body, or a method of collecting cells from human and then introducing them outside the body, and either method can be used. As the vector, retrovirus, adenovirus, vaccinia virus, etc. are known, but the retrovirus system is recommended. These viruses are replication defective. Although the dose varies depending on the degree of recognition of the polypeptide or peptide by CTL, it is generally 0.1 as the DNA content encoding the tumor antigen peptide of the present invention.
μg to 100 mg / day / adult human, preferably 1 μg to
50 mg / day / adult human. This is administered once every several days to several months.

The above-mentioned medicine, pharmaceutical composition, inducer of CTL,
And the method for inducing CTL is useful in the treatment of cancer, such as colorectal cancer, oral cancer, lung cancer, prostate cancer, or gynecological cancer (cervical cancer, endometrial cancer, ovarian cancer, vulvar cancer, breast cancer, etc.). is there. Further, among the above-mentioned drugs, pharmaceutical compositions, CTL inducers, and CTL inducing methods, the active ingredient thereof is a peptide consisting of the amino acid sequence of any one of SEQ ID NOS: 1 to 6 in the sequence listing, and SEQ ID NO: 100. The one or more peptides and / or polypeptides selected from the group consisting of the polypeptides consisting of the amino acid sequences described in 1. above have a mutation in the p53 tumor suppressor gene and H
A therapeutic effect on a cancer carrying LA-B46 can be expected.

(Measurement Method and Reagents) The above-mentioned polypeptide or peptide, a polynucleotide encoding the polypeptide or peptide or its complementary chain, and an antibody that immunologically recognizes the polypeptide or peptide are themselves It can be used alone as a diagnostic marker or reagent. When these are reagents, buffers,
It may also contain substances such as salts, stabilizers and / or preservatives. The present invention also provides a reagent kit comprising one or more containers filled with one or more of these. For formulation, a formulation means suitable for a peptide or polypeptide, a polynucleotide, an antibody or the like known per se may be introduced.

These reagents and reagent kits can be used in the screening method of the present invention. Alternatively, it can be used for the quantitative or qualitative measurement of the polypeptide or peptide according to the present invention, or the polynucleotide encoding any one of them. A method for performing the measurement can be constructed by using a method well known to those skilled in the art. Available methods include radioimmunoassay,
Competitive binding assay, Western blot analysis and EL
ISA etc. can be illustrated. Nucleic acid may be, for example, amplified, P
CR, RT-PCR, RNase protection, Northern blotting and other hybridization methods can be used for detection and quantification at the RNA level.

The sample to be measured includes cells, blood, urine, saliva, spinal fluid, tissue biopsy or autopsy material derived from an individual. The nucleic acid to be measured can be obtained from each of the above-mentioned samples by a nucleic acid preparation method known per se. Nucleic acid is Genome D
NA may be used directly for detection, or P
It may be enzymatically amplified using CR or other amplification methods. RNA or cDNA may be used as well.
By measuring the size change of the amplification product, the deletion and insertion of the gene can be detected in comparison with the normal genotype. In addition, a point mutation can be identified by hybridizing an amplification product to labeled DNA encoding the above-mentioned polypeptide.

By detecting the mutation, decrease or increase in the polypeptide of the present invention and the DNA encoding the polypeptide by the above-mentioned measurement, diseases associated with the polypeptide, such as epithelial cancer and adenocarcinoma, are detected. Can be diagnosed.

[0062]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

Example 1 (Establishment of Cytotoxic T Cell Line) Tumor-specific cytotoxic T cells were used for colon cancer patient (HLA-A0207).
/ 3101, HLA-B46 / 51, HLA-Cw1)
Were established from the tumor-infiltrating lymphocytes (TIL) of Int. J. Cancer (199
9) 81: 459-466; Immunol. (1
999) 163: 4997-5004]. First, 100 U / ml of recombinant human IL obtained from a colon cancer patient was used.
-2 was added and long-term culture was performed for 50 days or more. By collecting a part of these IL-2 activated TILs every 7 days of culture and culturing them with various tumor cells or normal cells, by measuring IFN-γ production and ⁵¹ Cr release experiment from cancer cells,
The CTL activity was assayed [J. Immunol. (1
999) 163: 4997-5004]. IFN-γ was measured by enzyme-linked immunosorbent assay (ELISA).
On the 58th day of culture, CTLs (referred to as OK-CTLs) exhibiting HLA-A2-restricted tumor-specific cytotoxic activity were obtained. 80% of OK-CTLs are CD3 ⁺ CD4 ^−.
It was found to have a CD8 ⁺ phenotype (the remaining 20% was CD3 ⁺ CD4 ⁺ CD8 ⁻ ).

Since OK-CTL is not a cloned cell line, it is considered to contain a plurality of types of CTL having different HLA-restricted properties. The types of HLA in colorectal cancer patients from which OK-CTL was derived are HLA-A2 / A31 and H.
Since it is LA-B46 / 51, these types of HL
It was possible that a CTL that recognizes A was included. O
OK-CTL-d, which is one of the sub-lines of K-CTL
55 recognized tumor cells in a HLA-B46 restricted manner.

OK-CTL-d55 is a HLA-B46-carrying (HLA-B46 ⁺ ) cancer cell, for example, QG5.
^{6 (HLA-B46 + / A2} -) and Ca9-22 (HL
A-B46 ⁺ / A2 ⁺ ) and the like to produce IFN-γ, but HLA-B46 ^- cancer cells such as KWS.
^{(HLA-B46 - / A2 +} ), COLO320, and COS-7 did not recognize. In addition, HLA-B46
⁺ Cancer cells such as QG56, Ca9-22, and OS
Although it showed cytotoxic activity against C20 (HLA-B46 ⁺ / A2 ⁺ ), HLA-B46 ^- cancer cells, for example K.
Uma-1, COLO320, and SW620 did not lyse. That is, OK-CTL-
It was revealed that d55 is a CTL that damages tumor cells in an HLA-B46-restricted manner but not in an HLA-A2-restricted manner.

[0065]

[Example 2] (Identification of cDNA clone encoding tumor antigen) The gene encoding the tumor antigen recognized by OK-CTL-d55 obtained in Example 1 was obtained from human colon cancer cell line SW620 by a known method. [J. Exp. Me
d. (1998) 187: 277-288]. First, the poly of SW620 cells
(A) ⁺ RNA is converted into cDNA and ligated with SalI adaptor, and then expression vector pCMV-SPO
It was inserted into RT-2 (manufactured by Invitrogen). Further, HLA-B4601 cDNA was obtained by reverse transcription polymerase chain reaction (RT-PCR) and cloned into a eukaryotic expression vector pCR3 (Invitrogen).

One SW620 cell cDNA library
00 clones pooled in each well and pooled in each well
NA200ng and HLA-B4601cDNA200n
g and 100 μl of lipofectoamine
(Manufactured by Invitrogen) / Opti-MEM (I
nvitrogen) was mixed for 30 minutes in a 1: 200 mixture. 50 μl of this mixture was added to COS-7 cells (1
× 10 ⁴ ) and co-transfected by incubation for 6 hours. Then RPMI-1 with 10% FCS
640 medium was added and cultured for 2 days, and OK-CTL-d5
5 (2 × 10 ⁵ ) was added to each well. After further incubation for 18 hours, 100 μl of the supernatant was taken and the produced IFN-γ was measured by ELISA,
A pool of cDNA libraries was screened.

A cDNA which promotes IFN-γ production from OK-CTL-d55 was determined to have a positive CTL activating ability, and a pool of cDNA libraries was screened by this criterion. After confirming the reproducibility of the pool in which the CTL activating ability was observed, clones were individually taken out from the CTL activating positive pool and further screened to select CTL activating positive clones derived from the independent pool. The dose dependency of OK-CTL activation of the obtained clones was confirmed, and finally, 5 clones of clone 7F, clone 3H, clone 7G, clone 9E, and clone 11A were obtained. These cDNA clones activated OK-CTL-d55 in a HLA-B46-restricted and dose-dependent manner and promoted IFN-γ production. On the other hand, the expression vector pCMV-SPORT
IFN-γ from OK-CTL was observed in COS-7 cells in which only C-2 was co-transfected with HLA-B4601.
Production was not promoted. In addition, regarding a gene encoding a tumor antigen capable of activating CTL in an HLA-A2-restricted manner, which has already been isolated and identified by the same method, HLA-B4
It was examined whether CTL could be activated in a 6-restricted manner using the same cogene transfer method as described above, using IFN-γ production as an index.
As a result, among genes encoding tumor antigens capable of activating HLA-A2-restricted CTL, OK-CTL-
37 cDNA clones expressing a gene product recognized by d55 HLA-B46-restricted were obtained.
As a representative example, the results for Clone 3, Clone 9, and Clone 10 are shown in FIGS. 1, 2, and 3, respectively.
It was shown to. Similar results were obtained with other clones.

The nucleotide sequence of the obtained cDNA clone was determined by the DNA sequencing kit (Perkin-
ABI PRISM ^™ 37
7DNA Sequencer (Perkin-Elm
(manufactured by er, Inc.) was used for the dideoxynucleotide sequencing method. Furthermore, the amino acid sequence encoded by the cDNA clone was deduced from the nucleotide sequence (see Tables 1 to 3 above).

For each of the obtained genes, GenBan
A homology search was performed on k / DDBJ, and the results are shown in Tables 1 to 3 above. In addition, the SEREX database (http: //www-ludwig.unil.c
h / SEREX. The homology search for html) revealed that the amino acid sequences encoded by clone 86 and clone 100 (SEQ ID NOS: 97 and 98 in the sequence listing) were S.
It was found to be identical to the known genes ID163 and ID116 identified by the EREX method and published in the SEREX database. The base sequences of clone 82 and clone 86 are ID1197 and ID163.
Clone 32, clone 41,
And clone 74 have ID1072 and ID1 respectively.
233, and partial homology with ID979 was revealed.

[0070]

Example 3 (Preparation of peptide) To obtain a tumor antigen peptide from the tumor antigen encoded by the gene obtained in Example 2, clone 7F, clone 3H, clone 7G, clone 9E, clone 11A, clone 3, clone 9,
The genes of clones and clone 10 have been reported previously [J. Ex
p. Med. (1996) 184: 735-740], a plurality of different 9-mer peptides were designed and synthesized.

(CTL activation test of peptide) HLA-
COS-7 cells expressing B4601 were pulsed with the synthesized peptides, and then the OK-CT obtained in Example 1 was obtained.
By culturing with L-d55 and measuring IFN-γ produced from OK-CTL-d55 as an index,
A peptide capable of activating HLA-B46-restricted CTL was selected. First, HLA-B460 was added to COS-7 cells.
After introducing and expressing 1 gene, 5% CO ₂ -95% together with each peptide synthesized above (final concentration 10 μM)
The peptide was bound to HLA-B46 expressed on the cell surface by incubating at 37 ° C. for 2 hours under the condition of Air. CO pulsed with peptides in this way
S-7 cells were used as target cells (T). Also OK
-CTL-d55 was used as effector cells (E). Target cells 1 × 10 ⁴ and effector cells 2 × 10 ⁴
Were mixed (E / T ratio = 2), and incubated for 18 hours. After the incubation, 100 μl of the supernatant was collected and IFN-γ was measured by ELISA. When examining the peptide derived from clone 7F, HLA-B was used instead of HLA-B46 as a negative control.
COS-7 cells expressing 52 in the same manner as above were used.
When the peptide derived from clone 3H was examined, T2 cells expressing HLA-A2 in a state in which the peptide was not bound instead of HLA-B46 were used as a negative control. When examining peptides derived from other clones, HIV (Human I) was used as a negative control instead of the peptide.
A peptide derived from mmunodeficiency virus was used. As a result, SEQ ID NOS: 1 to 5 in the sequence listing
50 peptides described in 0 are OK-CTL-d55
Recognized by the IFN from the OK-CTL-d55
-Promoted γ production. The 50 peptides obtained were 7F.P1, 7F.P2, 7F.P derived from clone 7F.
6, 7F / P7, 7F / P8, 7F / P9, and 7F
P10 (SEQ ID NOS: 1 to 7 in the sequence listing), 3H • P4, 3H • P5 derived from clone 3H, and 3H • P6 (SEQ ID NOS: 8 to 10 in the sequence listing), 3P1 derived from clone 3;
3 ・ P3, 3 ・ P5, 3 ・ P6, 3 ・ P8, 3 ・ P9,
3 ・ P10, 3 ・ P11, 3 ・ P12, 3 ・ P13, 3
・ P16, 3 ・ P18, 3 ・ P19, 3 ・ P21, and 3 ・ P22 (SEQ ID NOS: 11 to 25 in the sequence listing), 9 ・ P23, 9 ・ P24, 9 ・ P25, 9 ・ derived from clone 9
P26, and 9 · P37 (SEQ ID NOS: 26 to 3 in the sequence listing)
0), and 10 · P40, 10 · P from clone 10
P42, 10 / P43, 10 / P44, 10 / P45,
10 / P46, 10 / P47, 10 / P50, 10 / P
51, 10 ・ P53, 10 ・ P54, 10 ・ P55, 1
0 / P56, 10 / P58, 10 / P59, 10 / P6
0, 10 · P62, 10 · P63, 10 · P64, and 10 · P65 (SEQ ID NOS: 31 to 50 in the sequence listing). As a typical example, peptide 7F · P derived from clone 7F
Dose-dependent IFN-γ production from OK-CTL-d55 by 6 and 3H · P4 is shown in FIGS. 4 and 5, respectively.
It was shown to. Little IFN-γ production was seen when the negative control was used. The peptides derived from clone 3, clone 9 and clone 10 were HLA-A2 restricted and HLA-B4.
HLA derived from a gene encoding a tumor antigen capable of activating 6-restricted CTL.
It was a peptide encoded in a region completely different from the A2-restricted tumor antigen peptide.

[0072]

Example 4 (CTL Induction in Cancer Patient PBMC by Peptide Derived from Clone 7F) Among the peptides derived from clone 7F synthesized in Example 3, 7F · P2 (SEQ ID NO: 2 in the sequence listing) and 7F · P6 ( Regarding SEQ ID NO: 3) in the sequence listing, CTL induction from mononuclear cells prepared from peripheral blood of cancer patients was examined.

Clone 7F is a tumor suppressor gene p53 having a missense point mutation. Although it has already been reported that SW620 expresses the mutant p53, 7F · P
1, 7F / P2, 7F / P6, 7F / P7, 7F / P
Neither 8, 7F.P9, nor 7F.P10 contains the mutant amino acid. Mutation of p53 and accumulation of non-functioning p53 mutant protein have been observed in about 50% of human cancers, and OK-CTL-d55 has p53.
Since it was established from T cells infiltrating a colorectal cancer having a mutation, clone 7F was focused on among the obtained genes encoding tumor antigens. Clone 7F
Is recognized by OK-CTL-d55 when co-transfected into COS-7 cells together with HLA-B4601,
IFN-γ production from OK-CTL-d55 was promoted (FIG. 6). Moreover, 7F used for the examination in this example
P2 and 7F • P6 were OK-CTL-d when pulsed on COS-7 cells expressing HLA-B46.
55, and IFN- from OK-CTL-d55
γ production was promoted (Fig. 7 and Fig. 4, respectively).

Induction of CTLs in PBMC by Peptide 7F.P2 or 7F.P6 was carried out in 6 HLA-B46-bearing cancer patients (2 cases of prostate cancer, 2 cases of lung adenocarcinoma, vulvar cancer and 2 cases of colon cancer). investigated. Also, HL
Similarly, PBMCs derived from three healthy persons carrying A-B46 were examined. The HLA class I serotypes of these PBMCs were assayed by the method described in the literature [Ito,
M. et al. , Cancer Res. (200
1) 61: 2038-2046]. Some HLA-B
When the genotype of 46 molecules was examined, they were all HLA-B4601. In the case of HLA-B46, its genotype is predominantly (> 95%) HLA-B460.
1 [Nakajima, F .; et al. , MH
C (2001) 8: 1-32].

PBMC from peripheral blood of cancer patients or healthy individuals
Was prepared by a known method, and each PBMC (1 × 10 ⁵ ) was
Culture medium 2 containing IL-2 with 0 μM of each peptide
Cultured in 00 μl [Suzuki, N. et al. et a
l. , Int. J. Cancer (2002) 98: 4
5-50]. On days 4 and 7 of culture, half of the medium was replaced with fresh medium containing the corresponding peptides. 10
On the day, the cells were collected and washed, and the IFN-γ producing ability of COS-7 cells transduced with HLA-B4601 and pulsed with the corresponding peptide was examined.

P stimulated with 7F · P2 or 7F · P6
Among the BMCs, PBMCs obtained from 3 and 4 of 6 cancer patients, respectively, had significant levels by recognizing COS-7 cells pulsed with the corresponding peptide of HLA-B46 gene transfer. Produced IFN-γ (Table 4). However, a control peptide (7F · P10) that was transduced with HLA-B46 but did not correspond
It did not react with COS-7 cells pulsed with. Among these, PBMCs from patient cases 1 and 2 were 7F
When stimulated with P2, it produced a significant level of IFN-γ in response to OSC20 cells (HLA-B46 having a mutation in p53 ⁺ oral cancer), but Kuma-1 cells (p
53 HLA-B46 with mutations ^- head and neck cancer) and COL
It did not react with O320 cells (HLA-B46 ^- colorectal cancer with p53 mutation) (Table 4). On the other hand, PBMCs derived from Patient Examples 1 and 2 did not show HLA-B46-restricted reactivity to tumor cells when stimulated with 7F · P6. In addition, PBMCs derived from healthy individuals did not show reactivity to tumor cells when stimulated with any of the peptides (Table 4).

[0077]

[Table 4]

After incubating the peptide-stimulated PBMCs for a further 10 days or more, a standard 6-hour ⁵¹ Cr-release test was performed to test their cytotoxic activity [Ito, M. et al. et al. , Can
cer Res. (2001) 61: 2038-204.
6]. As target cells, OSC20 (HLA-B46 having p53 mutation ⁺ oral cancer), QG56 (HLA-B46 having p53 mutation ⁺ squamous cell lung cancer), Ca9-2
2 (HLA-B46 ⁺ , oral cancer having p53 mutation),
MKN45 (HLA-B46 without p53 mutation ⁺ gastric cancer), Kuma-1 (HLA-B4 with p53 mutation)
6 ^- head and neck cancer, SW620 (HL with p53 mutation)
A-B46 ^- colon cancer), COLO320 (HLA-B46 ^- colon cancer with p53 mutation), KWS (HLA-B46 ^- gastric cancer with p53 mutation), and COS-7.
Using labeled with ^- (HLA-B46 fibroblasts) and ⁵¹ Cr. In addition, PHA-blastified T cells (PHA-blastoid T cells) prepared from PBMC were also used as target cells. In addition, it was confirmed by cold target inhibition assay that lysis of target cells by PBMC was not an artificial phenomenon due to ⁵¹ Cr labeling of target cells. The assay uses unlabeled HLA-B4
6 ⁺ PHA blast T cells were incubated with the peptide for 2 hours and then washed and used as unlabeled target cells,
It was performed in addition to target cells labeled with ⁵¹ Cr so that the ratio of unlabeled target cells to labeled target cells was 10: 1.

Patient Examples 1 (Prostate Cancer) and 2 (Lung Adenocarcinoma)
PBMC derived from OSC2 when stimulated with 7F · P2
0 cells (HLA-B46 ⁺ , having a mutation of p53 and accumulating the p53 mutant in the nucleus) showed a significant level of cytotoxic activity, but Kuma-1
Cells and MKN45 cells (HLA-B46 ⁺ , p5
3 mutations) and PHA blastogenic T cells were not lysed (FIG. 8A). PBMC not stimulated with peptides
Showed no such cytotoxic activity. The cytotoxic activity observed here was inhibited by anti-CD8 antibody or anti-HLA-BC antibody (FIG. 8B). From these, cells showing cytotoxic activity in PBMC were identified as HLA-B46-restricted C
It was considered to be D8 positive cells. Further, the cytotoxic activity of PBMC stimulated with 7F • P2 was found to be higher when OSC20 cells pre-pulsed with an excess amount of 7F • P2 were used as target cells than when OSC cells not pulsed were used. It was significantly higher (Fig. 8C). When OSC20 cells pre-pulsed with another peptide 7F · P10 that was not used for PBMC stimulation were used as target cells,
Such enhancement of cytotoxic activity was not observed. Furthermore, in the cold target inhibition assay, PHA pulsed with 7F · P2 was used as unlabeled cells.
When using blast cells (PHA-blast), 7F ・ P
The cytotoxic activity of PBMC stimulated with 2 on OSC20 cells was significantly inhibited (FIG. 8C). However, PHA blasts (PH
When A-blast) was used, there was no change in the cytotoxic activity of PBMC stimulated with 7F · P2 on OSC20 cells (Fig. 8C).

From these results, PBMC stimulated with peptide 7F.P2 was found to have H on OSC20 cells.
7F on the groove structure of LA-B46 molecule
It was found that P2 was recognized as a peptide specifically and showed cytotoxic activity on OSC20 cells. Also, 7F ・ P
Stimulation in vitro with 2 can induce HLA-B46-restricted antigen-specific CTLs that respond to tumor cells having p53 mutations from PBMCs of cancer patients bearing various types of tumors Became clear.

[0081]

INDUSTRIAL APPLICABILITY According to the present invention, HLA-B46-restricted cytotoxic T cells can be induced and / or activated, and specific immunotherapy for cancer or the like becomes possible. Therefore, the present invention can be expected to make a great contribution in the treatment of cancer. Further, the present invention greatly contributes to basic research on molecules relating to tumor recognition by T cells.

[0082]

[Sequence listing free text] Sequence listing SEQ ID No. 1: HLA
-A designed peptide recognized by B46 restricted cytotoxic T cells. Sequence number 2 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence ID No. 3 in the sequence listing: a designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence number 4 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence number 5 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence number 6 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence number 7 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence ID No. 8 in the sequence listing: a designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence ID No. 9 in the sequence listing: a designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence number 10 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence number 11 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence number 12 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence number 13 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence ID No. 14 of the Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence number 15 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence number 16 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence number 17 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence ID No. 18 of the Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence number 19 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence number 20 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. SEQ ID NO: 21 of Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence ID No. 22 of the Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence ID No. 23 of the Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. SEQ ID NO: 24 in Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence number 25 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence number 26 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence ID No. 27 of the Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence ID No. 28 of the Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence ID No. 29 in the Sequence Listing: a designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence number 30 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence ID No. 31 of the Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence number 32 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence ID No. 33 in the sequence listing: a designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence ID No. 34 of the Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence number 35 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence number 36 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence ID No. 37 of the Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence ID No. 38 of the Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence number 39 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence ID No. 40 of the Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence ID No. 41 of the Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence ID No. 42 of the Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence number 43 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence ID No. 44 of the Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence ID No. 45 of the Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence ID No. 46 of the Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. SEQ ID NO: 47 of Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence number 48 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell. Sequence ID No. 49 of the Sequence Listing: designed peptide recognized by HLA-B46-restricted cytotoxic T cells. Sequence number 50 of a sequence table: The designed peptide recognized by HLA-B46 restricted cytotoxic T cell.

[0083]

[Sequence list]                                SEQUENCE LISTING         <110> ITOH, Kyogo <120> Tumor Antigen <130> NP02-1057 <140> <141> <150> 2001-191974 <151> 2001-06-25 <160> 141 <170> PatentIn Ver. 2.1 <210> 1 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 1 Glu Pro Pro Leu Ser Gln Glu Thr Phe   1 5 <210> 2 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 2 Ser Gln Lys Thr Tyr Gln Gly Ser Tyr   1 5 <210> 3 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 3 Leu Gln Ile Arg Gly Arg Glu Arg Phe   1 5 <210> 4 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 4 Arg Gly Arg Glu Arg Phe Glu Met Phe   1 5 <210> 5 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 5 Thr Ser Arg His Lys Lys Leu Met Phe   1 5 <210> 6 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 6 Ser Pro Asp Asp Ile Glu Gln Trp Phe   1 5 <210> 7 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 7 Glu Tyr Leu Asp Asp Arg Asn Thr Phe   1 5 <210> 8 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 8 Glu Tyr Lys Gly Glu Thr Lys Ser Phe   1 5 <210> 9 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 9 Lys Met Lys Glu Ile Ala Glu Ala Tyr   1 5 <210> 10 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 10 Phe Asp Asn Arg Met Val Asn His Phe   1 5 <210> 11 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 11 Ala Gly Asn Asn Asp Cys Arg Ile Tyr   1 5 <210> 12 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 12 Thr Lys Asp Ile Glu Asp Val Phe Tyr   1 5 <210> 13 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 13 Lys Asn Arg Arg Gly Gly Pro Pro Phe   1 5 <210> 14 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 14 Arg Arg Gly Gly Pro Pro Phe Ala Phe   1 5 <210> 15 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 15 Pro Arg Asp Ala Glu Asp Ala Val Tyr   1 5 <210> 16 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 16 Asp Ala Val Tyr Gly Arg Asp Gly Tyr   1 5 <210> 17 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 17 Val Tyr Gly Arg Asp Gly Tyr Asp Tyr   1 5 <210> 18 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 18 Arg Asp Gly Tyr Asp Tyr Asp Gly Tyr   1 5 <210> 19 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 19 Asp Gly Tyr Arg Leu Arg Val Glu Phe   1 5 <210> 20 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 20 Gly Gly Gly Ala Pro Arg Gly Arg Tyr   1 5 <210> 21 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 21 Arg Asp Gly Thr Gly Val Val Glu Phe   1 5 <210> 22 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 22 Val Arg Lys Leu Asp Asn Thr Lys Phe   1 5 <210> 23 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 23 Arg Ser His Glu Gly Glu Thr Ala Tyr   1 5 <210> 24 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 24 Arg Ser Asn Ser Arg Ser Arg Ser Tyr   1 5 <210> 25 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 25 Arg Arg Ser Arg Gly Ser Pro Arg Tyr   1 5 <210> 26 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 26 Ser Leu Val Gly Lys Lys Ile Val Phe   1 5 <210> 27 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 27 Val Val Gln Ile Leu Gly Asp Lys Phe   1 5 <210> 28 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 28 Ala Gln Lys Ile Asp Leu Pro Glu Tyr   1 5 <210> 29 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 29 Leu Val Glu Asp Thr Cys Leu Cys Phe   1 5 <210> 30 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 30 Glu Lys Asn Ala Val Ser His Arg Phe   1 5 <210> 31 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 31 Ser Pro Ala Ser Leu Ala Ser Leu Tyr   1 5 <210> 32 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 32 Leu Lys Val Leu Pro Pro Thr Val Tyr   1 5 <210> 33 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 33 Glu Asn Ile Pro Gln Ile Ile Ser Phe   1 5 <210> 34 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 34 Ile Ile Ala Ser Trp Glu Arg Leu Phe   1 5 <210> 35 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 35 Ser Glu Ser Leu Glu Glu Thr Lys Tyr   1 5 <210> 36 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 36 Leu Thr Ser Arg His Ala Asn Asp Phe   1 5 <210> 37 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 37 Lys Ala Ala Lys Pro Gln Glu Val Phe   1 5 <210> 38 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 38 Asn Glu Ile Ala Gln Cys Glu Val Phe   1 5 <210> 39 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 39 His Gln Cys Glu Gln Trp Gly Asn Tyr   1 5 <210> 40 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 40 Lys Met Ser Lys Ser Leu Lys Asn Tyr   1 5 <210> 41 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 41 Lys Asn Tyr Ile Thr Ile Lys Asp Phe   1 5 <210> 42 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 42 Thr Ile Lys Asp Phe Leu Lys Thr Phe   1 5 <210> 43 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 43 Leu Lys Thr Phe Ser Pro Asp Val Phe   1 5 <210> 44 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 44 Phe Ser Pro Asp Val Phe Arg Phe Phe   1 5 <210> 45 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 45 Arg Phe Phe Cys Leu Arg Ser Ser Tyr   1 5 <210> 46 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 46 Ser Ser Tyr Arg Ser Ala Ile Asp Tyr   1 5 <210> 47 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 47 Ser Phe Leu Glu Asp Ala Arg Ala Tyr   1 5 <210> 48 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 48 Val Lys Ala Ala Leu Ala Asp Asp Phe   1 5 <210> 49 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 49 Glu Gly Pro Arg Ser Pro Ala Val Phe   1 5 <210> 50 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Designed       peptide recognized by HLA-B46 restricted cytotoxic       T lymphocytes <400> 50 Ala Val Phe Gly Ala Ile Ile Ser Tyr   1 5 <210> 51 <211> 393 <212> PRT <213> Homo sapiens <400> 51 Met Glu Glu Pro Gln Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln   1 5 10 15 Glu Thr Phe Ser Asp Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu              20 25 30 Ser Pro Leu Pro Ser Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp          35 40 45 Asp Ile Glu Gln Trp Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro      50 55 60 Arg Met Pro Glu Ala Ala Pro Arg Val Ala Pro Ala Pro Ala Ala Pro  65 70 75 80 Thr Pro Ala Ala Pro Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser                  85 90 95 Val Pro Ser Gln Lys Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly             100 105 110 Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro         115 120 125 Ala Leu Asn Lys Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln     130 135 140 Leu Trp Val Asp Ser Thr Pro Pro Gly Thr Arg Val Arg Ala Met 145 150 155 160 Ala Ile Tyr Lys Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys                 165 170 175 Pro His His Glu Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln             180 185 190 His Leu Ile Arg Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp         195 200 205 Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu     210 215 220 Val Gly Ser Asp Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser 225 230 235 240 Ser Cys Met Gly Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr                 245 250 255 Leu Glu Asp Ser Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val             260 265 270 His Val Cys Ala Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn         275 280 285 Leu Arg Lys Lys Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr     290 295 300 Lys Arg Ala Leu Ser Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys 305 310 315 320 Lys Pro Leu Asp Gly Glu Tyr Phe Thr Leu Gln Ile Arg Gly Arg Glu                 325 330 335 Arg Phe Glu Met Phe Arg Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp             340 345 350 Ala Gln Ala Gly Lys Glu Pro Gly Gly Ser Arg Ala His Ser Ser His         355 360 365 Leu Lys Ser Lys Lys Gly Gln Ser Thr Ser Arg His Lys Lys Leu Met     370 375 380 Phe Lys Thr Glu Gly Pro Asp Ser Asp 385 390 <210> 52 <211> 646 <212> PRT <213> Homo sapiens <400> 52 Met Ser Lys Gly Pro Ala Val Gly Ile Asp Leu Gly Thr Thr Tyr Ser   1 5 10 15 Cys Val Gly Val Phe Gln His Gly Lys Val Glu Ile Ile Ala Asn Asp              20 25 30 Gln Gly Asn Arg Thr Thr Pro Ser Tyr Val Ala Phe Thr Asp Thr Glu          35 40 45 Arg Leu Ile Gly Asp Ala Ala Lys Asn Gln Val Ala Met Asn Pro Thr      50 55 60 Asn Thr Val Phe Asp Ala Lys Arg Leu Ile Gly Arg Arg Phe Asp Asp  65 70 75 80 Ala Val Val Gln Ser Asp Met Lys His Trp Pro Phe Met Val Val Asn                  85 90 95 Asp Ala Gly Arg Pro Lys Val Gln Val Glu Tyr Lys Gly Glu Thr Lys             100 105 110 Ser Phe Tyr Pro Glu Glu Val Ser Ser Met Val Leu Thr Lys Met Lys         115 120 125 Glu Ile Ala Glu Ala Tyr Leu Gly Lys Thr Val Thr Asn Ala Val Val     130 135 140 Thr Val Pro Ala Tyr Phe Asn Asp Ser Gln Arg Gln Ala Thr Lys Asp 145 150 155 160 Ala Gly Thr Ile Ala Gly Leu Asn Val Leu Arg Ile Ile Asn Glu Pro                 165 170 175 Thr Ala Ala Ala Ile Ala Tyr Gly Leu Asp Lys Lys Val Gly Ala Glu             180 185 190 Arg Asn Val Leu Ile Phe Asp Leu Gly Gly Gly Thr Phe Asp Val Ser         195 200 205 Ile Leu Thr Ile Glu Asp Gly Ile Phe Glu Val Lys Ser Thr Ala Gly     210 215 220 Asp Thr His Leu Gly Gly Glu Asp Phe Asp Asn Arg Met Val Asn His 225 230 235 240 Phe Ile Ala Glu Phe Lys Arg Lys His Lys Lys Asp Ile Ser Glu Asn                 245 250 255 Lys Arg Ala Val Arg Arg Leu Arg Thr Ala Cys Glu Arg Ala Lys Arg             260 265 270 Thr Leu Ser Ser Ser Thr Gln Ala Ser Ile Glu Ile Asp Ser Leu Tyr         275 280 285 Glu Gly Ile Asp Phe Tyr Thr Ser Ile Thr Arg Ala Arg Phe Glu Glu     290 295 300 Leu Asn Ala Asp Leu Phe Arg Gly Thr Leu Asp Pro Val Glu Lys Ala 305 310 315 320 Leu Arg Asp Ala Lys Leu Asp Lys Ser Gln Ile His Asp Ile Val Leu                 325 330 335 Val Gly Gly Ser Thr Arg Ile Pro Lys Ile Gln Lys Leu Leu Gln Asp             340 345 350 Phe Phe Asn Gly Lys Glu Leu Asn Lys Ser Ile Asn Pro Asp Glu Ala         355 360 365 Val Ala Tyr Gly Ala Ala Val Gln Ala Ala Ile Leu Ser Gly Asp Lys     370 375 380 Ser Glu Asn Val Gln Asp Leu Leu Leu Leu Asp Val Thr Pro Leu Ser 385 390 395 400 Leu Gly Ile Glu Thr Ala Gly Gly Val Met Thr Val Leu Ile Lys Arg                 405 410 415 Asn Thr Thr Ile Pro Thr Lys Gln Thr Gln Thr Phe Thr Thr Tyr Ser             420 425 430 Asp Asn Gln Pro Gly Val Leu Ile Gln Val Tyr Glu Gly Glu Arg Ala         435 440 445 Met Thr Lys Asp Asn Asn Leu Leu Gly Lys Phe Glu Leu Thr Gly Ile     450 455 460 Pro Pro Ala Pro Arg Gly Val Pro Gln Ile Glu Val Thr Phe Asp Ile 465 470 475 480 Asp Ala Asn Gly Ile Leu Asn Val Ser Ala Val Asp Lys Ser Thr Gly                 485 490 495 Lys Glu Asn Lys Ile Thr Ile Thr Asn Asp Lys Gly Arg Leu Ser Lys             500 505 510 Glu Asp Ile Glu Arg Met Val Gln Glu Ala Glu Lys Tyr Lys Ala Glu         515 520 525 Asp Glu Lys Gln Arg Asp Lys Val Ser Ser Lys Asn Ser Leu Glu Ser     530 535 540 Tyr Ala Phe Asn Met Lys Ala Thr Val Glu Asp Glu Lys Leu Gln Gly 545 550 555 560 Lys Ile Asn Asp Glu Asp Lys Gln Lys Ile Leu Asp Lys Cys Asn Glu                 565 570 575 Ile Ile Asn Trp Leu Asp Lys Asn Gln Thr Ala Glu Lys Glu Glu Phe             580 585 590 Glu His Gln Gln Lys Glu Leu Glu Lys Val Cys Asn Pro Ile Ile Thr         595 600 605 Lys Leu Tyr Gln Ser Ala Gly Gly Met Pro Gly Gly Met Pro Gly Gly     610 615 620 Phe Pro Gly Gly Gly Ala Pro Pro Ser Gly Gly Ala Ser Ser Gly Pro 625 630 635 640 Thr Ile Glu Glu Val Asp                 645 <210> 53 <211> 248 <212> PRT <213> Homo sapiens <400> 53 Met Ser Gly Gly Gly Val Ile Arg Gly Pro Ala Gly Asn Asn Asp Cys   1 5 10 15 Arg Ile Tyr Val Gly Asn Leu Pro Pro Asp Ile Arg Thr Lys Asp Ile              20 25 30 Glu Asp Val Phe Tyr Lys Tyr Gly Ala Ile Arg Asp Ile Asp Leu Lys          35 40 45 Asn Arg Arg Gly Gly Pro Pro Phe Ala Phe Val Glu Phe Glu Asp Pro      50 55 60 Arg Asp Ala Glu Asp Ala Val Tyr Gly Arg Asp Gly Tyr Asp Tyr Asp  65 70 75 80 Gly Tyr Arg Leu Arg Val Glu Phe Pro Arg Ser Gly Arg Gly Thr Gly                  85 90 95 Arg Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Pro Arg Gly Arg Tyr             100 105 110 Gly Pro Pro Ser Arg Arg Ser Glu Asn Arg Val Val Val Ser Gly Leu         115 120 125 Pro Pro Ser Gly Ser Trp Gln Asp Leu Lys Asp His Met Arg Glu Ala     130 135 140 Gly Asp Val Cys Tyr Ala Asp Val Tyr Arg Asp Gly Thr Gly Val Val 145 150 155 160 Glu Phe Val Arg Lys Glu Asp Met Thr Tyr Ala Val Arg Lys Leu Asp                 165 170 175 Asn Thr Lys Phe Arg Ser His Glu Gly Glu Thr Ala Tyr Ile Arg Val             180 185 190 Lys Val Asp Gly Pro Arg Ser Pro Ser Tyr Gly Arg Ser Arg Ser Arg         195 200 205 Ser Arg Ser Arg Ser Arg Ser Arg Ser Arg Ser Asn Ser Arg Ser Arg     210 215 220 Ser Tyr Ser Pro Arg Arg Ser Arg Gly Ser Pro Arg Tyr Ser Pro Arg 225 230 235 240 His Ser Arg Ser Arg Ser Arg Thr                 245 <210> 54 <211> 194 <212> PRT <213> Homo sapiens <400> 54 Met Ala Ala Ser Leu Val Gly Lys Lys Ile Val Phe Val Thr Gly Asn   1 5 10 15 Ala Lys Lys Leu Glu Glu Val Val Gln Ile Leu Gly Asp Lys Phe Pro              20 25 30 Cys Thr Leu Val Ala Gln Lys Ile Asp Leu Pro Glu Tyr Gln Gly Glu          35 40 45 Pro Asp Glu Ile Ser Ile Gln Lys Cys Gln Glu Ala Val Arg Gln Val      50 55 60 Gln Gly Pro Val Leu Val Glu Asp Thr Cys Leu Cys Phe Asn Ala Leu  65 70 75 80 Gly Gly Leu Pro Gly Pro Tyr Ile Lys Trp Phe Leu Glu Lys Leu Lys                  85 90 95 Pro Glu Gly Leu His Gln Leu Leu Ala Gly Phe Glu Asp Lys Ser Ala             100 105 110 Tyr Ala Leu Cys Thr Phe Ala Leu Ser Thr Gly Asp Pro Ser Gln Pro         115 120 125 Val Arg Leu Phe Arg Gly Arg Thr Ser Gly Arg Ile Val Ala Pro Arg     130 135 140 Gly Cys Gln Asp Phe Gly Trp Asp Pro Cys Phe Gln Pro Asp Gly Tyr 145 150 155 160 Glu Gln Thr Tyr Ala Glu Met Pro Lys Ala Glu Lys Asn Ala Val Ser                 165 170 175 His Arg Phe Arg Ala Leu Leu Glu Leu Gln Glu Tyr Phe Gly Ser Leu             180 185 190 Ala Ala         <210> 55 <211> 453 <212> PRT <213> Homo sapiens <400> 55 Met Val Met Gly Ile Thr Asp Val Asp Asp Lys Ile Ile Lys Arg Ala   1 5 10 15 Asn Glu Met Asn Ile Ser Pro Ala Ser Leu Ala Ser Leu Tyr Glu Glu              20 25 30 Asp Phe Lys Gln Asp Met Ala Ala Leu Lys Val Leu Pro Pro Thr Val          35 40 45 Tyr Leu Arg Val Thr Glu Asn Ile Pro Gln Ile Ile Ser Phe Ile Glu      50 55 60 Gly Ile Ile Ala Ser Trp Glu Arg Leu Phe Asn Gly Lys Arg Gln Cys  65 70 75 80 Leu Leu Arg Ser Glu Ser Leu Glu Glu Thr Lys Tyr Gly Lys Ile Gly                  85 90 95 Arg Arg Gly Pro Trp Ser Ser Pro Glu Thr Ser Gly Leu Leu Thr Ser             100 105 110 Arg His Ala Asn Asp Phe Ala Leu Trp Lys Ala Ala Lys Pro Gln Glu         115 120 125 Val Phe Trp Ala Ser Pro Trp Gly Pro Gly Arg Pro Gly Trp His Ile     130 135 140 Glu Cys Ser Ala Ile Ala Ser Met Val Phe Gly Ser Gln Leu Asp Ile 145 150 155 160 His Ser Gly Gly Ile Asp Leu Ala Phe Pro His His Glu Asn Glu Ile                 165 170 175 Ala Gln Cys Glu Val Phe His Gln Cys Glu Gln Trp Gly Asn Tyr Phe             180 185 190 Leu His Ser Gly His Leu His Ala Lys Gly Lys Glu Glu Lys Met Ser         195 200 205 Lys Ser Leu Lys Asn Tyr Ile Thr Ile Lys Asp Phe Leu Lys Thr Phe     210 215 220 Ser Pro Asp Val Phe Arg Phe Phe Cys Leu Arg Ser Ser Tyr Arg Ser 225 230 235 240 Ala Ile Asp Tyr Ser Asp Ser Ala Met Leu Gln Ala Gln Gln Leu Leu                 245 250 255 Leu Gly Leu Gly Ser Phe Leu Glu Asp Ala Arg Ala Tyr Met Lys Gly             260 265 270 Gln Leu Ala Cys Gly Ser Val Arg Glu Ala Met Leu Trp Glu Arg Leu         275 280 285 Ser Ser Thr Lys Arg Ala Val Lys Ala Ala Leu Ala Asp Asp Phe Asp     290 295 300 Thr Pro Arg Val Val Asp Ala Ile Leu Gly Leu Ala His His Gly Asn 305 310 315 320 Gly Gln Leu Arg Ala Ser Leu Lys Glu Pro Glu Gly Pro Arg Ser Pro                 325 330 335 Ala Val Phe Gly Ala Ile Ile Ser Tyr Phe Glu Gln Phe Phe Glu Thr             340 345 350 Val Gly Ile Ser Leu Ala Asn Gln Gln Tyr Val Ser Gly Asp Gly Ser         355 360 365 Glu Ala Thr Leu His Gly Val Val Asp Glu Leu Val Arg Phe Arg Gln     370 375 380 Lys Val Arg Gln Phe Ala Leu Ala Met Pro Glu Ala Thr Gly Asp Ala 385 390 395 400 Arg Arg Gln Gln Leu Leu Glu Arg Gln Pro Leu Leu Glu Ala Cys Asp                 405 410 415 Thr Leu Arg Arg Gly Leu Thr Ala His Gly Ile Asn Ile Lys Asp Arg             420 425 430 Ser Ser Thr Thr Ser Thr Trp Glu Leu Leu Asp Gln Arg Thr Lys Asp         435 440 445 Gln Lys Ser Ala Gly     450 <210> 56 <211> 377 <212> PRT <213> Homo sapiens <400> 56 Met Arg Arg Leu Asn Arg Lys Lys Thr Leu Ser Leu Val Lys Glu Leu   1 5 10 15 Asp Ala Phe Pro Lys Val Pro Glu Ser Tyr Val Glu Thr Ser Ala Ser              20 25 30 Gly Gly Thr Val Ser Leu Ile Ala Phe Thr Thr Met Ala Leu Leu Thr          35 40 45 Ile Met Glu Phe Ser Val Tyr Gln Asp Thr Trp Met Lys Tyr Glu Tyr      50 55 60 Glu Val Asp Lys Asp Phe Ser Ser Lys Leu Arg Ile Asn Ile Asp Ile  65 70 75 80 Thr Val Ala Met Lys Cys Gln Tyr Val Gly Ala Asp Val Leu Asp Leu                  85 90 95 Ala Glu Thr Met Val Ala Ser Ala Asp Gly Leu Val Tyr Glu Pro Thr             100 105 110 Val Phe Asp Leu Ser Pro Gln Gln Lys Glu Trp Gln Arg Met Leu Gln         115 120 125 Leu Ile Gln Ser Arg Leu Gln Glu Glu His Ser Leu Gln Asp Val Ile     130 135 140 Phe Lys Ser Ala Phe Lys Ser Thr Ser Thr Ala Leu Pro Pro Arg Glu 145 150 155 160 Asp Asp Ser Ser Gln Ser Pro Asn Ala Cys Arg Ile His Gly His Leu                 165 170 175 Tyr Val Asn Lys Val Ala Gly Asn Phe His Ile Thr Val Gly Lys Ala             180 185 190 Ile Pro His Pro Arg Gly His Ala His Leu Ala Ala Leu Val Asn His         195 200 205 Glu Ser Tyr Asn Phe Ser His Arg Ile Asp His Leu Ser Phe Gly Glu     210 215 220 Leu Val Pro Ala Ile Ile Asn Pro Leu Asp Gly Thr Gly Lys Ile Ala 225 230 235 240 Ile Asp His Asn Gln Met Phe Gln Tyr Phe Ile Thr Val Val Pro Thr                 245 250 255 Lys Leu His Thr Tyr Lys Ile Ser Ala Asp Thr His Gln Phe Ser Val             260 265 270 Thr Glu Arg Glu Arg Ile Ile Asn His Ala Ala Gly Ser His Gly Val         275 280 285 Ser Gly Ile Phe Met Lys Tyr Asp Leu Ser Ser Leu Met Val Thr Val     290 295 300 Thr Glu Glu His Met Pro Phe Trp Gln Phe Phe Val Arg Leu Cys Gly 305 310 315 320 Ile Val Gly Gly Ile Phe Ser Thr Thr Gly Met Leu His Gly Ile Gly                 325 330 335 Lys Phe Ile Val Glu Ile Ile Cys Cys Arg Phe Arg Leu Gly Ser Tyr             340 345 350 Lys Pro Val Asn Ser Val Pro Phe Glu Asp Gly His Thr Asp Asn His         355 360 365 Leu Pro Leu Leu Glu Asn Asn Thr His     370 375 <210> 57 <211> 417 <212> PRT <213> Homo sapiens <400> 57 Met Leu Leu Ser Val Pro Leu Leu Leu Gly Leu Leu Gly Leu Ala Val   1 5 10 15 Ala Glu Pro Ala Val Tyr Phe Lys Glu Gln Phe Leu Asp Gly Asp Gly              20 25 30 Trp Thr Ser Arg Trp Ile Glu Ser Lys His Lys Ser Asp Phe Gly Lys          35 40 45 Phe Val Leu Ser Ser Gly Lys Phe Tyr Gly Asp Glu Glu Lys Asp Lys      50 55 60 Gly Leu Gln Thr Ser Gln Asp Ala Arg Phe Tyr Ala Leu Ser Ala Ser  65 70 75 80 Phe Glu Pro Phe Ser Asn Lys Gly Gln Thr Leu Val Val Gln Phe Thr                  85 90 95 Val Lys His Glu Gln Asn Ile Asp Cys Gly Gly Gly Tyr Val Lys Leu             100 105 110 Phe Pro Asn Ser Leu Asp Gln Thr Asp Met His Gly Asp Ser Glu Tyr         115 120 125 Asn Ile Met Phe Gly Pro Asp Ile Cys Gly Pro Gly Thr Lys Lys Val     130 135 140 His Val Ile Phe Asn Tyr Lys Gly Lys Asn Val Leu Ile Asn Lys Asp 145 150 155 160 Ile Arg Cys Lys Asp Asp Glu Phe Thr His Leu Tyr Thr Leu Ile Val                 165 170 175 Arg Pro Asp Asn Thr Tyr Glu Val Lys Ile Asp Asn Ser Gln Val Glu             180 185 190 Ser Gly Ser Leu Glu Asp Asp Trp Asp Phe Leu Pro Pro Lys Lys Ile         195 200 205 Lys Asp Pro Asp Ala Ser Lys Pro Glu Asp Trp Asp Glu Arg Ala Lys     210 215 220 Ile Asp Asp Pro Thr Asp Ser Lys Pro Glu Asp Trp Asp Lys Pro Glu 225 230 235 240 His Ile Pro Asp Pro Asp Ala Lys Lys Pro Glu Asp Trp Asp Glu Glu                 245 250 255 Met Asp Gly Glu Trp Glu Pro Pro Val Ile Gln Asn Pro Glu Tyr Lys             260 265 270 Gly Glu Trp Lys Pro Arg Gln Ile Asp Asn Pro Asp Tyr Lys Gly Thr         275 280 285 Trp Ile His Pro Glu Ile Asp Asn Pro Glu Tyr Ser Pro Asp Pro Ser     290 295 300 Ile Tyr Ala Tyr Asp Asn Phe Gly Val Leu Gly Leu Asp Leu Trp Gln 305 310 315 320 Val Lys Ser Gly Thr Ile Phe Asp Asn Phe Leu Ile Thr Asn Asp Glu                 325 330 335 Ala Tyr Ala Glu Glu Phe Gly Asn Glu Thr Trp Gly Val Thr Lys Ala             340 345 350 Ala Glu Lys Gln Met Lys Asp Lys Gln Asp Glu Glu Gln Arg Leu Lys         355 360 365 Glu Glu Glu Glu Asp Lys Lys Arg Lys Glu Glu Glu Glu Ala Glu Asp     370 375 380 Lys Glu Asp Asp Glu Asp Lys Asp Glu Asp Glu Glu Asp Glu Glu Asp 385 390 395 400 Lys Glu Glu Asp Glu Glu Glu Asp Val Pro Gly Gln Ala Lys Asp Glu                 405 410 415 Leu     <210> 58 <211> 114 <212> PRT <213> Homo sapiens <400> 58 Val Pro Leu His Ser Ser Leu Gly His Gln Ala Arg Leu Cys Leu Lys   1 5 10 15 Lys Lys Gly Glu Leu Leu Glu Arg Asn His Lys Met Val Gln Ser Val              20 25 30 Ala Pro Ala Asn Leu Tyr Phe Pro Thr Ser Thr Gly Pro Leu His His          35 40 45 Pro Ile Val Phe Leu Gly Ser His Ser Ser Gln Ser Ser Phe Cys Asn      50 55 60 Cys Cys His Phe Pro Gln Val Leu Phe Phe Tyr Ile Pro Thr Leu Thr  65 70 75 80 Leu Ser Lys Asp Ile Ser Phe Phe Phe Thr Glu Asn Met Glu Ser Ile                  85 90 95 Leu Phe Pro Thr Phe Ser Phe Pro Ala Val Ser Ala Ser Pro Ser Ile             100 105 110 Ser Gln         <210> 59 <211> 249 <212> PRT <213> Homo sapiens <400> 59 Met Lys Leu Asn Ile Ser Phe Pro Ala Thr Gly Cys Gln Lys Leu Ile   1 5 10 15 Glu Val Asp Asp Glu Arg Lys Leu Arg Thr Phe Tyr Glu Lys Arg Met              20 25 30 Ala Thr Glu Val Ala Ala Asp Ala Leu Gly Glu Glu Trp Lys Gly Tyr          35 40 45 Val Val Arg Ile Ser Gly Gly Asn Asp Lys Gln Gly Phe Pro Met Lys      50 55 60 Gln Gly Val Leu Thr His Gly Arg Val Arg Leu Leu Leu Ser Lys Gly  65 70 75 80 His Ser Cys Tyr Arg Pro Arg Arg Thr Gly Glu Arg Lys Arg Lys Ser                  85 90 95 Val Arg Gly Cys Ile Val Asp Ala Asn Leu Ser Val Leu Asn Leu Val             100 105 110 Ile Val Lys Lys Gly Glu Lys Asp Ile Pro Gly Leu Thr Asp Thr Thr         115 120 125 Val Pro Arg Arg Leu Gly Pro Lys Arg Ala Ser Arg Ile Arg Lys Leu     130 135 140 Phe Asn Leu Ser Lys Glu Asp Asp Val Arg Gln Tyr Val Val Arg Lys 145 150 155 160 Pro Leu Asn Lys Glu Gly Lys Lys Pro Arg Thr Lys Ala Pro Lys Ile                 165 170 175 Gln Arg Leu Val Thr Pro Arg Val Leu Gln His Lys Arg Arg Arg Ile             180 185 190 Ala Leu Lys Lys Gln Arg Thr Lys Lys Asn Lys Glu Glu Ala Ala Glu         195 200 205 Tyr Ala Lys Leu Leu Ala Lys Arg Met Lys Glu Ala Lys Glu Lys Arg     210 215 220 Gln Glu Gln Ile Ala Lys Arg Arg Arg Leu Ser Ser Leu Arg Ala Ser 225 230 235 240 Thr Ser Lys Ser Glu Ser Ser Gln Lys                 245 <210> 60 <211> 67 <212> PRT <213> Homo sapiens <400> 60 Met Leu Leu Tyr Ile Asn Arg Ala Arg Pro Glu Gly Gly Arg Gly Ala   1 5 10 15 Gly Ala Glu Gly Arg Ser Asn Gln Ile Ser Asn Phe Leu Leu Ile Ile              20 25 30 Asn Pro Leu Phe Thr Ala Val Ser Val Val Ile Phe Lys Ile Phe Leu          35 40 45 Ile Phe Phe Phe Phe Leu Leu Leu Leu Phe Thr Ser Cys Val Tyr Val      50 55 60 Gly Asn Leu  65 <210> 61 <211> 92 <212> PRT <213> Homo sapiens <400> 61 Met Asp Glu Gln Ile Arg Leu Met Asp Gln Asn Leu Lys Cys Leu Ser   1 5 10 15 Ala Ala Glu Glu Lys Tyr Ser Gln Lys Glu Asp Lys Tyr Glu Glu Glu              20 25 30 Ile Lys Ile Leu Thr Asp Lys Leu Lys Glu Ala Glu Thr Arg Ala Glu          35 40 45 Phe Ala Glu Arg Ser Val Ala Lys Leu Glu Lys Thr Ile Asp Asp Leu      50 55 60 Glu Asp Lys Leu Lys Cys Thr Lys Glu Glu His Leu Cys Thr Gln Arg  65 70 75 80 Met Leu Asp Gln Thr Leu Leu Asp Leu Asn Glu Met                  85 90 <210> 62 <211> 54 <212> PRT <213> Homo sapiens <400> 62 Met Leu Cys Gly Asn Ile Tyr Pro Ile Asp His Pro Ile Leu Met Cys   1 5 10 15 Leu Trp Leu Ser Asp Gln Leu Gln Asn Asn Cys Val Val Ile Leu Cys              20 25 30 Pro Lys Leu Leu Ile Asn Phe Tyr Leu Gln Ile Glu Lys Glu Gly Pro          35 40 45 Cys Lys Glu Asn Gly Lys      50 <210> 63 <211> 49 <212> PRT <213> Homo sapiens <400> 63 Met Arg Asn Ser Ala Thr Phe Lys Ser Phe Glu Asp Arg Val Gly Thr   1 5 10 15 Ile Lys Ser Lys Val Val Gly Asp Arg Glu Asn Gly Ser Asp Asn Leu              20 25 30 Pro Ser Ser Ala Gly Ser Gly Asp Lys Pro Leu Ser Asp Pro Ala Pro          35 40 45 Phe     <210> 64 <211> 162 <212> PRT <213> Homo sapiens <400> 64 Met Lys Glu Thr Ile Met Asn Gln Glu Lys Leu Ala Lys Leu Gln Ala   1 5 10 15 Gln Val Arg Ile Gly Gly Lys Gly Thr Ala Arg Arg Lys Lys Lys Val              20 25 30 Val His Arg Thr Ala Thr Ala Asp Asp Lys Lys Leu Gln Phe Ser Leu          35 40 45 Lys Lys Leu Gly Val Asn Asn Ile Ser Gly Ile Glu Glu Val Asn Met      50 55 60 Phe Thr Asn Gln Gly Thr Val Ile His Phe Asn Asn Pro Lys Val Gln  65 70 75 80 Ala Ser Leu Ala Ala Asn Thr Phe Thr Ile Thr Gly His Ala Glu Thr                  85 90 95 Lys Gln Leu Thr Glu Met Leu Pro Ser Ile Leu Asn Gln Leu Gly Ala             100 105 110 Asp Ser Leu Thr Ser Leu Arg Arg Leu Ala Glu Ala Leu Pro Lys Gln         115 120 125 Ser Val Asp Gly Lys Ala Pro Leu Ala Thr Gly Glu Asp Asp Asp Asp Asp     130 135 140 Glu Val Pro Asp Leu Val Glu Asn Phe Asp Glu Ala Ser Lys Asn Glu 145 150 155 160 Ala Asn         <210> 65 <211> 184 <212> PRT <213> Homo sapiens <400> 65 Met Arg Glu Tyr Lys Leu Val Val Leu Gly Ser Gly Gly Val Gly Lys   1 5 10 15 Ser Ala Leu Thr Val Gln Phe Val Gln Gly Ile Phe Val Glu Lys Tyr              20 25 30 Asp Pro Thr Ile Glu Asp Ser Tyr Arg Lys Gln Val Glu Val Asp Ala          35 40 45 Gln Gln Cys Met Leu Glu Ile Leu Asp Thr Ala Gly Thr Glu Gln Phe      50 55 60 Thr Ala Met Arg Asp Leu Tyr Met Lys Asn Gly Gln Gly Phe Ala Leu  65 70 75 80 Val Tyr Ser Ile Thr Ala Gln Ser Thr Phe Asn Asp Leu Gln Asp Leu                  85 90 95 Arg Glu Gln Ile Leu Arg Val Lys Asp Thr Asp Asp Val Pro Met Ile             100 105 110 Leu Val Gly Asn Lys Cys Asp Leu Glu Asp Glu Arg Val Val Gly Lys         115 120 125 Glu Gln Gly Gln Asn Leu Ala Arg Gln Trp Asn Asn Cys Ala Phe Leu     130 135 140 Glu Ser Ser Ala Lys Ser Lys Ile Asn Val Asn Glu Ile Phe Tyr Asp 145 150 155 160 Leu Val Arg Gln Ile Asn Arg Lys Thr Pro Val Pro Gly Lys Ala Arg                 165 170 175 Lys Lys Ser Ser Cys Gln Leu Leu             180 <210> 66 <211> 66 <212> PRT <213> Homo sapiens <400> 66 Met His Phe His Asn Ile Cys Leu Leu Glu Arg Ser Ile Ile Ser Glu   1 5 10 15 Lys Tyr Gln Val Phe Ile Lys Phe Leu Gly Met Ala Asp Ser Gln Asn              20 25 30 Met Leu Val Ser Leu Gln Tyr Ser Ser Arg Arg Ala Asn Gln Gly Arg          35 40 45 Ala Gly Met Arg Ser Asp Ile Cys Val Thr Lys Ser Ile Phe Leu Ile      50 55 60 Ser Leu  65 <210> 67 <211> 134 <212> PRT <213> Homo sapiens <400> 67 Met Thr Pro Asn Arg Gly Pro Leu Ser Pro Pro Asn Asp Leu Arg Pro   1 5 10 15 Ser His Val Ile Ser Leu Pro Leu His Asn Ala Pro His Thr Arg Pro              20 25 30 Thr Asn Gln His Thr Asn His Ile Pro Met Met Ala Arg Cys Asn Thr          35 40 45 Arg Lys His Ile Pro Arg Pro Pro His Thr Thr Cys Pro Lys Arg Pro      50 55 60 Ser Ile Arg Asp Asn Pro Ile Tyr Tyr Leu Arg Ser Phe Phe Leu Arg  65 70 75 80 Arg Ile Phe Leu Ser Leu Leu Pro Leu Gln Pro Ser Pro Tyr Pro Pro                  85 90 95 Ile Arg Arg Ala Leu Ala Pro Asn Arg His His Pro Ala Lys Ser Pro             100 105 110 Arg Ser Pro Thr Pro Lys His Ile Arg Ile Thr Arg Ile Arg Ser Ile         115 120 125 Asn His Leu Ser Ser Pro     130 <210> 68 <211> 61 <212> PRT <213> Homo sapiens <400> 68 Ile Gly Thr Val Phe Leu Glu Gly Asn Leu Val Lys Cys Ile Lys Arg   1 5 10 15 Leu Lys Asn Thr Asp Val Leu Cys Ala Gly Asn Ser Thr Ser Ser Asn              20 25 30 Phe Ser Leu Lys Pro Tyr Gln Arg Cys Ile Gln Arg Ile Ile Tyr Lys          35 40 45 Glu Gly Cys Leu Ile Met Ile Val Ile Ile Ile Asn Asn      50 55 60 <210> 69 <211> 73 <212> PRT <213> Homo sapiens <400> 69 Met Phe Asp Ser Pro Phe Tyr Glu Leu Asn Tyr Phe Ile Arg Val Gly   1 5 10 15 Asn Phe Cys Phe Leu Ile Lys Trp Lys Leu Ala Phe Leu Thr Leu Phe              20 25 30 Leu Leu Leu Phe Tyr Arg Asn Ala Phe Cys Trp Pro Gly Thr Val Ala          35 40 45 His Pro Cys Asn Pro Ser Thr Val Gly Gly Arg Asp Gly Trp Ile Thr      50 55 60 Arg Ser Gly Asp Arg Asp His Pro Gly  65 70 <210> 70 <211> 43 <212> PRT <213> Homo sapiens <400> 70 Met Leu Phe Val Gly Arg Ala Gln Leu Leu Ile His Val Ile Pro Ala   1 5 10 15 Leu Trp Glu Ala Glu Thr Gly Gly Ser Gln Gly Gln Glu Ile Glu Thr              20 25 30 Ile Leu Ala Asn Ala Leu Lys Leu Arg Leu Cys          35 40 <210> 71 <211> 136 <212> PRT <213> Homo sapiens <400> 71 Met Thr Ser Leu Cys Met Ala Met Thr Glu Glu Gln His Lys Ser Val   1 5 10 15 Val Ile Asp Cys Ser Ser Ser Gln Pro Gln Phe Cys Asn Ala Gly Ser              20 25 30 Asn Arg Phe Cys Glu Asp Trp Met Gln Ala Phe Leu Asn Gly Ala Lys          35 40 45 Gly Gly Asn Pro Phe Leu Phe Arg Gln Val Leu Glu Asn Phe Lys Leu      50 55 60 Lys Ala Ile Gln Asp Thr Asn Asn Leu Lys Arg Phe Ile Arg Gln Ala  65 70 75 80 Glu Met Asn His Tyr Ala Leu Phe Lys Cys Tyr Met Phe Leu Lys Asn                  85 90 95 Cys Gly Ser Gly Asp Ile Leu Leu Lys Ile Val Lys Val Glu His Glu             100 105 110 Glu Met Pro Glu Ala Lys Asn Val Ile Ala Val Leu Glu Glu Phe Met         115 120 125 Lys Glu Ala Leu Asp Gln Ser Phe     130 135 <210> 72 <211> 568 <212> PRT <213> Homo sapiens <400> 72 Met Val Leu Gly Pro Glu Gln Lys Met Ser Asp Asp Ser Val Ser Gly   1 5 10 15 Asp His Gly Glu Ser Ala Ser Leu Gly Asn Ile Asn Pro Ala Tyr Ser              20 25 30 Asn Pro Ser Leu Ser Gln Ser Pro Gly Asp Ser Glu Glu Tyr Phe Ala          35 40 45 Thr Tyr Phe Asn Glu Lys Ile Ser Ile Pro Glu Glu Glu Tyr Ser Cys      50 55 60 Phe Ser Phe Arg Lys Leu Trp Ala Phe Thr Gly Pro Gly Phe Leu Met  65 70 75 80 Ser Ile Ala Tyr Leu Asp Pro Gly Asn Ile Glu Ser Asp Leu Gln Ser                  85 90 95 Gly Ala Val Ala Gly Phe Lys Leu Leu Trp Ile Leu Leu Leu Ala Thr             100 105 110 Leu Val Gly Leu Leu Leu Gln Arg Leu Ala Ala Arg Leu Gly Val Val         115 120 125 Thr Gly Leu His Leu Ala Glu Val Cys His Arg Gln Tyr Pro Lys Val     130 135 140 Pro Arg Val Ile Leu Trp Leu Met Val Glu Leu Ala Ile Ile Gly Ser 145 150 155 160 Asp Met Gln Glu Val Ile Gly Ser Ala Ile Ala Ile Asn Leu Leu Ser                 165 170 175 Val Gly Arg Ile Pro Leu Trp Gly Gly Val Leu Ile Thr Ile Ala Asp             180 185 190 Thr Phe Val Phe Leu Phe Leu Asp Lys Tyr Gly Leu Arg Lys Leu Glu         195 200 205 Ala Phe Phe Gly Phe Leu Ile Thr Ile Met Ala Leu Thr Phe Gly Tyr     210 215 220 Glu Tyr Val Thr Val Lys Pro Ser Gln Ser Gln Val Leu Lys Gly Met 225 230 235 240 Phe Val Pro Ser Cys Ser Gly Cys Arg Thr Pro Gln Ile Glu Gln Ala                 245 250 255 Val Gly Ile Val Gly Ala Val Ile Met Pro His Asn Met Tyr Leu His             260 265 270 Ser Ala Leu Val Lys Ser Arg Gln Val Asn Arg Asn Asn Lys Gln Glu         275 280 285 Val Arg Glu Ala Asn Lys Tyr Phe Phe Ile Glu Ser Cys Ile Ala Leu     290 295 300 Phe Val Ser Phe Ile Ile Asn Val Phe Val Val Ser Val Phe Ala Glu 305 310 315 320 Ala Phe Phe Gly Lys Thr Asn Glu Gln Val Val Glu Val Cys Thr Asn                 325 330 335 Thr Ser Ser Pro His Ala Gly Leu Phe Pro Lys Asp Asn Ser Thr Leu             340 345 350 Ala Val Asp Ile Tyr Lys Gly Gly Val Val Leu Gly Cys Tyr Phe Gly         355 360 365 Pro Ala Ala Leu Tyr Ile Trp Ala Val Gly Ile Leu Ala Ala Gly Gln     370 375 380 Ser Ser Thr Met Thr Gly Thr Tyr Ser Gly Gln Phe Val Met Glu Gly 385 390 395 400 Phe Leu Asn Leu Lys Trp Ser Arg Phe Ala Arg Val Val Leu Thr Arg                 405 410 415 Ser Ile Ala Ile Ile Pro Thr Leu Leu Val Ala Val Phe Gln Asp Val             420 425 430 Glu His Leu Thr Gly Met Asn Asp Phe Leu Asn Val Leu Gln Ser Leu         435 440 445 Gln Leu Pro Phe Ala Leu Ile Pro Ile Leu Thr Phe Thr Ser Leu Arg     450 455 460 Pro Val Met Ser Asp Phe Ala Asn Gly Leu Gly Trp Arg Ile Ala Gly 465 470 475 480 Gly Ile Leu Val Leu Ile Ile Cys Ser Ile Asn Met Tyr Phe Val Val                 485 490 495 Val Tyr Val Arg Asp Leu Gly His Val Ala Leu Tyr Val Val Ala Ala             500 505 510 Val Val Ser Val Ala Tyr Leu Gly Phe Val Phe Tyr Leu Gly Trp Gln         515 520 525 Cys Leu Ile Ala Leu Gly Met Ser Phe Leu Asp Cys Gly His Thr Cys     530 535 540 His Leu Gly Leu Thr Ala Gln Pro Glu Leu Tyr Leu Leu Asn Thr Met 545 550 555 560 Asp Ala Asp Ser Leu Val Ser Arg                 565 <210> 73 <211> 87 <212> PRT <213> Homo sapiens <400> 73 Met Asn Cys Asn Thr Gln Ser Gln Thr Arg Ala Leu Pro Arg Pro Leu   1 5 10 15 Gly Gly Cys Thr Pro Ser Ser Ser Ala Arg Leu Arg Ser Leu Arg Pro              20 25 30 Arg Leu Lys Glu Gly Val Ala Gly Asn Pro Gly Asn Leu Ser Glu Val          35 40 45 Thr Pro His Pro Tyr Thr Pro Ser Val His Pro Arg Leu Phe Leu Leu      50 55 60 Leu Phe Gly Phe Trp Lys Gly Ile His Leu Gln Ala Ala His Pro Gly  65 70 75 80 Gly Ala Cys Phe Leu Lys Pro                  85 <210> 74 <211> 313 <212> PRT <213> Homo sapiens <400> 74 Met Pro Val Ala Gly Ser Glu Leu Pro Arg Arg Pro Leu Pro Pro Ala   1 5 10 15 Ala Gln Glu Arg Asp Ala Glu Pro Arg Pro Pro His Gly Glu Leu Gln              20 25 30 Tyr Leu Gly Gln Ile Gln His Ile Leu Arg Cys Gly Val Arg Lys Asp          35 40 45 Asp Arg Thr Gly Thr Gly Thr Leu Ser Val Phe Gly Met Gln Ala Arg      50 55 60 Tyr Ser Leu Arg Asp Glu Phe Pro Leu Leu Thr Thr Lys Arg Val Phe  65 70 75 80 Trp Lys Gly Val Leu Glu Glu Leu Leu Trp Phe Ile Lys Gly Ser Thr                  85 90 95 Asn Ala Lys Glu Leu Ser Ser Lys Gly Val Lys Ile Trp Asp Ala Asn             100 105 110 Gly Ser Arg Asp Phe Leu Asp Ser Leu Gly Phe Ser Thr Arg Glu Glu         115 120 125 Gly Asp Leu Gly Pro Val Tyr Gly Phe Gln Trp Arg His Phe Gly Ala     130 135 140 Glu Tyr Arg Asp Met Glu Ser Asp Tyr Ser Gly Gln Gly Val Asp Gln 145 150 155 160 Leu Gln Arg Val Ile Asp Thr Ile Lys Thr Asn Pro Asp Asp Arg Arg                 165 170 175 Ile Ile Met Cys Ala Trp Asn Pro Arg Asp Leu Pro Leu Met Ala Leu             180 185 190 Pro Pro Cys His Ala Leu Cys Gln Phe Tyr Val Val Asn Ser Glu Leu         195 200 205 Ser Cys Gln Leu Tyr Gln Arg Ser Gly Asp Met Gly Leu Gly Val Pro     210 215 220 Phe Asn Ile Ala Ser Tyr Ala Leu Leu Thr Tyr Met Ile Ala His Ile 225 230 235 240 Thr Gly Leu Lys Pro Gly Asp Phe Ile His Thr Leu Gly Asp Ala His                 245 250 255 Ile Tyr Leu Asn His Ile Glu Pro Leu Lys Ile Gln Leu Gln Arg Glu             260 265 270 Pro Arg Pro Phe Pro Lys Leu Arg Ile Leu Arg Lys Val Glu Lys Ile         275 280 285 Asp Asp Phe Lys Ala Glu Asp Phe Gln Ile Glu Gly Tyr Asn Pro His     290 295 300 Pro Thr Ile Lys Met Glu Met Ala Val 305 310 <210> 75 <211> 354 <212> PRT <213> Homo sapiens <400> 75 Met Arg Arg Leu Met Ser Ser Arg Asp Trp Pro Arg Thr Arg Thr Gly   1 5 10 15 Thr Gly Ile Leu Ser Ser Gln Pro Glu Glu Asn Pro Tyr Trp Trp Asn              20 25 30 Ala Asn Met Val Phe Ile Pro Tyr Cys Ser Ser Asp Val Trp Ser Gly          35 40 45 Ala Ser Ser Lys Ser Glu Lys Asn Glu Tyr Ala Phe Met Gly Ala Leu      50 55 60 Ile Ile Gln Glu Val Val Arg Glu Leu Leu Gly Arg Gly Leu Ser Gly  65 70 75 80 Ala Lys Val Leu Leu Leu Ala Gly Ser Ser Ala Gly Gly Thr Gly Val                  85 90 95 Leu Leu Asn Val Asp Arg Val Ala Glu Gln Leu Glu Lys Leu Gly Tyr             100 105 110 Pro Ala Ile Gln Val Arg Gly Leu Ala Asp Ser Gly Trp Phe Leu Asp         115 120 125 Asn Lys Gln Tyr Arg His Thr Asp Cys Val Asp Thr Ile Thr Cys Ala     130 135 140 Pro Thr Glu Ala Ile Arg Arg Gly Ile Arg Tyr Trp Asn Gly Val Val 145 150 155 160 Pro Glu Arg Cys Arg Arg Gln Phe Gln Glu Gly Glu Glu Trp Asn Cys                 165 170 175 Phe Phe Gly Tyr Lys Val Tyr Pro Thr Leu Arg Cys Pro Val Phe Val             180 185 190 Val Gln Trp Leu Phe Asp Glu Ala Gln Leu Thr Val Asp Asn Val His         195 200 205 Leu Thr Gly Gln Pro Val Gln Glu Gly Leu Arg Leu Tyr Ile Gln Asn     210 215 220 Leu Gly Arg Glu Leu Arg His Thr Leu Lys Asp Val Pro Ala Ser Phe 225 230 235 240 Ala Pro Ala Cys Leu Ser His Glu Ile Ile Ile Arg Ser His Trp Thr                 245 250 255 Asp Val Gln Val Lys Gly Thr Ser Leu Pro Arg Ala Leu His Cys Trp             260 265 270 Asp Arg Ser Leu His Asp Ser His Lys Ala Ser Lys Thr Pro Leu Lys         275 280 285 Gly Cys Pro Val His Leu Val Asp Ser Cys Pro Trp Pro His Cys Asn     290 295 300 Pro Ser Cys Pro Thr Val Arg Asp Gln Phe Thr Gly Gln Glu Met Asn 305 310 315 320 Val Ala Gln Phe Leu Met His Met Gly Phe Asp Met Gln Thr Val Ala                 325 330 335 Gln Pro Gln Gly Leu Glu Pro Ser Glu Leu Leu Gly Met Leu Ser Asn             340 345 350 Gly Ser         <210> 76 <211> 403 <212> PRT <213> Homo sapiens <400> 76 Met Ser His Arg Lys Phe Ser Ala Pro Arg His Gly Ser Leu Gly Phe   1 5 10 15 Leu Pro Arg Lys Arg Ser Ser Arg His Arg Gly Lys Val Lys Ser Phe              20 25 30 Pro Lys Asp Asp Pro Ser Lys Pro Val His Leu Thr Ala Phe Leu Gly          35 40 45 Tyr Lys Ala Gly Met Thr His Ile Val Arg Glu Val Asp Arg Pro Gly      50 55 60 Ser Lys Val Asn Lys Lys Glu Val Val Glu Ala Val Thr Ile Val Glu  65 70 75 80 Thr Pro Pro Met Val Val Val Gly Ile Val Gly Tyr Val Glu Thr Pro                  85 90 95 Arg Gly Leu Arg Thr Phe Lys Thr Val Phe Ala Glu His Ile Ser Asp             100 105 110 Glu Cys Lys Arg Arg Phe Tyr Lys Asn Trp His Lys Ser Lys Lys Lys         115 120 125 Ala Phe Thr Lys Tyr Cys Lys Lys Trp Gln Asp Glu Asp Gly Lys Lys     130 135 140 Gln Leu Glu Lys Asp Phe Ser Ser Met Lys Lys Tyr Cys Gln Val Ile 145 150 155 160 Arg Val Ile Ala His Thr Gln Met Arg Leu Leu Pro Leu Arg Gln Lys                 165 170 175 Lys Ala His Leu Met Glu Ile Gln Val Asn Gly Gly Thr Val Ala Glu             180 185 190 Lys Leu Asp Trp Ala Arg Glu Arg Leu Glu Gln Gln Val Pro Val Asn         195 200 205 Gln Val Phe Gly Gln Asp Glu Met Ile Asp Val Ile Gly Val Thr Lys     210 215 220 Gly Lys Gly Tyr Lys Gly Val Thr Ser Arg Trp His Thr Lys Lys Leu 225 230 235 240 Pro Arg Lys Thr His Arg Gly Leu Arg Lys Val Ala Cys Ile Gly Ala                 245 250 255 Trp His Pro Ala Arg Val Ala Phe Ser Val Ala Arg Ala Gly Gln Lys             260 265 270 Gly Tyr His His Arg Thr Glu Ile Asn Lys Lys Ile Tyr Lys Ile Gly         275 280 285 Gln Gly Tyr Leu Ile Lys Asp Gly Lys Leu Ile Lys Asn Asn Ala Ser     290 295 300 Thr Asp Tyr Asp Leu Ser Asp Lys Ser Ile Asn Pro Leu Gly Gly Phe 305 310 315 320 Val His Tyr Gly Glu Val Thr Asn Asp Phe Val Met Leu Lys Gly Cys                 325 330 335 Val Val Gly Thr Lys Lys Arg Val Leu Thr Leu Arg Lys Ser Leu Leu             340 345 350 Val Gln Thr Lys Arg Arg Ala Leu Glu Lys Ile Asp Leu Lys Phe Ile         355 360 365 Asp Thr Thr Ser Lys Phe Gly His Gly Arg Phe Gln Thr Met Glu Glu     370 375 380 Lys Lys Ala Phe Met Gly Pro Leu Lys Lys Asp Arg Ile Ala Lys Glu 385 390 395 400 Glu Gly Ala             <210> 77 <211> 86 <212> PRT <213> Homo sapiens <400> 77 Met Tyr Leu Tyr Leu Ile Ser Ser Cys Ile Lys Pro Ile Asn Leu Cys   1 5 10 15 Tyr Cys Ser Ser Asn Leu Met His Thr Val Ile Ser Cys Tyr Ile Cys              20 25 30 Lys Val Gly Asn Cys Phe Leu Ser Tyr Arg Ser Phe Lys Leu His Phe          35 40 45 Cys Ala Val Glu Thr Lys Val Gly Tyr Ser Leu Cys His Val Asp Val      50 55 60 Gln Phe Leu Lys Leu Phe Tyr Lys Thr Leu Ile Ile Lys Pro Leu Asn  65 70 75 80 Leu Lys Lys Lys Lys Lys                  85 <210> 78 <211> 511 <212> PRT <213> Homo sapiens <400> 78 Met Ala Val Arg Leu Ala Gly Gly Leu Gln Lys Met Val Ala Leu Leu   1 5 10 15 Asn Lys Thr Asn Val Lys Phe Leu Ala Ile Thr Thr Asp Cys Leu Gln              20 25 30 Ile Leu Ala Tyr Gly Asn Gln Glu Ser Lys Leu Ile Ile Leu Ala Ser          35 40 45 Gly Gly Pro Gln Ala Leu Val Asn Ile Met Arg Thr Tyr Thr Tyr Glu      50 55 60 Lys Leu Leu Trp Thr Thr Ser Arg Val Leu Lys Val Leu Ser Val Cys  65 70 75 80 Ser Ser Asn Lys Pro Ala Ile Val Glu Ala Gly Gly Met Gln Ala Leu                  85 90 95 Gly Leu His Leu Thr Asp Pro Ser Gln Arg Leu Val Gln Asn Cys Leu             100 105 110 Trp Thr Leu Arg Asn Leu Ser Asp Ala Ala Thr Lys Gln Glu Gly Met         115 120 125 Glu Gly Leu Leu Gly Thr Leu Val Gln Leu Leu Gly Ser Asp Asp Ile     130 135 140 Asn Val Val Thr Cys Ala Ala Gly Ile Leu Ser Asn Leu Thr Cys Asn 145 150 155 160 Asn Tyr Lys Asn Lys Met Met Val Cys Gln Val Gly Gly Ile Glu Ala                 165 170 175 Leu Val Arg Thr Val Leu Arg Ala Gly Asp Arg Glu Asp Ile Thr Glu             180 185 190 Pro Ala Ile Cys Ala Leu Arg His Leu Thr Ser Arg His Gln Glu Ala         195 200 205 Glu Met Ala Gln Asn Ala Val Arg Leu His Tyr Gly Leu Pro Val Val     210 215 220 Val Lys Leu Leu His Pro Pro Ser His Trp Pro Leu Ile Lys Ala Thr 225 230 235 240 Val Gly Leu Ile Arg Asn Leu Ala Leu Cys Pro Ala Asn His Ala Pro                 245 250 255 Leu Arg Glu Gln Gly Ala Ile Pro Arg Leu Val Gln Leu Leu Val Arg             260 265 270 Ala His Gln Asp Thr Gln Arg Arg Thr Ser Met Gly Gly Thr Gln Gln         275 280 285 Gln Phe Val Glu Gly Val Arg Met Glu Glu Ile Val Glu Gly Cys Thr     290 295 300 Gly Ala Leu His Ile Leu Ala Arg Asp Val His Asn Arg Ile Val Ile 305 310 315 320 Arg Gly Leu Asn Thr Ile Pro Leu Phe Val Gln Leu Leu Tyr Ser Pro                 325 330 335 Ile Glu Asn Ile Gln Arg Val Ala Ala Gly Val Leu Cys Glu Leu Ala             340 345 350 Gln Asp Lys Glu Ala Ala Glu Ala Ile Glu Ala Glu Gly Ala Thr Ala         355 360 365 Pro Leu Thr Glu Leu Leu His Ser Arg Asn Glu Gly Val Ala Thr Tyr     370 375 380 Ala Ala Ala Val Leu Phe Arg Met Ser Glu Asp Lys Pro Gln Asp Tyr 385 390 395 400 Lys Lys Arg Leu Ser Val Glu Leu Thr Ser Ser Leu Phe Arg Thr Glu                 405 410 415 Pro Met Ala Trp Asn Glu Thr Ala Asp Leu Gly Leu Asp Ile Gly Ala             420 425 430 Gln Gly Glu Pro Leu Gly Tyr Arg Gln Asp Asp Pro Ser Tyr Arg Ser         435 440 445 Phe His Ser Gly Gly Tyr Gly Gln Asp Ala Leu Gly Met Asp Pro Met     450 455 460 Met Glu His Glu Met Gly Gly His His Pro Gly Ala Asp Tyr Pro Val 465 470 475 480 Asp Gly Leu Pro Asp Leu Gly His Ala Gln Asp Leu Met Asp Gly Leu                 485 490 495 Pro Pro Gly Asp Ser Asn Gln Leu Ala Trp Phe Asp Thr Asp Leu             500 505 510 <210> 79 <211> 34 <212> PRT <213> Homo sapiens <400> 79 Met Gly Leu Glu Arg Gly Phe Asp Pro Arg Ser Leu Cys Ala Phe Ala   1 5 10 15 Ala Glu Pro His Asn Leu Ser Phe Gln Lys His Phe Gln Asn Ala Asn              20 25 30 Ile Phe         <210> 80 <211> 168 <212> PRT <213> Homo sapiens <400> 80 Met Leu Arg Val Asn Phe Phe Phe Phe Phe Phe Phe Phe Phe Ser Phe   1 5 10 15 Ser Leu Arg Leu Gly Leu Ala Leu Leu Pro Arg Leu Glu Trp Ser Gly              20 25 30 Val Ile Leu Ala Tyr Cys Ser Leu Cys Leu Pro Gly Ser Ser Ser Pro          35 40 45 Ala Ser Ala Ser Gly Val Ala Gly Thr Thr Gly Ser Cys His His Gly      50 55 60 Gln Pro Thr Phe Ala Cys Phe Val Lys Met Gly Ser His Ser Val Ala  65 70 75 80 Gln Ala Gly Leu Lys Leu Leu Gly Ser Gly Asp Pro Pro Val Ser Ala                  85 90 95 Ser Gln Ser Ala Gly Ile Thr Ile Val Ser His His Val Gln Leu Glu             100 105 110 Gly Ser Thr Ser Phe Thr Phe Cys Lys His Ile Cys Ile Phe Thr Pro         115 120 125 Pro Phe Pro Ser Phe Ser Leu Phe Ile Ser His Phe Tyr Ile Asp Leu     130 135 140 Leu Phe Tyr Asn Lys Thr Leu Leu Pro Lys Lys Lys Lys Lys Lys Lys 145 150 155 160 Lys Lys Lys Lys Lys Lys Lys Lys                 165 <210> 81 <211> 158 <212> PRT <213> Homo sapiens <400> 81 Met Met Ile Trp Ile His Gln Asp Leu Phe Tyr Ala Gln Gly Gln Phe   1 5 10 15 Leu Phe Phe Phe Phe Phe Phe Phe Phe Phe Phe Phe Glu Thr Gly Ser              20 25 30 Arg Phe Val Ala Gln Ala Gly Val Glu Trp Arg Asp Leu Gly Leu Leu          35 40 45 Gln Pro Leu Pro Pro Arg Leu Glu Gln Ser Cys Leu Ser Leu Arg Ser      50 55 60 Ser Trp Asp His Arg Phe Met Pro Pro Trp Pro Ala Asn Phe Cys Met  65 70 75 80 Phe Cys Lys Asp Gly Val Ser Gln Cys Cys Pro Gly Trp Ser Gln Thr                  85 90 95 Pro Gly Leu Arg Arg Ser Thr Cys Leu Ser Leu Pro Glu Cys Trp Asp             100 105 110 Tyr Asn Cys Glu Pro Pro Arg Pro Ala Gly Arg Val Asn Ile Phe Tyr         115 120 125 Ile Leu Gln Ala His Leu His Phe His Pro Thr Leu Pro Leu Leu Leu     130 135 140 Pro Phe Tyr Ile Pro Phe Leu Tyr Arg Ser Leu Ile Leu Gln 145 150 155 <210> 82 <211> 599 <212> PRT <213> Homo sapiens <400> 82 Met Ala Asp Lys Leu Thr Arg Ile Ala Ile Val Asn His Asp Lys Cys   1 5 10 15 Lys Pro Lys Lys Cys Arg Gln Glu Cys Lys Lys Ser Cys Pro Val Val              20 25 30 Arg Met Gly Lys Leu Cys Ile Glu Val Thr Pro Gln Ser Lys Ile Ala          35 40 45 Trp Ile Ser Glu Thr Leu Cys Ile Gly Cys Gly Ile Cys Ile Lys Lys      50 55 60 Cys Pro Phe Gly Ala Leu Ser Ile Val Asn Leu Pro Ser Asn Leu Glu  65 70 75 80 Lys Glu Thr Thr His Arg Tyr Cys Ala Asn Ala Phe Lys Leu His Arg                  85 90 95 Leu Pro Ile Pro Arg Pro Gly Glu Val Leu Gly Leu Val Gly Thr Asn             100 105 110 Gly Ile Gly Lys Ser Thr Ala Leu Lys Ile Leu Ala Gly Lys Gln Lys         115 120 125 Pro Asn Leu Gly Lys Tyr Asp Asp Pro Pro Asp Trp Gln Glu Ile Leu     130 135 140 Thr Tyr Phe Arg Gly Ser Glu Leu Gln Asn Tyr Phe Thr Lys Ile Leu 145 150 155 160 Glu Asp Asp Leu Lys Ala Ile Ile Lys Pro Gln Tyr Val Asp Gln Ile                 165 170 175 Pro Lys Ala Ala Lys Gly Thr Val Gly Ser Ile Leu Asp Arg Lys Asp             180 185 190 Glu Thr Lys Thr Gln Ala Ile Val Cys Gln Gln Leu Asp Leu Thr His         195 200 205 Leu Lys Glu Arg Asn Val Glu Asp Leu Ser Gly Gly Glu Leu Gln Arg     210 215 220 Phe Ala Cys Ala Val Val Cys Ile Gln Lys Ala Asp Ile Phe Met Phe 225 230 235 240 Asp Glu Pro Ser Ser Tyr Leu Asp Val Lys Gln Arg Leu Lys Ala Ala                 245 250 255 Ile Thr Ile Arg Ser Leu Ile Asn Pro Asp Arg Tyr Ile Ile Val Val             260 265 270 Glu His Asp Leu Ser Val Leu Asp Tyr Leu Ser Asp Phe Ile Cys Cys         275 280 285 Leu Tyr Gly Val Pro Ser Ala Tyr Gly Val Val Thr Met Pro Phe Ser     290 295 300 Val Arg Glu Gly Ile Asn Ile Phe Leu Asp Gly Tyr Val Pro Thr Glu 305 310 315 320 Asn Leu Arg Phe Arg Asp Ala Ser Leu Val Phe Lys Val Ala Glu Thr                 325 330 335 Ala Asn Glu Glu Glu Val Lys Lys Met Cys Met Tyr Lys Tyr Pro Gly             340 345 350 Met Lys Lys Lys Met Gly Glu Phe Glu Leu Ala Ile Val Ala Gly Glu         355 360 365 Phe Thr Asp Ser Glu Ile Met Val Met Leu Gly Glu Asn Gly Thr Gly     370 375 380 Lys Thr Thr Phe Ile Arg Met Leu Ala Gly Arg Leu Lys Pro Asp Glu 385 390 395 400 Gly Gly Glu Val Pro Val Leu Asn Val Ser Tyr Lys Pro Gln Lys Ile                 405 410 415 Ser Pro Lys Ser Thr Gly Ser Val Arg Gln Leu Leu His Glu Lys Ile             420 425 430 Arg Asp Ala Tyr Thr His Pro Gln Phe Val Thr Asp Val Met Lys Pro         435 440 445 Leu Gln Ile Glu Asn Ile Ile Asp Gln Glu Val Gln Thr Leu Ser Gly     450 455 460 Gly Glu Leu Gln Arg Val Ala Leu Ala Leu Cys Leu Gly Lys Pro Ala 465 470 475 480 Asp Val Tyr Leu Ile Asp Glu Pro Ser Ala Tyr Leu Asp Ser Glu Gln                 485 490 495 Arg Leu Met Ala Ala Arg Val Val Lys Arg Phe Ile Leu His Ala Lys             500 505 510 Lys Thr Ala Phe Val Val Glu His Asp Phe Ile Met Ala Thr Tyr Leu         515 520 525 Ala Asp Arg Val Ile Val Phe Asp Gly Val Pro Ser Lys Asn Thr Val     530 535 540 Ala Asn Ser Pro Gln Thr Leu Leu Ala Gly Met Asn Lys Phe Leu Ser 545 550 555 560 Gln Leu Glu Ile Thr Phe Arg Arg Asp Pro Asn Asn Tyr Arg Pro Arg                 565 570 575 Ile Asn Lys Leu Asn Ser Ile Lys Asp Val Glu Gln Lys Lys Ser Gly             580 585 590 Asn Tyr Phe Phe Leu Asp Asp         595 <210> 83 <211> 49 <212> PRT <213> Homo sapiens <400> 83 Met Ser Phe Ser Ala Ile Leu Ser Pro Phe Ser Ser Leu Ser Val Asn   1 5 10 15 Val Arg Asn Leu Arg Gln Arg Gly Lys Gly Arg Gln Asn Ser Arg Ile              20 25 30 Leu Thr Leu Ile Val Lys Ile Leu Phe Lys Thr Trp His Leu Ile Phe          35 40 45 Leu     <210> 84 <211> 109 <212> PRT <213> Homo sapiens <400> 84 Met Glu Ser His Ser Val Thr Gln Ala Gly Val Gln Trp His Asp Leu   1 5 10 15 Gly Ser Leu His Ser Pro Leu Leu Gly Ser Ser Asp Ser Pro Thr Ser              20 25 30 Ala Ser Arg Val Ala Gly Ile Thr Gly Met Gln His His Thr Gln Leu          35 40 45 Ile Phe Leu Phe Leu Val Glu Met Gly Phe His His Val Gly Gln Ala      50 55 60 Gly Leu Lys Leu Leu Thr Ser Gly Asp Pro Pro Ala Ser Ala Ser Gln  65 70 75 80 Ser Ala Gly Ile Thr Gly Val Gly His His Thr Trp Pro Ile Met Glu                  85 90 95 Asp Phe Leu Met Val Met Phe Glu Leu Gly Phe Gly Glu             100 105 <210> 85 <211> 46 <212> PRT <213> Homo sapiens <400> 85 Met Gly Phe Lys Gly Pro Gly Val Phe Leu Asp Leu Gln Asp Ile Cys   1 5 10 15 Leu Pro Ser Gly Phe Pro Gly Leu Gly Trp Gly Gly Ile Arg Ser Leu              20 25 30 Ala Asn Leu Leu Ser Thr Pro Gly Phe Arg Pro Leu Phe Pro          35 40 45 <210> 86 <211> 56 <212> PRT <213> Homo sapiens <400> 86 Met Glu Thr Leu His Thr Trp Gly Ser Lys Val Leu Gly Tyr Ser Trp   1 5 10 15 Ile Phe Arg Thr Ser Ala Tyr Pro Gln Val Ser Gln Ala Ser Gly Gly              20 25 30 Glu Ala Ser Asp Pro Trp Pro Thr Cys Tyr Pro Pro Gln Gly Leu Asp          35 40 45 Leu Ser Ser Arg Glu Gly Thr Glu      50 55 <210> 87 <211> 46 <212> PRT <213> Homo sapiens <400> 87 Met Leu Phe Ile His Ala Glu Val Ile Gln Phe Pro Pro Ser Tyr Arg   1 5 10 15 Ser Ile Leu Ile His Pro Thr Leu Glu Met Gln His Leu Cys Gly Arg              20 25 30 Leu Phe His Lys Pro Pro Arg Leu Leu Arg Leu Gly Arg Tyr          35 40 45 <210> 88 <211> 36 <212> PRT <213> Homo sapiens <400> 88 Met Ala Ser Leu Gln Phe Val Ile Ser Leu Pro Val Cys Ser Leu Lys   1 5 10 15 Leu Ile Lys Arg Ser Gly Tyr Ile Glu Leu Leu Tyr Arg Cys Glu Gly              20 25 30 Met Asp Lys Ser          35 <210> 89 <211> 166 <212> PRT <213> Homo sapiens <400> 89 Met Ala Ala Thr Met Phe Arg Ala Thr Leu Arg Gly Trp Arg Thr Gly   1 5 10 15 Val Gln Arg Gly Cys Gly Leu Arg Leu Leu Ser Gln Thr Gln Gly Pro              20 25 30 Pro Asp Tyr Pro Arg Phe Val Glu Ser Val Asp Glu Tyr Gln Phe Val          35 40 45 Glu Arg Leu Leu Pro Ala Thr Arg Ile Pro Asp Pro Pro Lys His Glu      50 55 60 His Tyr Pro Thr Pro Ser Gly Trp Gln Pro Pro Arg Asp Pro Pro Pro  65 70 75 80 Asn Leu Pro Tyr Phe Val Arg Arg Ser Arg Met His Asn Ile Pro Val                  85 90 95 Tyr Lys Asp Ile Thr His Gly Asn Arg Gln Met Thr Val Ile Arg Lys             100 105 110 Val Glu Gly Asp Ile Trp Ala Leu Gln Lys Asp Val Glu Asp Phe Leu         115 120 125 Ser Pro Leu Leu Gly Lys Thr Pro Val Thr Gln Val Asn Glu Val Thr     130 135 140 Gly Thr Leu Arg Ile Lys Gly Tyr Phe Asp Gln Glu Leu Lys Ala Trp 145 150 155 160 Leu Leu Glu Lys Gly Phe                 165 <210> 90 <211> 222 <212> PRT <213> Homo sapiens <400> 90 Met Asn Ser Asn Val Glu Asn Leu Pro Pro His Ile Ile Arg Leu Val   1 5 10 15 Tyr Lys Glu Val Thr Thr Leu Thr Ala Asp Pro Pro Asp Gly Ile Lys              20 25 30 Val Phe Pro Asn Glu Glu Asp Leu Thr Asp Leu Gln Val Thr Ile Glu          35 40 45 Gly Pro Glu Gly Thr Pro Tyr Ala Gly Gly Leu Phe Arg Met Lys Leu      50 55 60 Leu Leu Gly Lys Asp Phe Pro Ala Ser Pro Pro Lys Gly Tyr Phe Leu  65 70 75 80 Thr Lys Ile Phe His Pro Asn Val Gly Ala Asn Gly Glu Ile Cys Val                  85 90 95 Asn Val Leu Lys Arg Asp Trp Thr Ala Glu Leu Gly Ile Arg His Val             100 105 110 Leu Leu Thr Ile Lys Cys Leu Leu Ile His Pro Asn Pro Glu Ser Ala         115 120 125 Leu Asn Glu Glu Ala Gly Arg Leu Leu Leu Glu Asn Tyr Glu Glu Tyr     130 135 140 Ala Ala Arg Ala Arg Leu Leu Thru Glu Ile His Gly Gly Ala Gly Gly 145 150 155 160 Pro Ser Gly Arg Ala Glu Ala Gly Arg Ala Leu Ala Ser Gly Thr Glu                 165 170 175 Ala Ser Ser Thr Asp Pro Gly Ala Pro Gly Gly Pro Gly Gly Ala Glu             180 185 190 Gly Thr Met Ala Lys Lys His Ala Gly Glu Arg Asp Lys Lys Leu Ala         195 200 205 Ala Lys Lys Lys Thr Asp Lys Lys Arg Ala Leu Arg Arg Leu     210 215 220 <210> 91 <211> 509 <212> PRT <213> Homo sapiens <400> 91 Met Phe Thr Asn Asp Met Met Glu Cys Lys Gln Asp Glu Ile Val Met   1 5 10 15 Gln Gly Met Asp Pro Ser Ala Leu Glu Ala Leu Ile Asn Phe Ala Tyr              20 25 30 Asn Gly Asn Leu Ala Ile Asp Gln Gln Asn Val Gln Ser Leu Leu Met          35 40 45 Gly Ala Ser Phe Leu Gln Leu Gln Ser Ile Lys Asp Ala Cys Cys Thr      50 55 60 Phe Leu Arg Glu Arg Leu His Pro Lys Asn Cys Leu Gly Val Arg Gln  65 70 75 80 Phe Ala Glu Thr Met Met Cys Ala Val Leu Tyr Asp Ala Ala Asn Ser                  85 90 95 Phe Ile His Gln His Phe Val Glu Val Ser Met Ser Glu Glu Phe Leu             100 105 110 Ala Leu Pro Leu Glu Asp Val Leu Glu Leu Val Ser Arg Asp Glu Leu         115 120 125 Asn Val Lys Ser Glu Glu Gln Val Phe Glu Ala Ala Leu Ala Trp Val     130 135 140 Arg Tyr Asp Arg Glu Gln Arg Gly Pro Tyr Leu Pro Glu Leu Leu Ser 145 150 155 160 Asn Ile Arg Leu Pro Leu Cys Arg Pro Gln Phe Leu Ser Asp Arg Val                 165 170 175 Gln Gln Asp Asp Leu Val Arg Cys Cys His Lys Cys Arg Asp Leu Val             180 185 190 Asp Glu Ala Lys Asp Tyr His Leu Met Pro Glu Arg Arg Pro His Leu         195 200 205 Pro Ala Phe Arg Thr Arg Pro Arg Cys Cys Thr Ser Ile Ala Gly Leu     210 215 220 Ile Tyr Ala Val Gly Gly Leu Asn Ser Ala Gly Asp Ser Leu Asn Val 225 230 235 240 Val Glu Val Phe Asp Pro Ile Ala Asn Cys Trp Glu Arg Cys Arg Pro                 245 250 255 Met Thr Thr Ala Arg Ser Arg Val Gly Val Ala Val Val Asn Gly Leu             260 265 270 Leu Tyr Ala Ile Gly Gly Tyr Asp Gly Gln Leu Arg Leu Ser Thr Val         275 280 285 Glu Ala Tyr Asn Pro Glu Thr Asp Thr Trp Thr Arg Val Gly Ser Met     290 295 300 Asn Ser Lys Arg Ser Ala Met Gly Thr Val Val Leu Asp Gly Gln Ile 305 310 315 320 Tyr Val Cys Gly Gly Tyr Asp Gly Asn Ser Ser Leu Ser Ser Val Glu                 325 330 335 Thr Tyr Ser Pro Glu Thr Asp Lys Trp Thr Val Val Thr Ser Met Ser             340 345 350 Ser Asn Arg Ser Ala Ala Gly Val Thr Val Phe Glu Gly Arg Ile Tyr         355 360 365 Val Ser Gly Gly His Asp Gly Leu Gln Ile Phe Ser Ser Val Glu His     370 375 380 Tyr Asn His His Thr Ala Thr Trp His Pro Ala Ala Gly Met Leu Asn 385 390 395 400 Lys Arg Cys Arg His Gly Ala Ala Ser Leu Gly Ser Lys Met Phe Val                 405 410 415 Cys Gly Gly Tyr Asp Gly Ser Gly Phe Leu Ser Ile Ala Glu Met Tyr             420 425 430 Ser Ser Val Ala Asp Gln Trp Cys Leu Ile Val Pro Met His Thr Arg         435 440 445 Arg Ser Arg Val Ser Leu Val Ala Ser Cys Gly Arg Leu Tyr Ala Val     450 455 460 Gly Gly Tyr Asp Gly Gln Ser Asn Leu Ser Ser Val Glu Met Tyr Asp 465 470 475 480 Pro Glu Thr Asp Cys Trp Thr Phe Met Ala Pro Met Ala Cys His Glu                 485 490 495 Gly Gly Val Gly Val Gly Cys Ile Pro Leu Leu Thr Ile             500 505 <210> 92 <211> 180 <212> PRT <213> Homo sapiens <400> 92 Met Arg Pro Leu Thr Glu Glu Glu Thr Arg Val Met Phe Glu Lys Ile   1 5 10 15 Ala Lys Tyr Ile Gly Glu Asn Leu Gln Leu Leu Val Asp Arg Pro Asp              20 25 30 Gly Thr Tyr Cys Phe Arg Leu His Asn Asp Arg Val Tyr Tyr Val Ser          35 40 45 Glu Lys Ile Met Lys Leu Ala Ala Asn Ile Ser Gly Asp Lys Leu Val      50 55 60 Ser Leu Gly Thr Cys Phe Gly Lys Phe Thr Lys Thr His Lys Phe Arg  65 70 75 80 Leu His Val Thr Ala Leu Asp Tyr Leu Ala Pro Tyr Ala Lys Tyr Lys                  85 90 95 Val Trp Ile Lys Pro Gly Ala Glu Gln Ser Phe Leu Tyr Gly Asn His             100 105 110 Val Leu Lys Ser Gly Leu Gly Arg Ile Thr Glu Asn Thr Ser Gln Tyr         115 120 125 Gln Gly Val Val Val Tyr Ser Met Ala Asp Ile Pro Leu Gly Phe Gly     130 135 140 Val Ala Ala Lys Ser Thr Gln Asp Cys Arg Lys Val Asp Pro Met Ala 145 150 155 160 Ile Val Val Phe His Gln Ala Asp Ile Gly Glu Tyr Val Arg His Glu                 165 170 175 Glu Thr Leu Thr             180 <210> 93 <211> 130 <212> PRT <213> Homo sapiens <400> 93 Met Val Arg Met Asn Val Leu Ala Asp Ala Leu Lys Ser Ile Asn Asn   1 5 10 15 Ala Glu Lys Arg Gly Lys Arg Gln Val Leu Ile Arg Pro Cys Ser Lys              20 25 30 Val Ile Val Arg Phe Leu Thr Val Met Met Lys His Gly Tyr Ile Gly          35 40 45 Glu Phe Glu Ile Ile Asp Asp His Arg Ala Gly Lys Ile Val Val Asn      50 55 60 Leu Thr Gly Arg Leu Asn Lys Cys Gly Val Ile Ser Pro Arg Phe Asp  65 70 75 80 Val Gln Leu Lys Asp Leu Glu Lys Trp Gln Asn Asn Leu Leu Pro Ser                  85 90 95 Arg Gln Phe Gly Phe Ile Val Leu Thr Thr Ser Ala Gly Ile Met Asp             100 105 110 His Glu Glu Ala Arg Arg Lys His Thr Gly Gly Lys Ile Leu Gly Phe         115 120 125 Phe Phe     130 <210> 94 <211> 183 <212> PRT <213> Homo sapiens <400> 94 Met Thr Thr Ala Ser Thr Ser Gln Val Arg Gln Asn Tyr His Gln Asp   1 5 10 15 Ser Glu Ala Ala Ile Asn Arg Gln Ile Asn Leu Glu Leu Tyr Ala Ser              20 25 30 Tyr Val Tyr Leu Ser Met Ser Tyr Tyr Phe Asp Arg Asp Asp Val Ala          35 40 45 Leu Lys Asn Phe Ala Lys Tyr Phe Leu His Gln Ser His Glu Glu Arg      50 55 60 Glu His Ala Glu Lys Leu Met Lys Leu Gln Asn Gln Arg Gly Gly Arg  65 70 75 80 Ile Phe Leu Gln Asp Ile Lys Lys Pro Asp Cys Asp Asp Trp Glu Ser                  85 90 95 Gly Leu Asn Ala Met Glu Cys Ala Leu His Leu Glu Lys Asn Val Asn             100 105 110 Gln Ser Leu Leu Glu Leu His Lys Leu Ala Thr Asp Lys Asn Asp Pro         115 120 125 His Leu Cys Asp Phe Ile Glu Thr His Tyr Leu Asn Glu Gln Val Lys     130 135 140 Ala Ile Lys Glu Leu Gly Asp His Val Thr Asn Leu Arg Lys Met Gly 145 150 155 160 Ala Pro Glu Ser Gly Leu Ala Glu Tyr Leu Phe Asp Lys His Thr Leu                 165 170 175 Gly Asp Ser Asp Asn Glu Ser             180 <210> 95 <211> 303 <212> PRT <213> Homo sapiens <400> 95 Met Lys Pro Thr Gly Thr Asp Pro Arg Ile Leu Ser Ile Ala Ala Glu   1 5 10 15 Val Ala Lys Ser Pro Glu Gln Asn Val Pro Val Ile Leu Leu Lys Leu              20 25 30 Lys Glu Ile Ile Asn Ile Thr Pro Leu Gly Ser Ser Glu Leu Lys Lys          35 40 45 Ile Lys Gln Asp Ile Tyr Cys Tyr Asp Leu Ile Gln Tyr Cys Leu Leu      50 55 60 Val Leu Ser Gln Asp Tyr Ser Arg Ile Gln Gly Gly Trp Thr Thr Ile  65 70 75 80 Ser Gln Leu Thr Gln Ile Leu Ser His Cys Cys Val Gly Leu Glu Pro                  85 90 95 Gly Glu Asp Ala Glu Glu Phe Tyr Asn Glu Leu Leu Pro Ser Ala Ala             100 105 110 Glu Asn Phe Leu Val Leu Gly Arg Gln Leu Gln Thr Cys Phe Ile Asn         115 120 125 Ala Ala Lys Ala Glu Glu Lys Asp Glu Leu Leu His Phe Phe Gln Ile     130 135 140 Val Thr Asp Ser Leu Phe Trp Leu Leu Gly Gly His Val Glu Leu Ile 145 150 155 160 Gln Asn Val Leu Gln Ser Asp His Phe Leu His Leu Leu Gln Ala Asp                 165 170 175 Asn Val Gln Ile Gly Ser Ala Val Met Met Met Leu Gln Asn Ile Leu             180 185 190 Gln Ile Asn Ser Gly Asp Leu Leu Arg Ile Gly Arg Lys Ala Leu Tyr         195 200 205 Ser Ile Leu Asp Glu Val Ile Phe Lys Leu Phe Ser Thr Pro Ser Pro     210 215 220 Val Ile Arg Ser Thr Ala Thr Lys Leu Leu Leu Leu Met Ala Glu Ser 225 230 235 240 His Gln Glu Ile Leu Ile Leu Leu Arg Gln Ser Thr Cys Tyr Lys Gly                 245 250 255 Leu Arg Arg Leu Leu Ser Lys Gln Glu Thr Gly Thr Glu Phe Ser Gln             260 265 270 Glu Leu Arg Gln Leu Val Gly Leu Leu Ser Pro Met Val Tyr Gln Glu         275 280 285 Val Glu Glu Gln Ile Gln Thr Ile Lys Asp Val Ala Gly Asp Lys     290 295 300 <210> 96 <211> 264 <212> PRT <213> Homo sapiens <400> 96 Met Leu Leu Glu Ile Asn Arg Gln Lys Glu Glu Glu Asp Leu Lys Leu   1 5 10 15 Gln Leu Gln Leu Gln Arg Gln Arg Ala Met Arg Leu Ser Arg Glu Leu              20 25 30 Gln Leu Ser Met Leu Glu Ile Val His Pro Gly Gln Val Glu Lys His          35 40 45 Tyr Arg Glu Met Glu Glu Lys Ser Ala Leu Ile Ile Gln Lys His Trp      50 55 60 Arg Gly Tyr Arg Glu Arg Lys Asn Phe His Gln Gln Arg Gln Ser Leu  65 70 75 80 Ile Glu Tyr Lys Ala Ala Val Thr Leu Gln Arg Ala Ala Leu Lys Phe                  85 90 95 Leu Ala Lys Tyr Arg Lys Lys Lys Lys Leu Phe Ala Pro Trp Arg Gly             100 105 110 Leu Gln Glu Leu Thr Asp Ala Arg Arg Val Glu Leu Lys Lys Arg Val         115 120 125 Asp Asp Tyr Val Arg Arg His Leu Gly Ser Pro Met Ser Asp Val Val     130 135 140 Ser Arg Glu Leu His Ala Gln Ala Gln Glu Arg Leu Gln His Tyr Phe 145 150 155 160 Met Gly Arg Ala Leu Glu Glu Arg Ala Gln Gln His Arg Glu Ala Leu                 165 170 175 Ile Ala Gln Ile Ser Thr Asn Val Glu Gln Leu Met Lys Ala Pro Ser             180 185 190 Leu Lys Glu Ala Glu Gly Lys Glu Pro Glu Leu Phe Leu Ser Arg Ser         195 200 205 Arg Pro Val Ala Ala Lys Ala Lys Gln Ala His Leu Thr Thr Leu Lys     210 215 220 His Ile Gln Ala Pro Trp Trp Lys Lys Leu Gly Glu Glu Ser Gly Asp 225 230 235 240 Glu Ile Asp Val Pro Lys Asp Glu Leu Ser Ile Glu Leu Glu Asn Leu                 245 250 255 Phe Ile Gly Gly Thr Lys Pro Pro             260 <210> 97 <211> 592 <212> PRT <213> Homo sapiens <400> 97 Met Ala Pro Gly Gln Leu Ala Leu Phe Ser Val Ser Asp Lys Thr Gly   1 5 10 15 Leu Val Glu Phe Ala Arg Asn Leu Thr Ala Leu Gly Leu Asn Leu Val              20 25 30 Ala Ser Gly Gly Thr Ala Lys Ala Leu Arg Asp Ala Gly Leu Ala Val          35 40 45 Arg Asp Val Ser Glu Leu Thr Gly Phe Pro Glu Met Leu Gly Gly Arg      50 55 60 Val Lys Thr Leu His Pro Ala Val His Ala Gly Ile Leu Ala Arg Asn  65 70 75 80 Ile Pro Glu Asp Asn Ala Asp Met Ala Arg Leu Asp Phe Asn Leu Ile                  85 90 95 Arg Val Val Ala Cys Asn Leu Tyr Pro Phe Val Lys Thr Val Ala Ser             100 105 110 Pro Gly Val Thr Val Glu Glu Ala Val Glu Gln Ile Asp Ile Gly Gly         115 120 125 Val Thr Leu Leu Arg Ala Ala Ala Lys Asn His Ala Arg Val Thr Val     130 135 140 Val Cys Glu Pro Glu Asp Tyr Val Val Val Ser Thr Glu Met Gln Ser 145 150 155 160 Ser Glu Ser Lys Asp Thr Ser Leu Glu Thr Arg Arg Gln Leu Ala Leu                 165 170 175 Lys Ala Phe Thr His Thr Ala Gln Tyr Asp Glu Ala Ile Ser Asp Tyr             180 185 190 Phe Arg Lys Gln Tyr Ser Lys Gly Val Ser Gln Met Pro Leu Arg Tyr         195 200 205 Gly Met Asn Pro His Gln Thr Pro Ala Gln Leu Tyr Thr Leu Gln Pro     210 215 220 Lys Leu Pro Ile Thr Val Leu Asn Gly Ala Pro Gly Phe Ile Asn Leu 225 230 235 240 Cys Asp Ala Leu Asn Ala Trp Gln Leu Val Lys Glu Leu Lys Glu Ala                 245 250 255 Leu Gly Ile Pro Ala Ala Ala Ser Phe Lys His Val Ser Pro Ala Gly             260 265 270 Ala Ala Val Gly Ile Pro Leu Ser Glu Asp Glu Ala Lys Val Cys Met         275 280 285 Val Tyr Asp Leu Tyr Lys Thr Leu Thr Pro Ile Ser Ala Ala Tyr Ala     290 295 300 Arg Ala Arg Gly Ala Asp Arg Met Ser Ser Phe Gly Asp Phe Val Ala 305 310 315 320 Leu Ser Asp Val Cys Asp Val Pro Thr Ala Lys Ile Ile Ser Arg Glu                 325 330 335 Val Ser Asp Gly Ile Ile Ala Pro Gly Tyr Glu Glu Glu Ala Leu Thr             340 345 350 Ile Leu Ser Lys Lys Lys Asn Gly Asn Tyr Cys Val Leu Gln Met Asp         355 360 365 Gln Ser Tyr Lys Pro Asp Glu Asn Glu Val Arg Thr Leu Phe Gly Leu     370 375 380 His Leu Ser Gln Lys Arg Asn Asn Gly Val Val Asp Lys Ser Leu Phe 385 390 395 400 Ser Asn Val Val Thr Lys Asn Lys Asp Leu Pro Glu Ser Ala Leu Arg                 405 410 415 Asp Leu Ile Val Ala Thr Ile Ala Val Lys Tyr Thr Gln Ser Asn Ser             420 425 430 Val Cys Tyr Ala Lys Asn Gly Gln Val Ile Gly Ile Gly Ala Gly Gln         435 440 445 Gln Ser Arg Ile His Cys Thr Arg Leu Ala Gly Asp Lys Ala Asn Tyr     450 455 460 Trp Trp Leu Arg His His Pro Gln Val Leu Ser Met Lys Phe Lys Thr 465 470 475 480 Gly Val Lys Arg Ala Glu Ile Ser Asn Ala Ile Asp Gln Tyr Val Thr                 485 490 495 Gly Thr Ile Gly Glu Asp Glu Asp Leu Ile Lys Trp Lys Ala Leu Phe             500 505 510 Glu Glu Val Pro Glu Leu Leu Thr Glu Ala Glu Lys Lys Glu Trp Val         515 520 525 Glu Lys Leu Thr Glu Val Ser Ile Ser Ser Asp Ala Phe Phe Pro Phe     530 535 540 Arg Asp Asn Val Asp Arg Ala Lys Arg Ser Gly Val Ala Tyr Ile Ala 545 550 555 560 Ala Pro Ser Gly Ser Ala Ala Asp Lys Val Val Ile Glu Ala Cys Asp                 565 570 575 Glu Leu Gly Ile Ile Leu Ala His Thr Asn Leu Arg Leu Phe His His             580 585 590                                                                   <210> 98 <211> 672 <212> PRT <213> Homo sapiens <400> 98 Met Gly Val Gly Arg Leu Asp Met Tyr Val Leu His Pro Pro Ser Ala   1 5 10 15 Gly Ala Glu Arg Thr Leu Ala Ser Val Cys Ala Leu Leu Val Trp His              20 25 30 Pro Ala Gly Pro Gly Glu Lys Val Val Arg Val Leu Phe Pro Gly Cys          35 40 45 Thr Pro Pro Ala Cys Leu Leu Asp Gly Leu Val Arg Leu Gln His Leu      50 55 60 Arg Phe Leu Arg Glu Pro Val Val Thr Pro Gln Asp Leu Glu Gly Pro  65 70 75 80 Gly Arg Ala Glu Ser Lys Glu Ser Val Gly Ser Arg Asp Ser Ser Lys                  85 90 95 Arg Glu Gly Leu Leu Ala Thr His Pro Arg Pro Gly Gln Glu Arg Pro             100 105 110 Gly Val Ala Arg Lys Glu Pro Ala Arg Ala Glu Ala Pro Arg Lys Thr         115 120 125 Glu Lys Glu Ala Lys Ala Pro Arg Glu Leu Lys Lys Asp Pro Lys Pro     130 135 140 Ser Val Ser Arg Thr Gln Pro Arg Glu Val Arg Arg Ala Ala Ser Ser 145 150 155 160 Val Pro Asn Leu Lys Lys Thr Asn Ala Gln Ala Ala Pro Lys Pro Arg                 165 170 175 Lys Ala Pro Ser Thr Ser His Ser Gly Phe Pro Pro Val Ala Asn Gly             180 185 190 Pro Arg Ser Pro Pro Ser Leu Arg Cys Gly Glu Ala Ser Pro Pro Ser         195 200 205 Ala Ala Cys Gly Ser Pro Ala Ser Gln Leu Val Ala Thr Pro Ser Leu     210 215 220 Glu Leu Gly Pro Ile Pro Ala Gly Glu Glu Lys Ala Leu Glu Leu Pro 225 230 235 240 Leu Ala Ala Ser Ser Ile Pro Arg Pro Arg Thr Pro Ser Pro Glu Ser                 245 250 255 His Arg Ser Pro Ala Glu Gly Ser Glu Arg Leu Ser Leu Ser Pro Leu             260 265 270 Arg Gly Gly Glu Ala Gly Pro Asp Ala Ser Pro Thr Val Thr Thr Pro         275 280 285 Thr Val Thr Thr Pro Ser Leu Pro Ala Glu Val Gly Ser Pro His Ser     290 295 300 Thr Glu Val Asp Glu Ser Leu Ser Val Ser Phe Glu Gln Val Leu Pro 305 310 315 320 Pro Ser Ala Pro Thr Ser Glu Ala Gly Leu Ser Leu Pro Leu Arg Gly                 325 330 335 Pro Arg Ala Arg Arg Ser Ala Ser Pro His Asp Val Asp Leu Cys Leu             340 345 350 Val Ser Pro Cys Glu Phe Glu His Arg Lys Ala Val Pro Met Ala Pro         355 360 365 Ala Pro Ala Ser Pro Gly Ser Ser Asn Asp Ser Ser Ala Arg Ser Gln     370 375 380 Glu Arg Ala Gly Gly Leu Gly Ala Glu Glu Thr Pro Pro Thr Ser Val 385 390 395 400 Ser Glu Ser Leu Pro Thr Leu Ser Asp Ser Asp Pro Val Pro Leu Ala                 405 410 415 Pro Gly Ala Ala Asp Ser Asp Glu Asp Thr Glu Gly Phe Gly Val Pro             420 425 430 Arg His Asp Pro Leu Pro Asp Pro Leu Lys Val Pro Pro Pro Leu Pro         435 440 445 Asp Pro Ser Ser Ile Cys Met Val Asp Pro Glu Met Leu Pro Pro Lys     450 455 460 Thr Ala Arg Gln Thr Glu Asn Val Ser Arg Thr Arg Lys Pro Leu Ala 465 470 475 480 Arg Pro Asn Ser Arg Ala Ala Ala Pro Lys Ala Thr Pro Val Ala Ala                 485 490 495 Ala Lys Thr Lys Gly Leu Ala Gly Gly Asp Arg Ala Ser Arg Pro Leu             500 505 510 Ser Ala Arg Ser Glu Pro Ser Glu Lys Gly Gly Arg Ala Pro Leu Ser         515 520 525 Arg Lys Ser Ser Thr Pro Lys Thr Ala Thr Arg Gly Pro Ser Gly Ser     530 535 540 Ala Ser Ser Arg Pro Gly Val Ser Ala Thr Pro Pro Lys Ser Pro Val 545 550 555 560 Tyr Leu Asp Leu Ala Tyr Leu Pro Ser Gly Ser Ser Ala His Leu Val                 565 570 575 Asp Glu Glu Phe Phe Gln Arg Val Arg Ala Leu Cys Tyr Val Ile Ser             580 585 590 Gly Gln Asp Gln Arg Lys Glu Glu Gly Met Arg Ala Val Leu Asp Ala         595 600 605 Leu Leu Ala Ser Lys Gln His Trp Asp Arg Asp Leu Gln Val Thr Leu     610 615 620 Ile Pro Thr Phe Asp Ser Val Ala Met His Thr Trp Tyr Ala Glu Thr 625 630 635 640 His Ala Arg His Gln Ala Leu Gly Ile Thr Val Leu Gly Ser Asn Ser                 645 650 655 Met Val Ser Met Gln Asp Asp Ala Phe Pro Ala Cys Lys Val Glu Phe             660 665 670                                                                   <210> 99 <211> 417 <212> PRT <213> Homo sapiens <400> 99 Met Ser Leu Ser Asn Lys Leu Thr Leu Asp Lys Leu Asp Val Lys Gly   1 5 10 15 Lys Arg Val Val Met Arg Val Asp Phe Asn Val Pro Met Lys Asn Asn              20 25 30 Gln Ile Thr Asn Asn Gln Arg Ile Lys Ala Ala Val Pro Ser Ile Lys          35 40 45 Phe Cys Leu Asp Asn Gly Ala Lys Ser Val Val Leu Met Ser His Leu      50 55 60 Gly Arg Pro Asp Gly Val Pro Met Pro Asp Lys Tyr Ser Leu Glu Pro  65 70 75 80 Val Ala Val Glu Leu Lys Ser Leu Leu Gly Lys Asp Val Leu Phe Leu                  85 90 95 Lys Asp Cys Val Gly Pro Glu Val Glu Lys Ala Cys Ala Asn Pro Ala             100 105 110 Ala Gly Ser Val Ile Leu Leu Glu Asn Leu Arg Phe His Val Glu Glu         115 120 125 Glu Gly Lys Gly Lys Asp Ala Ser Gly Asn Lys Val Lys Ala Glu Pro     130 135 140 Ala Lys Ile Glu Ala Phe Arg Ala Ser Leu Ser Lys Leu Gly Asp Val 145 150 155 160 Tyr Val Asn Asp Ala Phe Gly Thr Ala His Arg Ala His Ser Ser Met                 165 170 175 Val Gly Val Asn Leu Pro Gln Lys Ala Gly Gly Phe Leu Met Lys Lys             180 185 190 Glu Leu Asn Tyr Phe Ala Lys Ala Leu Glu Ser Pro Glu Arg Pro Phe         195 200 205 Leu Ala Ile Leu Gly Gly Ala Lys Val Ala Asp Lys Ile Gln Leu Ile     210 215 220 Asn Asn Met Leu Asp Lys Val Asn Glu Met Ile Ile Gly Gly Gly Met 225 230 235 240 Ala Phe Thr Phe Leu Lys Val Leu Asn Asn Met Glu Ile Gly Thr Ser                 245 250 255 Leu Phe Asp Glu Glu Gly Ala Lys Ile Val Lys Asp Leu Met Ser Lys             260 265 270 Ala Glu Lys Asn Gly Val Lys Ile Thr Leu Pro Val Asp Phe Val Thr         275 280 285 Ala Asp Lys Phe Asp Glu Asn Ala Lys Thr Gly Gln Ala Thr Val Ala     290 295 300 Ser Gly Ile Pro Ala Gly Trp Met Gly Leu Asp Cys Gly Pro Glu Ser 305 310 315 320 Ser Lys Lys Tyr Ala Glu Ala Val Thr Arg Ala Lys Gln Ile Val Trp                 325 330 335 Asn Gly Pro Val Gly Val Phe Glu Trp Glu Ala Phe Ala Arg Gly Thr             340 345 350 Lys Ala Leu Met Asp Glu Val Val Lys Ala Thr Ser Arg Gly Cys Ile         355 360 365 Thr Ile Ile Gly Gly Gly Asp Thr Ala Thr Cys Cys Ala Lys Trp Asn     370 375 380 Thr Glu Asp Lys Val Ser His Val Ser Thr Gly Gly Gly Ala Ser Leu 385 390 395 400 Glu Leu Leu Glu Gly Lys Val Leu Pro Gly Val Asp Ala Leu Ser Asn                 405 410 415 Ile     <210> 100 <211> 2451 <212> DNA <213> Homo sapiens <400> 100 cgtgctttcc acgacggtga cacgcttccc tggattggcc agactgcctt ccgggtcact 60 gccatggagg agccgcagtc agatcctagc gtcgagcccc ctctgagtca ggaaacattt 120 tcagacctat ggaaactact tcctgaaaac aacgttctgt cccccttgcc gtcccaagca 180 atggatgatt tgatgctgtc cccggacgat attgaacaat ggttcactga agacccaggt 240 ccagatgaag ctcccagaat gccagaggct gctccccgcg tggcccctgc accagcagct 300 cctacaccgg cggcccctgc accagccccc tcctggcccc tgtcatcttc tgtcccttcc 360 cagaaaacct accagggcag ctacggtttc cgtctgggct tcttgcattc tgggacagcc 420 aagtctgtga cttgcacgta ctcccctgcc ctcaacaaga tgttttgcca actggccaag 480 acctgccctg tgcagctgtg ggttgattcc acacccccgc ccggcacccg cgtccgcgcc 540 atggccatct acaagcagtc acagcacatg acggaggttg tgaggcgctg cccccaccat 600 gagcgctgct cagatagcga tggtctggcc cctcctcagc atcttatccg agtggaagga 660 aatttgcgtg tggagtattt ggatgacaga aacacttttc gacatagtgt ggtggtgccc 720 tatgagccgc ctgaggttgg ctctgactgt accaccatcc actacaacta catgtgtaac 780 agttcctgca tgggcggcat gaaccggagg cccatcctca ccatcatcac actggaagac 840 tccagtggta atctactggg acggaacagc tttgaggtgc atgtttgtgc ctgtcctggg 900 agagaccggc gcacagagga agagaatctc cgcaagaaag gggagcctca ccacgagctg 960 cccccaggga gcactaagcg agcactgtcc aacaacacca gctcctctcc ccagccaaag 1020 aagaaaccac tggatggaga atatttcacc cttcagatcc gtgggcgtga gcgcttcgag 1080 atgttccgag agctgaatga ggccttggaa ctcaaggatg cccaggctgg gaaggagcca 1140 ggggggagca gggctcactc cagccacctg aagtccaaaa agggtcagtc tacctcccgc 1200 cataaaaaac tcatgttcaa gacagaaggg cctgactcag actgacattc tccacttctt 1260 gttccccact gacagcctcc cacccccatc tctccctccc ctgccatttt gggttttggg 1320 tctttgaacc cttgcttgca ataggtgtgc gtcagaagca cccaggactt ccatttgctt 1380 tgtcccgggg ctccactgaa caagttggcc tgcactggtg ttttgttgtgg gggaggagga 1440 tggggagtag gacataccag cttagatttt aaggttttta ctgtgaggga tgtttgggag 1500 atgtaagaaa tgttcttgca gttaagggtt agtttacaat cagccacatt ctaggtaggg 1560 gcccacttca ccgtactaac cagggaagct gtccctcact gttgaatttt ctctaacttc 1620 aaggcccata tctgtgaaat gctggcattt gcacctacct cacagagtgc attgtgaggg 1680 ttaatgaaat aatgtacatc tggccttgaa accacctttt attacatggg gtctagaact 1740 tgaccccctt gagggtgctt gttccctctc cctgttggtc ggtgggttgg tagtttctac 1800 agttgggcag ctggttaggt agagggagtt gtcaagtctc tgctggccca gccaaaccct 1860 gtctgacaac ctcttggtga accttagtac ctaaaaggaa atctcacccc atcccacacc 1920 ctggaggatt tcatctcttg tatatgatga tctggatcca ccaagacttg ttttatgctc 1980 agggtcaatt tcttttttct tttttttttt ttttttcttt ttctttgaga ctgggtctcg 2040 ctttgttgcc caggctggag tggagtggcg tgatcttggc ttactgcagc ctttgcctcc 2100 ccggctcgag cagtcctgcc tcagcctccg gagtagctgg gaccacaggt tcatgccacc 2160 atggccagcc aacttttgca tgttttgtag agatggggtc tcacagtgtt gcccaggctg 2220 gtctcaaact cctgggctca ggcgatccac ctgtctcagc ctcccagagt gctgggatta 2280 caattgtgag ccaccacgtc cagctggaag ggtcaacatc ttttacattc tgcaagcaca 2340 tctgcatttt caccccaccc ttcccctcct tctccctttt tatatcccat ttttatatcg 2400 atctcttatt ttacaataaa actttgctgc caaaaaaaaa aaaaaaaaaa a 2451 <210> 101 <211> 2233 <212> DNA <213> Homo sapiens <400> 101 ggcttccttc gttattggag ccaggcctac accccagcaa ccatgtccaa gggacctgca 60 gttggtattg atcttggcac cacctactct tgtgtgggtg ttttccagca cggaaaagtc 120 gagataattg ccaatgatca gggaaaccga accactccaa gctatgtcgc ctttacggac 180 actgaacggt tgatcggtga tgccgcaaag aatcaagttg caatgaaccc caccaacaca 240 gtttttgatg ccaaacgtct gattggacgc agatttgatg atgctgttgt ccagtctgat 300 atgaaacatt ggccctttat ggtggtgaat gatgctggca ggcccaaggt ccaagtagaa 360 tacaagggag agaccaaaag cttctatcca gaggaggtgt cttctatggt tctgacaaag 420 atgaaggaaa ttgcagaagc ctaccttggg aagactgtta ccaatgctgt ggtcacagtg 480 ccagcttact ttaatgactc tcagcgtcag gctaccaaag atgctggaac tattgctggt 540 ctcaatgtac ttagaattat taatgagcca actgctgctg ctattgctta cggcttagac 600 aaaaaggttg gagcagaaag aaacgtgctc atctttgacc tgggaggtgg cacttttgat 660 gtgtcaatcc tcactattga ggatggaatc tttgaggtca agtctacagc tggagacacc 720 cacttgggtg gagaagattt tgacaaccga atggtcaacc attttattgc tgagtttaag 780 cgcaagcata agaaggacat cagtgagaac aagagagctg taagacgcct ccgtactgct 840 tgtgaacgtg ctaagcgtac cctctcttcc agcacccagg ccagtattga gatcgattct 900 ctctatgaag gaatcgactt ctatacctcc attacccgtg cccgatttga agaactgaat 960 gctgacctgt tccgtggcac cctggaccca gtagagaaag cccttcgaga tgccaaacta 1020 gacaagtcac agattcatga tattgtcctg gttggtggtt ctactcgtat ccccaagatt 1080 cagaagcttc tccaagactt cttcaatgga aaagaactga ataagagcat caaccctgat 1140 gaagctgttg cttatggtgc agctgtccag gcagccatct tgtctggaga caagtctgag 1200 aatgttcaag atttgctgct cttggatgtc actcctcttt cccttggtat tgaaactgct 1260 ggtggagtca tgactgtcct catcaagcgt aataccacca ttcctaccaa gcagacacag 1320 accttcacta cctattctga caaccagcct ggtgtgctta ttcaggttta tgaaggcgag 1380 cgtgccatga caaaggataa caacctgctt ggcaagtttg aactcacagg catacctcct 1440 gcaccccgag gtgttcctca gattgaagtc acttttgaca ttgatgccaa tggtatactc 1500 aatgtctctg ctgtggacaa gagtacggga aaagagaaca agattactat cactaatgac 1560 aagggccgtt tgagcaagga agacattgaa cgtatggtcc aggaagctga gaagtacaaa 1620 gctgaagatg agaagcagag ggacaaggtg tcatccaaga attcacttga gtcctatgcc 1680 ttcaacatga aagcaactgt tgaagatgag aaacttcaag gcaagattaa cgatgaggac 1740 aaacagaaga ttctggacaa gtgtaatgaa attatcaact ggcttgataa gaatcagact 1800 gctgagaagg aagaatttga acatcaacag aaagagctgg agaaagtttg caaccccatc 1860 atcaccaagc tgtaccagag tgcaggaggc atgccaggag gaatgcctgg gggatttcct 1920 ggtggtggag ctcctccctc tggtggtgct tcctcagggc ccaccattga agaggttgat 1980 taagccaacc aagtgtagat gtagcattgt tccacacatt taaaacattt gaaggaccta 2040 aattcgtagc aaattctgtg gcagttttaa aaagttaagc tgctatagta agttactggg 2100 cattctcaat acttgaatat ggaacatatg cacaggggaa ggaaataaca ttgcacttta 2160 taaacactgt attgtaagtg gaaaatgcaa tgtcttaaat aaaactattt aaaattggaa 2220 aaaaaaaaaa aaa 2233 <210> 102 <211> 2765 <212> DNA <213> Homo sapiens <400> 102 gggagacgtg gtgccgctgc gggctcgctc tgccgtgcgc taggcttggt gggaaggcct 60 gttctcgagt ccgcgctttt cgtcaccgcc atgtcgggag gtggtgtgat tcgtggcccc 120 gcagggaaca acgattgccg catctacgtg ggtaacttac ctccagacat ccgaaccaag 180 gacattgagg acgtgttcta caaatacggc gctatccgcg acatcgacct caagaatcgc 240 cgcgggggac cgcccttcgc cttcgttgag ttcgaggacc cgcgagacgc ggaagacgcg 300 gtgtatggtc gcgacggcta tgattacgat gggtaccgtc tgcgggtgga gtttcctcga 360 agcggccgtg gaacaggccg aggcggcggc gggggtggag gtggccggag ctccccgagg 420 tcgctatggc ccccatccag gcggtctgaa aacagagtgg ttgtctctgg actgcctcca 480 agtggaagtt ggcaggattt aaaggatcac atgcgtgaag caggtgatgt atgttatgct 540 gatgtttacc gagatggcac tggtgtcgtg gagtttgtac ggaaagaaga tatgacctat 600 gcagttcgaa aactggataa cactaagttt agatctcatg agggagaaac tgcctacatc 660 cgggttaaag ttgatgggcc cagaagtcca agttatggaa gatctcgatc tcgaagccgt 720 agtcgtagca gaagccgtag cagaagcaac agcaggagtc gcagttactc cccaaggaga 780 agcagaggat caccacgcta ttctccccgt catagcagat ctcgctctcg tacataagat 840 gattggtgac actttttgta gaacccatgt tgtatacagt tttcctttat tcagtacaat 900 cttttcattt tttaattcaa actgttttgt tcagaatggg ctaaagtgtt gaattgcatt 960 cttgtaatat ccccttgctc ctaacatcta cattcccttc gtgtctttga taaattgtat 1020 tttaagtgat gtcatagaca ggattgttta aatttagtta actccatact cttcagactg 1080 tgatattgtg taaatgtcta tctgccctgg tttgtgtgaa ctgggatgtt gggggtgttt 1140 gtggttatct tacctgggga agttcttatg tttatcttgc ttttcatgtg tctttctgta 1200 gacatatctg aagagatgga ttaagaatgc tttggattaa ggattgtgga gcacatttca 1260 atcattttag gattgtcaaa aggaggattg aggaggatca gatcaataat ggaggcaatg 1320 gtatgactcc aagtgctatt gtcacagatg aaattggcag tattgacctt atactaaaag 1380 gcaggggtta aaaatgatta tatacatttt ccttaaaaca cttgcaaaca ttttattcag 1440 ttgtctttag ctacaattgc tttgcttttt aaaccttggc aattgtggca aaattatatt 1500 gcccattttg tagcaactta ttttgctccc ttccccccat ttttgtttta atagggacta 1560 atgtgggaag aactggctaa tttgtcacag tgcttagtta caactgttaa tgtgtgacct 1620 gctgttggtg tacatgtggg tacagggtgt ttttaaatcc aacaagatag agtataatat 1680 caatactgct aaatctgcat gtcctctgtg tgactgatag agcgttgcta tttcattttt 1740 ttaagacaaa atgaaagcaa aatatagagt tccaatgtat tggtgtagat aatctagttg 1800 ggaatacttt taagtctcac cttccccttt aaactaatat tcataattgg ttcatatgtt 1860 taaaagactt taatttacaa attaaattgc aaatgggagc attagattta gttttagact 1920 taggtgggta gcaatgccag taaacttaaa ttacgtaact tcttgcaacc acgaaacctg 1980 taatacgctg tacagtaaca agtgttggca ttatcagttg aactgtaaat acaaaatgct 2040 tcttccaatt agtctctatg atgattaagt ttctaaaatt tatctgaaca ccattcagaa 2100 acttgttttg gggaatttga tagttattga tgtgcatctg ttaaactgat gacagacata 2160 actcatcatt ccccagaaac cttttttgat tacagtatct aacattttgc ctcctctttt 2220 ttggttttgc tggttataaa ggtttggatt ggagagggct cactggatcc caatccttgg 2280 agctggatca ttggattcaa atcataatgt ggataggata gggaggatga attacccagg 2340 attcatggag cgggatcaga ttaccaggaa cataggagtg gattcctgcc ccaaccaaac 2400 cgcattcgtg tggatttttt tattcaactt aattggctat tccaaagatt ttttttttcc 2460 tatttttgac gattggagcc cttaagatgc acgatggaat tgtgtttttgg gttttttggt 2520 aaaaggagca aagcgaggac ctggagataa acgctggagc aatctccttg gaaggattca 2580 gcacgagtag atggtaaaca tttaaagggg aaaggggggg tttgtttaaa atagtaaatc 2640 agtaagtcac ttctaaattt aaagaaaaca aaattggagt tgaagaataa gtaggtttcc 2700 aattggctat tgccgttttc tttgaaaaaa taaacatttt ttaaaaaact aaaaaaaaaa 2760 aaaaa 2765 <210> 103 <211> 1059 <212> DNA <213> Homo sapiens <400> 103 gttttctgtc actggacgcc aaggagtttt cggtggctca gctgggtaac cggggatcac 60 catggcggcc tcattggtgg ggaagaagat cgtgtttgta acggggaacg ccaagaagct 120 ggaggaggtc gttcagattc taggagataa gtttccatgc actttggtgg cacagaaaat 180 tgacctgccg gagtaccaag gggagccgga tgagatttcc atacagaaat gtcaggaggc 240 agttcgccag gtacaggggc ccgtgctggt tgaggacact tgtctgtgct tcaatgccct 300 tggagggctc cccggcccct acataaagtg gtttctggag aagttaaagc ctgaaggtct 360 ccaccagctc ctggccgggt tcgaggacaa gtcagcctat gcgctctgca cgtttgcact 420 cagcaccggg gacccaagcc agcccgtgcg cctgttcagg ggccggacct cgggccggat 480 cgtggcaccc agaggctgcc aggactttgg ctgggacccc tgctttcagc ctgatggata 540 tgagcagacg tacgcagaga tgcctaaggc ggagaagaac gctgtctccc atcgcttccg 600 ggccctgctg gagctgcagg aatactttgg cagtttggca gcttgacttc tgcagctgga 660 ggaggcccct caggccgggg atctggggag ggctagccca aaacctcccg catcgggcag 720 gcaccccctg aagtacttcc ttcagggttt cccctttgtg agggtgtcga gtagcctcac 780 cggcctgtct ggaggagcag ctggctctgc tctgagaaac tctggcaagt ggacgccatt 840 ctcttgccct taggattcac tgctctctcc tacagccgcc aggcctgggg tcctgaaagg 900 accttgggtg gtaaagctgt acttggtggg agtgagggcg tggggaggaa ccatgcaaat 960 cgccttccat ggtttttaaa tgcagtaaat aacatttctg gatgagactt gtttccaaaa 1020 taaaccagct atatctgttt tgaaaaaaaa aaaaaaaaa 1059 <210> 104 <211> 1831 <212> DNA <213> Homo sapiens <400> 104 gttgaggact acgcgcggcc caggcctggg ccccccgctg ctccaggccg cgctgggcct 60 tgggcgggct gggtggcact ggcctgcggg ccgggcggcg agcggggggc gcgggcgggc 120 ctggctgcag cccacgggcc gggagacggg tgtgcaggtg tacaacagcc tcaccgggag 180 gaaggaaccc ctaatcgtgg cgcacgccga agccgcctcc tggtatagct gtggaccaac 240 tgtatatgat catgcgcacc ttggccatgc ttgctcatat gttagatttg atatcattcg 300 aaggatccta accaaggttt ttggatgcag catagtcatg gtgatgggta ttacagatgt 360 agatgataaa atcatcaaaa gagccaatga gatgaatatt tcccccgctt ccctcgccag 420 tctttatgag gaagacttca agcaggacat ggcagccctg aaggttctcc cacccacggt 480 gtacctgagg gtaaccgaaa atattcctca gataatttct ttcattgaag gaatcattgc 540 ttcgtgggaa cgcttattca acggcaaaag gcaatgtcta cttcgatctg aaagtctaga 600 ggagacaaag tatggcaaaa ttggtcggcg tggtccctgg tccagtccgg agaccagcgg 660 acttctgaca agccgtcatg ccaatgactt cgccctgtgg aaggcggcca aaccccagga 720 ggtgttctgg gcctctccct ggggacccgg gaggccgggc tggcacatcg agtgctctgc 780 catcgctagt atggtatttg gaagtcaact ggatatccat tcaggtggga tagatttagc 840 ttttccacat catgagaacg aaattgcaca gtgcgaagtc tttcatcagt gcgagcagtg 900 gggaaattat tttctgcatt ctgggcattt gcacgccaaa ggcaaagaag aaaaaatgtc 960 caaatcatta aagaactaca ttactattaa ggactttctg aagacctttt cccccgatgt 1020 cttccggttc ttctgcctgc ggagcagcta ccgctcagcc atcgactaca gtgacagcgc 1080 catgctccaa gctcagcagc tgctcctggg gctgggctct ttcctggagg acgcacgtgc 1140 ctacatgaag gggcagctgg cctgcggctc cgtcagggaa gcgatgctgt gggagaggct 1200 ctccagcacc aagagggccg tgaaggcggc cttggcagat gattttgaca cacccagggt 1260 ggttgatgcc atcctgggcc ttgcacacca cgggaatgga cagctcaggg cgtccctgaa 1320 ggaacctgaa gggccgagaa gtcctgctgt gtttggtgcc atcatctctt actttgaaca 1380 gttttttgaa actgttggaa tttctctggc aaatcaacag tacgtttcag gagacggcag 1440 cgaggctacc ttgcatggtg tggtggacga gctggtgcgg ttccggcaga aggtccggca 1500 gtttgcgctg gccatgcccg aggccacggg ggacgcccgg cggcagcagc tcctagaaag 1560 gcagcccctg ctggaagcat gcgacaccct gcgccggggc ctgactgccc acggcatcaa 1620 catcaaggac agaagcagta caacatccac gtgggaactg ctggatcaaa ggacaaaaga 1680 ccaaaaatca gcgggctgag gatggagcac agccatgaac ctgctcacga caagacgcac 1740 ccatgcttct cagggtcaag gctttatgtt aaagcttcct gtcggggctg ctaggtcagc 1800 attaaagtaa ggcaaccaaa aaaaaaaaaa a 1831 <210> 105 <211> 1356 <212> DNA <213> Homo sapiens <400> 105 cccgggcttc tgtgaaacat ggcggtaggc tgggaccata acacaagcat gactatatga 60 aggaagagga aggttttcct gaagatgagg cgactgaatc ggaaaaaaac tttaagtttg 120 gtaaaagagt tggatgcctt tccgaaggtt cctgagagct atgtagagac ttcagccagt 180 ggaggtacag tttctctaat agcatttaca actatggctt tattaaccat aatggaattc 240 tcagtatatc aagatacatg gatgaagtat gaatacgaag tagacaagga tttttctagc 300 aaattaagaa ttaatataga tattactgtt gccatgaagt gtcaatatgt tggagcggat 360 gtattggatt tagcagaaac aatggttgca tctgcagatg gtttagttta tgaaccaaca 420 gtatttgatc tttcaccaca gcagaaagag tggcagagga tgctgcagct gattcagagt 480 aggctacaag aagagcattc acttcaagat gtgatattta aaagtgcttt taaaagtaca 540 tcaacagctc ttccaccaag agaagatgat tcatcacagt ctccaaatgc atgcagaatt 600 catggccatc tatatgtcaa taaagtagca gggaattttc acataacagt gggcaaggca 660 attccacatc ctcgtggtca tgcacatttg gcagcacttg tcaaccatga atcttacaat 720 ttttctcata gaatagatca tttgtctttt ggagagcttg ttccagcaat tattaatcct 780 ttagatggaa ctggaaaaat tgctatagat cacaaccaga tgttccaata ttttattaca 840 gttgtgccaa caaaactaca tacatataaa atatcagcag acacccatca gttttctgtg 900 acagaaaggg aacgtatcat taaccatgct gcaggcagcc atggagtctc tgggatattt 960 atgaaatatg atctcagttc tcttatggtg acagttactg aggagcacat gccattctgg 1020 cagttttttg taagactctg tggtattgtt ggaggaatct tttcaacaac aggcatgtta 1080 catggaattg gaaaatttat agttgaaata atttgctgtc gtttcagact tggatcctat 1140 aaacctgtca attctgttcc ttttgaggat ggccacacag acaaccactt acctctttta 1200 gaaaataata cacattaaca cctcccgatt gaaggagaaa aactttttgc ctgagacata 1260 aaaccttttt ttaataataa aatattgtgc aatatattca aagaaaagaa aacacaaata 1320 agcagaaaac atacttattt taaaaaaaaa aaaaaa 1356 <210> 106 <211> 1890 <212> DNA <213> Homo sapiens <400> 106 cagagccgct gccggagggt cgttttaaag ggcccgcgcg ttgccgcccc ctcggcccgc 60 catgctgcta tccgtgccgc tgctgctcgg cctcctcggc ctggccgtcg ccgagcctgc 120 cgtctacttc aaggagcagt ttctggacgg agacgggtgg acttcccgct ggatcgaatc 180 caaacacaag tcagattttg gcaaattcgt tctcagttcc ggcaagttct acggtgacga 240 ggagaaagat aaaggtttgc agacaagcca ggatgcacgc ttttatgctc tgtcggccag 300 tttcgagcct ttcagcaaca aaggccagac gctggtggtg cagttcacgg tgaaacatga 360 gcagaacatc gactgtgggg gcggctatgt gaagctgttt cctaatagtt tggaccagac 420 agacatgcac ggagactcag aatacaacat catgtttggt cccgacatct gtggccctgg 480 caccaagaag gttcatgtca tcttcaacta caagggcaag aacgtgctga tcaacaagga 540 catccgttgc aaggatgatg agtttacaca cctgtacaca ctgattgtgc ggccagacaa 600 cacctatgag gtgaagattg acaacagcca ggtggagtcc ggctccttgg aagacgattg 660 ggacttcctg ccacccaaga agataaagga tcctgatgct tcaaaaccgg aagactggga 720 tgagcgggcc aagatcgatg atcccacaga ctccaagcct gaggactggg acaagcccga 780 gcatatccct gaccctgatg ctaagaagcc cgaggactgg gatgaagaga tggacggaga 840 gtgggaaccc ccagtgattc agaaccctga gtacaagggt gagtggaagc cccggcagat 900 cgacaaccca gattacaagg gcacttggat ccacccagaa attgacaacc ccgagtattc 960 tcccgatccc agtatctatg cctatgataa ctttggcgtg ctgggcctgg acctctggca 1020 ggtcaagtct ggcaccatct ttgacaactt cctcatcacc aacgatgagg catacgctga 1080 ggagtttggc aacgagacgt ggggcgtaac aaaggcagca gagaaacaaa tgaaggacaa 1140 acaggacgag gagcagaggc ttaaggagga ggaagaagac aagaaacgca aagaggagga 1200 ggaggcagag gacaaggagg atgatgagga caaagatgag gatgaggagg atgaggagga 1260 caaggaggaa gatgaggagg aagatgtccc cggccaggcc aaggacgagc tgtagagagg 1320 cctgcctcca gggctggact gaggcctgag cgctcctgcc gcagagctgg ccgcgccaaa 1380 taatgtctct gtgagactcg agaactttca tttttttcca ggctggttcg gatttggggt 1440 ggattttggt tttgttcccc tcctccactc tcccccaccc cctccccgcc cttttttttt 1500 ttttttttaa actggtattt tatctttgat tctccttcag ccctcacccc tggttctcat 1560 ctttcttgat caacatcttt tcttgcctct gtccccttct ctcatctctt agctcccctc 1620 caacctgggg ggcagtggtg tggagaagcc acaggcctga gatttcatct gctctccttc 1680 ctggagccca gaggagggca gcagaagggg gtggtgtctc caacccccca gcactgagga 1740 agaacggggc tcttctcatt tcacccctcc ctttctcccc tgcccccagg actgggccac 1800 ttctgggtgg ggcagtgggt cccagattgg ctcacactga gaatgtaaga actacaaaca 1860 aaatttctat taaattaaat tttgtgtctc 1890 <210> 107 <211> 1997 <212> DNA <213> Homo sapiens <400> 107 gggaggctga ggcacaagaa ttgcttgaac ccaggaggcg gaggtttcag tgagctaaca 60 tcgtgccatt gcactccagc ctgggccacc aagcaagact ctgtctcaaa aaaaaagggg 120 agttgctaga gagaaatcac aaaatggtcc agagtgttgc ccctgcaaat ctctactttc 180 caacctcaac tggacctctg caccacccaa tagttttcct aggatcacac tcctcccaga 240 gcagcttttg caactgttgt cactttcctc aagtcctctt tttttacatt cccaccctca 300 ctctcagcaa agacatttcc ttctttttca ctgagaacat ggagagcatc ttgtttccaa 360 cattctcttt tcctgcagta tctgcatctc cttccatttc tcagtgaaac agagtttctc 420 ccatccaaag ttactcctgc tgcctgtact ttgaatttgc gagctgccac ctccttcagt 480 cctttcctcc cttgatttcc cctcttttcc ctgatgtagt ccttcgcctc attgtcttta 540 gctgacatat ttatgtttac gtaatttaaa aaaaaaactc taatagcaac agaaacttct 600 ttaatacact tgcattgcaa actagttcca tatctctttc ttttatttca caatcaagct 660 tagacaaagt tgtctacact cactgtttat gtttcctggt actgacaatt gctggtttcc 720 aaatcattca caaattttta ttattccaaa tgctagtacg attgggaggc ctatttattt 780 atttattgtg agaaatataa ttcaagaaga atggaatgtt tgcatcaata tgatccattt 840 attctggaga caaagtgtag catattgttt aagcttgtag actatgtatt tagaactgag 900 tagctcacta tttatgtgat cttaggcaag ttaatttaca tgtctgagcc ccagtatttt 960 tatacgaata aaataggtaa gcaataatgc ctactttata gggttgtttt gaagatcaaa 1020 ttgatgcagg caaacccaaa aattggggct cttggcttca ggtaggaagg aaagaattca 1080 agggtggtga cagagtaaag taaaagcaaa gcaagtttat tagcacacca gagaacagga 1140 aaatggctgc tccatagaca gagcagggct accccattgg cagagtagca ctcatggatt 1200 gctgactaac aatatttata gctaatcctt aattatatgc taaataaggg gtgggttatt 1260 cacaaatttt ctatgaaagg gatggggagt tcctagaacc aagggttcct ccccttttaa 1320 accatatgag ggacacattt ttaagcagta aagtgctcaa aatgtaaaag aagacaatgc 1380 ccctgagaaa tgggtcagaa ctgagaggct gactcatatc caataaggac tcaatattgt 1440 tacctgctat gtaaagggtt accagaagct cctctgtgga gatagtaagg tgtccagtgg 1500 gagctgtggg ggatctcagg ccccatgagt cctctgttct cttggctatt atgggtttgg 1560 ttgaccccct cagagcctgg ggcagccctt ttccagtggt cctcttgctt acagagggca 1620 cactgacttt ggctcagggg ccactaagtc aggctctcat ttatgcatcc cagatgccaa 1680 tctcatggca cttcctcaag atgtgtaact ctgaggtggt agggggctca aggcagccac 1740 caggaactgt gtgttttgac tatttctttg gttttatctg cctcctntgc cctgttccta 1800 ctgttgtaaa ctccaaaggc catgtttaag agttggcctg gccaggtgtg gtggcttaca 1860 cctgtaatcc cagctntttg ggaggccgaa gcaggctgac ctcgtgattc gcccgcctcg 1920 gcctcccaaa gtgatgggat tacaggcgtg agccaccgcg tccggtcatt ttattagtct 1980 ttaaaaaaaa aaaaaaa 1997 <210> 108 <211> 825 <212> DNA <213> Homo sapiens <400> 108 cgcctcggag gcgttcagct gcttcaagat gaagctgaac atctccttcc cagccactgg 60 ctgccagaaa ctcattgaag tggacgatga acgcaaactt cgtactttct atgagaagcg 120 tatggccaca gaagttgctg ctgacgctct gggtgaagaa tggaagggtt atgtggtccg 180 aatcagtggt gggaacgaca aacaaggttt ccccatgaag cagggtgtct tgacccatgg 240 ccgtgtccgc ctgctactga gtaaggggca ttcctgttac agaccaagga gaactggaga 300 aagaaagaga aaatcagttc gtggttgcat tgtggatgca aatctgagcg ttctcaactt 360 ggttattgta aaaaaaggag agaaggatat tcctggactg actgatacta cagtgcctcg 420 ccgcctgggc cccaaaagag ctagcagaat ccgcaaactt ttcaatctct ctaaagaaga 480 tgatgtccgc cagtatgttg taagaaagcc cttaaataaa gaaggtaaga aacctaggac 540 caaagcaccc aagattcagc gtcttgttac tccacgtgtc ctgcagcaca aacggcggcg 600 tattgctctg aagaagcagc gtaccaagaa aaataaagaa gaggctgcag aatatgctaa 660 acttttggcc aagagaatga aggaggctaa ggagaagcgc caggaacaaa ttgcgaagag 720 acgcagactt tcctctctgc gagcttctac ttctaagtct gaatccagtc agaaataaga 780 ttttttgagt aacaaataaa taagatcaga ctctgaaaaa aaaaa 825 <210> 109 <211> 887 <212> DNA <213> Homo sapiens <400> 109 gcgggggcca ggggtgggcg cgggagacgg ggcggtaccc ggggtgggag agggacgggg 60 agggggcgag gggcggaggc cgagggggca gggggggtgg gcggcggcca gtgtttacag 120 atgagcttta actgccgcct caggcgtgga gacggagacc ccgcagcccg gcggcgcctc 180 agcccttcaa cgacagtatt gagtggtcag gttacaataa accggagaga aaaggtccgc 240 ttgcactttt tttagttttc ttatttttag acacccctcc cctccagggt gatctttaaa 300 aaagcaaaac aaaaaacacg acttttccag ccgctcagcc gttttttcct ttcgtccgaa 360 gccgttttct gatttgactt ttctcgccgg ccggtctcag gccgcacaga cgttccagag 420 gaggagggtg acatttttac tccctttttg gggctaacca tttatgcttt tgtacatcaa 480 ccgtgcgcgg ccggaggggg gcaggggggc gggggccgag gggcgttcca atcaaatttc 540 taactttctg ttaattatta atcccctttt tactgcggtt tctgttgtca tttttaaaat 600 ttttttaatt tttttttttt ttttactttt actttttacc tcttgtgtatatgtagggaa 660 tttataggga aatatgtact ttatggaata aattttaaga actaaaatat attttatttt 720 aaataaagta atggaccttt aatcttacgc agctaaatta ctgattatat atttgctgag 780 ctgatttaag ggttaaaaaa attgtatcaa gagttttatt ttttgacttc aaagccttgt 840 taataaagcc tcttttatac atgtgaaaaa aaaaaaaaaa aaaaaaa 887 <210> 110 <211> 1588 <212> DNA <213> Homo sapiens <400> 110 gttgccgaga gatggatgag cagattagac tgatggacca gaacctgaag tgtctgagtg 60 ctgctgaaga aaagtactct caaaaagaag ataaatatga ggaagaaatc aagattctta 120 ctgataaact caaggaggca gagacccgtg ctgagtttgc tgagagatcg gtagccaagc 180 tggaaaagac aattgatgac ctggaagata aactgaaatg caccaaagag gagcacctct 240 gtacacaaag gatgctggac cagaccctgc ttgacctgaa tgagatgtag aacgccccag 300 tcccaccctg ctgctgctcc tccctctgac ccagactccg cctgaggcca gcctgcggga 360 agctgacctt taactgaggg ctgatcttta actggaaggc tgctttctcc tttcaccacc 420 ccctccttcc ctgtgtcttt ttcgccaaac tgtctctgcc tcttcccgga gaatccagct 480 gggctagagg ctgagcacct ttggaaacaa catttaaggg aatgtgagca caatgcataa 540 tgtctttaaa aagcatgttg tgatgtacac attttgtaat tacctttttt gttgttttgt 600 agcaaccatt tgtaaaacat tccaaataat tccacagtcc tgaagcagca atcgaatccc 660 tttctcactt ttggaaggtg acttttcacc ttaatgcata ttcccctctc catagaggag 720 aggaaaaggt gtaggcctgc cttaccgaga gccaaacaga gcccagggag actccgctgt 780 gggaaacctc attgttctgt acaaagtact agctaaacca gaaaggtgat tccaggagga 840 gttagccaaa caacaacaaa aacaaaaaat gtgctgttca agttttcagc tttaagatat 900 ctttggataa tgttatttct attttttatt tttttcatta gaagttacca aattaagatg 960 gtaagacctc tgagaccaaa attttgtccc atctctaccc cctcacaact gcttacagaa 1020 tggatcatgt cccccttatg ttgaggtgac cacttaattg ctttcctgcc tccttgaaag 1080 aaagaaagaa agaagactgt gtttttgcca ctgatttagc catgtgaaac tcatctcatc 1140 acccttttct gggtttgaag ctgctgtctc tagaagtgcc atctcaattg tgctttgtat 1200 cagtcagtgc tggagaaatc ttgaatagct tatgtacaaa actttttaaa ttttatatta 1260 ttttgaaact ttgctttggg tttgtggcac cctggccacc ccatctggct gtgacagcct 1320 ctgcagtccg tgggctggca gtttgttgat cttttaagtt tccttcccta cccagtcccc 1380 attttctggt aaggtttcta ggaggtctgt taggtgtaca tcctgcagct tattggctta 1440 aaatgtactc tccttttatg tggtctcttt ggggccgatt gggagaaaga gaaatcaata 1500 gtgcaactgt tttgatactg aatattgaca agtgtctttt tgaaataaag aaccagtccc 1560 tccaaccctc aaaaaaaaaa aaaaaaaa 1588 <210> 111 <211> 1623 <212> DNA <213> Homo sapiens <400> 111 cccccagacc attatggcct ccctgcagtt tgtgatctct ttgcctgtat gcagcttaaa 60 gttgataaag agaagtggtt atatcgaact cctctacaga tgtgaaggaa tggacaagag 120 ttgagcagcc tttctgctga ttatcacaca tcatgagctg agtgactgca gcttgccaaa 180 tctttgtgtt tctgggtctg accaattagc ttagttcttc tcctgcctaa ttttgaacta 240 gtaaagcaaa gtgagtcatc agattatgag ttactgttta aaagaaaaat gctgtttatt 300 catgctgagg tgattcagtt ccctccttct tacagaagta ttttaattca ccccacacta 360 gaaatgcagc atctttgtgg acgtcttttt cacaagcctc caaggctcct tagattgggt 420 cgttactaaa agtacattaa aacactcttg tttatcgaag tatattgatg tattctaaag 480 ctagtaaact tccctaacgt ttaattgccc tacagatgct tctcttgctg tgggttttct 540 tttgttagtg gtctgaaata attattttcc tgttctatta atacatagtg tattttgcac 600 aaaaaaatta acctggtcaa tagtgattac caaaatatat attaataatc ttggcaattt 660 ttgacattaa ttatgaaaca ttttagccca cgttagttct acattattct tcacttaaac 720 tcagctactg caaattttgt ctttctgtaa atgttattaa aatatccagt gagctcttta 780 gaaggactca gtattatttc aagactattt ttgaggtaat tctagccttt taaaatattc 840 tacagaccta cggggcttaa aagaacccca gtaccgacta agcaaatagg caaaagacat 900 gttggaaatg tagtatagta cttgaaacag tcactatcat agggataatt ggtgcatcct 960 gtgtaaatgg aagctgagct tgacacctgg tgcttttaag tagggataaa gtcatcctct 1020 cactgcaagc acagcatacc tgtacctcca aaagtgacgt tttagtgaac aggccgtttt 1080 caacacttgt gccttggggt gttcattgaa gctttgtgaa aactactgat gttttctcag 1140 tctccttaaa gttacgtcca tgctttaaaa tgtctgtgta ggagagaagt ggggtttata 1200 atgttttctc taagatatct ttgctgcttt ccagactttg aaactattaa gcttcttaac 1260 tgcctcttac cggaaatact tctggggaaa cttcatggtc ccaaaatgtc attgccatac 1320 agcttcacta gagttctttg aaccacagct gaaaagagct ttgtattatt ttttaattcc 1380 ctccccagat atcatttagg agtattatat aaaggtggtg ggcaaaaaca atgtaaggag 1440 cctttccagt tatcttgagt tgcagctctg tagtttcttg aggccaaaca cactgtattt 1500 tacaagtcaa aatataattt acattaatca ctatgttaat gagtatgtaa aacattcttt 1560 tgcattgatg aattttgtat ctgcttccat taaaagcata acagccataa aaaaaaaaaa 1620 aaa 1623 <210> 112 <211> 895 <212> DNA <213> Homo sapiens <400> 112 gccatcttgc gtccccgcgt gtgtgcgcct aatctcaggt ggtccacccg agaccccttg 60 agcaccaacc ctagtccccc gcgcggcccc ttattcgctc cgacaagatg aaagaaacaa 120 tcatgaacca ggaaaaactc gccaaactgc aggcacaagt gcgcattggt gggaaaggaa 180 ctgctcgcag aaagaagaag gtggttcata gaacagccac agcagatgac aaaaaacttc 240 agttctcctt aaagaagtta ggggtaaaca atatctctgg tattgaagag gtgaatatgt 300 ttacaaacca aggaacagtg atccacttta acaaccctaa agttcaggca tctctggcag 360 cgaacacttt caccattaca ggccatgctg agacaaagca gctgacagaa atgctaccca 420 gcatcttaaa ccagcttggt gcggatagtc tgactagttt aaggagactg gccgaagctc 480 tgcccaaaca atctgtggat ggaaaagcac cacttgctac tggagaggat gatgatgatg 540 aagttccaga tcttgtggag aattttgatg aggcttccaa gaatgaggca aactgaattg 600 agtcaacttc tgaagataaa acctgaagaa gttactggga gctgctattt tatattatga 660 ctgcttttta agaaattttt gtttatggat ctgataaaat ctagatctct aatattttta 720 agcccaagcc ccttggacac tgcagctctt ttcagttttt gcttatacac aattcattct 780 ttgcagctaa ttaagccgaa gaagcctggg aatcaagttt gaaacaaaga ttaataaagt 840 tctttgccta gtaaaaaaaa aaaaaaaaaa aaaaataaaa aaaaaaaaaa aaaaa 895 <210> 113 <211> 1978 <212> DNA <213> Homo sapiens <400> 113 ggccggagcg gcgcggcagc ggcaggaccg ccgtggcgcc tagagtagcg acccgggggg 60 agcgcggggc gacgctggct gcagggaccc ggtgacagcg tgagaggtac taggttttga 120 caagcttgca tcatgcgtga gtataagcta gtcgttcttg gctcaggagg cgttggaaag 180 tctgctttga ctgtacaatt tgttcaagga atttttgtag aaaaatacga tcctacgata 240 gaagattctt atagaaagca agttgaagta gatgcacaac agtgtatgct tgaaatcttg 300 gatactgcag gaacggagca atttacagca atgagggatt tatacatgaa aaatggacaa 360 ggatttgcat tagtttattc catcacagca cagtccacat ttaacgattt acaagacctg 420 agagaacaga ttcttcgagt taaagacact gatgatgttc caatgattct tgttggtaat 480 aagtgtgact tggaagatga aagagttgta gggaaggaac aaggtcaaaa tctagcaaga 540 caatggaaca actgtgcatt cttagaatct tctgcaaaat caaaaataaa tgttaatgag 600 atcttttatg acctagtgcg gcaaattaac agaaaaactc cagtgcctgg gaaggctcgc 660 aaaaagtcat catgtcagct gctttaatat actaaatgca ttgtagctct gagccaggtc 720 tgaagaactg ttgcccaatt caacagtgcc agcattccaa ctttgttaaa cctaccaaca 780 tcttaaatgg actttcctgt ggtggtaccc tttaagaggc ggatgaaagc tactatatca 840 gtttgcacat tctaatcact ttccagtatc acaagagaga tttttactta tataatagtc 900 ctagagtttg cagctggtaa aaccagaggc tacatccagt attactgcta agagacattc 960 ttcatccacc aatgttgtac atgtatgaaa atggtgtact gtatacttta acatgcccca 1020 tactttgtat tggagagtac aataatgtaa atcctaaaag caccactatt ttagcataat 1080 aaaagaaagt ccaaagagct cctatataga ctactccaga taacttcgct tctttgatac 1140 ttgtagctta ttgtaatttt ttttaagaaa ttcaaggtca ttattattgt acaaaataag 1200 cgctttgatt aacacagcta tatagttttt ttaattttta aaaaacctgt ggagacggtg 1260 atcttgtctt taaaacatga tagtcctttc agtataatgt cttagattaa agacgttgcc 1320 tttaatatct gttgggaagg aaatgtccag acttttcaaa tctcttatta tatgtttcct 1380 ttttttgttt acatagggaa caatgtttat agtcgtgtgt acagtggggg tctacaacaa 1440 gaagtgtata ttttcaaaca attttttaat gatttaacaa tttttgtaaa tcattttcag 1500 gcttctgcag ctgtagattc tcactgtgaa tcccttgctt gctcatgcat aagtgtattt 1560 gcaataccaa atatacaggt ttagtatttt tgcctgttag tgattgtttc acatgtgtaa 1620 cgttttggtt gagatgttaa atggtggacg agtactgtgg atgtgaatgt gggaagtaat 1680 tttaatcata tgtaattggt cacaaggcct aatttgcagt aactattgct gttttattta 1740 acaatgcctt gttgctttgt atgcattaat gtttggatgt aaagattgtg tgtctatcca 1800 acagggagcc acagtattta aattgaccaa cctaatgtta caactacttt gaggtggcca 1860 aatgtaaact aaaagcctta attaaagtgg tgcaattttg tataacttag catcagtagt 1920 tcaataaatt tggattgcca tgcaagggct tgccttataa aaaaaaaaaa aaaaaaaa 1978 <210> 114 <211> 905 <212> DNA <213> Homo sapiens <400> 114 gttctagatc gcgagtggcc gccctttttt tttttttttt tgcaggaagg aattccattt 60 attgtggatg cattttcaca atatatgttt attggagcga tccattatca gtgaaaagta 120 tcaagtgttt ataaaatttt taggaatggc agattcacag aacatgctag tcagcctgca 180 gtattcctcc agaagagcta accagggcag ggctggcatg agaagtgaca tctgcgttac 240 aaagtctatc ttcctcataa gtctgtaaag agcaattgaa tcttctagct ttagcaaacc 300 taagccaaag gaaggaaagc cacgaagaat gcagaagtca aaccctcatg acaaagtagg 360 cacaagtcta caataagcta aatcagaatt tacaaataca agtgtcccag gtagcattga 420 ctcccgtcat tggagtgaaa tggatcaaag tttgaattaa ggcctatggt aaggtaacat 480 tgctttgttg tacttttgaa caagagctcc tcctgatcac tattacatat ttttctagaa 540 aatctaaagt tcagaagaga atgtatcact gctgactttt attccaatat ttggatggag 600 taagttttag ggtagaattt tgttcagttt ggatttaatc ttttgaaaag taaattcctt 660 gtttactggt ttgactataa ttctctgtta tctttacgag gtaaaactgc aagctgacta 720 gcatgttctg tgaatctgcc attcctaaaa attttataaa cacttgatac ttttcactga 780 taatggatcg ctccaataaa catatattgt gaaaatgcat ccacaataaa tggaattcct 840 tcctgcaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 900 aaaaa 905 <210> 115 <211> 1015 <212> DNA <213> Homo sapiens <400> 115 ctcatgcacc taattggaag cgccacccta gcaatatcaa ccattaacct tccctctaca 60 cttatcatct tcacaattct aattctactg actatcctag aaatcgctgt cgccttaatc 120 caagcctacg ttttcacact tctagtaagc ctctacctgc acgacaacac ataatgaccc 180 accaatcaca tgcctatcat atagtaaaac ccagcccatg acccctaaca ggggccctct 240 cagccctcct aatgacctcc ggcctagcca tgtgatttca cttccactcc ataacgctcc 300 tcatactagg cctactaacc aacacactaa ccatatacca atgatggcgc gatgtaacac 360 gagaaagcac ataccaaggc caccacacac cacctgtcca aaaaggcctt cgatacggga 420 taatcctatt tattacctca gaagtttttt tcttcgcagg atttttctga gccttttacc 480 actccagcct agcccctacc ccccaattag gagggcactg gcccccaaca ggcatcaccc 540 cgctaaatcc cctagaagtc ccactcctaa acacatccgt attactcgca tcaggagtat 600 caatcacctg agctcaccat agtctaatag aaaacaaccg aaaccaaata attcaagcac 660 tgcttattac aattttactg ggtctctatt ttaccctcct acgagtactt cgagtctccc 720 ttcaccattt ccgacggcat ctacggctca acattttttg tagccacagg cttccacgga 780 cttcacgtca ttattggctc aactttcctc actatctgct tcatccgcca actaatattt 840 cactttacat ccaaacatca ctttggcttc gaagccgccg cctgatactg gcattttgta 900 gatgtgggtt gactatttct gtatgtctcc atctattgat gagggtttta aaaaaaaaaa 960 aaaaaaaaaa taaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaa 1015 <210> 116 <211> 1317 <212> DNA <213> Homo sapiens <400> 116 gggtaatctc tactttccta tactgccaaa gaatgtgagg aagaaatggg actctttggt 60 tatttattga tgcgactgta aattggtaca gtatttctgg agggcaattt ggtaaaatgc 120 atcaaaagac ttaaaaatac ggacgtactt tgtgctggga actctacatc tagcaatttc 180 tctttaaaac catatcagag atgcatacaa agaattatat ataaagaagg gtgtttaata 240 atgatagtta taataataaa taattgaaac aatctgaatc ccttgcaatt ggaggtaaat 300 tatgtcttag ttataattag attgtgaatc agccaactga aaatcctttt tgcatatttc 360 aatgtcctaa aaagacacgg ttgctctata tatgaagtga aaaaaggata tggtagcatt 420 ttatagtact agttttgctt taaaatgcta tgtaaatata caaaaaaact agaaagaaat 480 atatataacc ttgttattgt atttggggga gggatactgg gataattttt attttctttg 540 aatctttctg tgtcttcaca tttttctaca gtgaatttaa tcaaatagta aagttgttgt 600 aaaaataaaa gtggatttag aaagatccag ttcttgaaaa cactgtttct ggtaatgaag 660 cagaatttaa gttggtaata ttaaggtgaa tgtcatttaa gggagttaca tctttattct 720 gctaaagaag aggatcattg atttctgtac agtcagaaca gtacttgggt ttgcaacagc 780 tttctgagaa aagctaggtg tttaatagtt taactgaaag tttaactatt taaaagacta 840 aatgcacatt ttatggtatc tgatatttta aaaagtaatg tttgattctc ctttttatga 900 gttaaattat tttatacgag ttggtaattt ttgcttttta ataaagtgga agcttgcttt 960 tttaactctt tttttattgt tattttatag aaatgctttt tgttggccgg gcacagttgc 1020 tcatccatgt aatcccagca ctgtgggagg ccgagacggg tggatcacaa ggtcaggaga 1080 tcgagaccat cctggctaat gcgttgaaac tccgtctctg ctaagaatac aaaaaattag 1140 ctgggcgtgg tggtgggcac ctgtagtccc agctactcag gaggctgagg caggagaatg 1200 gtgtgaacct gggaggtgga gcttgcagtg agcagagctt gcagtgagac gagcttgtgc 1260 cactgcactc cagcctgggc aacagagtaa gactcagtct caaaaaaaaa aaaaaaa 1317 <210> 117 <211> 696 <212> DNA <213> Homo sapiens <400> 117 gaaaaaacaa agagagacat taacaggttt ctgagtgtgg ccagtcttca aggacttatt 60 catgaaggca ccatgacttc tttgtgcatg gccatgacag aggagcagca taagtctgtg 120 gtcatcgatt gcagcagctc ccagcctcag ttctgcaatg caggaagtaa ccggttttgt 180 gaggattgga tgcaagcttt tttaaatggt gccaaaggag gtaacccttt tcttttccga 240 caagtactgg agaactttaa actaaaggcc atacaagaca caaacaattt gaagagattt 300 atccgacagg cagaaatgaa tcattatgct ttgtttaaat gttacatgtt cctaaagaac 360 tgtggtagtg gagatatact tttgaagatt gttaaagtgg aacatgaaga aatgcctgaa 420 gccaaaaatg tgatagctgt ccttgaagaa ttcatgaaag aagctcttga ccaaagtttt 480 tgatcatatg ttttgagata attgtatgat caagttgtat atttaagtct tagtgtttga 540 aattgcagtt ataattgttc ataggattgc tatttaagat gatttgaaac tcaatccaga 600 ttttcttttt gtattttacc aatttaactt aaataaaaat ctgaagaaca aaaaaaaaaa 660 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaa 696 <210> 118 <211> 2519 <212> DNA <213> Homo sapiens <400> 118 gcgtgtcagg tggttgcgga gctgaatcat attctaagaa ctcagccact caggtatcca 60 ccatggtgct gggtcctgaa cagaagatgt cagatgacag tgtttctgga gatcatgggg 120 agtctgccag tcttggtaac atcaaccctg cctatagtaa tccctctctt tcacagtccc 180 ctggggactc agaggagtac ttcgccactt actttaatga gaagatctcc attcctgagg 240 aggagtactc ttgttttagc tttcgtaaac tctgggcttt caccggacca ggttttctta 300 tgagcattgc ctacctggat ccaggaaata ttgaatccga tttgcagtct ggagcagtgg 360 ctggatttaa gttgctctgg atccttctgt tggccaccct tgtggggctg ctgctccagc 420 ggcttgcagc tagactggga gtggttactg ggctgcatct tgctgaagta tgtcaccgtc 480 agtatcccaa ggtcccacga gtcatcctgt ggctgatggt ggagttggct atcatcggct 540 cagacatgca agaagtcatt ggctcagcca ttgctatcaa tcttctgtct gtaggaagaa 600 ttcctctgtg gggtggcgtt ctcatcacca ttgcagatac ttttgtattt ctcttcttgg 660 acaaatatgg cttgcggaag ctagaagcat tttttggctt tctcatcact attatggccc 720 tcacatttgg atatgagtat gttacagtga aacccagcca gagccaggta ctcaagggca 780 tgttcgtacc atcctgttca ggctgtcgca ctccacagat tgaacaggct gtgggcatcg 840 tgggagctgt catcatgcca cacaacatgt acctgcattc tgccttagtc aagtctagac 900 aggtaaaccg gaacaataag caggaagttc gagaagccaa taagtacttt ttcattgaat 960 cctgcattgc actctttgtt tccttcatca tcaatgtctt tgttgtctca gtctttgctg 1020 aagcattttt tgggaaaacc aacgagcagg tggttgaagt ctgtacaaat accagcagtc 1080 ctcatgctgg cctctttcct aaagataact cgacactggc tgtggacatc tacaaagggg 1140 gtgttgtgct gggatgttac tttgggcctg ctgcactcta catttgggca gtggggatcc 1200 tggctgcagg acagagctcc accatgacag gaacctattc tggccagttt gtcatggagg 1260 gattcctgaa cctaaagtgg tcacgctttg cccgagtggt tctgactcgc tctattgcca 1320 tcatccccac tctgcttgtt gctgtcttcc aagatgtaga gcatctaaca gggatgaatg 1380 actttctgaa tgttctacag agcttacagc ttccctttgc tctcataccc atcctcacat 1440 ttacgagctt gcggccagta atgagtgact ttgccaatgg actaggctgg cggattgcag 1500 gaggaatctt ggtccttatc atctgttcca tcaatatgta ctttgtagtg gtttatgtcc 1560 gggacctagg gcatgtggca ttatatgtgg tggctgctgt ggtcagcgtg gcttatctgg 1620 gctttgtgtt ctacttgggt tggcaatgtt tgattgcact gggcatgtcc ttcctggact 1680 gtgggcatac gtgccatctg ggattgacag ctcagcctga actctatctt ctgaacacca 1740 tggacgctga ctcacttgtg tctagatgac tgacagcctg agagactcta taagaacatg 1800 tttttctaag ccctttttgt gccaggtgtc ccgttaacgt ctctgttagt tcaaaggtga 1860 gttttgttca gacgttttga acaaaaggca aagatttcct catgggaagg gtgttcaaaa 1920 ctgacagcta taaatgtagg tcagagaccc acccacctca taacagtcat acactcccag 1980 agttaaacga ttggcctctg atggccacac acccctatgg gcttgtgtct tggactctgg 2040 gatttaaaag atatatatgt atatatattt atgtaaacct gagcatctca gtttgggtag 2100 agttttaagg ttatatgaaa ctgatagaac ttttgtattt tttttttaaa tattgttttg 2160 atatatcaga tatttgtttt gtctggatca caagtgagaa agaaaagaga ataatgctct 2220 ttttcacaat gaactggtca aattgactat cttgtaaagt gatactttac tatgtcagtg 2280 aaatttcagt ttgattttag tcaaccagat tatatccttt gtatctactg atattaacac 2340 atcatattaa cacatcattt cttaaaaaaa catttcttct gtttggcaat cataattaac 2400 tctggttatc agcctatttt gtaattattg tctttgtcgt cacttttctt gaattgtttt 2460 ctagtcatta aacagatatg aaggcaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaa 2519 <210> 119 <211> 1067 <212> DNA <213> Homo sapiens <400> 119 gacggtcatc gattacaacg gggaacgcac gctggatggt tttaagaaat tcctggagag 60 cggtggccag gatggggcag gggatgatga cgatctcgag gacctggaag aagcagagga 120 gccagacatg gaggaagacg atgatcagaa agctgtgaaa gatgaactgt aatacgcaaa 180 gccagacccg ggcgctgccg agacccctcg ggggctgcac acccagcagc agcgcacgcc 240 tccgaagcct gcggcctcgc ttgaaggagg gcgtcgccgg aaacccaggg aacctctctg 300 aagtgacacc tcacccctac acaccgtccg ttcacccccg tctcttcctt ctgcttttcg 360 gtttttggaa agggatccat ctccaggcag cccaccctgg tggggcttgt ttcctgaaac 420 catgatgtac tttttcatac atgagtctgt ccagagtgct tgctaccgtg ttcggagtct 480 cgctgcctcc ctcccgcggg aggtttctcc tctttttgaa aattccgtct gtgggatttt 540 tagacatttt tcgacatcag ggtatttgtt ccaccttggc caggcctcct cggagaagct 600 tgtcccccgt gtgggaggga cggagccgga ctggacatgg tcactcagta ccgcctgcag 660 tgtcgccatg actgatcatg gctcttgcat ttttgggtaa atggagactt ccggatcctg 720 tcagggtgtc ccccatgcct ggaagaggag ctggtggctg ccagccctgg gtcccggcac 780 aggcctgggc cttccccttc cctcaagcca gggctcctcc tcctgtcgtg ggctcattgt 840 gaccactggc ctctctacag cacggcctgt ggcctgttca aggcagaacc acgacccttg 900 actcccgggt ggggaggtgg ccaaggatgc tggagctgaa tcagacgctg acagttcttc 960 aggcatttct atttcacaat cgaattgaac acattggcca aataaagttg aaattttccc 1020 ccccaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaa 1067 <210> 120 <211> 1567 <212> DNA <213> Homo sapiens <400> 120 ggggtcctgc caccgcgcca cttggcctgc ctccgtcccg ccgcgccact tcgcctgcct 60 ccgtcccccg cccgccgcgc catgcctgtg gccggctcgg agctgccgcg ccggcccttg 120 ccccccgccg cacaggagcg ggacgccgag ccgcgtccgc cgcacgggga gctgcagtac 180 ctggggcaga tccaacacat cctccgctgc ggcgtcagga aggacgaccg cacgggcacc 240 ggcaccctgt cggtattcgg catgcaggcg cgctacagcc tgagagatga attccctctg 300 ctgacaacca aacgtgtgtt ctggaagggt gttttggagg agttgctgtg gtttatcaag 360 ggatccacaa atgctaaaga gctgtcttcc aagggagtga aaatctggga tgccaatgga 420 tcccgagact ttttggacag cctgggattc tccaccagag aagaagggga cttgggccca 480 gtttatggct tccagtggag gcattttggg gcagaataca gagatatgga atcagattat 540 tcaggacagg gagttgacca actgcaaaga gtgattgaca ccatcaaaac caaccctgac 600 gacagaagaa tcatcatgtg cgcttggaat ccaagagatc ttcctctgat ggcgctgcct 660 ccatgccatg ccctctgcca gttctatgtg gtgaacagtg agctgtcctg ccagctgtac 720 cagagatcgg gagacatggg cctcggtgtg cctttcaaca tcgccagcta cgccctgctc 780 acgtacatga ttgcgcacat cacgggcctg aagccaggtg actttataca cactttggga 840 gatgcacata tttacctgaa tcacatcgag ccactgaaaa ttcagcttca gcgagaaccc 900 agacctttcc caaagctcag gattcttcga aaagttgaga aaattgatga cttcaaagct 960 gaagactttc agattgaagg gtacaatccg catccaacta ttaaaatgga aatggctgtt 1020 tagggtgctt tcaaaggagc tcgaaggata ttgtcagtct ttaggggttg ggctggatgc 1080 cgaggtaaaa gttctttttg ctctaaaaga aaaaggaact aggtcaaaaa tctgtccgtg 1140 acctatcagt tattaatttt taaggatgtt gccactggca aatgtaactg tgccagttct 1200 ttccataata aaaggctttg agttaactcc ctgagggtat ctgacaatgc tgaggttatg 1260 aacaaagtga ggagaatgaa atgtatgtgc tcttagcaaa aacatgtatg tgcatttcaa 1320 tcccacgtac ttataaagaa ggttggtgaa tttcccaagc tatttttgga atatttttag 1380 aatattttaa gaatttccca agctattccc tcaaatttga gggagctgag taaccccatc 1440 gatcatgatg tagagtgtgg ttatgaactt taaagttata gttgttttat atgttgctat 1500 aataaagaag tgttttgcat tcgtcaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1560 aaaaaaa 1567 <210> 121 <211> 1665 <212> DNA <213> Homo sapiens <400> 121 caacgacggc agccccgccg gctactacct gaaggagtcc aggggcagcc ggcggtggct 60 cctcttcctg gaaggcggct ggtactgctt caaccgcgag aactgcgact ccagatacga 120 caccatgcgg cgcctcatga gctcccggga ctggccgcgc actcgcacag gcacagggat 180 cctgtcctca cagccggagg agaaccccta ctggtggaac gcaaacatgg tcttcatccc 240 ctactgctcc agtgatgttt ggagcggggc ttcatccaag tctgagaaga acgagtacgc 300 cttcatgggc gccctcatca tccaggaggt ggtgcgggag cttctgggca gagggctgag 360 cggggccaag gtgctgctgc tggccgggag cagcgcgggg ggcaccgggg tgctcctgaa 420 tgtggaccgt gtggctgagc agctggagaa gctgggctac ccagccatcc aggtgcgagg 480 cctggctgac tccggctggt tcctggacaa caagcagtat cgccacacag actgcgtcga 540 cacgatcacg tgcgcgccca cggaggccat ccgccgtggc atcaggtact ggaacggggt 600 ggtcccggag cgctgccgac gccagttcca ggagggcgag gagtggaact gcttctttgg 660 ctacaaggtc tacccgaccc tgcgctgccc tgtgttcgtg gtgcagtggc tgtttgacga 720 ggcacagctg acggtggaca acgtgcacct gacggggcag ccggtgcagg agggcctgcg 780 gctgtacatc cagaacctcg gccgcgagct gcgccacaca ctcaaggacg tgccggccag 840 ctttgccccc gcctgcctct cccatgagat catcatccgg agccactgga cggatgtcca 900 ggtgaagggg acgtcgctgc cccgagcact gcactgctgg gacaggagcc tccatgacag 960 ccacaaggcc agcaagaccc ccctcaaggg ctgccccgtc cacctggtgg acagctgccc 1020 ctggccccac tgcaacccct catgccccac cgtccgagac cagttcacgg ggcaagagat 1080 gaacgtggcc cagttcctca tgcacatggg cttcgacatg cagacggtgg cccagccgca 1140 gggactggag cccagtgagc tgctggggat gctgagcaac ggaagctagg cagactgtct 1200 ggaggaggag ccggcactga ggggcccaga cacccgctgc cccagtgcca cctcaccccc 1260 caccagcagg ccctcccgtc tcttcgggac agggccccag ccgtcccccc tgtctgggtc 1320 tgcccactgc cctcctgccc cggctttccc tgcccctctc ccacagccca gccagagaca 1380 agggacctgc tgtcatcccc atctgtggcc tgggggtcct tcctgacaac gagggggtag 1440 ccagaagaga agcactggat tcctcagtcc accagctcag acagcaccca ccggccccac 1500 ccatcaagcc cttttatatt attttataaa gtgacttttt tattacttta attttttaaa 1560 aaaaggaaaa taagaatata tgatgaatga tattgttttg taacttttta aaaatgattt 1620 taaagagaca aaaaagaaaa aaaaaaaaaa aaaaaaaaaa aaaaa 1665 <210> 122 <211> 1281 <212> DNA <213> Homo sapiens <400> 122 gcgtgatgtc tcacagaaag ttctccgctc ccagacatgg gtccctcggc ttcctgcctc 60 ggaagcgcag cagcaggcat cgtgggaagg tgaagagctt ccctaaggat gacccatcca 120 agccggtcca cctcacagcc ttcctgggat acaaggctgg catgactcac atcgtgcggg 180 aagtcgacag gccgggatcc aaggtgaaca agaaggaggt ggtggaggct gtgaccattg 240 tagagacacc acccatggtg gttgtgggca ttgtgggcta cgtggaaacc cctcgaggcc 300 tccggacctt caagactgtc tttgctgagc acatcagtga tgaatgcaag aggcgtttct 360 ataagaattg gcataaatct aagaagaagg cctttaccaa gtactgcaag aaatggcagg 420 atgaggatgg caagaagcag ctggagaagg acttcagcag catgaagaag tactgccaag 480 tcatccgtgt cattgcccac acccagatgc gcctgcttcc tctgcgccag aagaaggccc 540 acctgatgga gatccaggtg aacggaggca ctgtggccga gaagctggac tgggcccgcg 600 agaggcttga gcagcaggta cctgtgaacc aagtgtttgg gcaggatgag atgatcgacg 660 tcatcggggt gaccaagggc aaaggctaca aaggggtcac cagtcgttgg cacaccaaga 720 agctgccccg caagacccac cgaggcctgc gcaaggtggc ctgtattggg gcatggcatc 780 ctgctcgtgt agccttctct gtggcacgcg ctgggcagaa aggctaccat caccgcactg 840 agatcaacaa gaagatttat aagattggcc agggctacct tatcaaggac ggcaagctga 900 tcaagaacaa tgcctccact gactatgacc tatctgacaa gagcatcaac cctctgggtg 960 gctttgtcca ctatggtgaa gtgaccaatg actttgtcat gctgaaaggc tgtgtggtgg 1020 gaaccaagaa gcgggtgctc accctccgca agtccttgct ggtgcagacg aagcggcggg 1080 ctctggagaa gattgacctt aagttcattg acaccacctc caagtttggc catggccgct 1140 tccagaccat ggaggagaag aaagcattca tgggaccact gaagaaagac cgaattgcaa 1200 aggaagaagg agcttaatgc caggaacaga ttttgcagtt ggtggggtct caataaaatt 1260 attttccact gaaaaaaaaa a 1281 <210> 123 <211> 1102 <212> DNA <213> Homo sapiens <400> 123 gttataaatg gttataaagc tcctgttact catattagtt atttacatca aaaagctttt 60 agaaaatggt acgaggtaac caattcttgt catggtgaaa tctgattgag taaccaagca 120 gttttactat tctggtgctg cttcataaca aaaatgaaaa gctgcatgca tctacagcag 180 gcatggattg tttatgtcgt atgatatcct ttattaagta agttcactta tagtatttct 240 ataatttgat tcattgccgt aatagagcca tgtaggaaat gcactgattg catgttattg 300 tggcaagaat atcctaaatg tcattaaaat cctccaacat gatggatcta cttatggtct 360 tgtttgttga catgacaaat taacattctt atagttacat ctggaaatga gcatttgaaa 420 tagataatcc tttaagcctt gtggcaaaat ttttgtggct tttgtttaac tttgaaaggt 480 tattatgcac taaccttttt tggtggctaa ttagggttta aatacagaaa caagatttca 540 aataaaactg tctttggcag tgagtaaata gcatattttg aagtagagtt gtatactttt 600 tcataagatg tttgggaatt tttttcctga agtaataatt tattccacat ctacatcagt 660 gaaagctatc tacctatcct gagtctatct taaaggaaaa aaagaaaaaa accttatctc 720 ttgcccttat tttgaatttt ccactctttc attaatttgt tttaagctcc gtgttggaaa 780 aaaggggtag tgcattttaa attgaccttc atacgctttt aaaataagac aaatctactt 840 gataatgtac ctttatttga tctcaagttg tataaaacca ataaatttgt gttactgcag 900 tagtaatctt atgcacacgg tgatttcatg ttatatatgc aaagtaggca actgttttct 960 tagttacaga agtttcaagc ttcacttttg tgcagtagaa acaaaagtag gctacagtct 1020 gtgccatgtt gatgtacagt ttctgaaatt gttttacaag actttgataa taaaaccctt 1080 aaacttaaaa aaaaaaaaaa aa 1102 <210> 124 <211> 2224 <212> DNA <213> Homo sapiens <400> 124 caactctcca caacctttta ttacatcaag aaggagctaa aatggcagtg cgtttagctg 60 gtgggctgca gaaaatggtt gccttgctca acaaaacaaa tgttaaattc ttggctatta 120 cgacagactg ccttcaaatt ttagcttatg gcaaccaaga aagcaagctc atcatactgg 180 ctagtggtgg accccaagct ttagtaaata taatgaggac ctatacttac gaaaaactac 240 tgtggaccac aagcagagtg ctgaaggtgc tatctgtctg ctctagtaat aagccggcta 300 ttgtagaagc tggtggaatg caagctttag gacttcacct gacagatcca agtcaacgtc 360 ttgttcagaa ctgtctttgg actctcagga atctttcaga tgctgcaact aaacaggaag 420 ggatggaagg tctccttggg actcttgttc agcttctggg ttcagatgat ataaatgtgg 480 tcacctgtgc agctggaatt ctttctaacc tcacttgcaa taattataag aacaagatga 540 tggtctgcca agtgggtggt atagaggctc ttgtgcgtac tgtccttcgg gctggtgaca 600 gggaagacat cactgagcct gccatctgtg ctcttcgtca tctgaccagc cgacaccaag 660 aagcagagat ggcccagaat gcagttcgcc ttcactatgg actaccagtt gtggttaagc 720 tcttacaccc accatcccac tggcctctga taaaggctac tgttggattg attcgaaatc 780 ttgccctttg tcccgcaaat catgcacctt tgcgtgagca gggtgccatt ccacgactag 840 ttcagttgct tgttcgtgca catcaggata cccagcgccg tacgtccatg ggtgggacac 900 agcagcaatt tgtggagggg gtccgcatgg aagaaatagt tgaaggttgt accggagccc 960 ttcacatcct agctcgggat gttcacaacc gaattgttat cagaggacta aataccattc 1020 cattgtttgt gcagctgctt tattctccca ttgaaaacat ccaaagagta gctgcagggg 1080 tcctctgtga acttgctcag gacaaggaag ctgcagaagc tattgaagct gagggagcca 1140 cagctcctct gacagagtta cttcactcta ggaatgaagg tgtggcgaca tatgcagctg 1200 ctgttttgtt ccgaatgtct gaggacaagc cacaagatta caagaaacgg ctttcagttg 1260 agctgaccag ctctctcttc agaacagagc caatggcttg gaatgagact gctgatcttg 1320 gacttgatat tggtgcccag ggagaacccc ttggatatcg ccaggatgat cctagctatc 1380 gttcttttca ctctggtgga tatggccagg atgccttggg tatggacccc atgatggaac 1440 atgagatggg tggccaccac cctggtgctg actatccagt tgatgggctg ccagatctgg 1500 ggcatgccca ggacctcatg gatgggctgc ctccaggtga cagcaatcag ctggcctggt 1560 ttgatactga cctgtaaatc atcctttagg taagaagttt taaaaagcca gtttgggtaa 1620 aatactttta ctctgcctac agaacaaaga cttggttggt agggtgggagg tggtttaggc 1680 tatttgtaaa tctgccacaa aaacaggtat atactttgaa aggagatgtc ttggaacatt 1740 ggaatgttct cagatttctg gttgttatgt gatcatgtgt ggaagttatt aactttaatg 1800 ttttttgcca cagcttttgc aacttaatac tcaaatgagt aacatttgct gttttaaaca 1860 ttaatagcag cctttctctc tttatacagc tgtattgtct gaacttgcat tgtgattggc 1920 ctgtagagtt gctgagaggg ctcgaggggt gggctggtat ctcagaaagt gcctgacaca 1980 ctaaccaagc tgagtttcct atgggaacaa ttgaagtaaa ctttttgttc tggtcccttt 2040 tggtcgagga gtaacaatac aaatggattt tgggagtgac tcaagaagtg aagaatgcac 2100 aagaatggat cacaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2160 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2220 aaaa 2224 <210> 125 <211> 1047 <212> DNA <213> Homo sapiens <400> 125 ctggatacca tttgttgaaa gatgttatta ctctagctga acttacaaga gactttagac 60 cagggatcta aattacagtg gccttagtga ccttgtcctt atcttcttag gacagctgag 120 aagccactgg gacttagagc ctttaaaagg agattaactg tcccaaaagg atctttgcta 180 ctgaccagca gacacttctt ccttcagtag cctttcatac tgtgttgagt aacaccctag 240 ggtgtccatt aaagttttga gttttaccta gggcccagag ccatgaatca ggattctgtc 300 tacatgattc gtgttttcat tggtgtcaaa atacaaaagc caaagttctg gctatgaatt 360 gttaacttgg aagaaatact aactgccacc acttattaag tgcctactgt gtgccaggct 420 ctgaactagg tgcttcatat acattatcct aaattatctc aacatatgag gtaggtgttt 480 taatttttat tttatagaac ttggtgtgtt tgactgttaa gctatggggc tagagagagg 540 gtttgatccc aggtccctct gtgcttttgc tgctgagcca cacaacctct catttcaaaa 600 acactttcaa aatgctaaca tattctaatt cactctaggc caccaaaaac tttaatacta 660 atatctgatt tgtaaatgac ttaatgtatc cttgacccta tcagctgaat ttaatgaaat 720 attcctctct gctgtgaaat tttaccagta tagtatttgg tctagtgaca gagcgagact 780 ccgtctacac acacacacac acacacacac acatccttcc tcctctaacc ccaaactaag 840 atcacagaag gtgatccagt cagagaacag agggaaatct taccaggaag ggcttaagta 900 cacttttttt taaaacagct ttattgtttt taaagcctac aatttgataa gccttgacat 960 atgtatacct gtgaaagcat caccacaatc aagacactgg acatatctat cacaccccat 1020 cctaaaaaaa aaaaaaaaaa aaaaaaa 1047 <210> 126 <211> 1306 <212> DNA <213> Homo sapiens <400> 126 tccaaaaagg gtcagtctac ctcccgccat aaaaaactca tgttcaagac agaagggcct 60 gactcagact gacattctcc acttcttgtt ccccactgac agcctcccac ccccatctct 120 ccctcccctg ccattttggg ttttgggtct ttgaaccctt gcttgcaata ggtgtgcgtc 180 agaagcaccc aggacttcca tttgctttgt cccggggctc cactgaacaa gttggcctgc 240 actggtgttt tgttgtgggg aggaggatgg ggagtaggac ataccagctt agattttaag 300 gtttttactg tgagggatgt ttgggagatg taagaaatgt tcttgcagtt aagggttagt 360 ttacaatcag ccacattcta ggtaggggcc cacttcaccg tactaaccag ggaagctgtc 420 cctcactgtt gaattttctc taacttcaag gcccatatct gtgaaatgct ggcatttgca 480 cctacctcac agagtgcatt gtgagggtta atgaaataat gtacatctgg ccttgaaacc 540 accttttatt acatggggtc tagaacttga cccccttgag ggtgcttgtt ccctctccct 600 gttggtcggt gggttggtag tttctacagt tgggcagctg gttaggtaga gggagttgtc 660 aagtctctgc tggcccagcc aaaccctgtc tgacaacctc ttggtgaacc ttagtaccta 720 aaaggaaatc tcaccccatc ccacaccctg gaggatttca tctcttgtat atgatgatct 780 ggatccacca agacttgttt tatgctcagg gtcaatttct tttttttttt tttttttttt 840 ttttcttttt ctttgagact gggtctcgct ttgttgccca ggctggagtg gagtggcgtg 900 atcttggctt actgcagcct ttgcctcccc ggctcgagca gtcctgcctc agcctccgga 960 gtagctggga ccacaggttc atgccaccat ggccagccaa cttttgcatg ttttgtaaag 1020 atggggtctc acagtgttgc ccaggctggt ctcaaactcc tgggctcagg cgatccacct 1080 gtctcagcct cccagagtgc tgggattaca attgtgagcc accacgtcca gctggaaggg 1140 tcaacatctt ttacattctg caagcacatc tgcattttca ccccaccctt cccctccttc 1200 tcccttttta tatcccattt ttatatcgat ctcttatttt acaataaaac tttgctgcca 1260 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaa 1306 <210> 127 <211> 2978 <212> DNA <213> Homo sapiens <400> 127 gccgtgagaa cacgctgtgt ggctgaaaag tgaaggcaag agctgatttg gcctctgtgc 60 tcccctccgc aaggggatcg ttttctccag aagagctgga tattctttcg cccagttatg 120 gcagacaagt taacgagaat tgctattgtc aaccatgaca aatgtaaacc taagaaatgt 180 cgacaggaat gcaaaaagag ttgtcctgta gttcgaatgg gaaaattatg catagaggtt 240 acaccccaga gcaaaatagc atggatttcc gaaactcttt gtattggttg tggtatctgt 300 attaagaaat gcccctttgg cgccttatca attgtcaatc taccaagcaa cttggaaaaa 360 gaaaccacac atcgatattg tgccaatgcc ttcaaacttc acaggttgcc tatccctcgt 420 ccaggtgaag ttttgggatt agttggaact aatggtattg gaaagtcaac tgctttaaaa 480 attttagcag gaaaacaaaa gccaaacctt ggaaagtacg atgatcctcc tgactggcag 540 gagattttga cttatttccg tggatctgaa ttacaaaatt actttacaaa gattctagaa 600 gatgacctaa aagccatcat caaacctcaa tatgtagacc agattcctaa ggctgcaaag 660 gggacagtgg gatctatttt ggaccgaaaa gatgaaacaa agacacaggc aattgtatgt 720 cagcagcttg atttaaccca cctaaaagaa cgaaatgttg aagatctttc aggaggagag 780 ttgcagagat ttgcttgtgc tgtcgtttgc atacagaaag ctgatatttt catgtttgat 840 gagccttcta gttacctaga tgtcaagcag cgtttaaagg ctgctattac tatacgatct 900 ctaataaatc cagatagata tatcattgtg gtggaacatg atctaagtgt attagactat 960 ctctccgact tcatctgctg tttatatggt gtaccaagcg cctatggagt tgtcactatg 1020 ccttttagtg taagagaagg cataaacatt tttttggatg gctatgttcc aacagaaaac 1080 ttgagattca gagatgcatc acttgttttt aaagtggctg agacagcaaa tgaagaagaa 1140 gttaaaaaga tgtgtatgta taaatatcca ggaatgaaga aaaaaatggg agaatttgag 1200 ctagcaattg tagctggaga gtttacagat tctgaaatta tggtgatgct gggggaaaat 1260 ggaacgggta aaacgacatt tatcagaatg cttgctggaa gacttaaacc tgatgaagga 1320 ggagaagtac cagttctaaa tgtcagttat aagccacaga aaattagtcc caaatcaact 1380 ggaagtgttc gccagttact acatgaaaag ataagagatg cttatactca cccacaattt 1440 gtgaccgatg taatgaagcc tctgcaaatt gaaaacatca ttgatcaaga ggtgcagaca 1500 ttatctggtg gtgaactaca gcgagtagct ttagcccttt gcttgggcaa acctgctgat 1560 gtctatttaa ttgatgaacc atctgcatat ttggattctg agcaaagact gatggcagct 1620 cgagttgtca aacgtttcat actccatgca aaaaagacag cctttgttgt ggaacatgac 1680 ttcatcatgg ccacctatct agcggatcgc gtcatcgttt ttgatggtgt tccatctaag 1740 aacacagttg caaacagtcc tcaaaccctt ttggctggca tgaataaatt tttgtctcag 1800 cttgaaatta cattcagaag agatccaaac aactataggc cacgaataaa caaacttaat 1860 tcaattaagg atgtagaaca aaagaagagt ggaaactact ttttcttgga tgattagact 1920 gactctgaga atattgataa gccatttatt aaaaggagta tttactagaa ttttttgtca 1980 tataaaactt gaatcaggat tttatgcccc acatactctg gaacttgaag tataatatac 2040 ttaatataac ataaaaagcc agttgggttc taaattgtag ttgaaacaca gaaaatgcca 2100 cttttctgtt cctgaagagg ctcttttgtg cataatattc taaaatgaag acatttcaag 2160 ctatacaaat tacttccaag ttttcatgat gtatgggaag attttcagta ggtgtattat 2220 attcacggta ccaaatgctg accagtgttg ctccattttt taaatcttga aaagggtttc 2280 tgtacttacc tggtttgcca agtatgccag tgtaatgaaa ctgcccttat tttaaaagcc 2340 agtcaaagat tccactgatt gacatttgat aaataaacat caggattatg tttattgttt 2400 gttttcagtc tttgcactat attaccagta tatggtttcc gaggaagatt atctactgca 2460 aaacaccact gttggaaaaa taggtatttt taaattgttt ttaatctttt ttggtgcttt 2520 taaacatgtt tagcaaaaac caattcagtt ccattccccg caaaaaaccc ctaactttac 2580 tctgaacttt ttttgttttt gcattccatg aggttctgta ttcagtcatt ctctaggtaa 2640 tgtcattttt gtacacatat atttatataa tcactgattg agatttagga aaaagcattt 2700 ctaaagaata tttgcttccc ttagaactac agactcgaaa tctttaaaga tggtgcctaa 2760 gcatctatgt atttttttta agttccacag atttttctgt tgggcagcca aggattataa 2820 accacttccc taaaggcaac attaatgcaa aagcccccac cccatggctt ccatcttttg 2880 catcaccacc actcctgaac ccccatttct gatttgtcag aatttttttt taacaaaact 2940 aaaaatgaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaa 2978 <210> 128 <211> 2731 <212> DNA <213> Homo sapiens <400> 128 gacacaagac caagtttgaa acagatgcaa ataaactaaa atacagctct aatgtctttt 60 tctgctattc tgtctccctt ttcctctttg tctgtaaatg taaggaattt gagacaaaga 120 ggaaaaggga gacagaatag cagaatcttg actttgatag tcaagatctt gttcaagact 180 tggcacttga tctttttgta aacctagtat tatgttatgg tcaagtggga agcatgaatt 240 taaatgtagt atttaaaaga ttacttggtc ttggctttcc aatctgtggg agtgtttgga 300 tcattttata cacacacaca cacacaca cacacacaca cacctttttt tttttttgat 360 atgaggtctt accctgtcac ccagactaga gtgcagtggc gcaatcttag ctcactgcaa 420 cctctgccta cctggctcaa gggatcctcc cacctcagcc tccagagtag ctgggactac 480 aggcacatgc caccaagccc agctaatttt tcatattttt ggtagagatg gggtttcact 540 ctgttgccca ggctggtctc aaactcctga gctcaagtga tccacccacc ttggccttcc 600 aaagtgctgg gattacaggt gtgagctact gcacctggta cattattata atttaataat 660 agtgacagga aaaggtaaaa attgcaagca acaataataa ccaataatgc agaaatacat 720 ataaaatgtt aactgtaaag gcagatattg ttgcctatat cagccaatgt agatcttctg 780 gttttatact tactggtata ctataaatga aatttagtga cagcatactg tataccaaac 840 tagagtttac ccattgttat ttcttattta gatttttaga tacattgtct tttgattcta 900 acattggcat tatcttaatt taatctctgt atatttttct tctttttgga aatatgcgtt 960 tgtaaaagct taccttataa gctactatgg tgaccttggc ctatcagatg ggtgttctct 1020 taaaccgttt tatactgctt tataccagac tcaaaattgc caacatagtt atctgctaat 1080 tctcaataac ttaaagccac attatttttg ctagagtaat tagtactaca ttgtttattt 1140 ctagatgcac tttaatattc atgtcaccag agtaatttag ttttactgtt ttattaatct 1200 gattgattaa gtctatccca atatgtctct gcagttgggt gacccaatat gtctctgcag 1260 ttgggtgacc caatatgtct ctgcagttgg gtgactacag aaataattca tgcagattac 1320 ctcgctattt gtatcatatt atatacaaat gacatactct agtgcatttg aaatgtaatt 1380 taatggaatc ttgtagttta caaaattaag attgtcttta aagtaaatca ttattccttt 1440 aatttactcc tctcatgacc cctgtaactg tttttcactt cagttcaaca tacatttatg 1500 ccttgcctcc tgtataccag ccagtaggtg ctggggttgc aaaataacta agatcaaccc 1560 atacatgctg gaagctctca atctagtagg agaggataga cacgaaagct cataatttgg 1620 ttggtttggt tttgagacag ggcagtctct gtcgccagct ggaggcagcg gcatgatctc 1680 agctcactgc agctttgacc tcccaggctg aagtgaccct ttcacctcag tacccaaaag 1740 tagctggaat tacaggtgcc cacctgccag aaaactcagt tttacttaaa ttatttattt 1800 tcaacgtgta gctcatgaag atactaactt taaatggcag ggagtagatt gagaatcatc 1860 atggaagacc tttttttttt tttcttgaga tggagtctca ctccgtcacc caagctggag 1920 tgcaatggca tgatcttggc tcactgcatt ctccacttct gggttcaagt gattctccta 1980 cctcagcctc ccgagtagct gggattacag gcatgcagca ccacacccag ctaatttttt 2040 tatttttagt agagatgggg tttcaccatg ttggccaggc tggtctaaaa ctcctgacct 2100 caggtgatcc acctgcctca gcctcccaaa gtgctgggat tacaggtgtg ggccaccaca 2160 cctggcccat catggaagac tttctgatgg tgatgtttga attgggtttt ggagagtgaa 2220 ttagaatgtt ttgaactaat acagtaaagg acagtagaaa gaaggaacaa catggacaga 2280 gaccttaagg catgaaatgt cattctgtat tcagttagac gtttagtctt gatagaagga 2340 ttttttcctt agaacagatt acacctatat gataagattt tattttgttt ttatttaata 2400 atagttcagt taaaatataa gcccaaaatt gctccataaa atttggcagc agttatgcta 2460 ttgacagcat ataaaaagca ctcaatcgag ctaggtgcag tggctcatgg ctgtaattcc 2520 agcactttgg gaggccccag caaaaggatc acttgattca aggaatttga gaccagtntg 2580 ggcaacatgg caagactcta tctgtatgaa aaaaaaaatt ttttaattag ctgggaatag 2640 tgatgtgtgc ccttgcagtg agctgtgatt tgctctactg cactccacct tgagtagcag 2700 agtgaaactg tctttgaaaa aaaaaaaaaa a 2731 <210> 129 <211> 2064 <212> DNA <213> Homo sapiens <400> 129 ctttgctccc ctgccgcctt ctagtgggcc gcctggtggt ggacttgtcc tgtgggatgg 60 agaccctcca tacatggggt tcaaaggtcc tggggtattc ctggatcttc aggacatctg 120 cctaccctca ggtttcccag gcctcgggtg gggaggcatc agatccctgg ccaacctgct 180 atccacccca gggtttagac ctctcttccc gtgagggaac agagtagtag cttcatttgt 240 ggcagattat ctgccttgtg ataaacttta gtggcctccc tttctgtttt gccataatct 300 gcctcctccc ccactcccat acccatctac aaagcagcct tgaaaataac cacccctgtg 360 gttcagtgtg ggtcatgatc tgtcaatcca ggcttagtac atttccaaat ggaattacca 420 gaaggatggg catcaaactg ggaaaatgat ttggtggctt gctagccgtg ttcctttttc 480 tcccaaggca ttcgttcaga tgtgcagtgt tggcagaccc aggggatgcc atttacctgg 540 cccactggtc gagatttggt catcccagga acttgggctt cagaaaagat gtttctgggc 600 tttggaccag attctggctg gtctgtggtt tgcccctcct gccacaccca gtggctttca 660 ttgggctttt ttcctctagt tattgtcagg aacagtgggg aatggcaggt attgcatttg 720 gtgaacacac tggataactg gaatcagagc cgtgtgactg agggaagagg ccttcacagc 780 ttcaatgcag aatgggatga ttatctgccc tgaaacgaag gatgcttctt tgaggggagt 840 tgggaccaat actgggaaca gcaccgctcc tggcttctct ggctttgctt ctctctgaag 900 taatttagac ttcgtgaacc ttacatactg gctccatctg tatattggga gagcctgtcc 960 ctctcagcct cacagtagtg aagttaggaa gcatggagtc cacagtgttc tttgaaagaa 1020 tcaaggcacc aagtccatgc atttacattt ctctcttgag atcagtcctt ttgttagcag 1080 cctgcaattc tgaccacggc aaccaaaaat ttctgaccgt ggcaaccaaa aatcaagcgc 1140 gaggaaacct gggggtttat ttggaggtgg gagaggatgt cccttcttct ggtaggacta 1200 tgtctggcta cattgtcttt ccattttttt ctgattgtcc ccttgccccc ctcccttttc 1260 tgggggcaca gagggcatgg caattttgtt tcctagcttt ccatattcct actgcagtgc 1320 tttcttcaga atacttgttc agatcggatt cttggctgtg agggcaacca gctgctttcc 1380 tgtttcttta aaagtggatc ccacactgcc gtgtcctgca cagtgagttc tgcgttgtag 1440 aaaccatcta gcagtggtga ctcagggagt ggcctctgct cggtatgggg cctctgcaac 1500 atgaggttat ggggcttcta cgctgtgggg tcaaaggaga catcatgatc cctactggca 1560 gaaagagcag agccccagag tgggttccac ttacggggtc agtgtctttt ctgagatatt 1620 cctcggaacc acatttaaat tctttttcat attgtttgca taataattgc cttctagtgc 1680 ctactttata ggactgagag gatttaaatg agataatcca tgttatggat ttaacacagc 1740 ctctggcaca agtctaaatg ttgcatgtaa gtgttaacta ttatactgga aagaaggctc 1800 agttccttga tttaggtgtg ggagaaaaat atatatatat tttgagacca gccctggcca 1860 acatggtgaa actcatgtct acgaaaaata caaaagttag cctggtgttg gtggcgcatg 1920 cctatagttg cagctactcg ggaggctgag acacaggaat cacttgaacc cgggaggcgg 1980 aggttgcagg gagccgagat cacaccactg cactccagcc tgggtaacag agtgagatac 2040 tgtctcaaaa aaaaaaaaaa aaaa 2064 <210> 130 <211> 2033 <212> DNA <213> Homo sapiens <400> 130 ggtaaagatg gcagctacca tgttccgggc tacgctgcgg ggatggagaa ccggtgtcca 60 gcggggctgc gggctacggc tgttgagcca gacccagggc cctccagatt accccaggtt 120 tgtggagtct gtggatgaat atcagtttgt ggagcgcctg ttaccggcta ccaggatccc 180 agatccccca aagcatgaac attatcctac ccctagtggc tggcagcctc ccagagaccc 240 cccacccaac ctgccttact ttgtacgacg ctctcggatg cacaacatcc ccgtctacaa 300 ggacatcacg catggcaacc ggcagatgac tgtgatccgg aaagtggaag gggacatctg 360 ggccctgcag aaagacgtgg aagattttct gagcccgctg ctggggaaga cacctgtcac 420 ccaggtcaat gaggtgacag gtaccctacg gatcaagggc tactttgacc aggagcttaa 480 agcctggctc ttggagaaag gcttctgagg cccagcccga gcagcctgct tgtcagcatg 540 ccctgtggat caagtctagg gggcctcagg aggagggagg tgggtgttgg agcccctgag 600 acaggggata cagaaactag ggctaaagga ctttggggtc aggccttgct tgcataaagg 660 agaaaacaac tctatgtaca tgctggggga gagtgcctaa tgtgggagac caaataggga 720 tcaccaggct aatggggggc gtcagcagct ttctctccct cctatcttgg cctgttcttt 780 tttgtttttt gagacggagt ctcactctgt tgcccagggt ggagtgcagt ggcatgatct 840 tggctcactg caacttccac ctctgggatc aagggattct cctgcctcag cctcttgagt 900 agctgggatt acaggcgccc accaccacag cctgctaatt tttgtatttt tagtagagat 960 ggggtttcac catgttggcc aggctggtct caaactcctg actcgaagtg atccgcccac 1020 cttggcctcc caaagcgttg ggattatagg catgagccat gtgcctggtc caccttggcc 1080 tgttttgttt ttctttcctt gggctcagca attcaaattc tagttgttat ttggtggaag 1140 cagtagccca accccagttt aggggaaggt agcacagggc agagccactg ggcactttgt 1200 ttccttggcc ctccgaagct cactgttgca aataccccca agcctttgct ctaggccaga 1260 tcttgtttgg tgcaggtgat ggagaacaca gatgactcgg gcatgggtct tggagatctt 1320 ctgttcaaag tacagtgctg gcactggggc acagagtgcc cacgttagcc ccgggctctg 1380 atagagaggt aggaggcacg ttcttggtca ctgttccatt gcagaccaga cttgctggcc 1440 tgaccacaag ggagtggctg ggaactcaca gccagcatag ggacatcccc ctgcagcctt 1500 ctgacctgca atcaaggctg gggaggggtt tgcaggcagg aatatgctga cctttcaccc 1560 tgccatccca tcccaacccc agctcactag ccttcatata tgccttatac ttggagtcac 1620 aggggccaaa ggcctgagac cccaccctgc ccccaaactg gctaagacag ctttcagttc 1680 ctgactcccc aacttggtct ctgccctgaa gcagggcact gaactctggg ctgcttctct 1740 gtgtgtaaaa tgggcacatc ttcctaatct gttaatggtc agtggtgtcc ccaaggatag 1800 tgctggcttc catggaaacc ctcactcctg gagattccat tccattttca agtgtacagc 1860 cacagcaagg agcccgacac tgatttgatc gattctgtga cacaaacccc accaattgtt 1920 aatgcaagtt tttatttggc tgtatataca atttaagcta ttaaaatttg tacaatattt 1980 acaaattaaa taatcatctg aaactgtcaa aaaaaaaaaa aaaaaaaaaa aaa 2033 <210> 131 <211> 519 <212> DNA <213> Homo sapiens <400> 131 tcaaaagtca aggcatcatt taaaataatc tgatttcaga caaatgctgt gtggaaacat 60 ctatcctata gatcatccta ttcttatgtg tctttggtta tcagatcaat tacagaataa 120 ttgtgttgtg atattgtgtc ctaaattgct cattaatttt tatttacaga ttgaaaaaga 180 gggaccgtgt aaagaaaatg gaaaataaat atctttcaaa gactctttta gataaacacg 240 atgaggcaaa atcaggttca ttcattcaac gatagtttct aaacagtact taaatagcgg 300 ttggaaaacg tagccttcat tttatgattt tttcatatgt ggaaatctat tacatgtaat 360 acaaaacaaa catgtagttt gaaggcggtc agatttcttt gagaaatctt tgtagagtta 420 attttatgga aattaaaatc agaattaaat gctaaaaaaa aaaaaaaaaa aaaaaaaaaa 480 taaaaaaaaa aaaaaataaa aaaaaaaaaa aaaaaaaaa 519 <210> 132 <211> 1824 <212> DNA <213> Homo sapiens <400> 132 ggcaggacag aagacttcag ctgccctgtc cacagtgggc tctgccatca gcaggaagct 60 tggagacatg aggaactctg cgaccttcaa gtcgtttgag gaccgagttg ggaccataaa 120 gtctaaggtt gtgggtgaca gagagaacgg cagtgacaac ctcccttcct cagcggggag 180 tggtgacaag cccctgtcgg atcccgcacc tttctaagcc tgtggttgct tcacccgctg 240 cagagcacac gcaacccagc ctcagcatca cagccgcagc tctgttcagc ggagcagcca 300 gccagggcgg atgagcagag ccggccctga ggacagtcct gcccatccac gcggagatgt 360 ggctgccgcg tttgcatgaa tttggagaaa acaggcttgt acacagatgt tttacactca 420 cgtttgtaga tgaaacagat cactgtgctg tccttcctag gggtgcagga agtggacagg 480 gcggagggtt tgaaagaata ttgagccaaa gcccaggctc cctttgggaa tcatgttagc 540 ccatcagaat gttgaaggat tgaagagttc taagcgtaaa ataagtggca ttttctgact 600 tcttcctcct cctccttccc tgactcacag aaggaatgca atcacccagc aagtcctacc 660 tgttacgcaa ttttttatct caaaatgccg aacgagaaaa ctgtccattt tctgagaccc 720 ccagaaagga aactgaccct cagcagctgc ctgattgtta cgcgaatcta gctttaacgg 780 aagcaaattc attatttttt aaatgcagtg gacttttcaa aaagtttaaa ttaggcaaag 840 cagctttagc ctcatagaat attatttctt tggactcaag ctgaaataca agccttacat 900 tgccttatgc tttatttctt tctaattttt atatgtatat agatgagggt tccttaatgg 960 ttgtgagcat tgtgtggaat tttacacctg gcctgcgtgg cagcctcttc cagttgaggt 1020 gttttatgtc acgcacactc catcccagtg tacaaaacct gcttctcttc tcaaccgtgg 1080 cagctcccgc tggctcctat gccctgccct aaagggctct tgagcctctg ggaatgggag 1140 gggccaagag aaggaaaacc ctgtctttag caccctttaa aagaactgtg ccccccttct 1200 cagtgctgcc tttgcatggg cctggcccgg ctcacattcg tcagtgactc caaccctcct 1260 gcttgctgta cttgggatga aacgacccca caggtcaagt ggagggtggg gcgtgggcat 1320 cagccaggat tgccgttaca gtctttttct caggagctac aaagatctct tcctgttact 1380 aaatggtcgc accccagcag cctctctcgc acaccggggc cctgcatgtc agatggcgtg 1440 gtctgcaggg ggagctctgt gccttagtgg ctcttggcag gacactgagg gcctgcctgt 1500 ggtgtgcccg gctctgccac tcccgggagg ggaagggctg ctcagctcaa ggtgtcctgt 1560 tcggtagagc aagtgtcctc tgacagccgt gtccccggac agttcagaca cccttgggga 1620 tggcactcca cacacgacag agatgcaggg gccagggaag cccagcgctc ggtgcccttc 1680 gtccagggtt aaaatcggcc tgtggggtgt ggtgagaagg caggttgtgc gggtgttgac 1740 cgatgtatct tttccttaaa gttattataa taatgggtaa tttgtcaata aagcattcct 1800 ttgggggaaa aaaaaaaaaa aaaa 1824 <210> 133 <211> 1027 <212> DNA <213> Homo sapiens <400> 133 ggggcggcgg gttggtctac gctgtgcgcg gcggacgtcg gaggcagcgg ggagcggagc 60 ggggccgccg gggcctctcc agggccgcag cggcagcagt tgggcccccc gccccggccg 120 gcggaccgaa gaacgcagga agggggccgg ggggacccgc ccccggccgg ccgcagccat 180 gaactccaac gtggagaacc tacccccgca catcatccgc ctggtgtaca aggaggtgac 240 gacactgacc gcagacccac ccgatggcat caaggtcttt cccaacgagg aggacctcac 300 cgacctccag gtcaccatcg agggccctga ggggacccca tatgctggag gtctgttccg 360 catgaaactc ctgctgggga aggacttccc tgcctcccca cccaagggct acttcctgac 420 caagatcttc cacccgaacg tgggcgccaa tggcgagatc tgcgtcaacg tgctcaagag 480 ggactggacg gctgagctgg gcatccgaca cgtactgctg accatcaagt gcctgctgat 540 ccaccctaac cccgagtctg cactcaacga ggaggcgggc cgcctgctct tggagaacta 600 cgaggagtat gcagctcggg cccgtctgct cacagagatc cacgggggcg ccggcgggcc 660 cagcggcagg gccgaagccg gtcgggccct ggccagtggc actgaagctt cctccaccga 720 ccctggggcc ccagggggcc cgggaggggc tgagggtacc atggccaaga agcatgctgg 780 cgagcgcgat aagaagctgg cggccaagaa aaagacggac aagaagcggg cgctgcggcg 840 gctgtagtgg gctctcttcc tccttccacc gtgaccccaa cctctcctgt cccctccctc 900 caactctgtc tctaagttat ttaaattatg gctggggtcg gggagggtac agggggcact 960 gggacctgga tttgtttttc taaataaagt tggaaaagca aaaaaaaaaa aaaaaaaaaa 1020 aaaaaaa 1027 <210> 134 <211> 4912 <212> DNA <213> Homo sapiens <400> 134 cttttttgtt tttgagactc catcccaggc aggagtgcag tggcacgatc ttggctcact 60 gcagcctctg cctcccaggt tcaagcgact ctcctgcccc agtgacccaa gtagctggga 120 ttacaggcat gcgcccacta atttttgtat ttattgtaga gacagggttt catcatgttg 180 cccaggctgc tctcaaactc ctgatccacc ctcaagcaat ccaccttcct tggcctccca 240 aagtgctggg attacaggca tgagccaccc tgcgtccggc ccaaaattta gtgacttaaa 300 acaagtattt attatctcac agtttctgct ggccaggagt tcagaagcag cttagacatt 360 tctcacaaag ttgctgtcat ctgaaggctt ggctggagct ggaggatgct cttccaagct 420 cactcagatt ggggaccaca aattcagtgc ccaccggatt gtcttagcag cctcgatccc 480 gtatttccat gctatgttta caaatgacat gatggagtgc aagcaggatg agattgtaat 540 gcaaggaatg gacccaagtg ccctggaggc tctgatcaac tttgcctaca acggcaacct 600 tgccattgac cagcaaaatg tccagtcatt gctgatgggg gcgagcttcc tgcagctgca 660 gagcatcaaa gacgcctgct gcacattcct tcgagaacgg cttcacccaa aaaactgcct 720 gggtgtgcgc cagtttgctg agacaatgat gtgtgctgtg ctgtacgacg ctgccaacag 780 cttcatccac cagcactttg tggaggtgtc catgtcagaa gagttcctgg ccctgccctt 840 ggaagacgtg cttgagctgg tgtctcggga tgagctgaat gtcaaatctg aggagcaggt 900 ctttgaagct gcattggcct gggtcagata cgaccgggag cagaggggtc cctacctgcc 960 tgagctgctg tccaatatcc gcctgcccct ctgtcggccc cagttccttt cagacagagt 1020 acagcaggat gacctggtgc gttgctgcca caaatgcagg gacctggtag acgaagcaaa 1080 ggactaccac ctcatgccag agcgccggcc ccacctgcca gctttcagaa cccggccacg 1140 ctgctgcaca tccatcgctg gacttatcta cgctgtaggg ggcctcaact cagcaggtga 1200 ttccctgaat gtggtggaag tgttcgaccc cattgccaat tgctgggaga gatgccgtcc 1260 catgacaaca gcccgcagcc gcgttggcgt ggctgtggtg aacgggcttc tctatgccat 1320 cggaggatat gacggccagc tacggctgag cactgtggag gcctacaacc cggagacaga 1380 cacatggacc agagtgggga gcatgaatag caagagaagt gccatgggga cagtcgtgct 1440 ggatgggcag atctacgtct gtgggggcta cgatggcaac tcttccctca gctccgtgga 1500 gacctactca cctgagacgg acaaatggac agtggtgacc tcgatgagct cgaatcgcag 1560 tgctgctggg gttacagtct ttgagggcag gatatatgtg tcaggcggcc atgatggttt 1620 gcagatcttc agcagtgtgg aacactacaa ccaccacaca gccacctggc accctgcagc 1680 tggcatgctc aacaagcgct gccggcacgg agccgcctcc ctggggagca agatgtttgt 1740 ctgcgggggc tacgatggct ctggcttcct cagcattgcc gagatgtaca gctctgtggc 1800 agaccagtgg tgcctgattg tccccatgca cacgcgcagg agccgggtct ccctggtggc 1860 cagctgtggg cgcctctacg ctgttggggg ctacgacgga cagtcaaacc taagctcagt 1920 ggagatgtat gacccagaga cagactgctg gacattcatg gcccccatgg cgtgccatga 1980 gggaggggtc ggtgtgggct gcatccctct cctcaccatc taaggcagag gatgggatgt 2040 ggtggggcag ggatctggta cagacatagg cgcttccttc caggaacagt ccctcaggag 2100 aggcagtgga ccagaagaga tggcgaaacg tgagctcgcc ggaggtacag tttttccagg 2160 tgcttaagcc ctccccaact gtgccaccct tgtgaccttc aggcttgggt catcaagatg 2220 cacagcatgg aacacaagct cctctggatc ctgcagctgg tgacatggaa ctgttttctg 2280 gtccacatga acacaggctc catccaggcc cagctcctac ccaccgcctc tctgtgggcc 2340 agctgttcac agaaggcctt ccatctgatg ctccccatcg cctgcttgct ctccagccga 2400 gtctggccaa tttgccatgg ggaggctgca gtgtccaagc ctgctggaaa ctgggatgta 2460 gctggggacg aaaggacaga cccaagcgtt ctccctgcct gagatggtgt ggccacagca 2520 gtggaaggct gcacacaggc acattccttc ttccacagtg gggcaccaag gattctgtcc 2580 tcattgctgg gtaagcaggg agaagagaag ttttccccat gtctaatttt gggatttcag 2640 tgaggccttt tccatctgtc caggagaaca gaagggaaaa aaagatactt gaaagaaact 2700 gaaggaaatt taaacaaaga aacacttgaa agaaactgga aagaaaaata atttttttat 2760 gtgaacaaat tttgcaagaa gaaaaaagca taaaagacac taacggcaaa tctatgttta 2820 aatggaaaat cgtctaactg gagaagggcg gtatccaccc cacattcgga tcccagggtc 2880 ctgaggcctc gcattgagct gggggttccc tctgagcccc agtgtgtgtggaatcagtgc 2940 actcttgact gggcctgtag taaggtgctc atggggtttg tcttctcacc caccatcaga 3000 ggacttttaa aatcataggc gtagagagtt agctatctgc tgaattactg ccactcttct 3060 tggtgggggc tcctagctgt ggctgggggc tccaggcgcc cctgtgatta cctcctactg 3120 ccaccatggc gctcattcag attccccact ctcactaaca ttgcttcctt ttttgaccag 3180 caggaaacag caggtctggc cagattctca cttgcccatc aatctcgttc ttggatgatt 3240 tccctcattg tgatgcttct ggggcacgtt gaccatatgc acctctagaa cctaaccagg 3300 gcttccttct accagctgtg ggcgggcttg gtctggtaac cttgtctgct ctgccattcc 3360 actgctcctc catccactcg ccaatcccaa gagtctggcc tccctccagc cctgggcaga 3420 ctgaccagca aggtggacct ttacattcaa gcacagctgg cttttatgac ataaagaact 3480 aaaggccgaa agaatctctt gctgctgcaa agaacagatt ttatatttct tcctctaatc 3540 ttggcaaatg acctttacct tttggaaaga tttcatattg cttcctcctc cctggatagg 3600 acctaatgta gcacagcggg actcaaagag gaggacattt tctcttgcca gtgcactggg 3660 cagtggggct gtccttcaac tgctgctgcc aaaattggtt ttctaaaatt cttccagtag 3720 agactaaaag aagattcaat tcctgtaacc caagactgag tcttagggct ccagtctcca 3780 cctgcttggt ttcctatcct ttgctgcctg cctggggtgg cctggaagcc tgttcagaaa 3840 ggcacaatgt ggagcctggg gtgtctcccc caccccagga ccgtcaggtt taccagtgtg 3900 tgcaatcgcc atgtattcag agggaagtac ctttgttacc tacaacttag gagctaggcc 3960 tctgctacaa gcacttgaaa atgatatttt tatttttaac gtctcaacaa tctgatatcg 4020 gatgtcgttt aacctgggct cgtggtaggg ctccagcatt tctccctcct tcctggtttg 4080 cctgtagggg tagactcgga aggtgggtgg ggtgtgcatt tcctgttagg agtgtatcag 4140 tgcttgtctt attataagcc cctttctttt gtgaatttga agtagcacca acaagcctgg 4200 attgtgaagg tattaagaat cggtctgtgg gctactgagt gggtccttag gatactggcc 4260 cagattttgc cactgggtat ggcagatcat tttctaccat ggcctgctgc tcttgtagtg 4320 gacttcctga gtccaatccc acctcctggt gtagaattta cactgctgca cctgaggtcg 4380 atgtttcaaa gtaagatcaa gccagtgttt tgatctgggc tctgagcaca agtcaggaaa 4440 caccaacata ttcacactct cccagtaggt tcctcagtcc gatggtgaat ggctattcgt 4500 aaatggctgg tctggctctt tggtgttgga gcctttccaa tagccccatg aaaagaagca 4560 tcacccaagg atattgtaaa aaggatgtaa caaggagata gggtagacat tgtactcagt 4620 gggccttggg gcctagccca gctctgagca gaggactgtg gcattcactg tccttgagtg 4680 tttcaccttc ttggataaca cacgggcctt ctcttctgga tttcatcaga gattacagcc 4740 agatgggggc tgaagaccat cctcttgacc acagaggtgt gactgtggga attcctccca 4800 atttatggtt tcccagaaaa tcttagttcc ttttatttat agaatgcatg tcttttgtgt 4860 taagaaacca aagagaaata aagagaacac tcctaataaa aaaaaaaaaa aa 4912 <210> 135 <211> 1358 <212> DNA <213> Homo sapiens <400> 135 gttccaaccc agggggaaaa atgcggcctt tgactgaaga ggagacccgt gtcatgtttg 60 agaagatagc gaaatacatt ggggagaatc ttcaactgct ggtggaccgg cccgatggca 120 cctactgttt ccgtctgcac aacgaccggg tgtactatgt gagtgagaag attatgaagc 180 tggccgccaa tatttccggg gacaagctgg tgtcgctggg gacctgcttt ggaaaattca 240 ctaaaaccca caagtttcgg ttgcacgtca cagctctgga ttaccttgca ccttatgcca 300 agtataaagt ttggataaag cctggtgcag agcagtcctt cctgtatggg aaccatgtgt 360 tgaaatctgg tctgggtcga atcactgaaa atacttctca gtaccagggc gtggtggtgt 420 actccatggc agacatccct ttgggttttg gggtggcagc caaatctaca caagactgca 480 gaaaagtaga ccccatggcg attgtggtat ttcatcaagc agacattggg gaatatgtgc 540 ggcatgaaga gacgttgact taaaacgaag ccattccaag gacagacggc tgtatggaaa 600 ggccgagctt tgtttcctgt gtttgtgtgg actccaccat catgttgaat tttgtcaaca 660 ctctggcctc ttcagggact tcttatttac tgtactctct atcactgaca aatgcaggct 720 ggattcttat tatatacaga gatggctcaa aaatggggtt tcagatcttt gtgacgaaat 780 agaatactgt ttcatatttg aatcagaggg cttcttgttc tgagaaatag gttcaaaatc 840 attggaacca ggaacaagaa tagcttattg ttatctgtga taacactgtt ttctaaacac 900 aaggattttc ttttttatta atatgcaaca tagacattgc cataacagaa taataaacca 960 catgtggggt tttaaaaatg aaatttggct aataggagca attcagctat ttttctatac 1020 agtaattggt gtgtggtata gaagaaaaac gggttcaaac cccacttctg ccacctacca 1080 gctatatggc cttgaatgag tcattcagct ttaataaggt tcattttctt ctgtttaaaa 1140 agacacaaaa cttgaaaatc agctttggcc atctacctga gaattagaaa gtctgatttt 1200 tggaattaga aatcatgatt gtaggctggg cacagtggct cgcgcctgta atcccagcac 1260 tttgggaggc caaggcggac ggatcacttg aggttaggag tttgagacca gcctggccaa 1320 catggtgaaa ccccatctct actaaaaaaa aaaaaaaa 1358 <210> 136 <211> 463 <212> DNA <213> Homo sapiens <400> 136 cgcgccgcca caatggtgcg catgaatgtc ctggcagatg ctctcaagag tatcaacaat 60 gccgaaaaga gaggcaaacg ccaggtgctt attaggccgt gctccaaagt catcgtccgg 120 tttctcactg tgatgatgaa gcatggttac attggcgaat ttgaaatcat tgatgaccac 180 agagctggga aaattgttgt gaacctcaca ggcaggctaa acaagtgtgg ggtgatcagc 240 cccagatttg acgtgcaact caaagacctg gaaaaatggc agaataatct gcttccatcc 300 cgccagtttg gtttcattgt actgacaacc tcagctggca tcatggacca tgaagaagca 360 agacgaaaac acacaggagg gaaaatcctg ggattctttt tctagggatg taatacatat 420 atttacaaat aaaatgcctc atggacaaaa aaaaaaaaaa aaa 463 <210> 137 <211> 938 <212> DNA <213> Homo sapiens <400> 137 gtcgtcgggg tttcctgctt caacagtgct tggacggaac ccggcgctcg ttccccaccc 60 cggccggccg cccatagcca gccctccgtc acctcttcac cgcaccctcg gactgcccca 120 aggcccccgc cgccgctcca gcgccgcgca gccaccgccg ccgccgccgc ctctccttag 180 tcgccgccat gacgaccgcg tccacctcgc aggtgcgcca gaactaccac caggactcag 240 aggccgccat caaccgccag atcaacctgg agctctacgc ctcctacgtt tacctgtcca 300 tgtcttacta ctttgaccgc gatgatgtgg ctttgaagaa ctttgccaaa tactttcttc 360 accaatctca tgaggagagg gaacatgctg agaaactgat gaagctgcag aaccaacgag 420 gtggccgaat ctttcttcag gatatcaaga aaccagactg tgatgactgg gagagcgggc 480 tgaatgcaat ggagtgtgca ttacatttgg aaaaaaatgt gaatcagtca ctactggaac 540 tgcacaaact ggccactgac aaaaatgacc cccatttgtg tgacttcatt gagacacatt 600 acctgaatga gcaggtgaaa gccatcaaag aattgggtga ccacgtgacc aacttgcgca 660 agatgggagc gcccgaatct ggcttggcgg aatatctctt tgacaagcac accctgggag 720 acagtgataa tgaaagctaa gcctcgggct aatttcccca tagccgtggg gtgacttccc 780 tggtcaccaa ggcagtgcat gcatgttggg gtttccttta ccttttctat aagttgtacc 840 aaaacatcca cttaagttct ttgatttgta ccattccttc aaataaagaa atttggtaaa 900 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaa 938 <210> 138 <211> 2283 <212> DNA <213> Homo sapiens <400> 138 cgcctccagg ccccttcccg cgccgcgacg cacgctgccc cggaaggccg cggcgctgta 60 gtgcggcgcc ccaggttctt tagtggaaga acgcgaagcg aggatgagtg atccgtggag 120 gcagtaacag gcgcggcgag ggagaagtga ttcccgaaga atcaaggctg ggccggaccc 180 ggtggcctgg caacaggtaa taagagaaat gaagccaaca ggtacagacc caaggatctt 240 atctatagct gctgaagttg caaaaagccc tgagcagaat gtccctgtta tactgttgaa 300 gttaaaagaa ataataaaca tcacaccttt aggaagctca gagttgaaga aaatcaaaca 360 agatatatat tgttatgatc tcattcaata ttgcctcttg gtcctcagtc aagattattc 420 tcgaatccag ggtggttgga ctacaatttc ccagcttaca cagatattaa gccattgctg 480 tgtgggcttg gagccaggag aagatgcaga ggaattttac aatgaattac ttccatcagc 540 tgcagaaaat tttctagttt tggggagaca attacaaaca tgttttatca atgcagctaa 600 ggctgaagaa aaagatgaat tactacactt tttccaaatt gtgactgatt ctctcttctg 660 gcttttggga ggccatgttg aacttattca gaatgtacta caaagtgatc atttcttaca 720 tttactgcaa gctgacaatg tccaaatagg atctgcagtc atgatgatgc tacagaatat 780 attacagatc aacagtggtg atttactcag aataggaaga aaagccctgt attcaatttt 840 agatgaagtt attttcaagc ttttttcaac tcctagtcca gttataagaa gtactgctac 900 aaaactccta ctgttgatgg ctgaatccca tcaggaaatt ttgattttac tgagacaaag 960 tacctgctac aaaggactca gacgtctact aagtaaacag gaaactggga ctgaattcag 1020 tcaagaactt agacagcttg ttggcctttt aagcccaatg gtctatcagg aagtagaaga 1080 gcagatccaa acgatcaaag atgttgctgg agataaatag gcagaaggaa gaagaggacc 1140 tcaaattaca attgcaactt caaagacaga gagccatgag actttcccga gaattgcagc 1200 tgagtatgct cgaaatagtt catccaggtc aggtggagaa acactatcgg gaaatggaag 1260 agaaatcagc actgattatc cagaaacatt ggagagggta cagggaaagg aaaaattttc 1320 accaacagag gcagtctctc atagagtata aagcagctgt cacacttcaa agagcagcgc 1380 ttaaattcct agcgaagtac cgtaagaaaa agaaactatt tgctccttgg cgaggactcc 1440 aagaactcac tgatgcacgc cgagttgaac tgaagaaacg agtggatgac tatgtcagaa 1500 gacatttggg ctctccaatg tcagatgtgg tcagtaggga gctccatgcc caagctcaag 1560 aacgactgca acactacttt atgggcaggg ccctagaaga gcgagcccag cagcacagag 1620 aagctctgat agcacagatc agcaccaacg ttgaacagct aatgaaggca ccaagtctga 1680 aggaggcaga agggaaagaa cctgagctct tcctaagtag atccaggcct gtggcagcca 1740 aggccaagca ggcccatctc acaaccctga agcacataca agcaccctgg tggaagaagc 1800 ttggagaaga atctggagat gagattgatg ttccaaagga tgagcttagt atagaattag 1860 aaaatttatt cattggtgga accaaaccac cttagtgagt aaccctaaga attgacacaa 1920 atctcatatt ttaggagatt atattggttc tgcctctggc atgctggtag actagggcca 1980 tcctaactta ttattttcca gaggttctcc tccagacaag acctgcagta agcaaagagt 2040 tatattctac ctctctctca attttctttt tcttttctct gtatcctcat ccttagccac 2100 acacagattt gtgtggcttt tattgtagaa ctaaacttag catagtgttc tgttgtttac 2160 atgaagtgtg tttttctttg gtttcttctg ttttccaact aaatattttt ttctaaataa 2220 atattttcaa caattgattt gaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2280 aaa 2283 <210> 139 <211> 1937 <212> DNA <213> Homo sapiens <400> 139 gcctcccgct cgccctgaac ccagtgcctg cagccatggc tcccggccag ctcgccttat 60 ttagtgtctc tgacaaaacc ggccttgtgg aatttgcaag aaacctgacc gctcttggtt 120 tgaatctggt cgcttccgga gggactgcaa aagctctcag ggatgctggt ctggcagtca 180 gagatgtctc tgagttgacg ggatttcctg aaatgttggg gggacgtgtg aaaactttgc 240 atcctgcagt ccatgctgga atcctagctc gtaatattcc agaagataat gctgacatgg 300 ccagacttga tttcaatctt ataagagttg ttgcctgcaa tctctatccc tttgtaaaga 360 cagtggcttc tccaggtgta actgttgagg aggctgtgga gcaaattgac attggtggag 420 taaccttact gagagctgca gccaaaaacc acgctcgagt gacagtggtg tgtgaaccag 480 aggactatgt ggtggtgtcc acggagatgc agagctccga gagtaaggac acctccttgg 540 agactagacg ccagttagcc ttgaaggcat tcactcatac ggcacaatat gatgaagcaa 600 tttcagatta tttcaggaaa cagtacagca aaggcgtatc tcagatgccc ttgagatatg 660 gaatgaaccc acatcagacc cctgcccagc tgtacacact gcagcccaag cttcccatca 720 cagttctaaa tggagcccct ggatttataa acttgtgcga tgctttgaac gcctggcagc 780 tggtgaagga actcaaggag gctttaggta ttccagccgc tgcctctttc aaacatgtca 840 gcccagcagg tgctgctgtt ggaattccac tcagtgaaga tgaggccaaa gtctgcatgg 900 tttatgatct ctataaaacc ctcacaccca tctcagcggc atatgcaaga gcaagagggg 960 ctgataggat gtcttcattt ggtgattttg ttgcattgtc cgatgtttgt gatgtaccaa 1020 ctgcaaaaat tatttccaga gaagtatctg atggtataat tgccccagga tatgaagaag 1080 aagccttgac aatactttcc aaaaagaaaa atggaaacta ttgtgtcctt cagatggacc 1140 aatcttacaa accagatgaa aatgaagttc gaactctctt tggtcttcat ttaagccaga 1200 agagaaataa tggtgtcgtc gacaagtcat tatttagcaa tgttgttacc aaaaataaag 1260 atttgccaga gtctgccctc cgagacctca tcgtagccac cattgctgtc aagtacactc 1320 agtctaactc tgtgtgctac gccaagaacg ggcaggttat cggcattgga gcaggacagc 1380 agtctcgtat acactgcact cgccttgcag gagataaggc aaactattgg tggcttagac 1440 accatccaca agtgctttcg atgaagttta aaacaggagt gaagagagca gaaatctcca 1500 atgccatcga tcaatatgtg actggaacca ttggcgagga tgaagatttg ataaagtgga 1560 aggcactgtt tgaggaagtc cctgagttac tcactgaggc agagaagaag gaatgggttg 1620 agaaactgac tgaagtttct atcagctctg atgccttctt ccctttccga gataacgtag 1680 acagagctaa aaggagtggt gtggcgtaca ttgcggctcc ctccggttct gctgctgaca 1740 aagttgtgat tgaggcctgc gacgaactgg gaatcatcct cgctcatacg aaccttcggc 1800 tcttccacca ctgattttac cacacactgt tttttggctt gcttatgtgt aggtgaacag 1860 tcacgcctga aactttgagg ataacttttt aaaaaaataa aacagtatct cttaatcact 1920 ggaaaaaaaa aaaaaaa 1937 <210> 140 <211> 2335 <212> DNA <213> Homo sapiens <400> 140 ccgaggtggc tgctggtggg ggctcctggg acgacaggct gcgcaggctc atctccccca 60 acctgggggt cgtgttcttc aacgcctgcg aggccgcgtc gcggctggcg cgcggcgagg 120 atgaggcgga gctggcgctg agcctcctgg cgcagctggg catcacgcct ctgccactca 180 gccgcggccc cgtgccagcc aaacccaccg tgctcttcga gaagatgggc gtgggccggc 240 tggacatgta tgtgctgcac ccgccctccg ccggcgccga gcgcacgctg gcctctgtgt 300 gcgccctgct ggtgtggcac cccgccggcc ccggcgagaa ggtggtgcgc gtgctgttcc 360 ccggttgcac cccgcccgcc tgcctcctgg acggcctggt ccgcctgcag cacttgaggt 420 tcctgcgaga gcccgtggtg acgccccagg acctggaggg gccggggcga gccgagagca 480 aagagagcgt gggctcccgg gacagctcga agagagaggg cctcctggcc acccacccta 540 gacctggcca ggagcgccct ggggtggccc gcaaggagcc agcacgggct gaggccccac 600 gcaagactga gaaagaagcc aaggcccccc gggagttgaa gaaagacccc aaaccgagtg 660 tctcccggac ccagccgcgg gaggtgcgcc gggcagcctc ttctgtgccc aacctcaaga 720 agacgaatgc ccaggcggca cccaagcccc gcaaagcgcc cagcacgtcc cactctggct 780 tcccgccggt ggcaaatgga ccccgcagcc cgcccagcct ccgatgtgga gaagccagcc 840 cccccagtgc agcctgcggc tctccggcct cccagctggt ggccacgccc agcctggagc 900 tggggccgat cccagccggg gaggagaagg cactggagct gcctttggcc gccagctcaa 960 tcccaaggcc acgcacaccc tcccctgagt cccaccggag ccccgcagag ggcagcgagc 1020 ggctgtcgct gagcccactg cggggcgggg aggccgggcc agacgcctca cccacagtga 1080 ccacacccac ggtgaccacg ccctcactac ccgcagaggt gggctccccg cactcgaccg 1140 aggtggacga gtccctgtcg gtgtcctttg agcaggtgct gccgccatcc gcccccacca 1200 gtgaggctgg gctgagcctc ccgctgcgtg gcccccgggc gcggcgctcg gcttccccac 1260 acgatgtgga cctgtgcctg gtgtcaccct gtgaatttga gcatcgcaag gcggtgccaa 1320 tggcaccggc acctgcgtcc cccggcagct cgaatgacag cagtgcccgg tcacaggaac 1380 gggcaggtgg gctgggggcc gaggagacgc cacccacatc ggtcagcgag tccctgccca 1440 ccctgtctga ctcggatccc gtgcccctgg cccccggtgc ggcagactca gacgaagaca 1500 cagagggctt tggagtccct cgccacgacc ctttgcctga ccccctcaag gtccccccac 1560 cactgcctga cccatccagc atctgcatgg tggaccccga gatgctgccc cccaagacag 1620 cacggcaaac ggagaacgtc agccgcaccc ggaagcccct ggcccgcccc aactcacgcg 1680 ctgccgcccc caaagccact ccagtggctg ctgccaaaac caaggggctt gctggtgggg 1740 accgtgccag ccgaccactc agtgcccgga gtgagcccag tgagaaggga ggccgggcac 1800 ccctgtccag aaagtcctca acccccaaga ctgccactcg aggcccgtcg gggtcagcca 1860 gcagccggcc cggggtgtca gccaccccac ccaagtcccc ggtctacctg gacctggcct 1920 acctgcccag cgggagcagc gcccacctgg tggatgagga gttcttccag cgcgtgcgcg 1980 cgctctgcta cgtcatcagt ggccaggacc agcgcaagga ggaaggcatg cgggccgtcc 2040 tggacgcgct actggccagc aagcagcatt gggaccgtga cctgcaggtg accctgatcc 2100 ccactttcga ctcggtggcc atgcatacgt ggtacgcaga gacgcacgcc cggcaccagg 2160 cgctgggcat cacggtgttg ggcagcaaca gcatggtgtc catgcaggat gacgccttcc 2220 cggcctgcaa ggtggagttc tagccccatc gccgacacgc cccccactca gcccagcccg 2280 cctgtcccta gattcagcca catcagaaat aaactgtgac ttccaaaaaa aaaaa 2335 <210> 141 <211> 2338 <212> DNA <213> Homo sapiens <400> 141 agcgcacgtc ggcagtcggc tccctcgttg accgaatcac cgacctctct ccccagctgt 60 atttccaaaa tgtcgctttc taacaagctg acgctggaca agctggacgt taaagggaag 120 cgggtcgtta tgagagtcga cttcaatgtt cctatgaaga acaaccagat aacaaacaac 180 cagaggatta aggctgctgt cccaagcatc aaattctgct tggacaatgg agccaagtcg 240 gtagtcctta tgagccacct aggccggcct gatggtgtgc ccatgcctga caagtactcc 300 ttagagccag ttgctgtaga actcaaatct ctgctgggca aggatgttct gttcttgaag 360 gactgtgtag gcccagaagt ggagaaagcc tgtgccaacc cagctgctgg gtctgtcatc 420 ctgctggaga acctccgctt tcatgtggag gaagaaggga agggaaaaga tgcttctggg 480 aacaaggtta aagccgagcc agccaaaata gaagctttcc gagcttcact ttccaagcta 540 ggggatgtct atgtcaatga tgcttttggc actgctcaca gagcccacag ctccatggta 600 ggagtcaatc tgccacagaa ggctggtggg tttttgatga agaaggagct gaactacttt 660 gcaaaggcct tggagagccc agagcgaccc ttcctggcca tcctgggcgg agctaaagtt 720 gcagacaaga tccagctcat caataatatg ctggacaaag tcaatgagat gattattggt 780 ggtggaatgg cttttacctt ccttaaggtg ctcaacaaca tggagattgg cacttctctg 840 tttgatgaag agggagccaa gattgtcaaa gacctaatgt ccaaagctga gaagaatggt 900 gtgaagatta ccttgcctgt tgactttgtc actgctgaca agtttgatga gaatgccaag 960 actggccaag ccactgtggc ttctggcata cctgctggct ggatgggctt ggactgtggt 1020 cctgaaagca gcaagaagta tgctgaggct gtcactcggg ctaagcagat tgtgtggaat 1080 ggtcctgtgg gggtatttga atgggaagct tttgcccggg gaaccaaagc tctcatggat 1140 gaggtggtga aagccacttc taggggctgc atcaccatca taggtggtgg agacactgcc 1200 acttgctgtg ccaaatggaa cacggaggat aaagtcagcc atgtgagcac tgggggtggt 1260 gccagtttgg agctcctgga aggtaaagtc cttcctgggg tggatgctct cagcaatatt 1320 tagtactttc ctgcctttta gttcctgtgc acagccccta agtcaactta gcattttctg 1380 catctccact tggcattagc taaaaccttc catgtcaaga ttcagctagt ggccaagaga 1440 tgcagtgcca ggaaccctta aacagttgca cagcatctca gctcatcttc actgcaccct 1500 ggatttgcat acattcttca agatcccatt tgaatttttt agtgactaaa ccattgtgca 1560 ttctagagtg catatattta tattttgcct gttaaaaaga aagtgagcag tgttagctta 1620 gttctctttt gatgtaggtt attatgatta gctttgtcac tgtttcacta ctcagcatgg 1680 aaacaagatg aaattccatt tgtaggtagt gagacaaaat tgatgatcca ttaagtaaac 1740 aataaaagtg tccattgaaa ccgtgatttt tttttttttc ctgtcatact ttgttaggaa 1800 gggtgagaat agaatcttga ggaacggatc agatgtctat attgctgaat gcaagaagtg 1860 gggcagcagc agtggagaga tgggacaatt agataaatgt ccattcttta tcaagggcct 1920 actttatggc agacattgtg ctagtgcttt tattctaact tttattttta tcagttacac 1980 atgatcataa tttaaaaagt caaggcttat aacaaaaaag ccccagccca ttcctcccat 2040 tcaagattcc cactccccag aggtgaccac tttcaactct tgagtttttc aggtatatac 2100 ctccatgttt ctaagtaata tgcttatatt gttcacttcc ttttttttta ttttttaaag 2160 aaatctattt cataccatgg aggaaggctc tgttccacat atatttccac ttcttcattc 2220 tctcggtata gttttgtcac aattatagat tagatcaaaa gtctacataa ctaatacagc 2280 tgagctatgt agtatgctat gattaaattt acttatgtaa aaaaaaaaaa aaaaaaaa 2338

[Brief description of drawings]

FIG. 1: cDNA clone 3 was recognized by HLA-B46-restricted cytotoxic T cell OK-CTL-d55,
It is shown that IFN-γ production of K-CTL-d55 was promoted.

FIG. 2: cDNA clone 9 was recognized by HLA-B46-restricted cytotoxic T cell OK-CTL-d55,
It is shown that IFN-γ production of K-CTL-d55 was promoted.

FIG. 3: cDNA clone 10 was recognized by HLA-B46-restricted cytotoxic T cell OK-CTL-d55,
It is shown that IFN-γ production of OK-CTL-d55 was promoted.

FIG. 4: Peptide 7F derived from cDNA clone 7F
P6 is HLA-B46 restricted cytotoxic T cell OK-C
Recognized by TL-d55, IF of OK-CTL-d55
It shows that N-γ production was promoted.

FIG. 5: Peptide 3H derived from cDNA clone 3H
P4 is HLA-B46 restricted cytotoxic T cell OK-C
Recognized by TL-d55, IF of OK-CTL-d55
It shows that N-γ production was promoted.

FIG. 6: cDNA clone 7F was recognized by HLA-B46-restricted cytotoxic T cell OK-CTL-d55,
It is shown that IFN-γ production of OK-CTL-d55 was promoted.

FIG. 7: Peptide 7F derived from cDNA clone 7F
P2 is HLA-B46 restricted cytotoxic T cell OK-C
Recognized by TL-d55, IF of OK-CTL-d55
It shows that N-γ production was promoted.

FIG. 8: Peptide 7F derived from cDNA clone 7F
Peripheral blood mononuclear cells (PBMC) derived from cancer patients by P2
To HLA-B46-restricted peptide-specific cell injury
Shows that injurious T cells have been induced and / or activated
You FIG. 8A shows PBMC pre-stimulated with 7F · P2.
HLA-B46 having a p53 mutation ⁺Tumor cell OS
It shows that C20 was recognized and dissolved. FIG. 8B shows 7F
・ To PBMC OSC20 cells pre-stimulated with P2
IFN-γ production from the PBMC by the reaction
Inhibited by anti-HLA-BC antibody or anti-CD8 antibody
Indicates that FIG. 8C shows⁵¹In the Cr release test,
Pre-pulsing OSC20 cells with excess 7F · P2
And PBMC OSC20 pre-stimulated with 7F / P2
7F · P1 has enhanced cytotoxic activity against cells
This phenomenon was not observed when 0 was pulsed to OSC20 cells.
Not labeled, and not labeled with 7F / P2 pulsed
PHA-blasts to OSC20 cells
When mixed with, the cytotoxic activity against OSC20 cells is blocked.
Damaged but not labeled with 7F / P10 pulsed
This phenomenon was not observed in PHA-blast.
Indicates that it was not done. In the figure, * indicates Student T test
It was also confirmed that there was a significant difference (P <0.05)
Indicates.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 39/395 A61K 45/00 4C084 45/00 48/00 4C085 48/00 A61P 35/00 4C086 A61P 35 / 00 C07K 14/725 4C087 C07K 14/725 14/82 4H045 14/82 16/30 16/30 C12N 1/15 C12N 1/15 1/19 1/19 1/21 1/21 C12P 21/02 C 5 / 06 C12Q 1/02 5/10 1/68 A C12P 21/02 G01N 33/15 Z C12Q 1/02 33/50 Z 1/68 33/53 D G01N 33/15 M 33/50 33/566 33/53 C12N 15/00 ZNAA 5/00 E 33/566 A F term (reference) 2G045 AA34 AA35 CB01 DA13 DA36 FB02 FB03 4B024 AA01 BA36 CA04 CA09 DA02 EA04 GA11 GA18 GA19 HA03 HA12 4B063 QA01 QA18 QQ20 QQ42 QRQ79 QRQR QR QR79 QRQR QRQQ QR QR QR QR QR80 QR82 QS12 QS25 QS34 QS36 QX01 4B064 AG20 CA10 CA19 CC24 DA05 DA20 4B065 AA90X AA93Y AB01 AC14 BA01 CA24 CA44 CA60 4C084 AA13 AA17 NA14 ZB262 4C085 AA13 AA14 AA19 NA14 NA16A02 NA16A02 NA16A02 A16 NA16A02 NA16A06 A02 NA16A02 A16 NA16A02 ZB26 4H045 AA10 AA11 AA20 AA30 BA10 CA41 DA50 DA75 DA86 EA28 EA31 FA71 FA74

Claims (22)

[Claims] 1. A peptide comprising the amino acid sequence of any one of SEQ ID NOs: 1 to 50 in the sequence listing. 2. An HLA-B46-restricted cytotoxic T cell-derived and / or HL consisting of the amino acid sequence of any one of SEQ ID NOs: 51 to 99 in the sequence listing.
A-B46 Polypeptide recognized by cytotoxic T cells in a restricted manner. 3. One or more peptides selected from the peptides consisting of the amino acid sequences set forth in any one of SEQ ID NOS: 1 to 50 in the sequence listing, and / or the sequence set forth in any one of SEQ ID NOS: 51 to 99. HL consisting of amino acid sequence
A drug comprising one or more polypeptides selected from polypeptides that induce A-B46-restricted cytotoxic T cells and / or are recognized by HLA-B46-restricted cytotoxic T cells. 4. One or more kinds of peptides selected from the peptides consisting of the amino acid sequences set forth in any one of SEQ ID NOS: 1 to 50 in the sequence listing, and / or the sequence set forth in any one of SEQ ID NOS: 51 to 99 HL consisting of amino acid sequence
A cancer vaccine containing one or more polypeptides selected from polypeptides that induce A-B46-restricted cytotoxic T cells and / or are recognized by HLA-B46-restricted cytotoxic T cells. 5. The cancer vaccine according to claim 4, which is used for treatment of colon cancer, oral cancer, lung cancer, prostate cancer, or gynecologic cancer. 6. Any one of SEQ ID NOS: 1 to 6 in the sequence listing
1 selected from the peptides consisting of the amino acid sequence described in 1.
Or more peptides, and / or HLA-B46-inducing cytotoxic T cells consisting of the amino acid sequence of SEQ ID NO: 100 and / or HLA-B4
A cancer vaccine comprising a 6-restricted polypeptide recognized by cytotoxic T cells, which is used for the treatment of cancer carrying HLA-B46 and having a mutation in the p53 tumor suppressor gene. 7. One or more kinds of peptides selected from the peptides consisting of the amino acid sequences set forth in any one of SEQ ID NOS: 1 to 50 of the sequence listing, and / or the sequence set forth in any one of SEQ ID NOS: 51 to 99 HL consisting of amino acid sequence
A-B46-restricted cytotoxic T cell-inducing and / or one or more polypeptides selected from polypeptides recognized by HLA-B46-restricted cytotoxic T cells, and cytotoxicity An inducer of T cells. 8. One or more peptides selected from the peptides consisting of the amino acid sequences set forth in any one of SEQ ID NOS: 1 to 50 in the sequence listing, and / or the sequence set forth in any one of SEQ ID NOS: 51 to 99 HL consisting of amino acid sequence
A-B46-restricted cytotoxic T cell-inducing and / or one or more polypeptides selected from polypeptides recognized by HLA-B46-restricted cytotoxic T cells are used. And a method for inducing cytotoxic T cells. 9. A peptide comprising the amino acid sequence set forth in any one of SEQ ID NOS: 1 to 50 in the sequence listing, or the amino acid sequence set forth in any one of SEQ ID NOS: 51 to 99, which is HLA-B46 restricted. A polynucleotide encoding a polypeptide that induces a cytotoxic T cell and / or is recognized by a cytotoxic T cell in a HLA-B46-restricted manner, or a complementary strand thereof. 10. A polynucleotide comprising the nucleotide sequence set forth in any one of SEQ ID NOs: 100 to 141 in the sequence listing, wherein the polypeptide encoded by the polynucleotide is an HLA-B46-restricted cytotoxic T cell. And / or HLA-B46-restricted cytotoxic T
A polynucleotide or its complementary strand that is recognized by a cell. 11. A polynucleotide which hybridizes with the polynucleotide according to claim 9 or 10 or a complementary strand thereof under stringent conditions. 12. A recombinant vector containing the polynucleotide according to any one of claims 9 to 11 or a complementary strand thereof. 13. The recombinant vector according to claim 12, which is an expression recombinant vector. 14. A transformant transformed with the recombinant vector according to claim 12 or 13. 15. A step of culturing a transformant transformed with the recombinant vector according to claim 13,
A method for producing the peptide according to claim 1 or the polypeptide according to claim 2. 16. An antibody which immunologically recognizes the peptide according to claim 1 or the polypeptide according to claim 2. 17. A peptide according to claim 1 or a polypeptide according to claim 2 and / or HLA-B.
A compound which interacts with 46 molecules to enhance the recognition of said peptide or said polypeptide by at least HLA-B46 restricted cytotoxic T cells, and / or the poly according to any one of claims 9 to 11. A method for screening a compound that interacts with a nucleotide or its complementary strand to enhance its expression, comprising the peptide according to claim 1, the polypeptide according to claim 2, and any one of claims 9 to 11. Use of at least one of the polynucleotide or complementary strand thereof according to claim 12, the recombinant vector according to claim 12 or 13, the transformant according to claim 14, or the antibody according to claim 16. And a screening method. 18. A compound obtained by the screening method according to claim 17. 19. A compound which enhances the recognition by HLA-B46-restricted cytotoxic T cells for at least one of the peptide according to claim 1 or the polypeptide according to claim 2, or claims 9 to 11. One of
A compound which interacts with the polynucleotide or the complementary strand thereof to enhance its expression. 20. The peptide according to claim 1, 2.
The polypeptide according to any one of claims 9 to 11,
The polynucleotide according to claim 1 or a complementary strand thereof, the recombinant vector according to claim 12 or 13, and the recombinant vector according to claim 1.
A pharmaceutical composition for treating cancer, which comprises at least one of the transformant according to claim 4, the antibody according to claim 16, or the compound according to claim 18 or 19. 21. The peptide according to claim 1 or the polypeptide according to claim 2 or claim 9 or 1.
A method of quantitatively or qualitatively measuring the polynucleotide according to 0. 22. A reagent kit for use in the screening method according to claim 17 or the method according to claim 21, wherein the peptide according to claim 1, the polypeptide according to claim 2, and the reagent kit according to claim 9. 21. A reagent kit comprising at least one of the polynucleotide according to any one of 1 to 11 or a complementary strand thereof, or the antibody according to claim 16.