CA2404233A1 - Compositions and methods for the therapy and diagnosis of lung cancer - Google Patents

Abstract

Compositions and methods for the therapy and diagnosis of cancer, particularly lung cancer, are disclosed. Illustrative compositions comprise one or more lung tumor polypeptides, immunogenic portions thereof, polynucleotides that encode such polypeptides, antigen presenting cell that expresses such polypeptides, and T cells that are specific for cells expressing such polypeptides. The disclosed compositions are useful, for example, in the diagnosis, prevention and/or treatment of diseases, particularly lung cancer.

Description

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

~~ TTENANT LES PAGES 1 A 264 NOTE : Pour les tomes additionels, veuillez contacter 1e Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME
NOTE POUR LE TOME / VOLUME NOTE:

COMPOSITIONS AND METHODS FOR THE THERAPY
AND DIAGNOSIS OF LUNG CANCER
TECHNICAL FIELD OF THE INVENTION
The present invention relates generally to therapy and diagnosis of cancer, such as lung cancer. The invention is more specifically related to polypeptides, comprising at least a portion of a lung tumor protein, and to polynucleotides encoding such ~polypeptides. Such polypeptides and polynucleotides are useful in pharmaceutical compositions, e.g., vaccines, and other compositions for the diagnosis and treatment of lung cancer.
BACKGROUND OF THE INVENTION
Lung cancer is the primary cause of cancer death among both men and women in the U.S., with an estimated 172,000 new cases being reported in 1994.
The five-year survival rate among all lung cancer patients, regardless of the stage of disease at diagnosis, is only 13%. This contrasts with a five-year survival rate of 46% among cases detected while the disease is still localized. However, only 16% of lung cancers are discovered before the disease has spread.
Early detection is difficult since clinical symptoms are often not seen until the disease has reached an advanced stage. Currently, diagnosis is aided by the use of chest x-rays, analysis of the type of cells contained in sputum and fiberoptic examination of the bronchial passages. Treatment regimens are determined by the type and stage of the cancer, and include surgery, radiation therapy and/or chemotherapy. In spite of considerable research into therapies for the disease, lung cancer remains difficult to treat.
Accordingly, there remains a need in the art for improved vaccines, treatment methods and diagnostic techniques for lung cancer.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides polynucleotide compositions comprising a sequence selected from the group consisting of:

2 (a) sequences provided in SEQ ID NO: 217-390, 392, 394, 396, 398-420 422-424, 428-433 and 440-583;
(b) complements of the sequences provided in SEQ ID NO: 217-390, 392, 394, 396, 398-420 422-424, 428-433 and 440-583;
(c) sequences consisting of at least 20 contiguous residues of a sequence provided in SEQ ID NO: 217-390, 392, 394, 396, 398-420 422-424, 428-and 440-583;
(d) sequences that hybridize to a sequence provided in SEQ ID NO:
217-390, 392, 394, 396, 398-420 422-424, 428-433 and 440-583, under moderately stringent conditions;
(e) sequences having at least 75% identity to a sequence of SEQ ID
NO: 217-390, 392, 394, 396, 398-420 422-424, 428-433 and 440-583;
(fj sequences having at least 90% identity to a sequence of SEQ ID
NO: 217-390, 392, 394, 396, 398-420 422-424, 428-433 and 440-583; and (g) degenerate variants of a sequence provided i.n SEQ ID NO: 217-390, 392, 394, 396, 398-420 422-424, 428-433 and 440-583.
In one preferred embodiment, the polynucleotide compositions of the invention are expressed in at least about 20%, more preferably in at least about 30%, and most preferably in at least about 50% of lung tumors samples tested, at a level that , is at least about 2-fold, preferably at least about 5-fold, and most preferably at least about 10-fold higher than that for normal tissues.
The present invention, in another aspect, provides polypeptide compositions comprising an amino acid sequence that is encoded by a polynucleotide sequence described above.
In specific embodiments, the present invention provides polypeptide compositions comprising an amino acid sequence selected from the group consisting of sequences recited in SEQ ID NO: 391, 393, 395, 397, 421, 425-427, 434-439 and 587.
In certain preferred embodiments, the polypeptides and/or polynucleotides of the present invention are immunogenic, i.e., they are capable of

3 eliciting an immune response, particularly a humoral and/or cellular immune response, as further described herein.
The present invention further provides fragments, variants and/or derivatives of the disclosed polypeptide and/or polynucleotide sequences, wherein the fragments, variants and/or derivatives preferably have a level of immunogenic activity of at least about 50%, preferably at least about 70% and more preferably at least about 90% of the level of immunogenic activity of a polypeptide sequence set forth in SEQ ID
NOs: 391, 393, 395, 397, 421, 425-427, 434-439 and 584-587 or a polypeptide sequence encoded by a polynucleotide sequence set forth in SEQ ID NOs: 217-390, 392, 394, 396, 398-420 422-424, 428-433 and 440-583.
The present invention further provides polynucleotides that encode a polypeptide described above, expression vectors comprising such polynucleotides and host cells transformed or transfected with such expression vectors.
Within other aspects, the present invention provides pharmaceutical compositions comprising a polypeptide or polynucleotide as described above and a physiologically acceptable carrier.
Within a related aspect of the present invention, the pharmaceutical compositions, e.g., vaccine compositions, are provided for prophylactic or therapeutic applications. Such compositions generally comprise an immunogenic polypeptide or polynucleotide of the invention and an immunostimulant, such as an adjuvant.
The present invention further provides pharmaceutical compositions that comprise: (a) an antibody or antigen-binding fragment thereof that specifically binds to a polypeptide of the present invention, or a fragment thereof; and (b) a physiologically acceptable carrier.
Within further aspects, the present invention provides pharmaceutical compositions comprising: (a) an antigen presenting cell that expresses a polypeptide as described above and (b) a pharmaceutically acceptable carrier or excipient.
Illustrative antigen presenting cells include dendritic cells, macrophages, monocytes, fibroblasts and B cells.

4 Within related aspects, pharmaceutical compositions are provided that comprise: (a) an antigen presenting cell that expresses a polypeptide as described above and (b) an immunostimulant.
The present invention further provides, in other aspects, fusion proteins that comprise at least one polypeptide as described above, as well as polynucleotides encoding such fusion proteins, typically in the form of pharmaceutical compositions, e.g., vaccine compositions, comprising a physiologically acceptable carrier and/or an immunostimulant. The fusions proteins may comprise multiple immunogenic polypeptides or portions/variants thereof, as described herein, and may further comprise one or more polypeptide segments for facilitating the expression, purification and/or immunogenicity of the polypeptide(s).
Within further aspects, the present invention provides methods for stimulating an immune response in a patient, preferably a T cell response in a human patient, comprising administering a pharmaceutical composition described herein. The patient may be afflicted with lung cancer, in which case the methods provide treatment for the disease, or patient considered at risk fox such a disease may be treated prophylactically.
Within further aspects, the present invention provides methods for inhibiting the development of a cancer in a patient, comprising administering to a patient a pharmaceutical composition as recited above. The patient may be afflicted with lung cancer, in which case the methods provide treatment for the disease, or patient considered at risk for such a disease may be treated prophylactically.
The present invention further provides, within other aspects, methods for removing tumor cells from a biological sample, comprising contacting a biological sample with T cells that specifically react with a polypeptide of the present invention, wherein the step of contacting is performed under conditions and for a time sufficient to permit the removal of cells expressing the protein from the sample.
Within related aspects, methods are provided for inhibiting the development of a cancer in a patient, comprising administering to a patient a biological sample treated as described above.

5 PCT/USO1/09991 Methods are further provided, within other aspects, for stimulating and/or expanding T cells specific for a polypeptide of the present invention, comprising contacting T cells with one or more of: (i) a polypeptide as described above;
(ii) a polynucleotide encoding such a polypeptide; and/or (iii) an antigen presenting cell that S expresses such a polypeptide; under conditions and for a time sufficient to permit the stimulation and/or expansion of T cells. Isolated T cell populations comprising T cells prepared as described above are also provided.
Within further aspects, the present invention provides methods for inhibiting the development of a cancer in a patient, comprising administering to a patient an effective amount of a T cell population as described above.
The present invention further provides methods for inhibiting the development of a cancer in a patient, comprising the steps of: (a) incubating CD4+
and/or CD~+ T cells isolated from a patient with one or more of: (i) a polypeptide comprising at least an immunogenic portion of polypeptide disclosed herein;
(ii) a polynucleotide encoding such a polypeptide; and (iii) an antigen-presenting cell that expressed such a polypeptide; and (b) administering to the patient an effective amount of the proliferated T cells, and thereby inhibiting the development of a cancer in the patient. Proliferated cells may, but need not, be cloned prior to administration to the patient.
Within further aspects, the present invention provides methods for determining the presence or absence of a cancer, preferably a lung cancer, in a patient comprising: (a) contacting a biological sample obtained from a patient with a binding agent that binds to a polypeptide as recited above; (b) detecting in the sample an amount of polypeptide that binds to the binding agent; and (c) comparing the amount of polypeptide with a predetermined cut-off value, and therefrom determining the presence or absence of a cancer in the patient. Within preferred embodiments, the binding agent is an antibody, more preferably a monoclonal antibody.
The present invention also provides, within other aspects, methods for monitoring the progression of a cancer in a patient. Such methods comprise the steps 0~ (a) contacting a biological sample obtained from a patient at a first point in time

6 with a binding agent that binds to a polypeptide as recited above; (b) detecting in the sample an amount of polypeptide that binds to the binding agent; (c) repeating steps (a) and (b) using a biological sample obtained from the patient at a subsequent point in time; and (d) comparing the amount of polypeptide detected in step (c) with the amount detected in step (b) and therefrom monitoring the progression of the cancer in the patient.
The present invention further provides, within other aspects, methods for determining the presence or absence of a cancer in a patient, comprising the steps of: (a) contacting a biological sample obtained from a patient with an oligonucleotide that hybridizes to a polynucleotide that encodes a polypeptide of the present invention; (b) detecting in the sample a level of a polynucleotide, preferably mRNA, that hybridizes to the oligonucleotide; and (c) comparing the level of polynucleotide that hybridizes to the oligonucleotide with a predetermined cut-off value, and therefrom determining the presence or absence of a cancer in the patient. Within certain embodiments, the amount of mRNA is detected via polymerase chain reaction using, for example, at least one oligonucleotide primer that hybridizes to a polynucleotide encoding a polypeptide as recited above, or a complement of such a polynucleotide. Within other embodiments, the amount of mRNA is detected using a hybridization technique, employing an oligonucleotide probe that hybridizes to a polynucleotide that encodes a polypeptide as recited above, or a complement of such a polynucleotide.
In related aspects, methods are provided for monitoring the progression of a cancer in a patient, comprising the steps of: (a) contacting a biological sample obtained from a patient with an oligonucleotide that hybridizes to a polynucleotide that encodes a polypeptide of the present invention; (b) detecting in the sample an amount of a polynucleotide that hybridizes to the oligonucleotide; (c) repeating steps (a) and (b) using a biological sample obtained from the patient at a subsequent point in time; and (d) comparing the amount of polynucleotide detected in step (c) with the amount detected in step (b) and therefrom monitoring the progression of the cancer in the patient.

7 Within further aspects, the present invention provides antibodies, such as monoclonal antibodies, that bind to a polypeptide as described above, as well as diagnostic kits comprising such antibodies. Diagnostic kits comprising one or more oligonucleotide probes or primers as described above are also provided.
These and other aspects of the present invention will become apparent upon reference to the following detailed description. All references disclosed herein are hereby incorporated by reference in their entirety as if each was incorporated individually.
SEQUENCE IDENTIFIERS
SEQ ID NO: 1 is the determined cDNA sequence for L363Cl.cons SEQ ID NO: 2 is the determined cDNA sequence for L263C2.cons SEQ ID NO: 3 is the determined cDNA sequence for L263C2c SEQ ID NO: 4 is the determined cDNA sequence for L263Cl.cons SEQ ID NO: 5 is the determined cDNA sequence for L263C1b SEQ ID NO: 6 is the determined cDNA sequence for L164C2.cons SEQ ID NO: 7 is the determined cDNA sequence for L 164C l .cons SEQ ID NO: 8 is the determined cDNA sequence for L366CIa SEQ ID NO: 9 is the determined cDNA sequence for L260Cl.cons SEQ ID NO: 10 is the determined cDNA sequence for L163C1c SEQ ID NO: 11 is the determined cDNA sequence for L163CIb SEQ ID NO: 12 is the determined cDNA sequence for L255Cl.cons SEQ ID NO: 13 is the determined cDNA sequence for L255C1b SEQ ID NO: 14 is the determined cDNA sequence for L355Cl.cons SEQ ID NO: 15 is the determined cDNA sequence for L366Cl.cons SEQ ID NO: 16 is the determined cDNA sequence for L 163 C 1 a SEQ ID NO: 17 is the determined cDNA sequence for LT86-1 SEQ ID NO: 18 is the determined cDNA sequence for LT86-2 SEQ ID NO: 19 is the determined cDNA sequence for LT86-3 SEQ ID NO: 20 is the determined cDNA sequence for LT86-4

8 SEQ ID NO: 21 is the determined cDNA sequence for LT86-S
SEQ ID NO: 22 is the determined cDNA sequence for LT86-6 SEQ ID NO: 23 is the determined cDNA sequence for LT86-7 SEQ ID NO: 24 is the determined cDNA sequence for LT86-8 SEQ ID NO: 25 is the determined cDNA sequence for LT86-9 SEQ ID NO: 26 is the determined cDNA sequence for LT86-10 SEQ ID NO: 27 is the determined cDNA sequence for LT86-11 SEQ ID NO: 28 is the determined cDNA sequence for LT86-12 SEQ ID NO: 29 is the determined cDNA sequence for LT86-13 SEQ ID NO: 30 is the determined cDNA sequence for LT86-14 SEQ ID NO: 31 is the determined cDNA sequence for LT86-15 SEQ ID NO: 32 is the predicted amino acid sequence for LT86-1 SEQ ID NO: 33 is the predicted amino acid sequence for LT86-2 SEQ ID NO: 34 is the predicted amino acid sequence for LT86-3 SEQ ID NO: 35 is the predicted amino acid sequence for LT86-4 SEQ ID NO: 36 is the predicted amino acid sequence for LT86-5 SEQ ID NO: 37 is the predicted amino acid sequence for LT86-6 SEQ ID NO: 38 is the predicted amino acid sequence for LT86-7 SEQ ID NO: 39 is the predicted amino acid sequence for LT86-8 SEQ ID NO: 40 is the predicted amino acid sequence for LT86-9 SEQ ID NO: 41 is the predicted amino acid sequence for LT86-10 SEQ ID NO: 42 is the predicted amino acid sequence for LT86-11 SEQ ID NO: 43 is the predicted amino acid sequence for LT86-12 SEQ ID NO: 44 is the predicted amino acid sequence for LT86-13 SEQ ID NO: 45 is the predicted amino acid sequence for LT86-14 SEQ ID NO: 46 is the predicted amino acid sequence for LT86-15 SEQ ID NO: 47 is a (dT)i2AG primer SEQ ID NO: 48 is a primer SEQ ID NO: 49 is the determined 5' cDNA sequence for L86S-3 SEQ ID NO: 50 is the determined 5' cDNA sequence for L86S-12

9 SEQ ID NO: 51 is the determined 5' cDNA sequence for L86S-16 SEQ ID NO: 52 is the determined 5' cDNA sequence for L86S-25 SEQ ID NO: 53 is the determined 5' cDNA sequence for L86S-36 SEQ ID NO: 54 is the determined 5' cDNA sequence for L86S-40 SEQ ID NO: 55 is the determined 5' cDNA sequence for L86S-46 SEQ ID NO: 56 is the predicted amino acid sequence for L86S-3 SEQ ID NO: 57 is the predicted amino acid sequence for L86S-12 SEQ ID NO: 58 is the predicted amino acid sequence for L86S-16 SEQ ID NO: 59 is the predicted amino acid sequence for L86S-25 SEQ ID NO: 60 is the predicted amino acid sequence for L86S-36 SEQ ID NO: 61 is the predicted amino acid sequence for L86S-40 SEQ ID NO: 62 is the predicted amino acid sequence for L86S-46 SEQ ID NO: 63 is the determined 5' cDNA sequence for L86S-30 SEQ ID NO: 64 is the determined 5' cDNA sequence for L86S-41 SEQ ID NO: 65 is the predicted amino acid sequence from the 5' end of SEQ ID NO: 66 is the determined extended cDNA sequence for LT86-4 SEQ ID NO: 67 is the predicted extended amino acid sequence for SEQ ID NO: 68 is the determined 5' cDNA sequence for LT86-20 SEQ ID NO: 69 is the determined 3' cDNA sequence for LT86-21 SEQ ID NO: 70 is the determined 5' cDNA sequence for LT86-22 SEQ ID NO: 71 is the determined 5' cDNA sequence for LT86-26 SEQ ID NO: 72 is the determined 5' cDNA sequence for LT86-27 SEQ ID NO: 73 is the predicted amino acid sequence for LT86-20 SEQ ID NO: 74 is the predicted amino acid sequence for LT86-21 SEQ ID NO: 75 is the predicted amino acid sequence for LT86-22 SEQ ID NO: 76 is the predicted amino acid sequence for LT86-26 SEQ ID NO: 77 is the predicted amino acid sequence for LT86-27 SEQ ID NO: 78 is the determined extended cDNA sequence for L86S-12 SEQ ID NO: 79 is the determined extended cDNA sequence for L86S-36 SEQ ID NO: 80 is the determined extended cDNA sequence for L86S-46 SEQ ID NO: 81 is the predicted extended amino acid sequence for 5 SEQ ID NO: 82 is the predicted extended amino acid sequence for L86S-SEQ ID NO: 83 is the predicted extended amino acid sequence for SEQ ID NO: 84 is the determined 5'cDNA sequence for L86S-6

10 SEQ ID NO: 85 is the determined 5'cDNA sequence for L86S-11 SEQ ID NO: 86 is the determined 5'cDNA sequence for L86S-14 SEQ ID NO: 87 is the determined 5'cDNA sequence for L86S-29 SEQ ID NO: 88 is the determined 5'cDNA sequence for L86S-34 SEQ ID NO: 89 is the determined'S °cDNA sequence for L86S-39 SEQ ID NO: 90 is the determined 5'cDNA sequence for L86S-47 SEQ ID NO: 91 is the determined 5'cDNA sequence for L86S-49 SEQ ID NO: 92 is the determined 5'cDNA sequence for L86S-51 SEQ ID NO: 93 is the predicted amino acid sequence for L86S-6 SEQ ID NO: 94 is the predicted amino acid sequence for L86S-11 SEQ ID NO: 95 is the predicted amino acid sequence for L86S-14 SEQ ID NO: 96 is the predicted amino acid sequence for L86S-29 SEQ ID NO: 97 is the predicted amino acid sequence for L86S-34 SEQ ID NO: 98 is the predicted amino acid sequence for L86S-39 SEQ ID NO: 99 is the predicted amino acid sequence for L86S-47 SEQ ID NO: 100 is the predicted amino acid sequence for L86S-49 SEQ ID NO: 101 is the predicted amino acid sequence for L86S-51 SEQ ID NO: 102 is the determined DNA sequence for SLT-T1 SEQ ID NO: 103 is the determined 5' cDNA sequence for SLT-T2 SEQ ID NO: 104 is the determined 5' cDNA sequence for SLT-T3 SEQ ID NO: 105 is the determined 5' cDNA sequence for SLT-TS

11 SEQ ID NO: 106 is the determined 5' cDNA sequence for SLT-T7 SEQ ID NO: 107 is the determined 5' cDNA sequence for SLT-T9 SEQ ID NO: 108 is the determined 5' cDNA sequence for SLT-T10 SEQ ID NO: 109 is the determined 5' cDNA sequence for SLT-Tl 1 SEQ ID NO: 110 is the determined 5° cDNA sequence for SLT-T12 SEQ ID NO: 111 is the predicted amino acid sequence for SLT-T1 SEQ ID NO: 112 is the predicted amino acid sequence for SLT-T2 SEQ ID NO: 113 is the predicted amino acid sequence for SLT-T3 SEQ ID NO: 114 is the predicted amino acid sequence for SLT-T10 SEQ ID NO: 115 is the predicted amino acid sequence for SLT-T12 SEQ ID NO: 116 is the determined 5' cDNA sequence for SALT-T3 SEQ ID NO: 117 is the determined 5 ° cDNA sequence for SALT-T4 SEQ ID NO: 118 is the determined 5' cDNA sequence for SALT-T7 SEQ ID NO: 119 is the determined 5' cDNA sequence for SALT-T8 SEQ ID NO: 120 is the determined 5 ° cDNA sequence for SALT-T9 SEQ ID NO: 121 is the predicted amino acid sequence for SALT-T3 SEQ ID NO: 122 is the predicted amino acid sequence for SALT-T4 SEQ ID NO: 123 is the predicted amino acid sequence for SALT-T7 SEQ ID NO: 124 is the predicted amino acid sequence for SALT-T8 SEQ ID NO: 125 is the predicted amino acid sequence for SALT-T9 SEQ ID NO: 126 is the determined cDNA sequence for PSLT-1 SEQ ID NO: 127 is the determined cDNA sequence for PSLT-2 SEQ ID NO: 128 is the determined cDNA sequence for PSLT-7 SEQ ID NO: 129 is the determined cDNA sequence for PSLT-13 SEQ ID NO: 130 is the determined cDNA sequence for PSLT-27 SEQ ID NO: 131 is the determined cDNA sequence for PSLT-28 SEQ ID NO: 132 is the determined cDNA sequence for PELT-30 SEQ ID NO: 133 is the determined cDNA sequence for PSLT-40 SEQ ID NO: 134 is the determined cDNA sequence for PSLT-69 SEQ ID NO: 135 is the determined cDNA sequence for PSLT-71

12 SEQ ID NO: 136 is the determined cDNA sequence for PSLT-73 SEQ ID NO: 137 is the determined cDNA sequence for PSLT-79 SEQ ID NO: 138 is the determined cDNA sequence for PSLT-03 SEQ ID NO: 139 is the determined cDNA sequence for PSLT-09 SEQ ID NO: 140 is the determined cDNA sequence for PSLT-O11 SEQ ID NO: 141 is the determined cDNA sequence for PSLT-041 SEQ ID NO: 142 is the determined cDNA sequence for PSLT-62 SEQ ID NO: 143 is the determined cDNA sequence for PSLT-6 SEQ ID NO: 144 is the determined cDNA sequence for PSLT-37 SEQ ID NO: 145 is the determined cDNA sequence for PSLT-74 SEQ ID NO: 146 is the determined cDNA sequence for PSLT-O10 SEQ ID NO: 147 is the determined cDNA sequence for PSLT-012 SEQ ID NO: 148 is the determined cDNA sequence for PSLT-037 SEQ ID NO: 149 is the determined 5' cDNA sequence for SAL-3 SEQ ID NO: 150 is the determined 5 ° cDNA sequence for SAL-24 SEQ ID NO: 151 is the determined 5' cDNA sequence for SAL-25 SEQ ID NO: 152 is the determined 5' cDNA sequence for SAL-33 SEQ ID NO: 153 is the determined 5 ° cDNA sequence for SAL-50 SEQ ID NO: 154 is the determined 5' cDNA sequence for SAL-57 SEQ ID NO: ~ 55 is the determined 5' cDNA sequence for SAL-66 SEQ ID NO: 156 is the determined 5' cDNA sequence for SAL-82 SEQ ID NO: 157 is the determined 5' cDNA sequence for SAL-99 SEQ ID NO: 158 is the determined 5' cDNA sequence for SAL-104 SEQ ID NO: 159 is the determined 5' cDNA sequence for SAL-109 SEQ ID NO: 160 is the determined 5' cDNA sequence for SAL-5 SEQ ID NO: 161 is the determined 5' cDNA sequence for SAL-8 SEQ ID NO: 162 is the determined 5' cDNA sequence for SAL-12 SEQ ID NO: 163 is the determined 5' cDNA sequence for SAL-14 SEQ ID NO: 164 is the determined 5' cDNA sequence for SAL-16 SEQ ID NO: 165 is the determined 5' cDNA sequence for SAL-23

13 SEQ ID NO: 166 is the determined 5' cDNA sequence for SAL-26 SEQ ID NO: 167 is the determined 5' cDNA sequence for SAL-29 SEQ ID NO: 168 is the determined 5' cDNA sequence for SAL-32 SEQ ID NO: 169 is the determined 5' cDNA sequence for SAL-39 SEQ ID NO: 170 is the determined 5' cDNA sequence for SAL-42 SEQ ID NO: 171 is the determined 5' cDNA sequence for SAL-43 SEQ ID NO: 172 is the determined 5' cDNA sequence for SAL-44 SEQ ID NO: 173 is the determined 5' cDNA sequence for SAL-48 SEQ ID NO: 174 is the determined 5' cDNA sequence for SAL-68 SEQ ID NO: 175 is the determined 5' cDNA sequence for SAL-72 SEQ ID NO: 176 is the determined 5' cDNA sequence for SAL-77 SEQ ID NO: 177 is the determined 5' cDNA sequence for SAL-86 SEQ ID NO: 178 is the determined 5' cDNA sequence for SAL-88 SEQ ID NO: 179 is the determined 5' cDNA sequence for SAL-93 SEQ ID NO: 180 is the determined 5' cDNA sequence for SAL-100 SEQ ID NO: 181 is the determined 5' cDNA sequence for SAL-105 SEQ ID NO: 182 is the predicted amino acid sequence for SAL-3 SEQ ID NO: 183 is the predicted amino acid sequence for SAL-24 SEQ ID NO: 184 is a first predicted amino acid sequence for SAL-25 SEQ ID NO: 185 is a second predicted amino acid sequence for SAL-25 SEQ ID NO: 186 is the predicted amino acid sequence for SAL-33 SEQ ID NO: 187 is a first predicted amino acid sequence for SAL-50 SEQ ID NO: 188 is the predicted amino acid sequence for SAL-57 SEQ ID NO: 189 is a first predicted amino acid sequence for SAL-66 SEQ ID NO: 190 is a second predicted amino acid sequence for SAL-66 SEQ ID NO: 191 is the predicted amino acid sequence for SAL-82 SEQ ID NO: 192 is the predicted amino acid sequence for SAL-99 SEQ ID NO: 193 is the predicted amino acid sequence for SAL-104 SEQ ID NO: 194 is the predicted amino acid sequence for SAL-5 SEQ ID NO: 195 is the predicted amino acid sequence for SAL-8

14 SEQ ID NO: 196 is the predicted amino acid sequence for SAL-12 SEQ ID NO: 197 is the predicted amino acid sequence for SAL-14 SEQ ID NO: 198 is the predicted amino acid sequence for SAL-16 SEQ ID NO: 199 is the predicted amino acid sequence for SAL-23 SEQ ID NO: 200 is the predicted amino acid sequence for SAL-26 SEQ ID NO: 201 is the predicted amino acid sequence for SAL-29 SEQ ID NO: 202 is the predicted amino acid sequence for SAL-32 SEQ ID NO: 203 is the predicted amino acid sequence for SAL-39 SEQ ID NO: 204 is the predicted amino acid sequence for SAL-42 SEQ ID NO: 205 is the predicted amino acid sequence for SAL-43 SEQ ID NO: 206 is the predicted amino acid sequence for SAL-44 SEQ ID NO: 207 is the predicted amino acid sequence for SAL-48 SEQ ID NO: 208 is the predicted amino acid sequence for SAL-68 SEQ ID NO: 209 is the predicted amino acid sequence for SAL-72 SEQ ID NO: 210 is the predicted amino acid sequence for SAL-77 SEQ ID NO: 211 is the predicted amino acid sequence for SAL-86 SEQ ID NO: 212 is the predicted amino acid sequence for SAL-88 SEQ ID NO: 213 is the predicted amino acid sequence for SAL-93 SEQ ID NO: 214 is the predicted amino acid sequence for SAL-100 SEQ ID NO: 215 is the predicted amino acid sequence for SAL-105 SEQ ID NO: 216 is a second predicted amino acid sequence for SAL-50 SEQ ID NO: 217 is the determined cDNA sequence for SSLT-4 SEQ ID NO: 218 is the determined cDNA sequence for SSLT-9 SEQ ID NO: 219 is the determined cDNA sequence for SSLT-10 SEQ ID NO: 220 is the determined cDNA sequence for SSLT-12 SEQ ID NO: 221 is the determined cDNA sequence for SSLT-19 SEQ ID NO: 222 is the determined cDNA sequence for SSLT-31 SEQ ID NO: 223 is the determined cDNA sequence for SSLT-38 SEQ ID NO: 224 is the determined cDNA sequence for LT4690-2 SEQ ID NO: 225 is the determined cDNA sequence for LT4690-3 SEQ ID NO: 226 is the determined cDNA sequence for LT4690-22 SEQ ID NO: 227 is the determined cDNA sequence for LT4690-24 SEQ ID NO: 228 is the determined cDNA sequence for LT4690-37 SEQ ID NO: 229 is the determined cDNA sequence for LT4690-39 5 SEQ ID NO: 230 is the determined cDNA sequence for LT4690-40 SEQ ID NO: 231 is the determined cDNA sequence for LT4690-41 SEQ ID NO: 232 is the determined cDNA sequence for LT4690-49 SEQ ID NO: 233 is the determined 3' cDNA sequence for LT4690-55 SEQ ID NO: 234 is the determined 5' cDNA sequence for LT4690-55 10 SEQ ID NO: 235 is the determined cDNA sequence for LT4690-59 SEQ ID NO: 236 is the determined cDNA sequence for LT4690-63 SEQ ID NO: 237 is the determined cDNA sequence for LT4690-71 SEQ ID NO: 238 is the determined cDNA sequence for 2LT-3 SEQ ID NO: 239 is the determined cDNA sequence for 2LT-6

15 SEQ ID NO: 240 is the determined cDNA sequence for 2LT-22 SEQ ID NO: 241 is the determined cDNA sequence for 2LT-25 SEQ ID NO: 242 is the determined cDNA sequence for 2LT-26 SEQ ID NO: 243 is the determined cDNA sequence for 2LT-31 SEQ ID NO: 244 is the determined cDNA sequence for 2LT-36 SEQ ID NO: 245 is the determined cDNA sequence for 2LT-42 SEQ ID NO: 246 is the determined cDNA sequence for 2LT-44 SEQ ID NO: 247 is the determined cDNA sequence for 2LT-54 SEQ ID NO: 248 is the determined cDNA sequence for 2LT-55 SEQ ID NO: 249 is the determined cDNA sequence for 2LT-57 SEQ ID NO: 250 is the determined cDNA sequence for 2LT-58 SEQ ID NO: 251 is the determined cDNA sequence for 2LT-59 SEQ ID NO: 252 is the determined cDNA sequence for 2LT-62 SEQ ID NO: 253 is the determined cDNA sequence for 2LT-63 SEQ ID NO: 254 is the determined cDNA sequence for 2LT-65 SEQ ID NO: 255 is the determined cDNA sequence for 2LT-66

16 SEQ ID NO: 256 is the determined cDNA sequence for 2LT-70 SEQ ID NO: 257 is the determined cDNA sequence for 2LT-73 SEQ ID NO: 258 is the determined cDNA sequence for 2LT-74 SEQ ID NO: 259 is the determined cDNA sequence for 2LT-76 SEQ ID NO: 260 is the determined cDNA sequence for 2LT-77 SEQ ID NO: 261 is the determined cDNA sequence for 2LT-78 SEQ ID NO: 262 is the determined cDNA sequence for 2LT-80 SEQ ID NO: 263 is the determined cDNA sequence for 2LT-85 SEQ ID NO: 264 is the determined cDNA sequence for 2LT-87 SEQ ID NO: 265 is the determined cDNA sequence for 2LT-89 SEQ ID NO: 266 is the determined cDNA sequence for 2LT-94 SEQ ID NO: 267 is the determined cDNA sequence for 2LT-95 SEQ ID NO: 268 is the determined cDNA sequence for 2LT-98 SEQ ID NO: 269 is the determined cDNA sequence for 2LT-100 SEQ ID NO: 270 is the determined cDNA sequence for 2LT-103 SEQ ID NO: 271 is the determined cDNA sequence for 2LT-105 SEQ ID NO: 272 is the determined cDNA sequence for 2LT-107 SEQ ID NO: 273 is the determined cDNA sequence for 2LT-108 SEQ ID NO: 274 is the determined cDNA sequence for 2LT-109 SEQ ID NO: 275 is the determined cDNA sequence for 2LT-118 SEQ ID NO: 276 is the determined cDNA sequence for 2LT-120 SEQ ID NO: 277 is the determined cDNA sequence for 2LT-121 SEQ ID NO: 278 is the determined cDNA sequence for 2LT-122 SEQ ID NO: 279 is the determined cDNA sequence for 2LT-124 SEQ ID NO: 280 is the determined cDNA sequence for 2LT-126 SEQ ID NO: 281 is the determined cDNA sequence for 2LT-127 SEQ ID NO: 282 is the determined cDNA sequence for 2LT-128 SEQ ID NO: 283 is the determined cDNA sequence for 2LT-129 SEQ ID NO: 284 is the determined cDNA sequence for 2LT-133 SEQ ID NO: 285 is the determined cDNA sequence for 2LT-137

17 SEQ ID NO: 286 is the determined cDNA sequence for LT4690-71 SEQ ID NO: 287 is the determined cDNA sequence for LT4690-82 SEQ ID NO: 288 is the determined full-length cDNA sequence for SEQ ID NO: 289 is the determined cDNA sequence for SSLT-78 SEQ ID NO: 290 is the determined cDNA sequence for SCC1-8.
SEQ ID NO: 291 is the determined cDNA sequence for SCCl-12.
SEQ ID NO: 292 is the determined cDNA sequence for SCCl-336 SEQ ID NO: 293 is the determined cDNA sequence for SCC1-344 SEQ ID NO: 294 is the determined cDNA sequence for SCC1-345 SEQ ID NO: 295 is the determined cDNA sequence for SCC1-346 SEQ ID NO: 296 is the determined cDNA sequence for SCC1-348 SEQ ID NO: 297 is the determined cDNA sequence for SCC1-350 SEQ ID NO: 298 is the determined cDNA sequence for SCC1-352 SEQ ID NO: 299 is the determined cDNA sequence for SCCl-354 SEQ ID NO: 300 is the determined cDNA sequence for SCC1-355 SEQ ID NO: 301 is the determined cDNA sequence for SCCl-356 SEQ ID NO: 302 is the determined cDNA sequence for SCC1-357 SEQ ID NO: 303 is the determined cDNA sequence for SCCl-501 SEQ ID NO: 304 is the determined cDNA sequence for SCC1-503 SEQ ID NO: 305 is the determined cDNA sequence for SCC1-513 SEQ ID NO: 306 is the determined cDNA sequence for SCC1-516 SEQ ID NO: 307 is the determined cDNA sequence for SCC1-518 SEQ ID NO: 308 is the determined cDNA sequence for SCCl-519 SEQ ID NO: 309 is the determined cDNA sequence for SCCl-522 SEQ ID NO: 310 is the determined cDNA sequence for SCC1-523 SEQ ID NO: 311 is the determined cDNA sequence for SCC1-525 SEQ ID NO: 312 is the determined cDNA sequence for SCCl-527 SEQ ID NO: 313 is the determined cDNA sequence for SCC1-529 SEQ ID NO: 314 is the determined cDNA sequence for SCC1-530

18 SEQ ID NO: 315 is the determined cDNA sequence for SCCl-531 SEQ ID NO: 316 is-the determined cDNA sequence for SCC1-532 ~EQ ID NO: 317 .is the determined cDNA sequence for SCCl-533 SEQ ID NO: 318 is the determined cDNA sequence for SCC1-536 SEQ ID NO: 319 is the determined cDNA sequence for SCC1-538 SEQ-ID NO: 320 is the determined cDNA sequence for SCC1-539 SEQ: ID NO: 321 is the determined cDNA sequence for SCCl-541 SEQ ID NO: 322 is the determined cDNA sequence for SCC1-542 SEQ II7:~ NO: 323 is the determined cDNA sequence for SCCl-546 SEQ ID NO: 324 is,the determined cDNA-sequence for SCC1-549 SEQ ID NO: 325 is-the determined cDNA sequence for SCC1-551 SEQ ID NO: 326 is the determined cDNA seqti~nce fox SCCl-552 SEQ ID NO: 327 is-the determined cDNA sequence for SCC1-554 SEQ ID NO: 328 is the determined cDNA sequence for SCCl-558 SEQ ID NO: 329 is the determined cDNA sequence for SCC1-559 SEQ ID NO: 330 is the determined cDNA sequence for SCC1-561 SEQ ID NO: 331 is the deterrilined eDNA sequence for SCC1-562 SEQ ID NO: 332 is the.determiried cDNA sequence for SCCl-564 SEQ ID NO: 333 is the determined cDNA sequence for SCC1-565 SEQ ID NO: 334 is the:determined.cDNA sequence for SCCl-566 SEQ ID NO: 335 is the determined cDNA sequence for SCC1-567 SEQ ID NO: 336 is the determined cDNA sequence for SCCl-568 SEQ ID NO: 337 is the determined cDNA sequence for SCC1-570 SEQ ID NO: 33$ is~the determined cDNA sequence for SCC1-572 SEQ ID NO: 339 is the determined cDNA sequence for SCC1-575 SEQ ID NO: 340 is the determined cDNA sequence for SCCl-576 SEQ ID NO: 341 is the determined cDNA sequence for SCC1-577 SEQ ID NO: 342 is the determined cDNA sequence for SCCI-578 SEQ ID NO: 343 is the determined cDNA sequence for SCC1-582 . SEQ ID NO: 344 is the determined cDNA sequence for SCCl-583

19 SEQ ID NO: 345 is the determined cDNA sequence for SCC1-586 SEQ ID NO: 346. is the determined cDNA sequence for SCC1-588 SEQ ID NO.: 347 is the determined cDNA sequence for SCC1-590 SEQ ID NO: 34'8 is the determined cDNA sequence for SCC1-591 5EQ ID NO: 349 is the determined cDNA sequence for SCCl-592 SEQ ID NO: 350 is the determined cDNA sequence for SCC1-593 SEQ ID NO: 351 is the determined cDNA sequence for SCCl-594 SEQ ID NO: 352 is the determined cDNA sequence for S.CC1-595 SEQ ID NO: 353 is the determined~cDNA. sequence for SCCl-596 SEQ IDrNO: 354 i~ the determined cDNA sequence for SCCl-59.8 SEQ ID I'~O: 355 is the determined cDNA sequence-for SCCl-599 SEQ ID NO: 356 is the determined cDNA sequence for SCCl-602 SEQ ID NO: 357 is the dcterinined cDNA sequence for SCC1-604 SEQ ID NO: 358 is he determined cDNA sequence for SCC1-605 SEQ ID NO: 359 is the determined cDNA sequence for SCCl-606 SEQ ID NO: 360' is the determined cDNA sequence for SCC1-607 SEQ ID NO: 361 is the determined cDNA sequence for SCC1-608 SEQ ID NO: 362 is the determined cDNA sequence for SGC1-610 SEQ ID NO: 363 is the determined cDNA sequence for clone DMS79T1 SEQ ID NO: 364 is the determined cDNA sequence for clone DMS79T2 SEQ ID NO: 365 is the determined cDNA sequence for clone DMS79T3 SEQ ID NO: 366 is the deteimii~ed cDNA sequence for clone DMS79T5 SEQ ID NO: 367 is the determined cDNA sequence forclone DMS79T6 SEQ ID NO: 368 is the determined cDNA sequence for clone DMS79T7 SEQ ID NO: 369 is the determined cDNA sequence for clone DMS79T9 SEQ ID NO: 370 is the determined cDNA sequence for clone DMS'79T 10 SEQ ID NO: 371 is the determined cDNA sequence for clone SEQ ID NO: 372 is the determined cDNA sequence for clone 128T1 SEQ ID NO: 373 is the determined cDNA sequence for clone 128T2 SEQ ID NO: 374 is the determined cDNA sequence for.clone 128T3 SEQ ID NO: 375 is the determined cDNA sequence for clone 128T4 SEQ ID NO: 376 is the determined cDNA sequence far clone 128T5 5 SEQ ID NQ: 377 is the determined cDNA sequence for clone 128T7 SEQ ID NO: 378 is the detern~ined.cDNA sequence for clone 128T9 SEQ ID NO: 379 is the determined eDI~A sequence for clone 128T10 rEQ ID NO: 380 is the determined cDNA sequence for clone 128TH
SEQ ID NO: 381 is the d~'termined cDNA sequence for clone 128T12 10 SEQ. ID NO: 3,82 is the determined cDNA sequence for clone SEQ- ID NO: 3$3 is the determined cDNA sequence for clone SEQ ID NO: 384 is the determined cDNA sequence for clone 15 ' NCIH69T6 SEQ ID NO: 385 is the determined cDNA sequence for clone SEQ ID NO: 386 is the determined cDN.A sequence for clone

20 SEQ ID NO: 387 is the determined cDNA sequence for clone SEQ -II7 NO: 388 is the determined cDNA sequence for clone ~SEQ ID NO: 389 is the determined cDNA sequence for clone SEQ ID NO: 390 is the full-length cDNA sequence for 128T1 SEQ ID NO: 391 is the amino acid sequence for 128T1 SEQ ID NO: 392 is the full-length cDNA sequence for 2LT-128 SEQ ID NO: 393 is the amino acid sequence for 2LT-I28 SEQ ID NO: 394 is an extended cDNA sequence for clone SCC1-542

21 SEQ ID. NO: 395 is the amino acid sequence corres~ondirig to SEQ ID
N0:394 SEQ-ID NO: 396 is.an extended cDNA sequence fox clone SCCl-593 SEQ ID NO: 397 is the amino acid sequence corresponding to SEQ ID
N0:396 SEQ ID N0:398 is the determined cDNA sequence for 55508.1 SEQ ID NO:399 is the determined cDNA sequence for 55509.1 SEQ ID N0:400 is the determined .cDNA sequence for 54243.1 SEQ~ ID N,0:401 is the determined cDNA sequence for 54251.1 SEQ- ID N0:402 is the determined cDNA sequence for 54252.1 SEQ ID. N0:4,03 is the determined cDNA sequence for 54253.1 SEQ ID N0:404 is the determined cDNA sequence for 55518.1 SEQ ID N0:405 is the deterrriined cDNA sequence for 54258.1 SEQ ID N0:406 is the determined cDNA sequence for 54575.1 SEQ II7 NO:407 is the determined cDNA sequence for 54577.1 ~SEQ..ID N0:408. is the determined cDNA sequence for 54584.1 SEQ ID N0:409 is the determined cDNA sequence for 55521.1 SEQ ID NO;410 is the determined cDNA sequence for 54589.1 SEQ ID. NO:~11 is the determined cDNA sequence for 54592.1 SEQ ID N0:412 is the deterrriined cDNA sequence for 55134.1 SEQ iD N0:413 is the determined cDNA sequence for 55137.1 SEQ ID N0:414 is the determined cDNA sequence for 55140.1 SEQ ID. N0:415 is the determined cDNA sequence for 55531.1 SEQ ID N0:416 is the determined.cDNA sequence for 55532.1 SEQ ID N0:417 is the determined cDNA sequence for 54621.1 SEQ ID N0:418 is the determined cDNA sequence for 55548.1 SEQ ID N0:419 is the determined cDNA sequence for 54623.1 SEQ ID N0:420 is the determined cDNA sequence for L39 SEQ ID N0:421 is the predicted amino acid sequence for L39 SEQ ID N0:422 is the determined cDNA sequence for SCC2-29

22 SEQ ID-N0:423.is the.determined cDNA sequence for SCC2-36 SEQ ID N0:424 is the determined cDNA sequence for SCC2-60 SEQ ID N0:425 is the predicted amino acid sequence for SCC2-29 ~SEQ ID N.0:426 is the predicted amino acid sequence for SCC2-36 SEQ ID IV0:427 is the predicted amino acid sequence for SCC2-60 SEQ ID N0:428 :is an extended cDNA .sequence -for the clone 20129, also referred to as 2LT-3, set fob in SEQ: ID'NO: 238 SEQ ID N0:429 is ari extended cDNA sequence for the clone 20347, also referred to as 2LT-26, set forth irz-SEQ II7 N0: 242 1-0 SEQ ID NO430 is an extended cDNA sequence for the clone 21282, also referred to as 2LT-57, set forth in SEQ ID NO: 249 SEQ ID NO:431 is an extended cDNA sequence .for the clone 21283, also referred to as 2LT-58, set forth in SEQ ID NO: 250 SEQ. ID N0:432 is an .extended cDNA sequence for the clone 21484, also referred to as 2LT-98, set forth in SEQ ID NO: 268 SEQ ID N0:433 is an extended cDNA sequence for the clone 21871, also referred to as 2LT-124, set forth in SEQ ID N.O: 279 SEQ ID N0:434 is an amino acid sequence enCOdeel by SEQ ID NO: 428 SEQ ID NO:435 is an amino acid sequence -,encoded by SEQ ID NO: 429 SEQ ID N0:436 is an amino acid sequence encoded by SEQ ID NO: 430 SEQ ID N.0:437 is an amino acid sequence encoded by SEQ ID NO: 431 SEQ ID N0:438.is an anima acid sequence encoded by SEQ ID NO: 432 SEQ ID N0:439 is an amino acid sequence.encoded by SEQ ID NO: 433 SEQ ID N0:440 is the determined cDNA sequence for clone 19A4 SEQ ID NO: 441 is the determined frill-length cDNA sequence for clone 14F10.
SEQ ID NO: 442 is the determined 5' cDNA sequence for clone 20E10.
SEQ ID NO: 443 is a f rst determined cDNA sequence for clone 55153.
SEQ iD NO: 444 is a second deteririined ,cDNA sequence for clone 55153.

23 SEQ ID NO: 445 is a.first determined cDNA sequence for clone 55154.
SEQ ID NO: 446 is a second determined cDNA sequence for clone 55154.
SEQ ID' NO: 447 is the determined cDNA sequence for clone 55155.
SEQ ID NO: 448 is a first determined cDNA sequence for clone 55156.
.SEQ ID NO: 449 is a second determined cDNA sequence for clone 55156.
~SEQ ID NO: 450 is a first determined cL7NA sequence for clone 55157.
SEQ ID NO: 451 is a second .determined cDNA sequence for clone 55157.
S,EQ ID NO: 452 is the determined cDNA sequence for clone 55158.
SEQ ID NO: 453 is the determined cDNA sequence for clone 55159.
SEQ ID NO: 454 is a first determined cDNA sequence for clone 55161.
SEQ ID NO: 455 is a second determined cI7NA sequence for clone 55161.
SEQ ID NO: 456 is ~ first determined cDNA sequence for clone 55162.
S.EQ ID NO: 457 is a second determined cDNA sequence for clone 55162.
SEQ ID NO: 458 is a first dete~rriiried cDNA sequence~for clone 55163.
SEQ ID NO: 459 is a second deterriiined cDNA sequence for clone 55163.
SEQ ID NO: 460 is a first determined cDNA sequence for.clone 55164.
SEQ ID NO: 461 is ~. second determined cDNA sequence for clone 55164.
SEQ ID NO: 462 is a first-determined cDNA sequence for clone 55165.
'SEQ ID NO: 463 is a second determined cDNA sequence for clone 55165.
SEQ ID NO: 464 is a first determined cDNA sequence for clone 55166.
SEQ ID NO: 465 is a second determined cDNA sequence for clone 55166.

24 SEQ ID. NO: 466 is a-first deteriniried cDNA sequence for clone 55167.
~SEQ ID NO: 467 is a second determined cDNA sequenEe for clone 55167.
SEQ ID NO: 468 is a first determined cDNA sequence for clone 55168.
SEQ ID NO: 469 is a second determined cDNA sequence for clone 55168:.
SEQ ID NO: 470 is a first determined cDNA sequence for clone 55169.
SEQ ID NO: 471 is a second deterrriined cDNA sequence for clone 55169.
SEQ ID 1t0: 472 is a first detei~ilined cDNA sequence for clone 55170.
SEQ ill NO: 473 is a second determined cDNA sequence for clone 55170.
SEQ ID NO: 474 is the determined cDNA sequence fot clone 55171.
SEQ ID NO: 475 is the deteimined cDNA sequence for-clone 55172.
S-EQ ID NO: 476 is the determined cDNA sequence for clone 55173.
SEQ ID NO: 477 is a first determined cDNA sequence for clone 55174.
SEQ ID NO: 478 is a second determined cDNA sequence for clone 551'74.
'SEQ ID NO: 479 is the detei~rnine~l~ cDNA sequence for clone 55175.
SEQ ID NO: 480 is the determined cDNA sequence for clone 55176.
SEQ ID. NO: 481 is the determined cDNA sequence for.contig 525.
SEQ ID NQ: 482 is the determined cDNA sequence for conlig 526:
SEQ ID NO: 483 is the determined cDNA sequence for contig 527.
SEQ ID NO: 484 is the deterriiined cDNA sequence for corltig 528.
SEQ .ID NO: 485 is the determined cDNA sequence for contig 529.
SEQ ID NO: 486 is the determined cDNA sequence for contig 530.
SEQ ID NO: 487 is the determined cDNA sequence for contig 531.
SEQ ID NO: 488 is the determined cDNA sequence for contig 532.
SEQ ID NO: 489 is the :determined cDNA sequence for coritig 533.
SEQ ID NO: 490 is the determined cDNA sequence for contig 534.

SEQ ID NO: 491 is the detei~nined cDNA sequence for.contig 535.
SEQ ID NO.: 492 is the determined cDNA sequence for coring 536.
SEQ ID NO: 493 is the determined cDNA sequence for contig 537.
SEQ ID NO: 494 is-the determined cDNA sequence for contig 538.
5 SEQ ID NO: 495 is the determined eDNA sequence for contig 539.
SEQ ID NO: 496 is the determined cDNA sequence for contig. 540.
SEQ ID NO: 497 is the determined cDNA sequence for contig 541.
SEQ ID NO.: 498 is the determined cDNA sequence for contig 542.
SEQ~ID NO: X99 is the determined cDNA sequence for contig 543.
l0 SEQ II7 NO: 500 is the determined cDNA sequence for contig 544.
SEQ ID NO: 501 is the determined .cDN~. sequence for contig 545.
~SEQ TD NO: 502 is the determined' cDNA sequence for contig 546.
~SEQ ID NO: 503 is the determined cDNA sequence for contig 547.
SEQ ID NO: 504 is the determined cDNA sequence for contig 548.
15 SEQ ID NO: 505 is the determined cDNA sequence for contig 549.
SEQ ~ID NO: 506 is the determined cDNA sequence for contig 550.
SEQ ID NO: 507 is the determined cDNA sequence for contig 551.
SEQ ID NO: 508. is the determiried cDNA sequence for contig 552.
SEQ ID NO: 509 is the' determined cDNA sequence for contig 553.
20 SEQ ID NO: 510 is the determined cDNA sequence for contig 554.
SEQ ID NO: 511 is the determined cDNA sequence for contig 555.
~SEQ- II,l NO: 512 is the determined cDNA sequence for clone 57207.
SEQ ~ID Nl'~: 513 is the determined.cDNA sequence for clone 57209.
SEQ ID NO.: 514 is the determined cDNA sequence for clone 57210.

25 SEQ ID NO: 515 is the determined cDNA sequence for clone 57211.
SEQ ID NO: 516 is the determined cDNA sequence for clone 57212.
SEQ ID NO: 517 is the determined cDNA sequence for clone 57213.
SEQ ID NO: 518 is the determined cDNA sequence for clone 57215.
SEQ ID NO: 519 is the determined cDNA sequence for clone 57219.
SEQ ID NO: 520 is the determined cDNA sequence for clone 57221.

26 SEQ ID NO: 521 is the determined cDNA sequence -for clone 57222.
SEQ ID' NQ: 522 is the determined: cDNA sequence for clone 57223.
SEQ ID NO: 5-23- is the determined .cDNA sequence for clone 57225.
SEQ ID NO: 524 is the determined cDNA sequence for.clone 57227.
SEQ ID NO: 525 is the determined cDNA sequence for clone 57228.
SEQ ID~NO: 526 is the determined-cDNA sequence for.clone 57229:
SEQ ID.NO: 527 is the determined cDNA sequence for clone 57230.
SEQ ID NO: 528. is the deterriiined cDlVA sequence for .clone 57231.
SEQ ID N(7: 529' is the determined cDNA sequence for clone 57232.
SEQ ID.NCO: 53,0 is the determined cDNA sequence for clone 57233.
~SEQ ID NO: 531 is the determined cDNA sequence for clone 57234.
SEQ ID NO: 532 is the determined cDNA sequence for clone 57235.
SEQ ID NO: 533 is the determined cDNA sequence for clone 57236.
SEQ ID NO: 534 is the determined cDNA sequence for clone 57237.
SEQ ID NO: 535 is the determined cDNA sequence for clone 57238.
SEQ ID NO: 536 is the-determined.cDNA sequence for clone 57239.
SEQ ID NO: 537 is the determined cDNA sequence for clone 57240-.
SEQ ID-NO: 538 is the determined. cDNA sequence for clone 57242.
SEQ IID NO: 539 is the determined cDNA sequence for clone 57243.
SEQ ID NO: 540 is the determined cDNA sequence for clone 57245.
SEQ ID NO: 541 is the determined cDNA sequence for clone 57248.
SEQ ID NO: 542 is the determined cDNA sequence for clone 57249.
SEQ ID NO: 543 is the :determined cI?NA sequence for clone 57250.
SEQ ID NO: 544 is the determined cDNA sequence for .clone 57251.
SEQ ID NO; 545 is the determined cDNA sequence for clone 57253.
SEQ ID NO: 546 is the determined cDNA sequence for clone 57254.
SEQ ID NO: 547 is the determined cDNA sequence for clone 57255.
SEQ ID NO: 548 is the determined cDNA sequence for clone 57257.
SEQ ID NO: 549 is the determined cDNA sequence for clone 57258.
SEQ ID NO: 550 is the .determined cDNA sequence for clone 57259.

27 SEQ ID NO: 551 is the determiri~d cIDNA sequence' for.clone 57261.
~SEQ ID NO: 552 is the determined cDNA sequence for clone 57262.
SEQ ID NO: 553 is the determined cDNA sequence for clone 57263.
SEQ ID NO: 554 is the determined cDNA sequence for clone 57264.
SEQ ID NO: 555 is the determined cDIsIA sequence for clone 57265.
SEQ ID NO: 556 is the .determined cDNA sequence for clone 57266.
SEQ ID NO: 557 is the determined cDNA sequence for clone 57267.
SEQ ID NO: 558 is the determined cDNA sequence for clone 57268.
SEQ ID NO: 559 is the determined cDNA sequence for clone 57269:
SEQ ID NO: 560 is the determined cDNA sequence for clone 57270.
SEQ ID NO: 561 is the determined cDNA sequence for clone 57271.
SEQ ID NO: 5'6,2 is the determined cDNA sequence for clone 57272.
SEQ ID NO: 563 is the determined cDNA sequence for.clone 57274.
SEQ ID NO: 564 is the determined cDNA sequence for clone 57275.
'SEQ ID NO: 565 is the determined cDNA sequence for clone 57277.
SEQ ID NO: 566 is the deferinined cDNA sequence for clone 57280.
SEQ ID NO: 567 is the determined cDNA sequence for clone 57281.
SEQ ID NO: 568 is the determined cDNA sequence for clone 57282.
SEQ ID NO: 569 is the determined cDNA sequence for,clone 57283.
SEQ ID' NO: 570 is the determined cIDNA sequence for clone 57285.
SEQ ID NO: 571 is the determined cDNA sequence for clone 57287.
SEQ ID NO: 572 is the determined cDNA sequence for clone 57288.
SEQ ID NO: 573 is the determined cDNA sequence for clone 57289.
SEQ ID NO: 574 is the determined cDNA sequence for-clone 57290.
SEQ ID NO: 575 is the determined cDNA sequence for clone 57292.
SEQ ID NO: 576 is the deterrriined cDNA sequence for clone 57295.
SEQ ID NO: 577 is the determined cDNA sequence for clone 57296.
SEQ ID NO: 578 is the determined eDNA sequence for clone 57297.
SEQ ID NO: 579 is the determined cDNA sequence for clone 57299.
SEQ ID NO: 580 is the determined cDNA sequence for clone 57301.

28 SEQ ID NO: 581 is the determined cDNA sequence for clone 57302.
S~Q ID NO: 582 is the determined cDNA sequence for the beta.chain of _a lung tumor specific T .cell= receptor.
SEQ ID NO: 583 is the determined cDNA sequence for the alpha chain of a lung tumor specific T cellrreceptor.
SEQ =ID NO: 584 is, the axyino acid sequence encoded by SEQ ID INTO:
583.
SEQ. ID NO: 585 is the amino acid sequence encoded by SEQ ID NO:
582.
1~0 SEQ ID NO: 586 is the amino acid sequence encoded by tl~e 5' terminus of 14F10.
SEQ ID- NO ; 58T is the amino acid sequence of a T cell epitope contained within SEQ ID NO: 586.
DETAILED DESCRIPTION OF THE INVENTION
The present .invention is directed generally to .compositions .and their use in the therapy .and diagnosis of cancer, particularly lung cancer. As described further below, illustrative compositions of the present invention include, but are not restricted to, polypeptides, particularly immunogenic :polypeptides, -.polynucleotides encoding such polypeptides, .antibodies and other binding agents, antigen presenting cells (APCs) and immune system cells (e.g., T cells).
The practice of the present invention will employ, unless indicated specifically to the contrary, conventional methods of virology, immunology, microbiology, -rilolecular biology and recombinant DNA techniques within the skill of the art, many of which are described below for -the purpose of illustration.
Such techniques .are explained fully in the literature. See, e.g., Sambrook, et al.
Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); lVlaniatis et al. Molecular Cloning:
A Laboratory -Manual (1982); DNA Cloning: A Practical Approach, vol. I & II
(D.
Glover, ed.); Oligonucleotide Synthesis (N. Gait, ed., 1984); Nucleic Acid Hybridization (B. Hames & S. Higgins, eds., 1985); Transcription and Translation (B.

29 Hames & S. Higgins, eds., 1984); Animal Cell Culture (R. F~eshney, ed., 1986);
Perbal, A Practical Guide to Molecular Cloning (1984):
All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their.entirety, As used iy this specification and the .appended claims, the singular forms " » " » " »
a, an arid. the include plural references. unless the content clearly dictates otherwise.
Polypeptide Compositions As used herein, the teim "polypeptide" is used in its conventional meaning, i.e., as a sequence ~of amino. acids. The polypeptides are not limited to a specific length of the plroduct; thus, peptides, oligopeptides, and proteins are included within the definition of.polypeptide, and such terms may be used interchangeably herein unless specifically indicated otherwise. This term also does. not refer to or exclude post-expression modifications of the polypeptide, for example, glyeosylations, acetylations, phosphorylations and the :like, as well as other modifications known in the art, both naturally occurring and non-naturally occurring. A polypeptide may be an entire protein, or a- subsequence thereof. Particular polypeptides of interest .in the context of this -invention are amino acid subsequenees comprising epitopes, i.e., antigenic determinants substantially responsible for the immunogenic properties of a polypeptide and being capable of evoking an .immune response.
Particularly illustrative polypeptides of the .present invention comprise those encoded by a.polynucleotide sequence set forth in,any one.of SEQ ID NOs:

390, 392, 394, 396, 398-420 422,424, 428-433 and 440-583 or a sequence that hybridizes under yoderately stringent conditions, or, alternatively, under highly stringent conditions, to a polynucleotide sequence set forth in any one of SEQ
ID NOs:
217-390, 392, 394, 396, 398-420 422-424, 428-433 and 440-583. Certain other illustrative polypeptides of the .invention comprise amino acid sequences as set forth in anyone of SEQ ID NOs: 391, f93, 395, 397, 421, 425-427, 434-439 and 584-587.

The polypeptides of the present invention are sometiriles herein referred to as lung tumor proteins or lung tumor polypeptides, as an indieatioy that their identif canon has been based at least in part upon their increased levels of expression in lung tumor samples. Thus, a "lung tumor polypeptide" or "lung tumor protein,"
refers 5 generally to a polypeptide sequence of the present invention, or a polynucleotide sequence .encoding such a- polypeptide, that is expressed in a substantial proportion of lung tumor samples, for example preferably vgreater than about 20%, -more preferably greater that about 30%, and most preferably greater than about ~0% or rilore of lung tumor sarizples tested .at a level that-is at least two fold, and preferably at least five fold, 10 greater than the level of expt~essiQn in normal tissues, as detei-tniried using a repreSentati~e assay provided herein. A lung turrior polypeptide sequence of the invention, based upon its increased level of expression -in tumor cells, has particular utility .b,oth as a diagnostic marker as well as a therapeutic target, as further described below.
15 In certain preferred .embodiments, the polypeptides of the invention are immunogenic, i.e., they react detestably within an immunoassay (such as an ELISA or T-cell stimulation assay) with antisera andlor T-cells from a :patient with lung cancer.
Screening for immunogenic activity can be performed using techniques well-known to the skilled artisan. For example, such screens can be performed: using methods such as 20those .described in Harlow and Lane, Antibodies: A Lab'or'atory Manual, Cold Spring Harbor Laboratory, 1988. In one illustrative example, a polypeptide may be immobilized on a solid support and contacted with patient sera to allow binding of antibodies within the sera to the immobilized polypeptide, Unbound sera may then be removed arid -bound antibodies detected using, for example, 'z5I-labeled-Protein A.
25 As would be recognized by the skilled artisan, immunogenic portions of the polypeptides disclosed herein are also encompassed by the present invention. An "immunogenic portion," as used herein, is .a fragment of.an .immunogenic polypeptide of the invention. that itself is immunologically reactive (i. e., specifically binds) with the B-cells ,and/or T-cell surface antigen receptors that recognize the polypeptide.

30 Immunogenic portions may generally be identified using well known techniques, such

31 as those summarized in Paul, Fundamental Imrr~unology, 3rd ed., 243-247 (Raven Press, 1993) and refer"ences cited therein. Such techniques include screening polypeptides for the ability to react with antigen-specific antibodies, antisera and/or T-cell lines or clones. As used herein, antisera arid antibodies are "antigen-specific" if they spesif sally bind: to an antigen (i. e., -they react with the protein in an ELISA or other immunoassay, and do not react detestably with .unrelated proteins). Such antisera and antibodies may be prepared as described herein, and using well-known techniques.
In one preferred embodiment, an immunogenic portion of a polypeptide ~of the present invention is a portion that-reacts with amisera and/or T-cells at a level that is :not substantially -less than the reactivity .of the full-length polypepiide (e:g., in an ELISA andlor T-cell reactivity assay). Preferably, the level of irnmunogenis activity .of the immunogeiiic portion is at least about 50%, preferably at least about 70%
and most preferably greater than about 90% .of the iriimunogenicity for the full-length polypeptide. In some instances, preferred immunogenic portions will be identif ed that have a -level of timmunogenic activity greater than that of the corresponding full-length, polypeptide, e.g., having .greater than about 100% or 1~0% or more immunogenic activity.
In certain other embodi~nerits, illustrative immunogenic portions may inslucte peptides in which an N-te~~ninal leader sequence and/or transmembrane domain have been .deleted. Other illustrative imriznnogeriic portions. will contain a small N-and/or C-terminal deletion (e.g., 1-30 amino acids, preferably 5-15 amino acids), relative to the Triature protein.
In another embodiiiient, a polyp~ptide composition of the invention may also comprise one or rilore polypeptides that are imriynologisally reactive with T cells and/or antibodies generated against a polypeptide of the invention, particularly a polypeptide having an amino acid sequence .disclosed herein, or to an immunogenic fragment or variant thereof.
In another embodiment of the invention, polypeptides axe provided that comprise one or more polypeptides that are capable of eliciting T cells and/or antibodies -that are immunologically reactive with one or more polypeptides described herein, or

32 one -or more polypeptides encoded by contiguous nucleic acid sequences contained in the polynucleotide sequences disclosed herein, or immunogenic fragments or-.
variants thereof, or to one or more nucleic acid sequences which hybridize to one or more of these sequences under conditions of moderate to high stringency.
The present invention, in another aspect, provides polypeptide fragments comprising at-least about 5, 10, 15, 20, 25, 50, or 10.0 contiguous amino acids, or more;
including all intermediate lengths, of a polypeptide compositions set forth herein, such as those set forth in SEQ ID. NOs: 391, 393, 395, 397, 421, 425'-427, 434-439 and 584 587, or those encoded ~by a palynucleotide sequence set forth in a sequence of SEQ ID
hTOs: 217-390, 39~, 394, ff6, 398;420 422-424, 42f-433 and 440-583.
In another :aspect, the present iriventiori provides variants of -the -polypeptide compositions described herein. Polypeptide variants generally encompassed by the present invention will- typically exhibit at least about.
70%, 75%, 80%, 85%, 90%, 91 %, 9.2%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or more identity (detei~ilined as described below), along its length, S;o a polypeptide sequences set forth herein.
In .one preferred embodiment, the polypeptide fragments and variants provide by the present invention .are immunologically reactive with an antibody andlor T-cell that reacts with a full-length polypeptide specifically set for the herein.
In another preferred embodiment, the polypeptide fragments and variants provided by the present invention exhibit a level of immunogenic activity of at least about 50%, preferably at least about 70%, and most preferably at least about 90% or .more of th~.t exhibited -by a full-length polypeptide sequence specifically set forth herein.
A polypeptide "variant," as the term is used herein, is a polypeptide that typically differs from a polypeptide specifically disclosed herein in .one or more substitutions, deletions, additions and/or insertions. Such variants may be naturally occurring or maybe synthetically generated, for example, by modifying one or more of the above polypeptide sequences of the invention and evaluating their immunogenic

33 activity as described herein and/or using ,any of a number of techniques Well known in -the art.
For example, certain illustrative variants of the polypeptides of the invention include -those in which one or more portions; such as an N-terminal leader sequence or transmembrane domain, have been removed. Other -illustrative variants include variants in which a small portion (e.g., 1-30 amino acids, preferab~Iy 5-15 amino acids) has been removed from the N- and/or C-terminal of the-mature protein.
In many instances; a variant will contain conservative substitutions. A
"conservative substitution" is one in which. an amino acid is substituted for another atriino acid that has similar pP,operties, such that one skilled in the art of peptide chew istry would expect the secondary structure and hydropathic nature of the polypeptide to be substantially unchanged. As described above, modifications may 'be . made in the structure of the polynucleotides and polypeptides of the .present invention and still .obtain a functional molecule that encodes a variant or derivative polypeptide with desirable characteristics, e.g., with irrimunogenic characteristics. When it is desired to alter the amino acid sequence of a polypeptide to create an .
equivalent, .or even an improved, immunogenic variant or portion of a polypeptide of the invention, one skilled in the art will typically .change orie or more of the -codons of the encoding DNA sequence according to Table 1.
For exairiple, .certain amino acids may be substituted for other amino acids in a protein- structure without appreciable loss of interactive binding capacity with structures such as, for example, antigen-binding regions of antibodies or binding sites on substrate molecules. Since it is 'the interactive capacity and nature of a protein that defines that protein's biological functional .activity, certain amino acid sequence substitutions can be made in a protein sequence, and, of course, uts underlying DNA' coding sequence, .and nevertheless obtain a protein -with :like properties. It is thus contemplated that various changes may be made in the peptide sequences of the disclosed compositions, or corresponding DNA sequences which :encode said peptides without appreciable loss of their biological utility or activity.

34 Amino Acids Codons Alanine Ala A GCA GCC GCG GCU

Cysteine Cys C UGC UGU

Aspartic Asp D GAC GAU
acid Glutamic Glu B GAA GAG
.acid PhenylalaniriePhe F UUC UUU

Glycine -Gly G GGA GGC GGG .GGU

Histidine His H CAC CAU

Isoleucine Ile I AUA AUC AUU

Lysine Ly5 K AAA AAG

Le~ucine Leu L UUA UUG CUA CUC CUG CUU

Methionine Met IVI AUG

Asparagine Ash N AAC AAU

Proline Pro -P CCA CCC CCG -CCU

Glutamlne Gln Q CAA CAG

Arginine Arg R AGA AGG CGA CGC ~CGG CGU

S.erin~ Ser S AGC AGU UCA UCC U:CG UCU

Threonine Thr T ACA ACC ACG ACU

Ualine Val V GUA GUC GUG ~GUU

Tryptophan Trp W UGG

Tyrosine Tyr Y UAC UAU

In making such changes, the hydropathic index of amino acids may be considered. The importance .of the hydropathic amino acid index in conferring interactive biologic function on ~. protein is generally understood in the art (Kyte and Doolittle, 1982, incorporated herein by reference). It is accepted that the relative hydropathic character of the amino acid contributes to the secondary structure of the resultant protein, which -in turn defines the interaction of the protein with other molecules, for example, enzymes, substrates, receptors, DNA, antibodies, antigens, and the like. Each amino acid has been assigned a hydropathic index on the basis of its hydrophobicity and charge characteristics (I~yte arid Doolittle, 1982). THese values are:
isoleuciue (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8);
cysteine/cystine (+2,5); mefhionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7);
serine (-0.8);
tryptophan (-0.9); tyrosine (-1.3); proline (-1,6); histidine (-3.2);
glutamate (-3.5);
5 glutamine (-3.5); aspartate (-3.5); asparagine (-3.5); lysine (-3.9); arid arginine (-4.5).
It is known in the art that certain amino acids may be substituted by other amino acids having a similar hydropathic index or score and still result in a protein with similar biological activity, i. e. still obtain a biological functionally equivalent protein. In making such changes, the substitution of amino acids whose 10 hydropathic indices are within ~2 is preferred, those within ~1 are particularly preferred, and those within ~0.5 are even more particularly preferred. It is also understood in the art that the substitution of like amino acids can be made effectively on the basis of hydrophilicity. U. 5. Patent 4,554,101 (specifically incorporated herein by reference in its entirety), states that the greatest local average hydrophilicity of a 15 protein, as governed by the hydrophilieity of its adjacent amino acids, correlates with a biological property of'the protein.
As detailed in U. S. Patent 4,554,101, -the following hydrophilicity values have been assigned to amino acid residues: argi~ine (+3~0); ~lysirie (+3.0);
aspartate (+~.0 ~ 1); glutamate (+3.0 ~ 1); serii~e (+0.3); asparagine (+0.2);
glutamine 20 (+p.2); glycine (0); threonine (-0.4); proline (-0.5 ~ 1); alanine (-0.5);
histidine (-0.5);
cysteine (-1.0); methionine (-1.3); valirie (-1.5).; leucine (-1.8);
isoleucine (-1.8);
tyrosine (-2.3); phenylalanine (-2.5); tryptophan (-3.4). Tt is understood that an amino acid can be substituted for another having a similar-hydrophilicity value and still obtain ,a biologically equivalent, and in particular, an irnmunologically equivalent protein. In 25 such changes, the substitution of amino acids whose hydrophilicity values are within ~2 is preferred, those within ~1 are particularly ,preferred, and those within ~0.5 are even more particularly preferred.
'As outlined above, amino acid substitutions are generally therefore based on the relative similarity of the amino acid side-chain substituerits, for example, their 30 hydrophobicity, hydrophilicity, charge, size, and the like. Exemplary substitutions that take various of the foregoing characteristics into consideration are well known to those of skill in the art and include: arginine arid lysine; glutamate and aspartate; serine and threonine; glutamine and asparagine; and valine; leucine and isoleucine.
In addition, any polynucleotide may be further modif ed to increase stability in vivo, Possible modifications include, but are not limited' to, the addition of flanking sequences- at the 5' and/or 3' ends; the use of phosphorothiaate or 2' O-methyl rather than phosphodiesterase linkages in the backbone; and/or the inclusion of nontraditional bases such as inosine, queosine and wybutosine, as well as acetyl methyl-, thin- and other modified forms of adenine, cytidine, guanine, thymine and 1.0 uridine.
Amino acid substitutions may further be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity and/or the amphipathic nature of the residues. For example, negatively charged amino acids include aspartic acid and glutainic acid; positively charged amino acids .include lysine and arginine; and amino acids with uncharged polar head groups having similar hydrophilicity values include leucine, isoleucine and valirie; glycine and alanine; asparagine and glutamine;
and seririe, threonine, plienylalanine and tyrosine. .Other groups of amino acids that may represent conservative changes include: (1) ala, pro, gly, glu, asp, gln, asn, ser, thr;
(2) cys, ser, tyr, thr; {3) val, ile, leu, met, ala, phe; (4) lys, arg, his;
and (5) phe, tyr, trp, his. A variant may also, or alternatively, contain rionconservative changes.
In a preferred embodiment, variant polypeptides .differ frorii a native sequence by substitution, deletion or addition of five amino acids or fewer. Variants may also (or alternatively) be modified by, for example, the.deletion or addition of amino acids that have minimal influence on the iinmunogenicity, secondary strut",tore and hydropathic nature of the polypeptide.
As noted above, polypeptides may ,comprise a signal (or leader) sequence at the N-terminal end of the protein; which co-translationally or post-translationally directs transfer of the protein. The polypeptide may also be conjugated to a linker or other sequence for .ease of synthesis, purification or identification of the polypeptide (e.g., poly-His); or to enhance binding of the polypeptide to a solid support.
For example, a polypeptide may be conjugated to an immunoglobulin Fc region.
When comparing polypeptide sequences, two sequences are said to be "identical" if the sequence .of amino acids .in the two sequences is the same when S aligned for maximum correspondence, as described below. Comparisons between twa sequences are typically perforrried :by comparing the sequences over a comparison window to identify arid coiripare local regions of sequence similarity. A
"comparison window" as used herein, refers to a segment of at least about 20 contiguous positions, usually 30 to about 75; 40 to about 50, in which a sequence. .may be eoriipared to- a reference sequence of the same number of contiguous positions after the two.
sequences are optimally aligned.
Optirilal aligivment of sequences for corilparisen may be conducted using the Megalign program in the Lasergene suite of bioinformaties software (DNASTAR, Inc., Madison, WI), using default parameters. This program embodies several alignment schemes described in the following references: Dayhoff, M.O. (1978) A
model of evolutionary change in proteins - Matrices for detecting distant relationships.
In Dayhoff, M.O. (ed.) Atlas, .of Protein Sequence and Structure, National Biomedical Research Foundation, Washington DC Vol. 5, Suppl. 3, pp. 345-358; Hein J.
(1990) Unified Approach to ~.lignment arid Phylo,genes pp. 626-645 Methods in Enzymology 20' vol. 183, Academic Press, Inc., San Diego, CA; Higgins, D,G. aid Sharp;
P.M. (1989) CABIOS 5:151-153; Myers, E.W. and Muller W. (1988) .CABIOS 4:11-17; Robinson, E.D. .(1971) Comb. Theor 71:105; Santou, N. Nes, M. (1987) Mol. Bi~l. Evol.
4:406-425; Sneath, P.H.A. and Sol~al, R.R. (1973) Nurner°ical Taxonomy - the Principles and Practice of Nuyrierical Taxonomy, Freeman Press, San Francisco, :CA; Wilbur, W.J. and Lipman, D.J. (1983) Proc. Natl. Acad., Sci. USA 80:726-730.
Alternatively, optimal alignment of sequences for comparison may be conducted by the local identity algorithm of Smith and Waterman (1981) Add.
APL.
Math 2:482, by the identity alignment algorithm of Needleman and Wunsch (1970) J.
Mol. Biol. 48:443, by the search- for similarity methods of Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85: 2444, -by computerized implementations of these algorithms (,GAP, BESTFIT, BLAST, FASTA, and TFASTA in the WisconsiwGenetics Softvv~re Package, Genetics CeiTiputei Group (GCG), 575 Science Dr., Madison, WI), or-by inspection.
One preferred example of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST arid BLAST 2.0 algorithms, which,are desciibed-in Altschul et al. (1977) Nucl. Acids Res.
25:3389-3402 and Altschul et al. (r990) J. Mol. Biol. 215:403-410, respectively. ~BLAS:T
and BLAST
2.0 can be used, for example with the parameters described herein, to determine percent sequence identity for the polynucleot'ides and :polypeptides of the invention.
Software for -per~or 'rn, irlg BI,A.ST analyses is publicly .available -through the TVational Center for Biotechnology Information. For amino acid sequences, a scoring matrix can be used to calculate the cumulative score. Extension- of the word hits in each direction are halted when: fhe cumulative alignment score falls .off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue aligiimients; .or the end of either sequence is reached. The BLAST algorithm parameters W, T and X determine =the sensitivity and .
speed of the alignment.
In one preferred approach, the "percentage of sequence identity" is determined by comparing two optimally aligned sequences ,over a window of comparison of at least 20 positions, wherein the :portion- of the .polypeptide seduence in the comparison window may comprise additions or deletions (i. e., gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference sequences (which does not comprise additions or deletions) far optimal alignment of the two sequences. ~'.he percentage is calculated by determining the number of positions at which the identical amino acid residue occurs in both sequences to yield the n~.unber of matched -positions, dividing the number of matched positions by the :total number of positions in the reference sequence (i.e., the window size) and multiplying the results by 100 to yield the percentage of sequence identity.
Within other illustrative embodiments, a polypeptide may be a fusion polypeptide that comprises multiple polypeptides as described~herein, or that comprises at least one polypeptide as.deseribed herein aiid an unrelated sequence, such as a known -tumor protein. A fusion partner may, for exa~riple, assist in providing T
helper epitopes (an immunological fusion partner); preferably T .helper epitopes recognized by humans, or may assist in .expressing the protein (an expression enhances) at higher yields than the native recombinant protein: Certain preferred fusion partners are both immunological and expression enhancing fusion paitrlers. Other fusion-partners niay be selected so as to increase the' solubility of the polypeptide or to .enable the polypeptide to be targeted to desired intracellular compautments. Still further fusion partners include affinity tags, which facilitate purification of the polypeptide.
1.0 Fusion polypepti -des may generally be prepared using standard techniques, including cherriical conjugation. Preferably, a fusion polypeptide is expressed as a .recorribiriant polypeptide, allouving the production of increased levels, relative to a~ non-fused polypeptide, in an expression system: $riefly, DNA
sequences encoding the polypeptide components may be assembled separately, and ligated into an appropriate eXpression vector. The 3' end of .the DNA sequence encoding one polypeptide component is ligated, with or without a peptide linker, to the 5' end of a .
DNA sequence encoding the second polypcptide corriponent so that the reading frames of the sequences are in phase. This permits translation into a single fusion po~ypeptide that retains the biological activity ofboth component polypeptides.
A .peptide linker sequence may be employed to separate the first anal second. polypeptide components by a distance sufficient to ensure that each polypeptide folds into its secondary and- tertiary structures. Such a peptide linker sequence is incoiporated into the fusion polypeptide using standard techniques well known in the art. Suitable peptide linker sequences may be chosen based- on the following factors.:
(1) their ability to- adopt a flexible extended conformation; (2) their inability to adopt a secondary structure that could interact with functional epftopes on the first and second polypeptides; and (3) the lack of hydrophobic or charged residues that might react with the polypeptide functional epitopes. Preferred peptide linker sequences contain Gly, Asn and Ser residues. Other near neutral amino acids, such as Thr and-Ala may also be used in the linker sequence. Amino acid sequences which maybe usefully employed as linkers include those diselosed~ in Maratea et al., Gene 40:39-46, 19$5;
Murphy et al., Pr~o,.c. Natl: Acad Sci. USA 83:8258-82-62, 1986; IJ.S. Patent No. 4,935,233 and U.S.
Patent No. 4,751,1'80: The linker sequence may generally be from 1 to about 50 amino acids in length. Linker sequences are not required when the first ~ and second 5 polypeptides have non-essential N-terminal amino acid regions tliat~ can be used to separate tl~e functional domains and prevent. steric interference.
The Iigated DMA sequences are operably linked to suitable transcriplioiial or translational. regulatory elements. The -regulatory eleriients responsible for expression of DNA are located only 5' to the DNA sequence encoding 1~0 the first polypeptides. Sirxiilarly, stop codons required to end translation and transcription terirination signals are only present 3' .to the I)NA sequence encoding the second polypeptide.
Tlle fusion polypeptide can comprise ~. polypeptide as described herein together with an unrelated immunogenic protein, such as an irnmunogenic protein 15 capable of eliciting a recall response. Examples of such proteins include tetanus, tuberculosis and hepatitis proteins (see, for example, Staute et a1. New Ehgl.
J. Med., 336:86-9I, 1997).
In .one preferred embodiment, the immunological fusion partner is derived from a Mycobacterium sp., such as a Mycobacterium tuberculosis-,derived Ral2 20 fragment. Ral2 compositions and methods for their use in enhancing the expression and/or immunogenicity of heterologous polyn~cleotide/polypeptide sequences is described in U.S. Patent Application 60/~ 58,585, the disclosure of which is incorporated herein by .reference in its- entirety. Briefly, Ral2 refers- to a polynucleotide region that is a subsequence of..a Mycobacteriur~i tuberculosis MTB32A nucleic acid.
25 MTB32A is a serirle protease of 32 KD molecular. weight encoded by ;a gene in virulent and avirulent strains of M. tuberculosis. The nucleotide sequence and amino acid sequence of MTB32A have been described (for .example, U.S. Patent- Application 60/158,585; see also, Skeiky et al., Itafection aid Imnaun. (1999) 67:3998-4007, incorporated herein by reference). C-terminal fragments of -the MTB32A coding 30 sequence express at high levels and remain as a soluble polypeptides throughout the purification process: Moreover, -Ral2 may enhance the immunogeriicity of heterologous immunogenic polypeptides vi~ith which it is fused. One preferred' Ral2 fusion polypeptide .,corriprises a 14 KD ~C-terminal fragment .coiTesponding to amino acid residues 192 to 323 of 1VITB32A. Other preferred. Ral2 ~polynualeotides generally -comprise at least about 15 consecutive nucleotides, at least about 3-0 nucleotides, at least about ~0:nucleotides, at least about 100 nucleotides, at least about 200 nucleotides, or at least about 300 nucleotides that encode a portion of a Ral2 .polypeptide. Ral2 polynucleotides may comprise a native sequence (r. e:, an endogenous sequence that encodes a Ral2 polypeptide or a portion thereof) ar may comprise a variant of such a sequeri~e. Ral2 polynucleotide variants may contain one or -mole substitutions, additions, deletions and/or insertions such .that the biological .activity .of the encoded fusion polypeptide is not substantially diminished; relative to a fusion polypeptide comprising a naive Ral2 polypeptide. ~,lariants preferably exhibit at least about 70%
identity, .more preferably at feast about ,80% identity grad most preferably at least about 90% identity to a polynucleotide sequence that encodes anative 1Za12 polypeptide or a portion thereof.
Within other preferred embodiments, ari imiiiitnological fusion partner is derived from- protein D, a surface protein. of the gram-negative bacterium Haemophilus influenza ~$- (WO. 91118926). Preferably, a .protein D -derivative comprises approximately the first third of the .protein (e.g., the first N-terminal 100-110 amino acids), and a protein D derivative may be lipidated. Within -certain preferred .eraibodiTalents, the first 109 residues of a Lipoprotein D fusion partner is included on the N-terminus to provide the polypeptide with additional exogenous T-cell epitopes and to increase the expression level in E. cola (thus functioning 'as an expression enhancer).
The lipid -tail -erasures optimal. presentation of the antigen to antigen presenting cells.
Other fusion partners include the non-structural protein from influenzae virus, NS 1 (hemaglutinin). Typically, the N-terminal 81 amino acids are used, although different fragments that include T-helper epitopes may be used.
In another embodiment, the immunological fusion partner is the protein known as LYTA, or a portion thereof (preferably a C-terminal portion). LYTA is derived from Streptococcus pneumouiae, which synthesizes am N-acetyl-L-alanine amidase known as aniidase LYTA (encoded -lay the LytA gene; Gene .3:265-292, 1986). LYTA is an autolysiri that specifically degrades certain bonds in the peptidoglycan backbone. The C-terminal domain of the LYTA protein is responsible for the affinity to the choline or .to soiiie choline analogues such- as DEAE.
This .property lias 'been .exploited for the -developmerit of E. coli C-LYTA
expressing plasmids useful for eXpressiorl of fusion .proteins. Purification of hybrid proteins containing the C-LYTA fraginerrt at the amino terminus has Been described (see Biotechnology 10:795-798, 1992). Within a preferred .embodiment, a repeat portion of LYTA may ~be incorporated into a fusion polypeptida. A repeat portion .is found in the C-terminal .-region ' stat-ting~ at residue 178. A particularly preferred repeat .portion incorporates residues 1.85-305.
Yet another illustrative embodiment involves fusion polypeptides, and the polynucleotides encoding them, wherein the fusion partner comprises a targeting signal capable of directing a polypeptide to -the endosomal/lysosornal compartment, as described in U.S. Patent No. 5,633,234-. An immunogenic polypeptide of the invention, when fused with this targeting signal, will associate more ..efficiently -with MHC class II
molecules and thereby .provide enhanced -in vivo stimulation of .CD4+ T-cells specific for the polypeptide.
Polypeptitles of the .invention are prepared-casing any of a variety of well known synthetic and/or .recombinant techniques, the latter of which are further described below. Polypeptides, portions and other variants generally less than about 15.0 amino acids can be generated by synthetic means, using techniques well known to those of ordinary skill in the art. In one illustrative -.example, such polypeptides are synthesized using any of he commercially available solid-phase techniques, such as the Merrif eld solid-phase synthesis method, where arriirio acids are sequentially added to a growing :amino acid chain. See Merrifield, J. An2. Chena. Soc. 85:2149-2146, 1963.
Equipment for .automated synthesis , of polypeptides is commercially available from suppliers such as Perkin ElmerlApplied BioSystems Division (Foster City, CA), and may be operated according to the manufacturer's instructions.

In general, polypeptide compositions (including fusion polypeptides) of the invention are isolated: An "isolated" polyp-eptide is one that is removed from its original environment. For example, .a naturally-occurring protein or polypeptide is isolated if it is separated from soye or all of the coexisting materials in the natural system. Preferably, such .polypeptides are' also -purif ed, e.g:, are at least about 90%
pure, .more preferably at least about 95% pure and most preferably at least about 99%
pure.
Polynucleotide Compositions The present -invention, in other aspects, provides .polynucleotide ~orhpositions. The .terms '"DNA" arid "polynucleotide" are used. essentially interchangeably herein to refer to a DNA molecule that has :been isolated free of total genomic DNA of a particular species. "Isolated," as used herein, means that a polynucleotide is substantially away from other coding sequences, and that the DNA
molecule does not .contain large portions of unrelated coding DNA, such as large chromosomal fragments or other functional genes or polypeptide coding regions.
Of course, this. refers, to .the DNA molecule as origiri~lly isolated, and does not exclude genes or coding regions later added to, the segment by the hand of man.
As will be understood by those skilled :in the art, the polynucleotide compositions of this invention can include genomic sequences, extra-genomic and plasmid-encoded sequences and smaller engineered gene segments that express, or may be adapted to express, proteins, polypeptides, peptides and the like. Such segments may ,be naturally isolated, or modified synthetically by the hand of man.
As will be also recognized by the skilled artisan, polynucleotide$ of the invention rriay be single-stranded (coding or antisense) or double-stranded, and may be DNA (genomic, .cDNA or synthetic) or RNA molecules. RNA molecules may include HnRNA .molecules, which contain introns and correspond to a DNA molecule in a one-to-one manner, and mRNA molecules, which do not contain introns. Additional coding or non-coding sequences may, but need not, be pz'esent within a polynucleotide of the present invention, and ~ polynucleotide may, but need not, be lii~lced to other molecules and/or support materials.
Polynucleotides may comprise a native sequence .(i. e., an endogenous sequence that encodes a polypeptide/protein of the invention or a portion thereof) or may comprise' a sequence that encodes a variant or derivative, preferably and immunogenic v~:riant or derivative, of such a sequence.
Therefore, according to another aspect of the present invention, polynucleotide compositions are provided that comprise sorrie o~ all of a polynucleotide sequence set forth in ~ny.one of SEQ ID N4s: 217-390, 392, 394; 396, 398-420 424, 428-433 and 440-583, complements- of a polynucleotide sequence set forth in any one of SEQ ID NOs: 217-390 392, 394; 396, 398-420 422-424, 428-433 and 440-583, arid degenerate variants of a polynucleatide sequence set forth in any one of SEQ IID
NOs: 217-390, 392, 394, 396, 398-420 422-424, 428-433 and 440-583. In certain preferred ~embodimertts, the polynucleotide sequences set forth -herein encode immunogenic polypeptides, as described above.
In other related embodiments, the present invention provides ,polynucleotide variants having substantial .identity to the sequences disclosed herein in ~EQ ID NOs: 217-390, .392, 394, 396, 398-420 422-424, 428-433 and 440-583, for example :those comprising at least 70% sequence identity, preferably at least 75%, 80%;
85%, 90%, 95%, 96%, 97%, 98%, or 99% or higher, sequence identity compared to a polynucleotide sequence of this invention using the methods described herein, (e.g., BLAST analysis using standard parameters, as described below). Orie skilled in this art Will recognize that these. values can be appropriately adjusted o determine corresponding identity of proteins eneoded by two nucleotide sequences by taking into account codon degeneracy, amimo- acid similarity, reading frame positioning and the like.
Typically, polynucleotide variants will contain one or more substitutions, additions, deletions and/or insertions, preferably such that the immunogenicity of the polypeptide encoded by the variant polynucleotide' is not substantially diminished relative to a polypeptide encoded by a polynucleotide sequence specifically set forth herein). The term "variants" should also -be understood to encompasses homologous genes of xenogenic origin.
In additional' embodirnents~ the present invention provides polynucleotide fragments comprising various lengths of contiguous stretches of 5 sequence -identical to or corriplezrientary to one or more of the sequences disclosed herein. For exayple, palynucleotides are provided by this invention 'that comprise at least about 10, 1.5, 20, 30, 40~ 50; 7S, 100, 150, 200, 300; 400, 500 or 1000 or more contiguous nucleotides of one or more of the sequences disclosed herein as well as all intermediate lengths there between, It= will be readily understood that "intermediate 1.0 lengths", in this. context, means any length between the quoted values, such as 16, 17, 18-, 19, etc.; 21, 22, 23, etc.; 30, 31, 32, etc.; 50, 51, 52, 53; ,etc.; 100;
101, 102, 103, etc.; 150; 151, 152, 153, etc.; including all integers through 200-500; 500-I,000, and the like.
In another embodiment of the invention, polynucleotide compositions 15 are provided that are capable of hybridizing under moderate to high stringency conditions to a polynucleotide sequence provided herein, or a fragment thereof, or a complementary sequence thereof. Hybridization techniques are wellknown in the art of molecular biology. For purposes of illustration, suitable moderately stringent coadit~ons for testing the hybridization of a polynttcleotide of this invention with other 20 polynucleotides include prewashing in a solution of 5 X S'SC, 0.5% SDS, 1.0 mM
EI?TA (pH 8:0); hybridizing at 50°C-60°C, 5 X SSC, overnight;
followed by washing twice at 65°C for 20 minutes with each- of 2X, O.SX and 0.2X SSC
containing 0.1%
SDS. 'One skilled in the art will understand' that .the stringency of hybridization can be readily manipulated, such as by altering the salt ,content of the hybridization solution 25 and/or the terriperature at which the .hybridization is performed. For example, in another embodiment, suitable highly stringent hybridization conditions include those described above, with the exception that the texriperature of hybridization is increased, e.g., to 60.-65°C or 65-70°C.
In certain preferred embodiments, the polynucleotides described above, 30 e.g., polynucleotide variants, fragments and hybridizing sequences, encode polypeptides that are immunologically .cross-reactive with a polypeptide sequence specifically set .forth herein. In other preferred embodiments such polynucleotides encode polypeptides that have a level of iminunogenic activity of at least about 50%,.preferably at least- about 70%, and more preferably at least about 90% of that for a polypeptide sequence specif cally set forth herein:
The puIynucleotides- of the present invention, or .fragrilerits thereof, regardless of the lengtli~ of the coding sequence itself, may be combined .with other DNA sequences, such as -promoters, polyadenylation signals, additional-restriction enzyrrie sites, multiple cloning sites, other.coding segments, and.the like, such that their overall length may.vary considerably. It is therefore contemplated that.a nucleic acid fragment of almost any length may be employed, with the total length preferably being limited by the ease of preparation and use ~in~ the interide~l recombinant DNA
protocol.
For example, illustrative polynucleotide segyents with total lengths of about 10,000, abort 5000, about 3000, about 2,000, ab-out 1,0,0Q, about 500, about 200, about 100;
about 50 base pairs in length, and the like, (including all intermediate lengths) are contemplated to be useful in many implementations of this .invention.
When comparing polynucleotide sequences, two sequences are said to be "identical" if the sequence of nucleotides in the two sequences is the same when aligned .for maximum .correspondence, as described below. eCoW parisons between two sequences are typically performed .by corizparing the sequences over a comparison window to identify and compare local .regions of sequence similarity. A
"comparison window" as used herein, refers to a segment of at least about 20 contiguous positions, usually 30 o about 75, 40 to about 50, in which a sequence may be compared to a reference sequence of the same number -,of contiguous positions after the two sequences are optimally aligned.
Optimal .alignment of sequences for comparison may be conducted using the Megalign -program in the Lasergene suite of bioinformatics software (DNASTAR, Inc., Madison, Vi~I), using default parameters. This .program embodies several alignment schemes described in the following references: Dayhoff, M.O. (1978) A
model of evolutionary change in proteins - Matrices for.detecting distant relationships.

~In Dayhoff, It4:Q. (ed.) Atlas of Protein- Sequence and Structure, National Biomedical Research Foundation, Washington DC Vol. 5, Suppl. 3, pp: 345-358; Hein J.
(1990) Unif ed Approach to Alignment and Phylogenes pp. 626-645 Methads i~
Evizyytiology vol. 183, Academic Press, Inc., 'San Diego, CA; Higgins, L?.G. and Sharp, P.M.
(1989) CABIOS 5:151--153; Myers, E.W. and lVluller W. (1988) CABIOS 4:11-17;
Robinson, E.D. (1971) Comb: ~'hea~ I1:105; Santou, N. Nes, IVI. (1987) Mol. Biol. Evol.
4:406-425; Sneath, P:H.A. and Sokal, R.R. (1973) Numerical Taxonomy - the Principles atzd Practice ofNuinerical Taxonomy, Freeman Press, San Fraricisco,=CA; Wilbur, W.J. and Lipman, D.J. (1983) Prac. Natl. Acad., Sci. USA 80:726-73b:
Alternatively, optimal. alignment of sequ~erices for comparison may tie conducted by the local identity algorithm of Smith and Waterinari (1981) Add.
APL.
Math: 2:482, by the identity alignment algorithm of Needleman and Wunsch (1970) J
Mol. Biol. 48:443, by the search for similarity methods of Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85: 2444, by computerized implementations of these algorithms (GAP, BESTFIT,-BLAST, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics .Computer Group (GCG), 575 Science Dr., la,~Iadison, WI), or by inspection.
One preferred ,example of algorithms that are suitable- for determining percent sequence .identity and sequence similarity are the HLAST and BLAST 2.0 algorithms, which are described- in Altschul et al. (i9'77) Nucl. Acid's Res.
25:3389-3402 and Altschul et al. -(1990) J. Mat. Biol. 215:403-410, respectively. BLAST and BLAST
20 cambe used; for- example with the paraW eters described herein, to determine percent sequence identity for the polynucleorides of the invention. Software for performing .BLAST .analyses is publicly available through the National Center for Biotechnology Information-. In one illustrative example, cumulative scores .can be calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues;
always >0) and N (penalty score for mismatching residues; .always <0).
Extension of the word hits in each.direction are-halted when: the cumulative alignment score falls off by .the quantity X from its maximum achieved value; the cumulative score goes to zero or 'below, due to the accumulation of one or more negative-scoring residue alignments;

~$
or the end of either sequence is reached. The BLAST algorithm parameters W, T
and X
determine the sensitivity and speed. of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a wordlength (W) of 11, and expectation (E) of -10, and the BLOSU11~I62 scoring matrix (see Henikoff and Henikoff (1989) Prac. Natl.
Acad. Sci. -USA 8.9:10915) alignments, (B) of 50; expectation. (E) of 10, M=5, N=-4 and a comparison of both straxids.
Preferably, the "percentage of sequence identity" is determined by conipating two optimally aligned sequences over a window of comparison of at least 20 positions, wherein the :portion of the polynucleotide sequence in the comparison window may comprise ~dditioris or deletions -(i. e-., gaps) of 20 percent or :less, usually 5 to 15 percent, or 10 to 12- percent, as compared to the reference sequences (which. does not comprise additions or deletions) for optirrial. alignment -of the two sequences. The percentage is calculated by determining the number of positions at which. the identical nucleic acid bases occurs in both sequences ~to yield the number ,of matched positions, dividing the number .of matched positions by the total number of positions -in the reference sequence (i. e., the window size) and multiplying the results by 100 to yield the percentage of sequence identity.
It will be appreciated by those of ordinary skill in the art that, as a result of °the degeneracy of the genetic code, there are many nucleotide sequences that encode .a polypeptide as described herein. Some of these polynucleotides bear minimal homology -to he nucleotide sequence of any native gene. Nonetheless, polynucleotides that vary .due to differences in colon usage are specifically contemplated by the present invention. Further, .aheles of the :genes comprising the polynucleotide sequences provided herein are within the scope of the present invention; Alleles are endogenous.
genes that are altered as a result of one or more mutations, such as :deletions, additions and/or substitutions of nucleotides. The resulting mRNA and protein may, but need not, have an altered structure or function. Alleles may be identified using standard techniques (such as hybridization, amplification and/or database sequence comparison)r Therefore, in another embodirrient of the invention, a mutagenesis approach, such as site-specific mutagenesis, is -employed for the preparation of immurlogenic variants and/or derivatives. of the polypeptides described herein. By this approach, specific modifications in a ~polypeptid~ sequence can be made through rriutagenesis of the underlying polynucleotides that -encode them. These techniques provides a straightforward approach to prepare aired test sequence variants, for example, incorporating. one or more of 'the foregoing considerations, by introducing one or more nucleotide sequence changes into the polynucleotide.
Site-specific mufiagenesis allows the production of mutants through the use of specific > oligonucleoticle sequences which ericode~ the DNA sequence of the desired mut~'tiori, as well as a sufficient number of adjacent nucleotides, to provide a primer sequence of sufficient size and sequence coinpleXity to form a stable Dudley on both; sides of -the deletion junction being traversed: Mutations may ~be employed. iii a selected polynucleotide sequence to improve, alter, decrease, rriodify, or otherwise change the properties of the palynucleotide itself, andlor alter the properties, activity, composition; stability, or primary sequence of the encoded polypeptide.
In certain embodiments of the .present invention, the inventors contemplate the mutagenesis of the disclosed polynucleotide sequences to alter one or more properties of the encoded polypeptide, such as the immunogenicity of a polypeptide vaccine. The techniques of site-specific mutagenesis are well-known in the art, and are widely used to create variants. -of both polypeptides and ~polynucleotides.
For .eXarilple, site-specific rriutagemesis is often used, to alter a specific portion of a DNA
molecule. In such embodiments, a primer comprising typically about 14 to about nucleotides or so in length is erilployed, with about 5 to about 10 residues on both sides of the junction of the sequence-being altered.
As will be appreciated by those .of skill in the art, site-specific rnutagenesis techniques have often eimployec~ a phage vector that exists in both a single stranded and double stranded form. Typical vectors useful in site-directed mutagenesis include vectors such as the M13 phage. These phage are readily commercially-available and their use is generally well-knovim to those skilled in the art.
Double-stranded plasmids are also routinely employed in site directed mutagenesis that eliminates the step of transferring the gene of interest from a plasmid to a phage.

In general, site-directed mutagenesis in accordance herewith is performed lay f rst obtaining a single-stranded vector or melting apart of two strands of a double-stranded vector that includes within its sequence a DNA sequence that encodes the desired peptide. An oligonucleotide primer bearing the desired mutated sequence is 5 prepared, generally synthetically. This primer is then annealed with the single-stranded -vector, aid subjected to DNA :polyrrierizing enzyriies such as E. coli polymerase I
I~lenow fragment, in .order to complete the synthesis of the mutation-bearing strand.
Thus, a heteroduplex is forriied wherein one strand encodes °the original non-mutated sequence arid the second strand bears the desired mutation. This heteroduplex vector is 10 ~tlieri. used to transform appropriate cells, such as E .ca~i cells, and clones are selected which include recombinant vectors bearing the mutated sequence arrangement.
The preparation of sequence variants of the selected peptide-encoding DNA segixa.ents -using site-directed mutagenesis provides a means of producing potentially useful species and is riot meant to be limiting as there are other ways in 15 which sequence variants of peptides and the DNA sequences encoding them may be obtained. For example, recombinant vectors encoding the desired peptide sequence may be -treated with mutagenic agents, such as hydroxylamine, to obtain sequence variants. Specific details regarding these methods and -protocols are found in the teachings of Maloy .et al., 1994; Segal, 1926; -Prokop. and' Bajpai, 1991;
Kuby, 1994;
20 and Maniatis et al., 1982, each incorporated herein ~by reference, for that purpose.
As used herein, the term "oligonucleotide directed mutagenesis procedure" refers to template-dependent -processes and. vector-mediated propagation which result in an increase in the concentration of a specific nucleic acid molecule relative -to its initial concentration, or in an increase in the concentration of a .detectable 25 signal, such as amplification. As used herein, he term "oligonucleotide directed mutagenesis procedure" is intended to -refer to a process that involves the template-dependent extension of a primer molecule. The term template dependent o:
process refers to nucleic acid synthesis of an RNA or a DNA molecule wherein the sequence of the newly synthesized strand. of nucleic acid is dictated by the well-known 30 rules of complementary base pairing (see, for example, Watson, 1987).
Typically, vector mediated ruethodologies involve the introduction of theta ucleic acid fragment into a DNA or RNA vector; the clonal amplif cation of the vector, arid the recovery of the amplified nucleic acid fragment. Examples of such methodologies are provided by U. S. Patent No'. 4,23'x,224, specifically incorporated herein by reference in its entirety, Iri another approach for. the production of polypeptide variants of the present invention; recursive sequence recombination; as described in U.S.
Patent No.
5,837,458, may be erriployed: In-this approach, iterative cycles of recombination and screening or selection are pe~foriried to "evolve" individual po-lynucleotide variants of the invention having, for cxairiple; enhanced immunogcnic activity.
In other embodirnerzts of the present invention; the polynucleotide sequences provided herein can be advantageously used as probes or prirriers for nucleic acid:hybridization. Ars such, it is contemplated that riucIeic acid segments that comprise a seq~erice region of at f east about 15 nucleotide long contiguous sequence that has the same sequence as, or is complementary to, a. 15 nucleotide long contiguous sequence disclosed herein will find particular utility. Longer contiguous identical or complementary sequences, e.g., those of about 20, 30; 40; 50, 100, 200, 500, (including all internriediate -lengths) and even up to full length sequences will also be of use in. certain embodiments.
The ability of such nucleic acid probes to specif cally hybridize to a sequence of interest will enable them to be of use in detecting the presence of complementary sequences in a given sample. However, other uses are also envisioned, such as the use Qf the sequence information for -the preparation of mutant species primers, or primers for use in preparing .other. genetic constructions.
Polynucleotide molecules having sequence regions consisting of contiguous nucleotide stretches of 10-14, 15-20, 30; 50, or even of 100-200 nucleotides or so (including intermediate -lengths as well), identical or complementary to a polynucleotide sequence disclosed herein, are particularly contemplated as hybridization probes for use in,-e.g., Southern and-Northern blotting. This would allow a gene product, or fragment thereof, to be analyzed, both in diverse cell types and also in various bacterial cells. The total size of fragment, as well as the size of the 52~
corilplerilentary stretch(es), v ill ultimately depend on the intended use or application of the particular nucleic acid' segment. Smaller fragments will generally frill use in hybridization embodiments, Wherein the length of the contiguous complementary -region may be varied, such as between about 15 and about 100 nucleotides, but larger contiguous .complementarity stretches may be used, according to the length complementary sequences one -wishes to detect.
The use of a hyliridizatiort probe of about 15-25 nucleotides in length allows the formation of a duplex molecule that is both stable and selective.
Molecules having contiguous complementary sequences over stretches greater than 15 bases in 1~0 length are generally preferred, ;though; in order to .increase stability arid -selectivity of the -,hybrids and thereby improve the quality and degree of specific hybrid molecules obtained. 'One will geriera~ty -prefer to design nucleic acid ri~oleeu~es having gene-coxnplementary stretches of 15 to 25 contiguous nucleotides, ar even longer where desired.
Hybridization probes may be selected from any portion . of any of the equences disclosed herein. All .that is required is to review the sequences set forth herein, or to any continuous portion of the sequences, from about 15-25 nucleotides in length up :to and including the foil length sequence, that one wishes to utilize as a probe ar primer. The choice of .probe and. primer sequences may be governed by various factors. For example, -one may wish to employ primers from towards the termini of the total sequence, Small polynucleotide segments or fragments may be readily prepared by, for example, directly synthesizing the fragment by chemical means, as is commonly practiced using an automated oligonueleotide synthesizer. Also, fragments may be obtainedr by .application of nucleic acid reproduction technology, such as the PCRTM
technology of U. S. Patent 4,683,202 (incorporated herein by reference), by introducing selected sequences into recombinant vectors for recombinant production, and by other recombinant DNA techniques generally known to those of skill in the art of molecular biology.

The nucleotide sequences of the invention may be used for their ability -to selectively form duplex molecules with complementary stretches of the entire gene or genie fragments of interest. Depending on the application envisioned; one will typically desire to erriploy varying conditions of hybridization to achieve varying degrees of selectivity of probe towards. target sequence. For applications requiring high selectivity, one will typic~l~ly desire to employ relatively stringent conditions to form the hybrids, e.g., one will select relatively low salt and/or high temperature conditions, such as piovided by a salt concentration of froth about 0.02 1V~ to about 0.15 M salt at temperatures of from about 50°C to about 70~°C. Such selective :conditions tolerate little, if any, mismatch between the.probe and the template or target sti'and, and would lie particularly suitable for isolating related seq~ierices.
Of course; for some applications, for example, whena one desires to prepare mutants employing a mutant primer strand hybridized to an underlying template, less stringent (reduced stringency) .hybridization conditions will typically be needed in .order .to- allow formation of the heteroduplex. In these circumstances, one may desire to eiiiploy salt conditions such as those of from about 0. i S M to about 0.9 M
salt, at temperatures ranging from about 20.°C to about 55°.C.
Cross-hybridizing species can thereby .be readily identified as positively hybridizing signals with respect to control hybridizati~tis. In any case, it is generally .appreciated that conditions can be rendered mote stringent by the addition of increasing amounts of formamide, which serves to destabilize the hybrid duplex in the same manner as increased temperature.
Thus, hybridization conditions can be readily manipulated, and thus will generally be a method of choice depe~iding on the desired results.
According to another .embodiment of the present invention, polynuclep'.tide -compositions cori~.prisiilg .antisense aligonucleotides -are provided.
Antisense oligonucleotides have -been demonstrated to be effective and targeted inhibitors of protein synthesis, and, consequently, provide a therapeutic approach by which a disease can be treated by inhibiting the synthesis of proteins that contribute to the disease. The efficacy of aiZtisense oligonucleotides for inhibiting protein synthesis is well established. For example, the synthesis of polygalactauronase and the muscarine type 2 acetyleholine receptor are inhibited: by antisense oligonucleotides directed to their respective mRNA sequences (LT. S. Patent 5,739,119 and U. S. Patent 5,759;829).
Further, examples of .antisense inhibition .have been demonstrated With the nuclear protein cyclin, the multiple drug resistance gene (MDG1), ICAM-1, E-selectin, STK-l, striatal GABAA receptor and human EGF (Jaskulski et al., Science. 1988 Jun 10;240(4858):1544-~; V~.santhakumar and Ahriled, Cancer Coymun. 1989;1(4):225-32; -Peris et al., Brain Res lYTol Brain Res. 1998 Jun 15;57(2):310-20; U. S.
Patent 5,801,154; U.S. Patent 5,789,573; U. S. Patent 5,718,709 and U.S. Patent 5,610,288).
Antisense constructs .have .also been described that inhibit and .can be used to treat a variety of abrLOriiral celhtlar piroliferatiorls, e.g. cancer (U. 5. Patent 5,747,470; U. S.
Patent 5;51,317 and U. S. -Patent 5,783,683).
Therefore, in- certain embodirrients, the present invention provides oligonucleotide sequences that comprise all, .or a portion of, any sequence that is capable of specifically binding to polynucleotide sequence described herein, or a complement thereof In one embodiment, the antisense oligonucleotides comprise DNA
or derivatives thereof. In another embodiment, the oligonucleotides oomprise RNA or derivatives thereof. In a third embodiment, the oligonucleotides are modified DNAs comprising a- phosphorothioated modified backbone. In a fourth embodiment, the oligonucleotide sequences -comprise -peptide nucleic acids or derivatives thereof. In each case, preferred compositions corilprise a sequence region that is complementary, and more preferably substantially-complementary, and even .more preferably, .completely coinplementaiy to one or more portions -of polynucleotides disclosed herein.
Selection of antisense compositions specific for a given gene sequence is based upon analysis of the ,chosen target sequence .and determination of secondary structure, T""
binding energy, and relative stability. Antisense comipositions may be selected based upon their relative inability to farm dimers; hairpins, or other secondary structures that would reduce or prohibit specific binding to .the target mRNA in a host cell.
Highly preferred taxget regions of the rilRNA, ara those which are at or near the AUG
translation initiation codon, and those sequences Which are-substantially complementary to 5' regions of the mRNA. These secondary structure analyses and target site selection considerations can be performed; for. example, using v.4 of .the ~LLGO primer analysis software and/or the BLASTN 2Ø5 algorithm software (Altschul et al., Nucleic Acids Res. 199'7, 25(17):338-402}
The use of .an antisense delivery method -employing a short peptide 5 vector, teriiied- MPG (~7 residues), is also contemplated. The MPG peptide contains a hydrophobic domain derived from the fusion sequence of HIV gp4v amd, a hydrophilic domain frorri the nuclear localization. sequence of ~SV40- T-antigen (Morris et al., Nucleic Acids Res. 1997 Jul 15;25(14):2730-G). It has been demonstrated that several molecules of the MPG.peptide coat the antisense oligonucleofides and can be delivered 10 into cultured mammalian cells irz less than 1 hour with relatively high.
efficiency (90%).
Further, the interaction with MPG strongly increases =both the -stability of the oligonucleotide to nuclease and the ability to cross the plasma-membraxie.
Ae~ordirig to another embodiment of the ipvention, the polynucleotide compositions described herein are used in the design and .preparation of ribozyme 15 molecules for inhibiting expression of the tumor polypeptides and proteins of the present invention in tumor cells. Ribozymes are RNA-.protein complexes -that cleave riu~leic acids in a site-specific fashion. Ribozyriies have specific catalytic domains that possess endonuclease activity (I~im and Cech, Proc Natl Acad Sci. U S A. 1987 IDec;84(24):8788-92; Forster and Symons, Cell: 1987 Apr 24;49(2):2.11-20). For 20 example, a large number of ribozymes accelerate phosphoester transfer reactions with a high degree of specificity, often cleaving only one of several phosphoesters in an oligonucleotide substrate (Cech et al., Cell. 1981 Dec;27(3 Pt 2):487-96;
Michel and Westhof, J Mol Biol. 1990 Dec 5;216(3):585-610; -Reinhold-Hurek and Shub, Nature.
1992 May 14;357(6374):173-6). This specificity has been attributed to-fihe requirement 25 that the substrate bind via specific .base-pairing interactions to the internal guide sequence ("IGS") of the ribozyme prior to chemical reaction.
Six basic varieties. of naturally-occurring enzyrriatic RNAs are known presently. Each can catalyze the hydrolysis of RNA phosphodiester bonds in tans (and thus can cleave other RNA molecules) under physiological conditions. In general, 30 enzymatic nucleic acids act by first binding to a target RNA. Such binding occurs through the target binding .portion of a enzymatic nucleic acid which is held in close proximity to am enzymatic portion of the molecule that acts ~to cleave the target RNA.
Thus, the enzymatic nuclete acid first recognizes and then binds a target RNA
through comple'rnentary base=pairing, and once bound to the correct site, acts erizymatically to cut the target RNA. Strategic cleavage of such a target RNA will destroy its ability to direct synthesis.of an encoded-protein. After an enzymatic nucleic acid l~~s bound and cleaved itS.RNA target, it is.released from that RNA to search for another target and can repeatedly bind and cleave new targets.
The enzymatic nature -of a ribozyme is advantageous over rriany teclinalogies~ such as antisehse technology (where a nucleic acid molecule simply binds to .a nucleic .acid target to block its translation) since the concentration of ribozyme necessary to affect a therapeutic treatment is lower than that .of art antisense oligonucleotide. This advantage reflects the ability of the ribozyme to act enzymatically. Thus, a single ribozyme molecule is able to cleave many molecules of target RNA. In addition, the ribozyme is a highly specific inhibitor, with the specificity of inhibition depending not only on the base pairing mechanism of binding to the target RNA, but also. on the -mechanism of target RNA cleavage. Single mismatches, or-base-suhstitutions, near the site of cleavage can completely .eliminate catalytic activity of a ribazym~e. Similar mismatches in- antisense molecules do not prevent their action (Woolf et al., Proc Natl Acad Sci U S A. 1992 Aug 15;$9(1'6);7305-9). Thus, the specificity of action of a ribozyme is greater than that of an antisense oligonucleotide binding the wine RNA site.
The enzymatic .nucleic acid molecule may he formed in a hammerhead_ 1;31(47):11$43-S2; an example- of the RNaseP motif is described by .Guerrier-Takada~
et al., Cell. 1983 Dee;35(3: Pt 2):849-57; Neurospora VS RNA ribozyme motif is described liy Collins (Saville and Collins, Cell. 1990 May 18;61(4):685-96;
Saville and Collins, Proc Natl Acad Sei U S A. 1991 Oet 1;88(19):8826-30; Collins and Olive, Biochemistry. 1993 Mar 23;32(11):2795=9); and van example of the Group =I
introit is described in (U. S. Patent 4,987,071). All~that is important in an enzymatic nucleic acid molecule of this invention. is that it has a specific substrate binding site which is complementary to one or -more of the target gene RNA. regions, and that it have nucleotide sequences within .or surrounding that substrate binding site which irr~part an RNA cleaving activity to the molecule. Thus the ribozyme constructs need not be limited to specif c motifs -mentioned herein,.
Ribozymes riiay be desi-fined- as .described in Int. Pat. Appl. Publ. No.
WO 93/23569 and I~t. Pat. Appl. Publ. No. WO 94/0259, each specifically incorporated herein by reference) and synthesized to be tested ih vitro and i~
vivo, as described. Such ribozymes can also .be optimized for delivery. While specific examples are provided, those in -the art will recognize that .equivalent RNA
targets in other species can be utilized when necessary.
Ribozyme activity .can be optimized by altering the length of the ribozyme -binding arms, .or chemically syrithesi~ing ribozyiries with modif cations that prevent their-degradation by serum ribonucleases (see e.g., Int. Pat. Appl.
.Publ. No. WO
92/07065; 'Int. Pat. Appl. Publ. No. WO 93/15187; Int. Pat. Appl. Publ. No. WO
91/03162; Eur. Pat. Appl. Publ. No. 92110298.4; U. S. Patent 5,334,711; and Int. Pat.
Appl. Publ. No. WO 94/13688, which describe various chemical modifications that can be made to the sugar moieties of enzymatic RNA molecules), modifications 'which enhance their efficacy in cells, and removal of stem II bases to shorten RNA
synthesis times and reduce chemical requirements.
Sullivan et al. (Int. Pat. Appl. Publ. No. WO 94/02595) describes the general rizethods for delivery of enzymatic RNA molecules. Ribozymes may be administered to cells by a variety of methods .known to those familiar to the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles, such as hydrogels, cyclodextrins, biodegradable nanocapsules, and bioadhesive nnicrospheres. For some indications, ~ribozym~s may be directly delivered ex vivo to cells or tissues with or without the aforementioned vehicles.
Alternatively, the RNA/vehicle combination may be locally delivered by direct inhalation, by direct injection or by use of a catheter, inftision pump-or stmt. Other routes of deli ery include; but are riot limited to, intravascula~, intramuscular, suli,cu~arleous or joint injection, aerosol inhalation; oral =(tablet .or pill form), topical, systemic, ocular, intraperitoneal and/or intrathecal. delivery. More detailed descriptions of -ribozyme delivery arid administration are provided in ant. Pat. Appl.
Publ. No. V~10 94/059.5 and- Int. Pat. Appl.. °Publ. No. WO 93/23569; :each specif cally incorporated herein by reference.
Another means of accumulating high concentrations of a ribozyme(s) within cells is to incorporate the ribozyme-encoding sequences into a DNA
expression vector. Transcription of the ribozyme sequences are driven from a promoter for 1 S eukaryotic.:RNA poly~rierase I (pol ~), RNA polymerase -II (pol II), or RNA polymerase III (pol III). Transcripts from pol II or pol III p~orrioters will. be eXpressed at high levels in all cells; the levels of a given pol II promoter in a given cell type will depend on the nature of the gene :regulatory sequences (eriharicers, silencers, etc. ) present nearby.
Prokaryotic RNA polymerase .promoters may also. be used, providing that the prokaryotic RNA polymerase enzyme is expressed in the appropriate cells Ribozymes expressed from such promoters have been shown to function in mammalian cells.
Such transcription units can be incorp.orated~ into a variety .of vectors for introduction into mammalian cells, including but not restricted to, plasrriid DNA vectors, viral DNA
ve, ctors (such as adenovirus or aderio-associate vectors); or viral RNA
vectors (such as retroviral, semliki forest virus, sindbis virus vectors).
In another embodiment of the invention, . peptide nucleic acids (PNAs) compositions are .provided. PNA is a DNA mimic in which the nucleobases are attached to a pseudopeptide backbone (Good and Nielseri, Antisense Nucleic Acid Drug Dev. 1997 7(4) 431-37). PNA -is; able to be v tilized in a number methods that traditionally have used RNA or DNA. Often PNA sequences perform better in techniques than the corresponding RNA or DN1~ sequences arid 'have utilities that are not .inherent to RNA or DNA. A review of PNA including methods of making, characteristics of, and: methods of using, is provided by Corey (Tre~a's Baotechnol 1997 Jun;15(6):224-9). As such, iri certain embodiments, one may prepare PNA
sequences =that are corriplementary to one or more -portions of the ACE mRlVA sequence, and such PNA compositions may :be used Io regulate, alter, decrease, or t;educe the translation of ACE-specific mRNA, and hereby alter the level of ACE activity iri= a host cell. tov vhich such PNA compositions have been administered.
PNAs have 2-aininoethyl-glycine linkages =replacing the norriial IO phospliodiester backbone .of DNA (Nielsen.et al., Science 1991 Dec 6;254(5037}:1497-5.00; .Hanvey et al., Science. 1992 Nov 27;258(5087):1481-5; Hyrup and Nielsen, ~Bioorg lVled Chem. 1.996 Jan;4(1):5-23). Thin chemistry has three important consequences: firstly, in contrast to DNA or phosphorothioate oligonucleotides, PNAs are neutral molecules; secondly, PNAs are achiral, which avoids the need to develop a stereoselective synthesis; and -thirdly, PNA synthesis uses standard Boc or Fmoc .protocols for solid-phase peptide synthesis, although other yethods, including a modified Merrifield method, have been used.
PNA monomers or ready-made oligoiners are ~comiiiercially available -from PerSoptive Biosysterns (Framingharri, ~MA). -PNA syntheses by either Boc or °Fmoc protocols are straightforward using manual or automated:protocols (Norton et al., Bioorg Med Chem. 1995 Apr;3(4):437-45). The rizanual protocol .lends itself to the production of chemically miodified PNAs or the simultaneous synthesis of families of closely related PNAs.
As with peptide synthesis, -the success of a particular PNA synthesis will depend on the properties of the chosen sequence. For exarriple, while in theory PNAs can incorporate any combination -of,nucleotide bases; .the presence of adjacent purines can lead to deletions of one or more residues in the product. In expectation of this difficulty, it is suggested that, in producing PNAs with .adjacent purines, one should repeat the coupling of residues likely to be added inefficiently. This should be followed by the purification of PNAs by reverse-phase high-pressure liquid chromatography, providing yields and .purity of product similar to those observed during the synthesis of peptides:
Modifications of PNAs for a given application may be accomplished by .coupling amino acids during solid-phase synthesis or by attaching compounds that 5 contain a :carboxylic .acid group to the exposed N-terminal amine.
Alternatively, PNAs can be modified after synthesis .by coupling to an introduced lysine ,or cysteine, The ease witlx whicli. ~PNAs can be modified facilitates optimization for better solubility or for specific functional requirements. Once synthesized; the identity of PNAs and- their derivatives can vbe canfinned by mass spectrometry. Several studies have made and 10 utilized ~odificatioris of PNAs (for example, Norton et al., Bioorg IVIed Chem. 19.9.5 Apr;3(4):437-,45; Petersen- et al., J ~Pept Sci. 1995 May-Jun;l(3):175-~3;
Orum et al., Biotechniques. 1995 Sep;l9(3):472-&0; Footer et al:, Biocherilistry. 1996 Aug 20~35(33):I0673-9; Griffith et al., Nucleic Acids Res. 1995 Aug 11;23(15):3003-8;
Pardridge et al., Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):559-6; Boffa et al., 15 Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):1901-5; Gambacorti-Passerine et al., Blood. 1996 Aug 15;88(~):14I1-7; Armitage et al., eProc Natl Acad S,ci U S A.

Nov 11;94(23):12320-S; Seeger et al., Biotechniques. 1997 Sep;23(~):SI2-7).
U.S.
Patent No. 5,700,92 discussed ;PNA-DNA-PNA chimeric molecules and their uses in diagnostics, modulating protein i~ organisms, and treadnent of conditions susceptible to 20 therapeutics.
Methods of characterizing the antisense binding properties of PNAs are discussed in. Rose (Anal Chern. 1993 Dec 15;65(24):3545-9) and Jerisen et al.
(Biochemistry. 1997 Apr 22;36(16):5072-7). Rose uses capillary gel electrophoresis to determine binding of PNAs to their complementary oligonucleotide, measuring the 25 relative binding. kinetics .and stoich'iometry. Similar types of measurements were made by Jensen et al. using BIAcoreTM technology.
Other applications of PNAs .-that have been described and will be apparent tb the skilled artisan include use ire DNA strand invasion, antisense inhibition, mutational analysis, enhancers of transcription, nucleic acid purification, isolation of transcriptiorially active genes, blocking of transcription factor binding, genome cleavage, biosensors~, in situ hybridization, and the like.
Polynucleotide Identification; Characterization: and Expression Polynucleotides compositions of the .present invention may be identified, :prepared and/or manipulated using any ..of a variety of well established techniques (see generally, Sambrook et al., Molecular Cloning: A Labo~ato~y Manual, Cold Spring -Harbor Laboratories Cold Spring Harbor, NY, 1989, and other like references).
For example, a polynucleotide rnay be identified,, as .described in more detail below, by screeniing a microarray of cDNAs for tumor-associated expression (i. e., expression that is at least twa -fold greater iri a tumor than in normal tissue, as determined using a representative' assay provided herein). Such. screens znay be performed, for example, using the microar~ay technology of Affymetrix, .Iric. -(Santa Clam, CA) according to the manufacturer's instructions (and essentially as described by Schena et al., Pr~oc. Natl.
Acid. Sci. USA 93:10614-10619, 1996 and .Heller et al., Proc. Natl. Acid. Sci.
USA
94:2150-2155, 1997). Alternatively, polynucleotides may -be amplified from cDNA
prepared from cells expressing the proteins described herein, such as tumor cells.
Many templafe dependent processes are available to ayplify a target sequences of interest present in,a sample. ~Orie ofthe best-known arriplification methods is the polymerise chain reaction (PCRTM) which is described in detail in U.S.
Patent Nos. 4,68.3,195, x;683,202 .arid 4,800,159, each of which is incorporated herein by -reference in its entirety. Briefly, in PCRTM, two primer sequences are prepared- which are coW plementary to regions .on opposite Gomplemeritary strands of the target sequence. An excess of deoxynucleoside triphosphates is added to a reaction mixture along with a DNA polymerise (e.g., Taq polymerise). If the target sequence is present in a sample, the primers will bind to the target and the polymerise will cause the primers to be ,extended along the target sequence by adding on nucleotides. By raising and .lowering the temperature of the reaction mixture, the extended primers will dissociate frorri the target to form reaction products, excess primers will bind to the target and to the reaction product and -the process is repeated. Preferably reverse transcription and PCRTM amplification procedure may be performed in order to quantify the amount of mRNA amplified. Polymerise chain reaction iTiethodologies are well known in the art.
Any of a number .of other template dependent processes, many of which ark variations of the PCR TM amplification technique; are readily known and available in the art. Illustratively, some such methods include the ligase chain reaction (referred to as LCR), described, for example, in 'Ei~r. Pat. Appl: Publ. No. 320;308 arid U.S. Patent No. 4,883,750; Qbeta. Replicas; described. in PC'T Intl~. Pat. Appl. Publ. NQ.
PCTlUS87/0088.0; Strand Displacement Amplification (SDA) and Repair Chain Reaction (RCR). 'Still other amplification methods. are .described iW:Great Britain Fat.
Appl. I~o. 2 202 328, and in=PCT Intl. Pat. Appl. Publ. No. PCT/USBg/Q1025.
Other ~nizcleic acid aiilplification procedures include ~transcriptiori-based amplification systems (TAS) .(PCT Intl. Pat. Appl. Publ. No. WO 88/10315), including nucleic acid sequence based amplification (NASgA) and 3SR. Eur. Pat. Appl..Publ. No. 329,822 describes a nucleic acid amplification process involving cyclically synthesizing single-stranded RNA ("ssRNA"), ssDNA, and doable-stranded DNA (dsDNA). PCT Intl. Pat. Appl.
Publ. No. WO $9/06700 describes a nucleic acid sequence amplification scheme based on the .hybridization of a promoter/primer sequence to a target single-stranded DNA
("ssDl~A") followed .by transcription. of many RNA copies of the sequence.
Other amplification methods such as "RACE" (Frohman, 1990), and "one-sided PCR"
(Ohara, 1-989) are also well-known to those of skill in the art.
An amplified. poz~ion of a polynucleotide of the present invention may be Bused to isolate a full length gene from a suitablelibrary (e.g., a tumor .cDNA library) using well known techniques. Within such techniques, a library (cDNA or genomic) is screened using one or more .polynucleotide probes or primers suitable for amplification.
Preferably, a library is size-selected to include larger molecules. Random primed libraries may also be preferred for identifying 5' and upstream regions of genes.
Genomic libraries are preferred for. obtaining introns and extending 5' sequences.
For hybridization techniques, a partial sequence may be labeled (e.g., by nick-translation or end-labeling with 32P) using well known techniques. A
bacterial or bacteriophage library is then generally screened -by hybridizing filters containing ,denatured- bacterial colonies (or Iawns containing phage plaques) with the labeled probe (see Sariibrook et al., Malecula~ Cloning: A Laboratory Manual; Cold Spring Harbor Laboratories, -Cold Spring Harbor, NY, 1989). Hybridizing colonies or plaques are selected and° expanded, and the DNA is isolated for further analysis.
cDNA clones may be axialyzed to determine the arnaunt of additional sequence by, for exariiple, ~PCR using a primer from the partial sequence and a-primer from the vectox. Restriction maps and partial sequences may be generated to identify one or more overlapping clones.
The complete sequence .may then be determined using standard techniques, which may involve .genera~irig a series of deletion clones. The resulting overlapping sequences can then assembled into a single contiguous sequence. A full length cDNA molecule can be generated by ligatirig suitable fragments,:using well known techniques.
Alternatively, amplif canon techniques, such .as those described above, can be useful for obtaining a full length coding sequence from a partial cDNA
sequence.
Qne such amplification technique is inverse PCR (see Triglia et al., Nuel.
Acids Res.
16:8186, 1988), which uses restriction enzymes to generate a fragment in the known region of the gene. The fragment is then .circularized by intramolecular ligation and used as a template for PCR -with divergent primers derived from the known region.
Within an alternative approach; sequences- adjacent to a partial .sequence may be ZO retrieved by amplification with a prirrier to a linker sequence and a primer specific to a know region. The amplified sequences are typically subjected- to a second round of amplification with the same linker primer and a second- ptimer specific to the' .known region. A variation on this procedure, which employs two primers that initiate .extension- in opposite directions -from the known sequence, is described in WO
96/38591. Another such technique .is known as "rapid amplification of-cDNA
ends" or RACE. This technique involves the use of an internal primer and an external primer, which hybridizes to a polyA region or vector sequence, to identify sequences that are 5' and 3' of a known sequence. Additional techniques include capture PCR
(Lagerstrom et al., PCR Methods Applic. 1:111-19, 1991) and walking PCR (Parker et al., Nucl.

Acids. Res. 19:3055-60; 1991). Other- methods employing amplification may also be employed to obtain a full length cDNA sequence.
In certain instances, it is possible to obtain a full length cI7NA sequence by analysis of sequences provided in an expressed sequence tag (EST) database, such as that ~.vailable from GenBank. Searches for overlapping. ESTs may generally be performed .using well kriowri programs (e.g., NCBI BLAST searches), and such ESTs may be' used to ~gen~r~,te a contiguous full length sequerice: Full- length DNA sequences may also be obtained-by analysis of genomic fragments.
In ather emtiodirnents of the invention, polynucleotide sequences or fragments therebf which encode polyp.~p~tides :of the invention, or fusion proteins or functional equivalents thereof, may be. used in recombinant DNA molecules to direct-expression of a polypeptide .in appropriate ha.st cells. Due to the inherent degeneracy of the genetic code, .other 1DI~1A sequences that encode substantially the same or a functionally equivalent amino acid sequence may be produced and these sequences may be used to clone .and express a given polypeptide.
As will be understood by those of skill in the art, it may be advantageous in some instances to produce polypeptide-.encoding -nucleotide sequences possessing non-naturally occurring codons. For exarriple, codons preferred by a particular prokaiyotic ~or eukaryotic host can be selected to -increase the rate of protein expression or to produce a recombinant RNA transcript-having desirable properties, such as a -half life which is longer than that of a transcript .generated from the naturally occurring sequerice.
Moreover, the polyn~cleotide sequences of the present invention can be engineered -using methods gerierahy -known in the art in order to alter polypeptide encoding sequences for a variety of reasons, including but not limited to, alterations which modify the cloning, processing, and/or expression of the gene .product.
For example, DNA shuffling by random fragrrientation and PCR reassembly of gene fragments and synthetic oligonucleotides may be used to engineer the nucleotide sequences. In addition, site-directed mutagenesis may gibe used to insert new restriction sites, alter glycosylation patterns, change codon preference, produce splice variants, or introduce mutations, and so forth:
In another embodiment of the invention, natural, modified or recombinant nucleic acid sequences may be ligated to a heterologous sequence to 5 encode a fusion protein. For example, to screen peptide libraries for-inhibitors of polypeptide activity, it may be useful to. encode a child eric protein that can be recognized by a comrriercially available antibody. A fusion protein may also be engineered to contain a cleavage site located between the polypeptide-encoding sequence and the lieterologous protein sequence, so that the pplypeptide may be cleaved 10 and purified. away from the heterologous moiety.
Sequences erieoding a desired polypeptide may be synthesized, in whole or in part, using chcrriical methods well known- in tlZe art (see -Caruthers, M. H. et al.
(1980) Nucl. Acids Res. Symp. Ser. 215-223, Hom, T. et ~1. (I980) Nucl. Acids Res.
Symp. Ser. 225-232). Alternatively, the protein itself may be produced using chemical 15 methods to synthesize the amino acid sequence of a polypeptide, or a portion thereof.
For example, peptide synthesis can be perforri~ed using various solid-phase techniques (Roberge, J. Y. et al. (19f5) Sciehce 269:202-204) and automated synthesis may be achieved; for example, using -the ABI' 431A Peptide Synthesizer (Perkin Elmer, Palo Alto; .CA).
20 A newly synthesized peptide may be substantially purified by preparative high performance liquid chromatography .(e.g., Creighton, T.
(1983) Proteins, Structures and Molecular -Principles, WH Freeman and Co., New York, N.Y.) or other comparable techniques available in the art. The composition of the synthetic peptides may be confirmed by aiizina .acid analysis or sequencing (e.g., the EdW an 25 degradation procedure). Additionally, the amino acid sequence of ~
polypeptide, or any part thereof, may be altered during direct synthesis and/or combined using chemical methods with sequences from other proteins, or any part thereof, to produce a variant polypeptide.
In order to express a desired polypeptide, the nucleotide sequences 30 encoding the polypeptide, or functional equivalents, may be inserted into appropriate expression vector, i.s., ~: vector which contains tie necessary elements for the transcription and translation of the inserted coding sequence. Methods which axe well known to those skilled in the art may be used to construct expression vectors containing sequences encoding a polypeptide of interest and appropriate trariscriptional and translational control elements. These methods include in vitro recombinant DNA
techniques, synthetic techniques; and iii vivo genetic recombination. Such techniques are described', 'for example, in Sarrib'rook, J. et .al. (1989) Molecular Cloning, A
Laboratory Manual, Cold Spring Harbor Press, Plainview, N.Y., and Ausubel, F.
M. et al. {19:89) Current Protocols in Molecular Biology, John Wiley ;& Soys, New York.
10. N.Y.
A variety of expression vector/host systeW s -may be utilized to contain arid- ekpress polynucleotide sequences. These include, but ate not limited to, microorganisms such as bacteria transformed with recombinant bacteriophage, plasmid, or cosmid -DNA expression vectors; yeast transformed with yeast expression vectors;
1~5 insect .cell systems infected with virus expression vectors (e.g., baculovirtis); plant cell systems transformed with virus expression vectors (e.g., cauliflower .mosaic virus, CaMV; tobacco mosaic virus, T1VIV) or with bacterial .expression vectors (e.g., Ti or ;pBR322 plasmids); or animal cell systems.
The "control -elements" or "regulatory sequences" present in. an ~0 expression vector are those .non-translated. regions of the vector--enhancers, promoters, 5' and 3' untranslated regions--which interact with host cellular .proteins to carry out transcription and translation. Such elements -may vary in their strength and specificity.
Depending on the vector system and host utilized, any number of suitable transcription and translation elements, including constitutive arid inducible promotersy may be used.
25 For example, when cloning in bacterial systems; inducible promoters such as the hybrid lacZ promoter of the PBLUESCRIPT phagemid (Stratagene, La Jolla, Calif.) or PSPORT1 plasmid (Gibco BRL, ~Gaithersburg, MD). and the like may be used. In mammalian cell systems, -promoters from mammalian genes or from mammalian viruses .are generally preferred. If it is necessary to generate a cell line that contains multiple copies. of the sequence encoding a polypeptide, vectors based on SV40 or EBV
may be advantageously used with an 'appropriate selectable marker.
-In bacterial. systems, any of a number of expression vectors may be selected depending upon the use intended for the expressed .polypeptide. For example, when large quantities are needed; for .example for the induction of antibodies, vectors which direct high level expression of fusion proteins that are readily purif ed may be used. Such vectors include, but are not liixiited 'to, the multifunctional E.
coli cloning and expression vectors such as BLUESCRIPT (Stratagene), in which the sequence encoding the polypeptide of interest may be ligated -into the vector in frame with sequences, for -the amino-terminal. Met and the subsequent 7 residues of .beta.-galactosidase so that a hybrid protein is produced; pIN vectors (Van. Heeke, ~G. and S.
1VI. Schuste~ (1989) J Bial: Chem: 264:5503-5509); and the like. pGEX Vectors (Promega, Madison, Wis.) may also be used to express foreign polypeptides as fusion proteins with glutathione S-transferase (.GST). In general, such fusion proteins are soluble and can easily be purified from lysed cells by adsorption to glutathione-agarose beads followed by elution .in the presence of free ,glutathiorie. Protei=ns made in such systeri~s may be designed to include heparin, thrombin, or factor XA protease cleavage sites so that 'the cloned polypeptide of interest can be released from the GST
moiety at will.
In -the yeast, Saceharorriyces cerevisiae, a number of vectors containing constitutive or inducible promoters such as alpha factor., alcohol oxidase, and PGH may be .used. For reviews, see Ausuliel et -al. (supra) amd Grant et al. .(1987) Methods Ertzymol. 153:516-544.
In cases where plant expression vectors are cased, -the expression .of sequences encoding polypeptides may be driven by any of a number of promoters.
For example; viral promoters such as the 35S and 19S promoters of CaMV may be used alone or in combination with the omega leader sequence from TMV (Takamatsu, N.
(1987) EMBO J. 6:307-311. Alternatively, plant promoters such as the small.
subunit of °RUBISCO or heat shock promoters may be used (Coruzzi, G. et al. (1984) EMBO J.
3:1671-1680; Brogue, R. et al. (1.984) Science 224:838-843; and Winter, J. et al. (1991) 6$
Results Pxobl: Cell Diffef~. 17:&5-105). These constructs can be introduced into plant cells by direct DIVA transformation or pathogen-mediated transfection. Such techniques are-described in a niixiiber of generally available reviews (set, for example, Hobbs, S. or Murry, L. E. in McGraw Hill Yearbook of Science and Technology (1992) McGraw Hill, New York, N.Y.; pp. 191-196).
Ari insect system may also be used to express. a polypeptide of interest.
For example, in one such system, Autographa ealifori~ica nuclear polyhedTOSis vines (AcNPV) is used as a vector to express foreign genes in S~odoptera frugiperda cells or in ~'richoplusia larvae. The sequences encoding ;the polyp.eptide may be coned into a 1,0 -non-essential region of the virus, such as the polyhedxiri gerl~, and placed. under control of the polyhedrin promoter. Successful insertion of tl~e polypeptide-:~ricoding sequence will render the polyhedrin gene inactive and produce recoW binant virus lacking coat protein. The recombinant viruses may then be used to infect, fox example, S, frugiperda cells or Tri~ho~lusia larvae in. which the polypeptide of interest may be expressed (Engelhard, E, K. et al. (1994) Proc. Natl. Acad. Sci. 91 :3224-3227).
In mammalian host cells, a number of viral-based expression systems are generally available. For .example, in cases where an adenovirus is qsed as an expression vector, sequences encoding a polypeptide of interest may be iigated into an adenovirus transcription/translation complex consisting- of the late promoter arid tripartite leader sequence. Insertion in a riori-essential E1 or E3 region of the viral genome xilay be used to obtain a viable virus whicli is capable of expressing the polypeptide in infected host -cells (Logari, ~. and~'Shenk, T. (-19$4) P~oc. Natl. Acad. Sci. 81:3655-3659). In addition, transcription ~rihancers, such as the Rous sarcoma virus .(RSV) enhancer, may be used to increase expression in mammalian host cells.
Specific initiation signals may also be used to achieve .more efficient translation of sequences encoding a polypeptide of interest. Such signals include the ATG initiation =colon . and adjacent sequences. In .cases where sequences encoding the polypeptide, its initiation colon, and upstream sequences are inserted into the appropriate expression vector, no additional transcriptional or translational control signals may be needed. However, in cases where only coding sequence, or a portion thereof, is inserted, exogenous translational control signals including the ATG initiation colon should be provided. Furthermore, the initiation colon should be in the correct reading frame to ensure translation of the entire insert. Exogenous translational elerrients, and initiation co-dons may be of various origins, both natural and synthetic.
The efficiency of expression may be enhanced by the inclusion of enhancers which are appropriate for the particular cell system which is used; such as these ,described in-the literature (Schar~, I~. et al: (1994) Results P~obl. Cell Differ. 20:125-1(2).
In addition, a host cell strain may be .chosen for its ability to modulate the expression .of the inserted sequences or to process the expressed protein in the 1 ~ desired fashion-. Such modific~tioris -of the palypeptide include, but are not limited to, acetylation, carboxylation. -gl-ycQSylation, phosphorylation, lipiciation, and acylation.
Post-translational processing which cleaves a "prepro" form of the protein may also be used to facilitate correct insertion, folding and/or function. Different host cells such as CHO, COS, HeLa, MDCK, H~K293, and WI38, which have specific cellular machinery and characteristic mechanisms for such post-translational activities, may be chosen to ensure the correct modlfrcation and-processing of the foreign protein.
For long-term, high-yield- production .of recombinant proteins, stable expression is generally preferred. For example, cell lines which stably express a polynucleotide of interest may be transformed using expression vectors which xriay 20. contain viral origins of replication and/or endogenous expression .elements and a selectable marker gene on the same or on a separate vector. Following the introduction of the vector, cells.-may be allowed to grow for 1-2 days in an enriched media-befo-re _they are switched to selective media. The purpose of the selecXable marker is to confer resistance to selection; and its .presence allows growth and recovery of cells which successfully express the introduced sequences. Resistant clones of stably transformed cells may be proliferated using tissue culture techniques appropriate to the cell type.
Any number of selection systems may 'be used to recover transformed cell lines. These include, but are not limited to, the herpes simplex virus thymidine kinase (Wigler, M. et al. (1977) Cell 11:223-32) and adenine phosphoribosyltransferase (Lowy, I. et al. (1990) Cell 22:17-23) genes which can be employed in tk^- or aprt.sup-.- cells, respectively. also, atltiinetabolite, antibiotic or herbicide resistance can be used as the basis for selection; for example, dhfr which confers resistance to methotrexate (Wigler, -1VI. et al. (198.0) P~oc. Natl. Acad. Sci. 77:3567-70);
npt, which confers resistance to the" aminoglycoside5, neomycin and G-418 (Colbere-Garapin, F. et 5 al (198.1) J. Mal. PioZ: 150:1-14); and als or -pat, which confer resistance to chlorsulfurorl a~c~ phosphinotricin acetyltrarisferase, respectively ,(hurry, supra).
Additional- selectable genes have been described, for exaW plc; tipB, which allows cells to utilize indole in place of tryptophan, or hisD; which allows .cells to utilize histinol in place of histidine (Hartinan; S. C. and -R. C. Mulligan (198:) Proc. Natl.
Acad Sci.
1.0 85:807-~1). The use of visible markers has gained popul'arify with such markers as arithocyanins, beta-glucuronidase and its substrate GUS, and lu~iferaae and its substrate luciferin, being widely used not only to identify transforrriants, but also to quantify the amount of transient or stable protein expression attributable to a specific vector system (Rhodes; C. A. .et al. (1995) ll~fethods Mol. Biol. .55:121-131).
15 Although the presence/absence of marker gene expression suggests that the gene of interest is also present, its presence and expression may need to be confirrried. For example, if the sequence encoding a polypeptide is inserted within a .marker gene sequence, recombinant cells containing sequences can be identified by the .
absence .of marker gene function. Alternatively, a marker gene can be .placed in tandem 20 with a polypeptide-encoding sequence under the control of a single promoter.
Expressipn of the marker gene in .response to induction or selection usually indicates expression of the tandem gene as well.
Alternatively, host cells that contain arid express a desired polynucleotide sequence may -b~ identified by a variety of procedures known .to those of 25 skill in: the art. These procedures include, but are not limited to, DNA-DNA or I~NA-RNA hybridizations and protein bioassay or immunoassay techniques which include, for .example, membrane, solution, or chip based technologies for the detection and/or quantification of nucleic acid or protein.
A variety of protocols .for detecting and measuring the expression of 30 polynucleotide-encoded products, using either .polyclonal or monoclonal antibodies specific for the .product are known in the art. Examples include enzyme-linked imrimnosorbent assay (ELISA), radioimmunoassay (RIA), and fluorescence activated cell sorting (FAGS). A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering epitopes on a given polypeptide may be prefei~ed~ for some applications, but a competitive binding assay may also be employed.
These .and- other assays are- described, among other.plac_es, in I~amptori, R.
et ,al. (1990;
Serological Methods, ~ Laboratory Manual, APS Press, St Paul. Minn.) and Maddox, D'.
E. et al. (1983; J. Exp. Med. 158:1211-1216).
A wide variety of labels arid conjugation techniques are known by those skilled in the art and riiay-he used in various nucleic acid and amino acid assays. Means for producing .labeled hybridization or F.GR probes for detecting sequences related to polynucleotides include oligolabeling, nick translation, end-labeling or PCR
amplification using a labehed nucleotide. Alternatively, the sequences, or any portions thereof wiay be cloned into a vector for the production of arL mRNA .probe.
Such vectors 1 S are -knov"Vn in the art, are commercially available, and may be used to synthesize RNA
probes in v-itro by addition of an appropriate RNA polymerise such as T7, T3, or SP6 and labeled nucleotides. These procedures may be conducted using a variety of commercially available kits. Suitable reporter molecules or labels, which may be used -include radionuclides,-enzymes, fluorescent, chemiluminescent, or.chromQgenic agents as well as substrates, .cofactors, inhibitors, riiagnetic particles, and the like.
Host cells transformed with a polynucleotide sequence of interest may be cultured -under- conditions suitable for the expression and recovery of he protein from cell culture. The protein.produced by a recombinant .cell may be secreted ,or contained iritracellularly depending on the sequence and/or the vector used. As will be understood by those of skill in the art, expression vectors containing polynucleotides of the invention may .be designed to contain signal sequences which direct secretion of the encoded ,polypeptide hrough .a prokaryotic or eukaryotic cell membrane. Other recombinant constructions may be used to join sequences encoding a polypeptide of interest to nucleotide sequence encoding a polypeptide domain which will facilitate purification of soluble proteins. Such purification facilitating domains include, but are not limited to, metal chelatirig peptides such as histidine-tryptophan modules that allow purification on immobilized metals, protein A .domains that allow purification on immobilized iinrnunoglabulin, and the.domain-utilized in the FLAGS
extension/affinity purification- system (Irrimuriex Corp., Seattle, Wash.). The inclusion of cleavable linker sequences such as those specific for Factor XA or enterokinase (Invitrogen.
San-Diego, ~Calif.) between the purification dorriain and the encoded. polyp~ptide maybe used- to facilitate purification. One such expression vector provides for expression of .a fusion protein containing a polypeptide of interest and a nucleic acid encoding 6 histidine residues preceding a thioredoxin or an.enterakirlase cleavage site. The histidine residues facilitate purification on IMIAC (immobili2ed xnelal ion affinity chromatography) as described in ~porath, J.-,et al. (19.92, Pt~ot. Exp. Purif. 3:263-281) while the enterokinase cleavage site provides a rilearis for purifying the desirey polypeptide from the fusion protein. A discussion of vectors which contain fusion proteins is provided in Kroll, D. J.
et al. (1993; DNA Cell Biol. 12:441-453).
~In addition to .recoinbinarlt production methods, polypept~des of the invention, and fragments thereof, may be produced by direct peptide synthesis using solid-phase techniques (Merrifield J. (1963) J. Am. Cheirt. Soe. 85:2149-2154). Protein synthesis may be performed using manual techniques or by automation. Automated synthesis -may be achieved, for example, -using Applied Biosysterris 431A
Peptide Synthesizer (Perl~iri Elmer). Alternatively, various fragments may be chemically synthesized separately and combined using chemical methods .to produce the full length molecule.
Antibody Compositions, Fragrrients Thereof.and Other Binding Agents According to another aspect, the present invention further provides.
binding agents, such as antibodies and antigen-binding fragments thereof, .that .exhibit immunological .binding to a tumor polypeptide disclosed herein, or to a portion, variant -,or derivative thereof. An antibody, or antigen-binding fragment thereof, is said to "specifically bind," "iminunogically bind," and/or is "inununologically reactive" to .a polypeptide of the invention if it reacts at a detectable level (within, for example, an ELISA assay) with the polypeptide; and does not react detestably with unrelated polypeptides~ under similar:conditions.
Immunological binding, as used in this. context, generally refers to the non-covalent interactions of the -type which occur between an immunoglobulin molecule and an antigen for which the immunoglobulin is specific. The strength, or affinity .of immuiiologica~ binding interactions can be expressed iri terms of the dissociation constant (Kd) of the interaction; wherein a smaller Kd represents a greater affinity. Immunological biridir~g properties of selected: polypeptides can be quantified using methods well known in the- art. One such rnetliod entails measuring the rates of 1,0 antigen-binding site/ai~tigen complex formation and dissociation, v'vherein those rates depend on the conceritrations of the complex partners, the aff nity of the interaction, and on geometric parameters that equally influence the rate in both directions.
Thus, both the "on rate constant" (Kon) and the "off rate constant" (Ko~.) can be determined by calculation of tl~e concentrations and the actual rates of association and dissociation.
The ratio of Ko~. /I~o" enables cancellation of .all parameters not related to affinity, and is thus equal to the dissociation constant Ka. See, generally, Davies .et.al.
(1990) Animal Rev. Biochem. 59:439-473.
An "antigen-binding site," or "binding portion" of an antibody refers to the part of the immnnoglobulin molecule that participates irx antigen binding.
The antigen binding site is formed by amino acid residues .of the N~terminal variable ("V") regions of the heavy ("H") :and light ("L") chains. Three highly divergent stretches within the V regions of the heavy and light chains are xeferred to as;
"hypervariable regions" which are interposed between more conserved flanking stretches known as framework regions, or FRs . Thus the term FR refers to amino acid sequences which are naturally found between and adjacent to hypervariable regions in irilmunoglobulins. In an antibody molecule, the three hypervariable regions of a light chain and the three hypervaxiable regions of a heavy chain are disposed relative to each other in three dimensional space to form an antigen-binding surface. The antigen-binding surface is complementary to the three-dimensional surface of a bound antigen, arid the three hypervariable regions of each of the heavy and light chains are referred to as "compleiilentarity-determining regions," or "-CDRs."
Binding agents inay be further capable of differentiating. between patierits with and without a cancer, such as lung cancer, using the representative assays 5provided herein. For example, antibodies or other binding agents that bind to a tumor protein will preferably generate ,~ signal indicating the presence .of a cancer in at least about 20% of patient with- the disease, more preferably at least about 30% of patients.
Alternatively, or in addition, the antibody will generate a negative signal indicating the absence of the _disease iri at least about 90°/d of individuals without the cancer. To determine whethe'r_ a binding agent satisfies this requtirement, biological samples (e.g., blood, sera; sputurii, urine and/or tumor biopsies) from patients with arid without a cancer-(as deteriiiined using staxzdard clinical tests) may be assayed as described herein for the presence of polypeptides that bind to the bindirig agent. Preferably, a statistically significant number of samples with and without the disease will be assayed.
Each binding agent should satisfy .the above criteria; however, those of ordinary skill in the art will recognize that :bimding agents may be used in corribination to improve sensitivity.
Any agent that satisfies the above requirements rnay be a binding agent.
For -example, .a binding agent ~rrray be a ribosome, with or without a peptide component, a,n -RNA molecule or' a polypeptide. In a preferred embodiment; .a binding agent is ail antibody or an antigen-binding -fragirient thereof. Antibodies may be prepared by any of a variety of techniques known to those of-ordinary skill in the art. See, e.g"
Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988. In general, antibodies .can be produced by cell culture techniques, including the generation of monoclonal antibodies as described herein, or via transfection of antibody genes into suitable bacterial or mammalian cell hosts, in order to allow for the -production of recorribinant antibodies. In one technique, an immunogen.comprising.the polypeptide is initially injected into any of a wide variety of mammals (e.g., mice, rats, rabbits, sheep or .goats). In this step, the polypeptides of this invention may serve as the immunogen without modification. Alternatively, particularly for relatively short polypeptides, 'a superior immune response may be elicited if -the polypeptide is joined to a carrier protein, such as bovine serum albumin or keyhole limpet hemocyanin. The immunogen is injected into the animal host, preferably according to a predetermined schedule incorp.or~ting one or-more booster immunizations, and the ariirilals are bled periodically.
5 Polyclonal antibodies specific for the polyp-eptide may then b~ .purified from such antisera by, for example, affinity chromatography using the polypeptide coupled to a suitable solid support.
Monoclonal antibodies specific for an antigenic polypeptide of interest may be prepared., for example, using the technique of Kohler and Milstein, Eur. .I.
10 Immu~ol. 6:511-519, 1976, -and improvements thereto. Briefly, these methods involve the preparation of immortal .cell lines capable of -producing antibodies having the desired specificity (i.e., reactivity with the polypeptide of interest). Such cell lines may be produced, for example, from spleen cells obtained from an animal immunized as described above. The spleen-cells are then immortalized by, for example, fusion with a 15 myeloma cell fusion -partner, -preferably one that is syngeneic with the immunized animal. A variety of fixsiorr techniques maybe employed. For example, the spleen cells and myeloriza cells may be combined with a nonionic detergent for a few minutes and then plated at low density on a selective medium. that supports the growth of hybrid cells, but vot :rnyelorria- cells. A preferred selection technique uses I-lAT
(Iiypoxantliine, 20 aminopterin, thymidirie) selection. After a sufficient time, usually about 1 to 2 weeks, colonies of 'hybrids are observed. Single colonies are selected and their culture supernatants tested for binding activity against the polypeptide. Hybridomas having high reactivity and specificity are preferred.
Monoclonal antibodies maybe isolated frorri the supernatants of growing 25 hybridoma colonies. In addition, various techniques may be employed to enhance the yield, such .as injection of the hybridoma.cell line into the peritoneal cavity of a suitable vertebrate host, such as a mouse. Monoclonal antibodies may .then be harvested from the ascites fluid or the blood. Contaminants -may be removed from the antibodies by conventional techniques, such as chromatography, gel filtration, precipitation, and extraction. The polypeptzdes of this invention may be used in the purification process in, for example, an affinity chromatography step.
A number of therapeutically useful molecules are known in the art which comprise antigen-binding sites that are capable of exhibiting immunological binding S properties of an antibody molecule. The ~proteolytic enzyme papain preferentially cleaves IgG rizoleeules to yield several fragments; two of which (the "F(ob)"
fragrrynts) each comprise a covalent heterodiiner that includes an .intact antigen-binding site. The enzyme pepsin is able' to cleave IgG molecules to provide several fragments, including the ".F(ali')z " fragment which comprises both antigen-binding sites. An "Fv"
fragment can be produced by preferential. protcolytic .cleavage of an IgIVI; and on rare occasions IgG or IgA immunnglobulin molecule. Fv fragments are, however, more commonly derived using recombinant techniques known in the art. The Fv fragment includes a non-covalent VH::V,, =heterodimer iricludin~ an antigen-binding site which retrains much of the antigen recognition and binding capabilities ~of the native antibody molecule.
mbar et al. (1972) Proc. Nat. Acad. Sci. USA 69:2659-2662; Hochman et aI.
(1976) Biochem 15:2706-271D;.atld Ehrlich et al.-(I980) ~iochem 19:4091-4096.
A single chain Fv ("sFv") polypeptide is a -covalently linked VH::VL
heterodimer which is expressed from a gene fusion including VH and VL-encoding genes linked by a peptide-encoding linker. Huston -.et ~1. (1988) Proc. Nat.
Acad: S,ci.
USA 85(16):5879-588.3. A number of methods have been described to-discern chemical structures for converting iie naturally .aggregated--but chemically separated--light and heavy polypeptide chains from an antibody V region into an sF'v molecule which will fold into a three dimensional structure substantially similar to the structure of an antigen-binding site. See, e.g., U.S. Pat. Nos. 5,091,513 and 5,132,405, to Hustorl et al.;
and U.S. Pat. No. 4;946,778, to Ladner et al.
Each of the .above-described molecules includes a .heavy chain and a light chain CDR set, respectively interposed between a heavy chain and a light chain FR
set which provide support -to the CDRS and define the spatial relationship of the CDRs relative to each other. As used .Herein, the :term "CDR set" refers to the three hypervariable regions of a heavy or light chain V region. Proceeding from the N-terminus of a heavy or light chain, ahese regions are denoted as "CDRl,"
"CDR2," and "CDR3" respectively. An antigen-binding site, therefore, includes six CDRs, comprising the CDR set frorri each .of a heavy arid a light chain V region. A
polypeptide comprising a single CDR, (.e.g., a CDR1, CDR2 or CDR3) is referred to herein as a "molecular recognition unit." Crystallographic analysis of a number of antigen-antibody couiplexes has demonstrated that the amino acid residues of ~CDRs form extensive contact with bound antigen, wherein the most .ex'terrsive antigen contact is with the heavy chain CDR3. Thus, the molecular recognition units are .primarily responsible for the specificity of an antigen=biiic~ing site.
~s usedrhe~ein, the term "FR set" refers -to the four flanking amino acid sequences which frame the CDRs .of a CDR set of a heavy or light .chain V
region.
Some FR residues inay eonlact b.otind antigen; however, FRs are .prirriarily responsible for folding- the V region into the antigen-binding site, particularly the FR
residues dixectly adjacent to the-CDRS. Within ~'Rs, certain amigo residues arid certain structural 1 ~ featu'res are very highly conserved. In this reg~.rd, all V region sequences contain an internal disulfide loop of around 90 amino acid residues. When the V regions fold into a binding-site, the CDRs are displayed as projecting loop motifs which form an antigen--binding surface. It is generally recognized that there are conserved structural regions of FRs which influence the folded shape of the CDR loops. into certain "canonical"
structures--regardless of the precise CDR amino acid sequence. Further, certain FR
residues are known to participate in non-covalent iriterdomain contacts which stabilize the interaction of the antibody heavy and light chains.
A number of "humanized" antibody molecules comprising an antigen-binding site derived from:a rion-human immunoglobulin have been described, including chimeric antibodies having -rodent V =regions and their associated CDRs fused to human constant domains (Winter et al, (1991) Nature 349:293-299; Lobuglio. et al.
(1989) Proc. Nat. Acad. Sci. US-A 86:4220=4224; Shaw et al. (1987) J Iminunol.
138:4534-4538; and Brown et al. (1987).:Cancer Res. 47:3577-35,83), .rodent CDRs grafted into a human supporting FR prior to fusion with ari appropriate ,human antibody constant domain (Riechmann et al. (1988). Nature 332:323-327; Verhoeyen et al. (1988) Science 239:1534-1536; and JorieS et al. (1980 Nature 321:522-525}; and rodent CDRs supported by recoinbinantly veneered .rodent FRs (European Patent Publication No.
519,596, published Dec. 23, 1992). These "humanized" molecules are designed .to minimize unwanted -immuriological response toward rodent antihuman antibody rriolecules which limits the duration and effectiveness of therapeutic applications of those moieties in Human recipients.
As used herein, the terms "veneered FRs" and "recombiriantly veneered FRs" refer to the selective replacement of FR residues from, e.g., a rodent heavy or light chain V =region, with human FR residues in .order to provide a xenogeneic molecule ~coinprising an antigen-binding site which retains substantially all of 'the native FR
polypeptide folding structure. Veneering techniques are based on the understanding that the ligand Binding characteristics of an antigen-binding site ale determined primarily by the structure and relative disposition of the heavy and light chain CDR sets within the antigen-binding surface. Davies ,et al. (1990) Ann. -Rev. Biochem. 59:439-473.
Thus, antigen binding specificity can be preserved in a =humanized antibody only wherein the :CDR. structures, their interaction with each other, and their interaction with the rest of the V region dcimains are carefully maintained. ry using veneering techniques, exterior (e.g:, solvent-accessible) FR residues which are -readily erlcauritered by the immure systerri are selectively replaced with human residues ~to provide a hybrid molecule that comprises either a weakly irnmunogenic, or substantially non-immunogenic veneered surface.
The process of veneering makes use of the available sequence data for human antibody variable domains compiled by-Kabat et al., in Sequences of Proteins of Immunological Interest, 4th :ed., (U:S. Dept. :of Health and Human Services, U:S.
Government Printing Office, 1987), updates to the .Kabat database, and other accessible U.S. .arid foreign databases (both nucleic acid and protein). Solvent accessibilities of V
-region amino acids can be deduced from the known three-dirriensional structure for human and -marine antibody -fragments. There are two general steps in veneering a marine antigen-binding site. Initially, the FRs .of the variable .domains of an antibody molecule of interest are compared with corresponding FR sequences of human variable domains obtained from the above-identified sources. The most homologous human V
regions are then compared residue by residue to corresponding marine amino acids. The residues in the marine FR which differ from the human counterpart are replaced by the residues present in the human moiety using recombinant techniques well- known in the art. Residue switching is only carried out with moieties which are at least partially exposed (solvent accessible), and- care is exercised in the replacement of amino acid residues which may have a sigiiif cant effect on the tertiary structure of V
region domains; such as proline, glycine and charged amino acids.
In tliis.manner, the resultant "veneered" inurine antigen-binding sites are 10- thus designed-to retain the marine CDR residues, the residues.
substantially adjacent to the .CDRs, the residues identified as buried or .mostly buried (solvent inaccessible), the residues believed to participate in riori-co~alerit (e.g., electrostatic arid-hydrophobic) contacts between heavy and light chain domains, and the residues from conserved struetura~ regions .of the FRs which are believedl tp influence the "canonical" tertiary structures. of the CAR loops. These design criteria are then used to prepare recombinant nucleotide sequences which combine the CD,Rs .of both .the heavy and light chain of a marine antigen-binding site into human-appearing FRs that can be used to transfect rriammalian cells fox the expression of recombinant human antibodies which exhibit the antigen' specificity-of the marine antibody molecule.
In another embodiment o~ the invention, rrionoclonal antibodies of the present invention rnay be coupled to one or more therapeutic agents. Suitable agents in this regard include -radioriuclides, differentiation induceirs, drugs, toxins, and derivatives thereof. Preferred radioriuclides include 9°Y, 123I~ ~zsh ~s~h ~ssRe~
~saRe~ zl'At, and z'zBi.
Preferred .drugs include methotreXate, and pyriinidin~ and puiine analogs.
Prefei~ed differentiation inducers include phorbol esters and -butyric acid. Preferred toxins include ricin, abrin, diptheria- toxin, cholera toxin, gelonin, Pseudomonas eXOtoxin, Shigella toxin, and pokeweed antiviral protein.
A therapeutic agent may be coupled (e.g., covalently bonded) to a suitable monoclonal antibody either directly or indirectly (e.g , via a linker group). A
direct reaction between an .agent and an antibody is possible when .each possesses a substituent capable of reacting with the other. For example; a nncleophilic group, such as an ari~ino or sulfhydryl group, on one inay be capable of reacting with a carbonyl-containing group; sueli as an anhydride ox an acid halide, or -with ari alkyl group containing a good leaving group (e.g., .a halide) on the other.
5 Alternatively, it may be desirable to couple a therapeutic agent and an antibody via a linker group: A linker group can function ~s a spacer to distance an.
antibody from ail agent in order to avoid interference witl~~ binding capabilities. A
linker group can also serve to increase the chemical reactivity of a substituent on an agent or an antibody, arid thus increase the coupling efficiency. An increase in 10 chemical reactivity may also facilitate the use of agents, -or functional groups on ,agents, which otherwise would not be possible.
It will be evident to those skilled in the art that a variety of bifunctional or polyfunctional reagents, both homa- and hetero-functional (such as those described in the catalog of the Pierce :Chemical Co., Rockford; IL), may 'be employed as the linker 15 group. Coupling may be effected, for example, through amino .groups, carboxyl groups, ~sulthydryl groups or oxidized carbohydrate residues. There are numerous references describing such-methodology, e.g., U.S. Patent No. 4;671,958, to Rodwell et al.
Where a therapeutic .agent is more potent when free from the antibody ~oilion of the imtriuuoconjugates ofahe present invention, it -may be desirable to use a 20 linker group which is cleavable..during or upon internalization into a .cell. A number of different cleavable .linker groups have been described. The mechanisms for the intracellular release of an agent from these linker groups include cleavage by reduc'tiori of a disulfide bond (e.g., U:S. Patent No. 4,489;710, to Spitler), =by irradiation of a pho'tolabile bond (e.g., U.S. Patent No. 4,625,014, .to Senter et al.), by hydrolysis of 25 derivatized..amino acid side chains -(e.g., U:S. ,Patent No. 4,638,045, to .Kohn et al.), by serum complement-mediated hydrolysis (e.g., U.S. Patent No. 4,671,958, to Rodwell et al.), aild acid-catalyzed hydrolysis (e.g., U.S. Patent No. 4,569,789, to Blattler et al.).
It may 'be desirable to couple more than one agent to an antibody. In one embodiment, multiple -molecules of an agent are coupled to .one antibody molecule. In 30 another embodiment, more than -one type .of .agent may be coupled to one antibody.

Regardless of-the particular embodiment, immunaconjugates with :more than one agent may be .prepared in a variety of ways. For example, more than one agent may be coupled directly to an antibody molecule; or linkers that provide multiple sites for attachmentcan be used. Alternatively, a carrier can be used.
S A carrier may Bear the agents in a variety of Ways, including covalent bonding ;either directly or via ~ linker group. Suitable .carriers include :proteins such as alburriins {e.g:, U.S. Patent No. 4,50'7,234, to Nato et al.), peptides and polysaccharides such as aminadextran (e.g., U.S. Patent No. 4,699,784, .to Shih et al.). A
carrier may also bear ari agent by noncov~lent bonding or -by encapsulation, such as within a liposome vesicle (e.g., U.S. Patent Nos. 4,429;008 and 4,8?3,08$). Carriers specific for radionuclide agents include radiohalogenated small molecules. and chelating compounds. For example, U.S. Patent No. 4;735,792 discloses representative radiohalogenated small molecules and their synthesis. A radionuclide chelate may be formed from chelating compounds that include those containing nitrogen and sulfur atoms as the donor atoms for binding the metal, or metal oxide, radian~clide.
For example, U.S. Patent No. 4,673,562, to Davison et al. discloses representative chelating compounds and their synthesis.
T=Cell.Compositions The present invention, in another aspect, provides T cells specific for a tumor polypeptide disclosed herein, or for a variant or derivative thereof.
Such cells may .generally be prepared i~ vitro or ex vavo, using standard procedures. For example, T cells may be isolated from bone marrow, peripheral blood, or a fraction of bone marrow or peripheral blood of a patient, using a commercially available cell separation system, such as the IsolexTM System, available from Nexell Therapeutics, Inc.
(Irvine, °CA; see also U.S. Patent No. 5,240,856; U.S. Patent No. 5,215,926; WO
89/06280; WO
91/161.16 and WO 92/07243). Alternatively, T cells may be derived from related or unrelated h~nians, non-human mammals, cell lines or cultures.
T cells may be stimulated with a polypeptide, polynucleotide encoding a -polypeptide and/or an antigen presenting cell (APC) that expresses such a polypeptide.

Such stimulation is performed under conditions and for a time sufficient to permit the generation of T cells that are specific for the polypeptide of interest.
Preferably, a tumor polypeptide or polynucleotide of the invention is -present within a delivery vehicle, such as a microsphere, to facilitate the generation of specif c T
cells.
T cells are considefed to be specific for a polypeptide :.of the present invention if the T cells specifically .proliferate, secrete cytokines or kill target cells eoa'ted with. -.the .polypeptide or expressing a gene encoding the polypeptide. T cell specificity xnay be evaluated using any of a variety of standard techniques.
For example, witlii~ a chromium release assay :or proliferation assay, a stimulation index of more than two fold increase in lysis and/or proliferation, compared to .negative controls, indicates T cell specificity. Such assays uiay lie performed, for exatriple, as described in Chen et al., -Cancer Res. 5~:10~5-1070; 1994. Alternatively, detection .of the proliferation of T cells may be accomplished by a variety of known techniques.
For example, T .cell proliferation can be detected by measuring an increased rate of DNA
synthesis (e.g., by pulse-labeling cultures of T cells with tritiated thymidine and measuring. the amount of tritiated thymidine incorporated into DNA). Contact with a tumor-polypeptide (100 ng/ml - 100 ~g/ml; preferably 200 ng/rril - 25 ~g/ml) for 3 - 7 days will typically result in at least a two fold increase in proliferation of the T cells.
Contact as described above for 2-3 hours should result in activation of the T
cells, as measured using standard cytokine assays in which a two fold increase in the level of cytokine release (e.g., TNF or IFN-y) is indicative of T cell activation (see .Coligan et al., Current Protocols in Immunology, vol. l, Wiley Interscience (Greene 1998)). T
ceps that have been activated in. response to a tumor polypeptide, polynucleotide or polypeptide-expressing APC rilay -be CD4* and/or CLl8~. Tumor polypeptide-specific T
cells may be expanded using standard techniques. Within-preferred embodiments, the T
cells are derived from a patient; a related donor or an unrelated donor, and are administered to the patient following stimulation arid expansion.
For therapeutic purposes, CD4+ or CD8+ T cells that proliferate in response to a -tumor polypeptide, polynucleotide or APC can -be .expanded in number either in vita°o or iya vivo. Proliferation of such T cells in vitro may be accomplished in a variety of ways. For=example, the T cells can be re exposed. to a tumor polypeptide, .or a short peptide corresponding to an immunogenic portion of sueh.a polypeptide, with or vi~ithout- the addition of T cell growth factors, such as interleukin-2, and/or ~stirriulator cells hat synthesize a tumor polypeptide. Alternatively, one or more T cells that proliferate in the presence of the tumor polypeptide .can be expanded in number by cloning. Methods for cloning cells are well known in the art, and include limiting dilution.
Pharmaceutical Compositions In additional .einbodimients; the present iriventiori. concerns forrriulatiorl of one or more of the polynucleotide, polypeptide, T-cell and/or antibody compositions disclosed herein in. pliarinaceutically-aeceptabHe cairiers far administration to a cell or an animal, either alone, or in combination.witli ane or more other ri~odalities of'therapy.
It will be understood that, if desired, a composition as disclosed herein may be administered in combination with other agents as well, such as, e.g., other proteins or polypeptides -or various pharmaceutically-active agents. In fact, there is virtually no limit to other components that may also be included, given that the additional agents do not cause.a significant ~clverse effect upon contact with the -taxget cells or host tissues. The compositions may thus be delivered along with various other agents as required iri the particular instance. Such compositions may be purified from host cells or other .biological sources, or alternatively may be .chemically synthesized as described herein. Likewise, such compositions may filrther comprise substituted or derivatized RIVA or DNA compositions.
Therefore, 'in another aspect of the present invention, -pharmaceutical compositions are provided cpmprising one nr more of the polyiucleotide, polypeptide;
antibody, and/or T-cell compositions described herein .in combination with .a physiologically acceptable carrier. In certain preferred embodiments, the pharmaceutical compositions of the invention comprise immunogenic polynucleotide and/or polypeptide compositions of the invention for use in prophylactic and theraputic vaccine applications. Vaccine preparation is generally described in, for example, M.F.

Powell and M.J. Newman,, eds., "Vaccine Design (the subunit ~d adj.uvarit approach},"
Plenum Press (NY, 19:95). Generally, such compositions will comprise one or more polynucleotide and/or polypeptide compositions of the present invention in combination with one or .more immunostirnulants.
It will be apparent that any of the pharmaceutical compositions described, herein .can contain pharmaceutically acceptable salts of the polyriucleotides and palypeptides of the invention. Such alts can _be prepared, for ~exarriple, from pharmaceutically acceptable -non-toxic -bases, including organic base"s (e.g., salts of primary, secondary aid tertiary amines end basic amino acids) and inorganic bases (e.g., sodium, potassium, lithium, arilmonium, calcium arid magnesium salts).
Iri another- eriibodiriient, illustrative iriiintuiogeriic compositions, e.g., vaccine .compositions, of the present invention corriprise DNA encoding one or more of the polypeptides as olescribcd above, such that the°polypeptide is generated ih situ. As noted above, .the polynucleoti~le -may be administered within any of a variety of delivery systems-known to those of ordinary.skill in the art. Indeed, numerous gene delivery techniques are well -known in the art, such as those described by Rolland, Cr°it. Rev.
Ther°~zp. Drug Cat°rier Systems 15:143-198, 1998, and references cited therein.
Appropriate polyriucleotide expression systems will; of course, contsin the necessary regulatory DNA regulatory sequences: for ,expression in a. patient (such as a suitable proino'ter and terminating signal)'. Alternatively, bacterial delivery syster~is may involve the administration of.a bacterium (such as Bacillus-Calniette-Guerrih) that expresses an immunogenic portion of the rpolypeptide on its cell surface or secretes such an epitope.
Therefore, in certain embodiments, polynucleotides encoding imrnunogenic polypeptides described herein are introduced into suitable mammalian ~5 host cells for expression using any of a number of knov~m viral-'based systems. In one illustrative embodiment, retroviruses provide a convenient and effective platform for gene .delivery systems. A selected nucleotide sequence encoding a polypeptide of the present invention can be inserted into a vector and packaged in retroviral particles using techniques -known in the art. The recombiriant virus earl then be isolated and delivered to a subject. A number of illustrative retroviral systems have been described (e.g:, U.S.

Pat. No. 5,219;740; Miller.arid Rosman.(1989) BioTechniques 7:980-99'0;
Miller, A. D.
(199.0) Human Gene Therapy 1:5-14; Scarpa.et al. (1991) Virology 180:849-852;
Burns et al. (j993) Proc. Natl. Acad. Sci. USA 90:8033-8037; and Boris-Lawrie and Temin (1993) Cur. Opin. Genet. Develop. 3:102-109.
S In addition, a nurriber of.illustrative adenovirus-based systems have also been described. Unlike' retroviruses vc~f~ich integrate into the host genoW e, adenoviruses persist extrachromosornally thus -rriinimizirig the risks associated pith insertional mutagenesis (Haj-Ahtnad arid Graham (1986) J. Virol. 57:267-274; Bett et al.
(1993) J.
Virol. 67:5911-S92I; Mittereder et al: .(1994) human Gene Therapy 5:717-729;
Seth et 10 ~1~. (1994).3. Virol. 68:933-940; Barn et al. (1994). Gene Therapy 1:51-S8;
Berkn~r, K. L.
(1988) BioTechniques 6:616=629; arid Rich .et al. (1993) Human gene Therapy 4:461-476).
Various adeno-associated virus (AAV) vector systems have also been developed far polynucleotide ;delivery. AAV vectors can be readily constructed using 1S techniques well known in the art. See, e.g., U.S. Pat. Nos. 5,173,414 and 5,139,941;
International publication NQs. WO 92/01070 .and Vd0 93/03769; Lebkowski et al.
(1988) Molec. Cell. Blot. 8.:3988-3996; Vincent et al. (1'990) Vaccines 90 (Cold Spring Harbor Laboratory~Press); Carter,:B. J. (1992) Current Opinion in Biotechnology 3533-539; IVIuzyczka, N. (1992) Current Topics in- lVIicrobio~. and Irrimunol.
158:97-129;
20 Ko'tin, R. lVt. (1994) Human Gene Therapy 5:793-801; Shelling arid Smith (1994) Gene Therapy 1:165-169; and Zhou et al. (1994) J. Exp. Med. 179:1867-1875.
Additional viral vectors useful for delivering the polynucleotides encoding polypeptides of the present invention by gene transfer include those derived from the pox family of viruses, such as vaccini~ virus and ;avian poxvirus. By way of 2S example, vaceinia virus recombinants expressing the novel molecules can be constructed as follows. The DNA encoding a polypeptide is first inserted into an appropriate vector so that it is adjacent to a vaccinia promoter arid flanking vaccinia DNA sequences, such as the sequence encoding thymidine kinase (TK). This vector is then used to transfect cells which are simultaneously infected with vaccinia.
30 -Homologous recombination serves to insert the vaccinia promoter plus the gene encoding the polypeptide of interest into the viral genome. The resulting TK (-}
recombinant can be selected by culturing the cells in the presence of 5-broinodeoxyuridine acid picking viral plaques resistant thereto.
A vaccinia-based infection/transfection system can be conveniently used to provide for inducible, .transient expression or -coexpression of one or more polypeptides -.described herein in host cells of an organism. Iri this particular system cells are first infected in vitro with. a vaccinia virus recombinant that encodes the bacteriophage T7 RNA polymexase. This polymerase displays exquisite specificity in that it only .transcribes templates bearing T7 promoters, Following infection, cells are transfected with the polynucleotide or polynucleotides of interest, driven by .a T7 promoter. The polymerase expressed in -the cytoplasm from the vaccinia virus recoW binant transcribes the transfected DNA into RNA which is then translated into polypeptide by the =host translational machinery. The method provides for high level, transient, ~cytoplasmic production of large quantities of RNA and its translation products. See, e.g., Elroy-Stein and Moss, Prcic. Natl. Acad. Sci. USA (1990) 87:6743-6747; Fuerst:et al. Proc. Natl. Acad. Sci. USA .(1986) 83:8122-8126.
Alternatively, avipoxviruses, such as the fowlpox and canarypox viruses, can also be used to deliver the coding sequences of interest. Rec,ombinarlt avipox viruses, .expressing imriW noggins from mammalian pathogens, are known- to confer -protective immunity when administered to non-avian species. The use of arl Avipox vector is particularly desirable in human and other mammalian species since members of the Avipox genus can only productively replicate in susceptible avian species and therefore are not infective in mammalian- cells. Methods -for produciyg recombinant Avipoxviruses are known in the art and employ genetic recombination, as described above with respect to the production .of vaccinia viruses. See, e.g., WO
91/I2882; yVO
89/03429; .and WO 92/03545.
Any of a number of alphavirus vectors can also be used for delivery of polynucleotide compositions of the present invention, such as those vectors described in U.S. Patent Nas. 5,843,723; 6,015,686; .6,008,035 and 6,015,694. Certain vectors based on Venezuelan Equine -Encephalitis .(VEE) can also be used, illustrative examples of which can be found in U.S. Patent Nos: 5,505,947.and 5;643,576.
Moreover, rriolecular conjugate vectors, such as the adenovirus chimeric vectors described in Michael et al. J. Biol. chem. (1993) 268:6866-68,69 and Wager et S al. Proc. Natl. Acad. Sci. USA (1992) 89:6099=6103, can also be used for gene delivery under the invention.
Additional illustrative information ari these and .other known viral-based deliveiy systems can ~be found, for example, in Fisher=Hoch et aL, P~oc. Natl.
Acad Sci.
USA 86:317-321, 1989; Fle~ner et al., Ann. N.Y Acad: Sci. 569:86-103, 1989;
Flexner et al., Yaccisie 8:17-21, 1990; U.S. .Patent Nos. 46Ø3,112, 4,769,330, and 5,017,487;
WO 89/01973; US.~P;aleritNo, 4,777,127; GB 2,200;651;~EP 0;345,24; WO
91/02805;
Berkrier, Biotecl~niques6:61'6-627, 1988.; Rosenfeld et al., Science 252:431-434, 199'1;
Kolls et al., P~oc. Natl. Acad. Sci, LISA 91:21 S-219, 1994; Kass-Eisler et aL, Proc. Natl.
v Acad. Sci. USA 90: 51498-11502, 1993; Guzman et al., Circulation 88:2838-2848, 1993;
and Guziiian et al., C'ir. Res. 73:1202-1207, 1993.
In certain embodiments, a polynucleotide may be integrated into the ge'nome of a target. cell. This integration may be in the specific location and orientation via homologous recombination (gene replacement) omit rnayvbe integrated in a random, non-specif c location (gent augmentation). In yet further embodiments, the polynucleotide may ~be stably maintained in the cell as a separate, ~pisomal segment of DNA. Such polynucleotide segments or "episomes" encode sequences sufficient to permit maintenance and replication independent of or iri synchronization with the host cell cycle. The manner in which the expression construct is delivered to a :cell and where in the cell the polynucleotide remains. -is dependent .on ahe type of expression 2S construct employed.
In another embodiment of the invention, a polynucleotide is administered/delivered as "naked" DNA, for example as :described in Ulmer et al., Science 259:1745-1749, 1993 .and reviewed by Cohen, Science 259:1691-1692, 1993.
The uptake of naked DNA may be increased by .coating the DNA onto .biodegradable beads, which are efficiently transported into the cells.

In still another ernbodirnent, a composition of the -present invention can be delivered via a particle bombardment approach, yang of which have been described.
In one illustrative example, gas=driven particle acceleration can. be achieved with .devices such as those -manufactured by Powderject PhaxmaceuticaIs PLC -(Oxford; UI~) and Powderject Vaccines Inc.-(Madison, VVI), some-examples of which are described in U.S. Patent Nos. 5,846,796; 6;010,478; 5;65,'796; 5,584,80f; ayi EP Patent No.

799.. This approach offers a needle-free delivery approach wherein a dry powder formulatiot? of rriicroscopic particles, such as polyriucleotide or polypeptide particles, are accelerated to high speed within a helium gas jet generated by a hand held device, propelling the particles into a target tissue of interest.
In a related eiribodiment, other devices and. rrret~ods that .may be useful for ,gas-driven needle-less 'injection of compositions. of alie present invention include those provided by Bioject, Inc. (Portland, OIL), some examples of which are described in U:S. Patent Nos. 4,790;824; 5064,413; 5,312,335; 5,383,851; 5,399,163;
S,S20,639 and 5;993,412.
According to another embodiment, the pharmaceutical .compositions described herein will .comprise one or more irnmunostimulants in addition to the immunogenic polynucleotide, polypeptide, antibody, T-cell and/or APC -compositions of this invention. An immunostimulant refers to essentially any substance that enhances or potentiates an immune response (aiitiliody and/or cell-mediated) to an exogenous antigen. One preferred type of immunostirnulant comprises an adjuvant. Many adjuvants contain a substance designed to p,'rotect the antigen .from rapid catabolism, such as aluminum hydroxide or mineral oil, and a stimulator~of immune responses, such as lipid A, Bortadella pe~tiessis or Mycobacterium tuberculosis derived proteins.
2S Cerkain adjuvants are commercially available as, for ex,~.mple, Freurid's Incomplete Adjuvant and Complete Adjuvant -(Difco Laboratories, Detroit, MI); Merck Adjuvant 65 (Merck and Company, Inc<, Rahway, NJ); AS-2 (SmithKline Beecham, Philadelphia, PA); aluminum salts such as alurtiinuni hydroxide gel (alum) or aluminum phosphate;
salts of calcium, iron or zinc; .an insoluble suspension -of acylated tyrosine; acylated sugars; cationically or anionically derivatized polysaccharides;
polyphosphazenes;

8.9 biodegradable microspheres; -monophosphoryl lipid A and quil A. Cytokines;
such as .G1VI-CSF, interleukin-2, -7, -12, and other .like growth factors; may also be used as adjuvants.
Within certain embodiments of the invention, the adjuvarit composition S is preferably one that induces an iW mun~ response predoiniriantly of the Thl type.
High levels of ThI-type cytokines (e.g:, IFN-y, TNFa, IL-2 and IL-12) tend-to favor the iriditction of cell mediated, irrimun~ responses. to an administered- antigen.
In contrast, high levels of Th2-type cytokines (e.g:, IL-4, IL-5, IL-6 and IL-10) tend to favor the induction of huriloral immune -responses. Following application of a vaccine as provided herein,.a patient will suppoit an immune ie'sponse that includes Thl-and Tli2-type responses. within a preferred..embodiment, in which a response is -predominantly Thl=type, the level of Thl~-type cytokines will. increase to a greater oxtei~t than the level of Th2-type cytokines. The levels of these cytokines may be readily assessed using stanchrd assays. For .a review of the families of cytokines, see lVlosmann and-Coffman, Anh. Rev. Immunol. 7:145-173, 1989.
Certain preferred. adjuvarits for .eliciting a predominantly Thl-type response include, fox example, a combination of monophosphoryl lipid A, preferably 3-de-O-acylated inonophosphoryl lipid A, .together with an- aluminuriu salt.
IVIPLm adjuvants are available from Corixa- Corpofation (Seattle, WA; see, for example, US
Patent Nos. 4,436,'727; 4,877,611; 4,866,034 .and 4,912,094). CpG-containing oligonucleotides (in which the CpG dinucleotide is unmethylated) also induce a predominantly Thl .-response. Such oligoriucleotides are well known and are described, for example, in WO 96/02555, WO 99/33488 and U.S. Patent Nos. 6;008,200 and 5,856,462. Immunostimulatory DNA sequences are also .described-, for example, by Sato et al-., Science 273:352, 1996: Another preferred adjuvant-,comprises a saponin, such as Quil A, or derivatives thereof, including QS21 and QS7 . (Aquila Biopharmaceuticals Inc., Frainingham, MA); Esciri; Digitonin; or Gypsophila or Chenopoclium quinoa saponins . Other preferred formulations include more than one saponin in -the adjuvant combinations of the present xn~ention, for example combinations of at least two .of 'the fallovving group comp~'ising .QS21, QS7, Quil A, (3-escin, or digitonin.
Alternatively the saponin formulations may be combined with vaccine vehicles composed of chitosari or other polycationic polymers, polylactide .and S polylactide-co-glycolide particles, poly-N-acetyl glucosami~e-based polymer matrix, particles composed of .polysaccharides or ,chemically modified polysaccharides, liposoines and lipid=based particles, particles composed of glycerol rriorioesters, etc.
The saponins may also be forr°nulated in the presence of .cholesterol to form particulate structures 'such- as liposomes .or ISCOMs. Furthermore, the saponins may be formulated 10 together with a polyoxyethylerle ether or ester, in either a~ non-particulate sohition or suspension, -.ot in a particulate structure such as a ~paucilamelar liposome or ISCOM.
The saporins may also be foitnulated with vexcipients such as CarbopolR -to increase viscosity, or may -be formulated in a dry povi~der- form with .a powder excipient such as lactose.
15 In one preferred embodirrient, the adjuvant system includes the combination. of a -monophosphoryl lipid A .arid a saponin. derivative, such as .the .combination of QS21 and 3D-MFL° adjuvant, as described in 'WO
94/00153, or a less reactogenic coinpo~ition where the QS21 is quenched with cholesterol; as described in WO 9~13373f. Other preferred formulations- 'comprise an oiI-in-water- emulsion and 20 tocopherol. Another particularly preferred adjuvant formulation employing QS21, 3D-MPL° adjuvant and tocopherol in an oil-in-water emulsion is described in WO
95/17210.
Another .enhanced.adjuvant system involves the combination of a CpG-containing :oligonucleotide and a saponiri derivative .particularly the combination of 25 CpG and QS21 is disclosed in WO 00/09159. Preferably -the formulation additionally comprises an.oil in water emulsion and tocopherol.
Additional illustrative adjuvants .for use in the pharmaceutical compositions of the invention include Moritariide ISA 720 (Seppic, France), SAF
(Chiron, 'California, United States), ISCOMS .(CSL), 1VIF-59 (Chiron), the SBAS series 30 of adjuvants (e.g., SBAS-2 or SBAS-4, available from SmithKline Beecham, Rixensart, .Belgium), Detox (Enhanzyn°) (Corixa; Hariiilton, MT), RC-529 (Cprixa;
Hamilton, MT) and other aminoalkyl glucosaminide 4-phosphates (AGPs), such as those described in pending U:S. Patent Application Serial Nos. 08/$53,826 .arid 09/074;720, the disclosures of which are incorpprated herein by reference in their entireties, and polyoxyethylene ether adjuvants: such as those described in WO 99/52549A1.
Other preferred adjuvants .include adjuvant molecules of the general formula (I): ~IO(CHZCH20)p A-R, wherein, n is 1-SQ, A is a bond or -C(O)-, R is C,_so ~Ikyl or Phenyl C,_so ~lkYl.
One etribodiment of the present invention .consists of a vaccine formulation. comprising -a polyoxyethylene ether of general formula (I);
whereinv n is between 1 and 50, -preferabl-y 4-24; most preferably 9; the R component is Cl_so preferably C4-CZO alkyl and most preferably C,2 alkyl, and A is a bond. The concentration of the polypxyethylene ethers should Lie in the range Ø1-20%, preferably from '0.1-10%, and mpst preferably in the range 0.1-1%. Preferred polyoxyethylene ethers are selected from the following group: polyoxyethylene-9-lauryl ether, polypxyethylene-9-steoryl ether, .polyoxyethylene-8-steoryl .ether, polyoxyethylene-4-lauryl .ether, polyoxyethylcne-35-Iauryl ether, and polyoxyethylene-23-l~uryl ether.
Polyoxyethylene ethers such as .polyoxyethylene lauryl .ether are de5cribed~
in the Merck index (12t'' edition: entry 7717). These adjuvant molecules are described in WO
99/52549.
The polyoxyethylene ether according to the general fornmla (I) above may, if desired; be combined With another adjuvarlt. For example, a preferred adjuvant ~coinbination is preferably With CpG ,as described' in the pending UK patent applicatipn GB 9820956.2.
According to another embodiment of this invention, an immunogenic composition described herein is delivered to a host via antigen presenting cells (APCs), such as dendritic cells, .macrophages, B cells, monocytes and other cells that may be engineered to :be eff cient APCs. Such cells may, but-need npt, be genetically modified to increase the capacity for presenting the antigen, to improve activation and/or -maintenance -of the T cell response, to have anti-tumor effects per se and/or to be inimunologically compatible with the receiver (i.e., matched HLA haplotype).
APCs may generally be isolated from any o~ a variety of biological fluids and .organs, including tumor and periturrioral tissues, and may be autologous, allogerieic, syngeneic S Q~ xencgeneic cells.
Certain- preferred° embodiments of the present invention use dendritic cells or progenitors thereof as antigeri~-presenting cells. Dendritic cells are highly potent APCs (Banchereau and Steinman, Nature 39:245-251, 199&) and have been shown to be effective as a physiological adjuvarit for eliciting prophylactic or therapeutic antityior irnrrittriity (see Timmerman arid Levy, Anh. Rev. ~Lfed 50:50'7-529, 1999). In general, :dendritic, cells rnay be identified: based-on their typical shape (stellate i~ situ, with marked cytoplasinic processes (deridri'tes) visible in vitro), their ability to take up, process arid present antigens with high efficiency and their ability to activate naive T
cell responses. Dendritic cells may, of course, be engineered to express specific cell-surface receptors or ligands that are not commonly found on dendritic cells in vivo or ex vivo, and such -modified dendritic cells .are contemplated by the present invention. As an alternative to dendritic .Cells, secreted vesicles antigen-loaded ,dendritic cells (called e~osotnes) may be used within a vaccine (see Zitvogel et al., Nature iLled.
4:594-600, 19.98).
Dendritic cells amd progenitors may be obtained from peripheral blood, bone marrow, tumor-infiltrating cells, peritumoral tissues-infiltrating cells, lymph nodes, spleen, skin, umbilical cord- blood or any other suitable tissue or fluid. For example, dendritie cells may be -differentiated .ex vivo by adding a combination of cytokines such as GM-CSF, I~,-4, IL-13 and/,or TNFoc to. cultures .of monocytes harvested from .peripheral blood. Alternatively, .CD34 positive cells harvested from peripheral blood, umbilical cord blood or bone marrow may be differentiated into dendritic cells by adding to the culture medium combinations of Gl~I-CSF, IL-3, TIVFa, ~CD40 ligand, LPS, flt3 ligand and/or other .compound(s) that induce .differentiation, maturation and proliferation of dcndritic cells.

Dendritic cells are conveniently categorized. as "immature" and "mature"
cells, which allows a simple way to discriminate between two well characterized phenotypes. However; this nomenclature should not be construed- to exclude all possible intermediate stages of differentiation. Immature dendritic cells are characterized as. APC with a high capacity for antigen uptake arid processing, which correlates v~ith the high-expression of Fcy -receptor.arid mannose receptor.
The mature phenotype is typically characterized by a lovuer expression of these markers, but a high expression of cell surface molecules responsible for T cell activation such as class I and class II IVIHC, adhesion molecules (e.g., CD54 arid. CD11) and costirimlatory molecules (e:g., CD40~ CD80,'CID86 anc~ 4~-IB.B).
APCs may generally be transfected with a polynucleotide of the invention (.or :portion or other variant thereof] such that the encoded-polypeptide, or an im~nunogenic portion thereof, is expressed on the cell surface. Such transfection may take place ex vivo, and a pharmaceutical -composition comprising such transfected cells may then be used for therapeutic purposes,. as described herein.
Alternatively, a gene delivery vehicle that targets a deridritic or other antigen presenting cell may be administered to a patient, resulting in transfection that occurs in vivo. In vivo and ex vivo tramsfection of dendritic cells, for example, rnay generally be performed using any methods known iri the art; such as those described in WO 97/24447, .or the gene gun approach described by Mahvi et a~., Immunology and cell Biology 75:45,6-4'60, 1997.
Antigen loading of dendritic cells may be achieved by incubating dendritic cells or progenitor cells with.the tumor polypeptide, DNA (naked or within a plasmid vector) or RNA; or with antigen-expressing recombinant bacterium or viruses (e.g., vaccinia, fowlpox, adenovirus or lentivirus vectors). Prior to loading, the polypeptide xnay be covalently conjugated to an immunological partner that provides T cell help (e.g., a carrier molecule). Alternatively, a .dendritic cell may be pulsed vi~ith a yon-conjugated immunological partner, separately or in the presence of the polypeptide.
V~Thile any suitable carrier known to those of ordinary skill in the art-may be employed in the pharmaceutical compositions of this invention, the type of carrier will typically vary depending on the mode .of administration. Compositions of the present invention may be formulated -for any appropriate rilanner of administration, including for -example, topical, oral, nasal; mucosal, intravenous, inlracranial, intraperitoneal, subcutaneous and intrarnuscular administration.
Carriers for use within such pharmaceutical compositions are -bioEOmpatible, and may also be biodegradable. In certain embodiments, the formulation preferably provides a relatively constant--level of active component release.
In other eiiibodiinents, however, a more rapid rate of r~Iease irrimediately upon adriiinistration may-be desired. The formulation of such compositions is well within the level of ordinary skill ire the art.usirtg known~techniques. Illustrative carriers useful in this regard include -microparticles of p'oly(lactide-co=glycalide), polyacrylate., latex, tarch, cellulose, dextran and -the like. Otlzcr illustrative delayed-release ,carriers include supramolecular laiovectors, which comprise a nQri-liquid hydrophilic core (e.g., a cross~linked polysaccharide or oligosaccharide) and, optionally, an external layer comprising an amphiphilic compound, such as a phospholipid tsee e.g., U.S.
Patent No.
5,151,254 and PCT applications WO 94/20078, WO/94/23701 and WO 96/06638). The amount of active -compound ;contained within. a sustained release formulation depends upon the site of implantation, the rate and expected-duration of release arid the nature of the condition to be treated or prevented:
In another illustrative embodiment, .biodegradable microspheres (e.g., polylactate polyglycolat~) are .employed ~.s carriers far the -compositions .of this invention. Suitable biodegradable microspheres .are disclosed, for example;
.in U.S.
-Patent Nos.4,897,268; 5,0.75,109; 5,928,647; 5811,128; 5;820883; 5,853,763;
5,814,344, 5;407,609 arid 5,942,252. Modified 'hepatitis B -core .protein carrier systems.
such as described in WO/99 40934, and references cited therein, will also be useful for many applications. Another illustrative carrier/delivery -system employs a carrier comprising -particulate-protein complexes, such as those ,described .in U.S.
Patent NQ.
5,928,647, which are capable of inducing a class ~I-restricted cytotoxic T
lymphocyte -responses in a host:
The pharmaceutical compositions of the invention will often fiu ther comprise one or more buffers (e.g., neutral buffered saline or phosphate buffered saline), carbohydrates-(e.g., -glucose, maniaose, sucrose or dextrans)~
maimitol, proteins, polypeptides or amino. acids such as glycine, antioxidants, ~bacteriostats, chelating agents such as EDTA-or glutathione, edjuyants. (e.g:, aluminum, hydroxide), solutes that render the formulation isotonic, hypotonic or weakly hypertonic with the blood of a 5 recipient, suspeyding: agents, thickening agents and/or preservatives.
Alternatively, compositions of the present invention may be formulated as a lyophi-lizate.
The pharmaceutical compositions .described herein may be presented in unit-dose or mufti-dose containers, such as~ sealed ampoules ar vials. -Such containers are typically sealed in such a way to -preserve the sterility and stability of the 10 ~ormulatiori until= use. In g~Ireral, formulations may be stored as suspensions, solutions -ar emulsions in oily or aqueous vehicles. Alternatively, a pharmaceutical-composition may be stored iri a freeae-dried condition requiring only the addition of a sterile liquid carrier immediately prior to use.
The developriient of suitable dosing and treatment regimens for using the 15 particular compositions described herein in a variety of treatment regimens, including ~e.g., oral, parenteral, Intravenous, intranasal, and iritramuscular adrriinistration and formulation, is well known in the art, some of which are briefly discussed below for general purposes of illustration.
In certain applications, the pharmaceutical compositions disclosed herein 20 may be delivered via oral administration to an animal. As such, these compositions may be formulated with an inert diluent or with an assiinilable edible carrier, or they may be enclosed in hard- or soft-sliell gelatin capsule, or they may be compressed into tablets; or they may be incorporated directly with the food af.tlie diet.
The active compounds may even be incorporated with .~excipients and 25 used in the form of ~ngestible tablets, buccal tables, troches, capsules, elixirs, suspensions, syrups, wafers, and the like (see, for example, Mathiowitz et al., Nature 1997 Mar 27;386(6623):410-4; Hwang et .al., Crit Rev Ther Drug Carrier Syst 1998;15(3):243-84; U. S. :Patent 5,641,515; U. S. Patent 5,580,579 and U. S.
Patent 5,792,451 ). Tablets, troches, pills, capsules and the like may also contain any of a 30 variety of additional components, for example, a binder, such as gum tragacanth, acacia, cornstarch, or gelatin; excipients, such as dicalcium phosphate; ~
disintegrating agent, such as corn starch; potato starch; .alginic acid and the like; a lubricant, such as magnesium stear~te; and-a sweetening agent, such as sucrose, lactose or saccharin may be added- or a flavoring agent, -s~cli as peppermint, oil -of Wintergreen, or cherry flavoring. When the dosage unit- form is a capsule, it may contain, in.
addition to riiaterials of the .above type, a liquid carrier. ~larious other materials may be present as coatings or to .otherwise modify the physical form of the dos~.ge unit. For instance, tablets, pills, or capsules may be coated With shellac, sugar, or both. Of course, any material,used in-prep~iring any .dosage unit form should be pharmaceutically pure and substantially .non-toxic irl the arirnounts employed. In addition, -the active compounds may .be incorporated into sustained-release preparation and formulations, Typically, these foi~tulations will contain at least about 0.1% of the active corizpound or more, although the percentage of the active ingredients) may, of . .course, be varied and may conveniently .be between about 1 or 2% ,and about 60% or 70% or more of the weight or volume of the total formulation. Naturally, the amount of active compounds) in each therapeutically useful composition may b~ prepared is such a Way that a suitable dosage will ,be obtained in any given unit dose of the compound.
Factors such as solubility, bioav~ilability, biological half life, route .of.administration, product shelf life, as Well as other pharmacological consideration's will be contemplated by one skilled in the art .of .preparing such pharmaceutical formulations, and as such, a variety of dosages and treatment regimens may lie desirable.
For oral administration the compositions of the present invention may alternatively-be incorporated W ith .one or more excipierits in .the form of a mouthwash, dentifrice, buccal tablet, oral spray, or sublingual orally-administered formulation.
Alternatively, the active ingredient may be incorporated into an .oral solution such as -one containing sodium borate, glycerin and potassium bicarbonate, or dispersed in a dentifrice, or added in a therapeutically-effective amount to a composition that may inclzxde water, binders, abrasives, flavoring agents, foaming agents, and humectants.
Alternatively the compositions maybe fashioned into a tablet or solution form that may be placed under the tongue or otherwise dissolved in the mouth.

In certain circumstances it will be desirable to deliver the pharmaceutical compositions .disclosed herein parenterally, intravenously, intramuscularly, or even intraperiton~ally. Such approaches are well lcnoW to the skilled-artisan, some of which are further described, for exaTriPIe, in U. S. Patent 5,543,158; U. S. Patent 5,641,515 and U. S. Patent 5,399;363. In certain .embodiments; solutions of tYle active compounds as free base or pharmacologica~.ly acceptable salts may b~ pxepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions may also be prepared in. glycerol, liquid polyethylene glycols, and mixtures thereof and in oils.
Under ordinary conditions of storage and use, ahese preparations generally will Contain a preservative tai Prevent the growth of microorganisms.
illustrative -pharmaceutical foims suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions o'r dispersions: (for example, see U. S. Patent 5,466,468). In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under ahe conditions of manufacture and storage and -must .be preserved against the coiitarninating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for exampie, water, ethanol, Polyal (e.g., glycerol, Propylene glycol, and.
liquid polyethylene glycol, and the like), suitable mixtures thereof, and/or vegetable 20' oils. Proper fluidity may be :maintained; for exariiple, by the use of .a Coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and/or by the use of surfactants. The prevention of the action of microorganisms can be facilitated by various antibacterial and antifungal~ agents; for :example, parabens, chlorobutanol, phenol, sorbic acid, thiinerosal~, and the like. In many cases., it will be preferable to include isotonic agents, for .example, sugars or sodium chloride.
Prolonged absorption of the injectable compositions .can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum inoriostearate and gelatin.
In one embodiment, for parenteral administration in an aqueous solution, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous. and intraperitoneal administration. In this connection, a sterile,.aqueous rimdiuiri that can -be employed will be known to those.of skill in the art in light .of the present disclosure. For example, one .dosage may be dissolved in 1 ml of isotonic NaCI solution arid either added to 1000 mI
:of hypoderrnoclysis fluid or injected at the proposed site of infusion, (see for .example, "Reriiirigton's Pharmaceutical Sciences" 15th Edition, .pages 1035-103 and 15$p). Some variation iri dosage will rreces-sarily occur deperldirrg .on the condition of the subject being treated. Moreover, for human administration, preparations will .of 1 Q course preferably meet sterility, .pyrogenicity, and the general safety and purity standards as required-liy FIfA Office of Biologics standards.
In another embodiment of the invention; the ~cotnpositioris disclosed herein may be formulated in a neutral or salt form. Illustrative pharmaceutically-acceptable salts include the acid addition salts (formed.
with the free amino groups of the protein) and which are .formed with -inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, 'tartaric, mandelic, and the like. Salts formed with the free carboxyl .groups can also be derived from inorganic bases such, as, for example, sod~uin, potassium, ammonium, calcium, or ferric hydroxides, and . such organic bases as isopropylamine, 20: trimethylarnine, histidine, procaine and. the like. Upon formulation, solutions will lie administered in a rrianner compatible with the dosage formulation and in such amount as is therapeutically effective.
The carriers can further comprise any arid all solvents, dispersion media;
vehicles; coatings, ,diluents, antibacterial .and .antifurigal agents, isotonic and absorption delaying agentsi buffers, carrier solutions, suspensions, colloids, and the like. The use .
of such media and agents for pharmaceutical .active substances is well known in the art.
Except -insofar- as .any -conventional media ~or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
Supplementary active ingredients can also be incorporated into he compositions. The phrase "phai~ilaceutically-acceptable" refers to molecular entities and= compositions that do not produce an allergic or similar untovi~ard reaction when administered to a human.
In certain erribodiments, the pharrriaceutical coriipositious may be delivered by intranasal sprays, inhalation, and/or other aerosol delivery vehicles.
Methods for delivering genes, .nucleic acids, and peptide .compositions directly to the lungs via nasal aerosol sprays has been described; e.g., in. IJ. S. ~l'~ ent 5;756,353 and U.
S. Patent 5,804,212. Likewise, the -delivery of thugs using intranasal microparticle resins (Takenaga .et al., J :Controlled Release 1998 Mar 2;52(1-2):81-7) and lysophosphatidyl-glycexol compounds (U. S. Patent 5,725,$71) are also well-known in .the -pharmaceutical arts. Likewise, illustrative transrr~ucosal arug~
delivery in the form of a polytetrafluoroetheylene suppoit matrix is describee~ in U. S. Patent 5,780,045.
I~ certain embodiments, liposomes, nanoeapsules, rriicroparticles, lipid particles, vesicles, and the like, are used for the introduction of the c, ompositions of the present invention into suitable host cells/organisms. ~In particular, the compositions of the present invention .may be formulated for -delivery either encapsulated in a lipid particle, a liposoye, a vesicle, a nanosphere, or a nanoparticle or the like.
Alternatively, compositions of the present invention can be bound, either covalently or non-covalently, to the surface.of such carrier vehicles.
The forrriation and use of liposome and lipasorne-like preparations as potential drug carriers is generally .known to those of skill in the art {see for example, Lasic, Trends Biotechnol 1998 Ju1;16(7):307-21; Takakura, Nippun Rinsho 1998 Mar;56(f):691-5; Chandran et al., Indian J Exp Biol. 1997 Aug;35(8):801-9;
Margalit, Crit 'Rev Ther Drug Carrier Syst. 1995;12(2-3):233-61; IJ.S. Patent 5,567,434;
U.S.
Patent 5,552,157; U.S. -Patent 5,565,213; U.S, Patent 5,738,868 and U:S.
Patent 5,795,587, each specifically incorporated herein by-reference in its entirety).
Liposomes have been used successfully with a. niurriber .of cell types that are normally difficult to transfect by :other procedures, including T cell suspensions, primary hepatocyte cultures and PC 12 cells (Renneisen et al., J°Biol Chem. 1990 Sep 25;265(27):16337-42; Muller et al., DNA CeII Biol. 1990 Apr;9(3):221-9). In addition, liposomes are free of the DNA length constraints that are typical of viral-based delivery loo.
systems. Liposomes have been used effectively to introduce -geries, various drags, radiotherapeutic agents, enzymes, viruses, transcription factors,.allosteric .effectors and the like, into. a .variety of cultured cell lines arid animals. Furthermore, he use of liposomes does not appear to be associated with;autoimmune responses or unacceptable toxicity after systemic delivery.
In certain embodiments, liposomes are formed from' phospholipids -that are dispersed in an aqueous medium arid-sporitaneously form multilamellar coycentris -bilayer vesicles (also termed multila~el~ar vesicles (1VILVs).
Alternatively, -in other embodiments, the invention provides for pharmaceutically-acceptable nanocapsule formulations of the .compositions of the present invention. Nanocapsules can generally entrap compounds in a stable arid reproducible way (see, for. example, Quintanar-Guerrero- et a~., Drug Dev Ind Pharm.
1998 Dec;24{12):1113-28). To avoid side effects due to intracellular polymeric overloading, such ultrafine particles {sized around 0.1 Vim) may be designed using polymers able to be degraded its vivo. Such particles can be made as described, for example, by .Couvreur .et al., Crit Rev Then =Drug Carrier Syst. 1988;5(1):1-20; zur IVIuhlen et al., Eur J -Pharrn Biopharm. 1998 Mar;45(2):149-55; Zambaux et cal. .J
Controlled Release. 1998 Jan 2;50(1-3):31-40; and U. S. Patent 5,145,684.
Cancer Therapeutic Methods In further aspects of the present invention, the pharmaceutical cornpositians described herein may be used for the treatment of cancer, particularly for the inimiunotherapy of lung canceir. Within such methods, the pharmaceutical compositions described herein are .administered to a patient, typically a warm-blooded' animal, preferably a human. A patient W ay -or may not be afflicted with cancer.
Accordingly, the above pharmaceutical compositions may be used to prevent the development of a cancer or to treat a patient afflicted with a cancer.
Pharmaceutical , compositions and vaccines may be administered either prior to or following surgical removal of -primary tumors and/or treatment such as administration of radiotherapy or conventional .chemotherapeutic .drugs. As discussed above, administration of the pharmaceutical corripositions niay be by any suitable method, including.
administration by intravenous, intraperitoneal, intramuscular, subcutaneous, intranasal, intradermial, anal, vaginal, topical and oral routes.
Within certain embodiments, imrriunotherapy may be active iinrnunotherapy, in which treatment relies on the in viyo stimulation of the endogenous host immune system to -react against :tumors with the admiriistratiori of .irrimune response=W odifying~ agents (such as polypepxides arid polynucleotides as provided herein).
V~ithin other embodiments, irnnTUnothe~apy may be passive imrimnotherapy, in which treatment involves the delivery of agents with established tumor-iriimune reactivity :(such as effec'tor .cells or antibodies), that can directly or indirectly mediate aritihzirior effects and does not necessarily depend on an intact host immune system. Examples of effector cells include T cells as discussed above, T
lymphocytes (such as CDB~ cyto'toxic T lymphocytes and .CD4+ T-helper tumor-infiltrating lymphocytes), killer cells (such as Natural Killer cells and lymphokine-activated killer cells), B cells and antigen-.presenting cells (such as,dendritic cells and macrophages) expressing :a polypeptide provided herein. T cell receptors and antibody receptors specific fcsr the _polypeptides recited herein may be cloned, expressed and transferred into other vectors or effector .cells for :adoptive immunotherapy.
The polypeptides provided herein may also be used to generate ~antibpdies or anti-idiotypic antibodies (as described above and in U.S. Patent No. 4,918;164) for .passive immunotherapy.
Effector cells, may generally be obtained in sufficient quantities for adoptive imyunothei~apy ~by .growth i~ vitr°o, as described herein.
Culture conditions for expanding single antigen-specific effector cells to several billion in number with retention of-antigen recognition in vivo are well known in the art. Such ih vitro culture conditions typically use intermittent stimulation with antigen, often in the presence of cytokines (such as 'IL-2) and non-dividing feeder cells. As noted above, iinmunoreactive .polypeptides as provided herein may be used to rapidly expand antigen-specific T cell cultures in order to generate a sufficient number of cells for iiiimunotherapy. In particular, antigen-presenting cells, such as dendritic, macrophage, rrionocyte, fibroblast and/or B cells, may be pulsed with immunoreactive polypeptides or transfected with one or more polynucleotides using standard techniques well .know n in the art. For example, antigen-presenting cells can be transfected with a polynucleotide having a promoter appropriate for increasing expression in a recombinant virus or other expression system. -Cultured- effector cells for use in therapy must be able ~to grow and distribute vi~idely; and to survive long term ih vivo. Studies have shown that cultured effector cells can be induced to grow in vivo and to survive fang term in .substantial numbers by repeated stimulation with antigen supplemented with IL-2 (see, for cxaniple,=Cheever et al., Immu~olagical Reviews 157:177;
1997).
Alternatively, .a vector expressing a polyp,eptide recited -herein may be introduced into antigeypresenting cells taken from a patient-arid clonally propagated ex vivo for transplant back into the same patient. Transfected cells may be reintroduced into the patient using any means ~lc~own in the art, preferably :in sterile form by ~intravei~ous, intracavitary, ~irltraperitoneal or intratumor administration.
Routes and frequency of administration of the therapeutic compositions described herein, as well as dosage, will vary from individual to individual, and may be readily established. .using standard techniques. In general, the .pharmaceutical .compositions and vaccines may be administered- by injection :(e.g., intracutaneous, intramuscular, intravenous or subcutaneous), intranasally (e.g.,--by.aspiration) or orally.
Preferably, between 1 and 10~ doses may be administered over a 52 week period.
Preferably, 6 doses are .administered, at intervals of 1 month, amd booster vaccinations may be given periodically thereafter. Alternate protocols ,may be appropriate for individual patients. A suitable dose is an. ariipunt of a compound that, when administered .as described ,above, is capable of :promoting an anti-tumor immune response, and is at least 10-50% above the basal (i. e., untreated) level.
Such response can be monitored -by measuring the anti-tumor antibodies in a patient or by vaccine-dependent generation of cytolytic effector cells capable of killing the patient's tumor cells i~ vitro. Such vaccines should also be capable of causing an immune response that leads to an improved clinical outcome (e.g., more frequent remissions, complete or partial or longer disease-free survival) in. vaccinated patients as compared to non-vaccinated patients. In general; for pharriiaceutical compositions and vaccines.
comprising one or more polypeptides; the amount of each polypeptide .present-in a dose ranges from about 25 ~.g to 5 rrig per kg of host. Suitable dose sizes will vary with the size of the patient, but will typically range from about 0:1 rriL to abdut 5 mL.
In generali axi appropriate dosage and treatment .regimen provides the active -compounds) in an amount stiff dent to provide therapeutic and/or prophylactic benefit. Such a response can be monitored by establishing an improved clinical outcome (e.g:, more frequent ~erriissions, ,corilplete or partial, or longer disease-free survival). in -treated .patients as compared to .nori-treated patieiifis.
Increases in preexisting immune responses to a tumor protein generally correlate with an improved clinical outcorxie. Such immune responses W ~y generally be evaluated using standard prolife~at~ari, cytatdxicity or cytokine assays, which may be performed using samples obtaived from a patient before and after treatment.
Cancer Detection and Diagnostic Compositions, Methods and Kits In general, a ;canceir may be detected in a patient based on the presence of one or more lu~i~ tumor proteins and/or poly~iucleotides encoding such proteins in a biological sample (for .exampte, blood, sera, sputum urine and/or tumor biopsies) obtained from the patient. In other words, such proteins may be used as markers to indicate the presence or absence of a cancer such as lung cancer. In addition, such proteins may be useful for the detection of other cancers. The binding agents provided herein generally permit detection of the level of antigen that .binds to the agent in the biological sample. Polynucleotide primers ayd- probes may be used to detect the level of mRNA encoding a tumor protein, which is also' indicative of the presence or absence of a cancer. In general, a lung tumor sequence should be present at a level that is at least three fold higher in tumor tissue than in normal tissue There axe a variety of assay formats known to those of ordinary skill in the art for using a binding .agent to detect polypeptide markers in a sample.
See, e.g., Harlow and Lane, Antibodies: A Laboratory ~l%Ta~ual, Cold Spring Harbor Laboratory, 10.4 198$, In general, the presence or absence of a cancer in a patient may be determined by (a) contacting a =biological sample obtained from a patient with a binding agent; (b) detecting in the sainpie a =level of polypeptide that binds to the binding agexit; and (e) comparing the .level of polypeptide with a predeterrriined cut-off value.
In a preferred embodiment, the assay inyalves the use of binding agent immobilized on :a solid- support to bind to and . reW ove the polypeptide from the remainder of the sample. The bound polypeptide may then be detected using a detection reagent that contains a reporter group and specifically binds to the binding agent/palypepticle corriplex. Such detection- reagents may .comprise, for example, a binding agent that speeif tally binds to. the polypeptide or an antibody or other agent that specifically binds ta-the binding agent, such as an anti-iminunoglobulin, protein G, protein ~. or a lectin. Alternatively, a cW ripetitive assay may be utilized, in whych a polypeptzde is labeled with a reporter group .and allowed to bind to the immobilized binding agent after incubation of the binding agent with the sample. The extent to which components of the sample inhibit the binding flf -the labeled polypeptide to the =binding agent .is indicative of the -reactivity of the sample with the immobilized binding agent. Suitable -polypeptides for use within such assays include full length lung tumor proteins arid polypeptide portions thereof to which the binding agent binds, as described above.
The solid. support may ~be any material known to those of ordinary skill in the art to which .the tumor protein may be attached. For example, the solid support may be a test well in a microtiter plate or a nitrocellulose or other suitable membrane.
Alternatively, the support may be a bead .or .disc, such as glass, fiberglass, latex or a plastic material such as polystyrene or polyvznylchloride. The support may also be a magnetic .particle or a fiber optic sensor, ueh as those disclosed, for example, in U.S.
Patent No. 5,359,681. The binding .agent may be immobilized on the solid support using a vaxiety of techniques known to those .of skill in the art, which are amply described in the patent and scientific literature. In the context of the present invention, the term "immobilization" refers to both noncovalent association, such as adsorption, and covalent attachment (which may be a direct linkage between the agent and ftinctional groups on the support or may be a linkage by way of a cross-linking agent).
Immobilization by adsorption to a well in a microtiter plate or to a membrane is preferred: In such cases, adsorption may be achieved lay .contacting the binding agent, in a suitable buffer, with the solid support for a suitable amount of time.
The contact time varies with temperature, but is typically between about l hour and about 1 day. In :general, .contacting a well of a plastic mzcrotiter plate (such as polystyrene or polyvinylchloride) with ,an amount of binding agent ranging from about 10 ng to about 1'0 fig, and preferably about 100 ng to about 1 fig, is sufficient to immobilize an adequate amount of binding agent.
1.0 -Covalent atta~l~irieiit of binding agent .to a solid support may generally be achieved by -f xst reacting 'the support with a ~ bifunetional reag~i~t that will react with both the support and a functioriah- group, such as a hydroXyl or amino group, on the binding agent, For exar~iple, the binding-agent may be covalently attached to supports having an .appropriate polymer coating using benzoquinone or by condensation ~f an 1 S aldehyde group on the support with an amine and an active hydrogen on the binding partner (see, e.g., 'Pierce Immurlotechnology Catalog and .Handbook, 1991, at A12-A13).
In certain embodiments, the assay is a two-antibody sandwich assay.
This assay may be perforrized by first contacting an antibody that has been immobilized 20 on ,a solid support, commonly the well of a microtiter plate, with the Sample, such that polypeptides within the sample' are allowed to bind to the .immobilized antibody.
Unbound sample' is .then removed from the immobilized _polypeptide-antibody complexes arid a detection reagent (preferably a second .antibody capable .of binding to a different site on the polypeptide) containing a reporter group is added. The amount of 25 detection. reagent that remains bound to the' solid support is then.
determined using a method appropriate for the specific reporter group.
More specifically, once the antibody is immobilized on the support as described above, the remaining protein -binding sites on the support are typically blacked. Any suitable blocking agent known to those of ordinary skill in the art, such 30 as bovine serum albumin or Tween 20TM (Sigma Chemical Co., St. Louis, MO).
The immobilized antibody is then irieubated with the sample, and polypeptide is allowed to bind to the antibody., The sample may be diluted W ith a~ suitable diluent, such as phosphate-buffered saline (PBS) prior to, incubation. In general, an appropriate contact time (i.e., incubation time) is-a period of time that is sufficient to detect the presence of _polypeptide within ~ sample .obtained from an individual with lung cancer.
Preferably, the corit~ct time is sufficient to -achieve a level of binding that is at least about 95% of 'that achieved at equiiibrium between bound. and unbound- polypeptide. Those of ordinary skill in the art will recognize that the time necessary to achieve equilibrium rriay be readily determined °by assaying the level of binding that occurs over a period of tiriie. At -room terfiperat~zre, .an .i~icubation time of .about 30 minutes is generally sufficient.
Unbound sariiple riiay then be removed by washing the solid support with an appropriate buffer, such as P$S containing 0:1 % Tweera 2OTM. The second antibody, which contains a reporter group; may then be added to the solid support.
Preferred reporter groups include those groups recited above.
The detection reagent is then incubated with the immobilized antibody-polypeptide complex for an amount -of time sufficient to detect the bound polypeptide.
An appropriate arriount of -time may generally be determined by assaying the level of binding that occurs .over a period of time. Unbound detection reagent is then removed and bound detection reagent is detected using the reporter group. The method-employed for detecting the reporter group depends upon the nature of the reporter group. For radioactive groups, scintillation counting or autoradiographic methods are generally appropriate.Spectroscopic methods may be used to detect dyes, luminescent groups and fluorescent groups. ~B,iotin may be detected using avidiri, coupled to a different repor-ter group (commonly .a radioactive or fluorescent group ox an enzyme).
Enzyme reporter groups rnay generally be detected by the addition of substrate ~(gerierally for a specific period of time), followed by spectroscopic or other analysis of the reaction products.
To .determine the presence or absence of a cancer, such as lung cancer, the signal detected from the reporter group that .remains bound to the solid support is generally compared to a signal- that corresponds to a predetermined cut-off value. In one preferred embodiment, the cut-off vahte for the detection of a cancer is the average mean signal obtained when :the iriimobilized antibody is incubated with samples from patients without the cancer. In general, a sample generating a signal that is three standard deviations-above the predetermined cut-off value is considered positive for the camcer. In an alte .mate preferred embottiment, the cut-off value is detei~ined . using a Receiver Qperator Curve, according to -the method of Sackett et al., Clinical Epidemiol~ogy: A Basic Science for vClihical Medicine, Little Brown arid Co., 1985, p. 106-7. Briefly, in this-embodiment, the .cut-off value may be determined from a plot of pairs of true.pcssitive rates (i.e., sensitivity) and false positive rates (1.00%-specif city) that correspond to each possible cut-off value for the diagnostic test result.
The cut-off value 'on he :plot that is the closest to the upper left-hand: corner (i.e., the value that.
encloses the largest area) is the most accurate cut-off value, and a sample generating a signal that is.higher than the cut-off value determined by this method riiay-be considered .positive. Alternatively, the cut-off value .may be shifted to the left along the plot, to .
:minimize the false positive rate, ..or to. the right, to minimize the false negative rate. In:
general, a sample generating a signal that is higher than the .cut-off value determined by this method is considered positive far a cancer.
Iu a related- embodiment; the assay is performed in a flaw-through or strip test format, wherein the binding agent is immobilized on a ~nembrarie, such as nitrocellulose. In the flow-through test, -polypeptides within the sample bind to the immobilized binding agent as the sample passes through the -membrane. A
second, labeled binding agent then binds to the binding agent-polypeptide complex as a solution containing the second- binding agent flaws through the membrane. The detection of bound second binding agent may then be performed- as described above. In the strip test format, one end -of the membrane to which binding agent is bound is iimmersed in a solution :containing the sample. The sample migrates along the membrane through a region containing second binding agent and to the area of immobilized -binding agent.
=Concentration of second binding agent- a't the area of immobilized antibody indicates the presence .of a cancer. Typically, the concentration of second binding agent at that site lOS
generates a pattern, ,such as a line, that can be read visually. The absence of such a pattern indicates a negative result. In general, the amount of binding agent iininobilized~
on the membrane is selected to generate a visually discernible pattern when the biological sample contains a level of polypeptide that would be sufficient to generate a positive signal in the two-antibody sandwich: assay, ~in the forrriat discussed above.
Preferred bindirig~ agents for use in such assays axe antibodies and antigen-binding fragments thereof-. Preferably, the amo'.urit of antibody immobilized on the membrane ranges from about 25 ng o about 1 ~,g, and more preferably from about 50 ng to about 500 ng. Such tests can typically be performed with ~ very small amount. of biological 1.0 sample.
'~f course, numerous other assay protocols. exist. that are suitable for use with the tnma~' proteins or binding agents of -.the present invoi~tion. The above descriptions aie intended to be exemplary only. . For -example, it will be apparent to those ~of o~dirl~.ry skill in the art that the above protocols may be readily modified to use tumor polypeptides to .detect antibodies that bind to such polypeptides. in .a biological-sample: The detection of such tumor protein specific antibodies may correlate with the presence of a cancer.
A cancer -may also, or alternatively, be detected based on the presence of T cells that specifically react with a tumor protein in a .biological sample.
Within certain methods, a biological sample comprising CD4+ and/or CD8~" T cells isolated from a patient is incubated. with a tumor polypeptide, a ,polynucleotide encoding such a polypeptide and/or an APC that expresses at least ari iW munogenic .portion of such a polypeptide, and the presence or absence of specific activation of the T cells is detected.
Suitable biological samples include, but are not limited to, isolated T cells.
'For example, T -cells may be isolated from a patient ~by .routine techniques (such as by Ficoll/Hypaque density gradient centrifugation of peripheral blood lymphocytes). T
cells may be incubated in vitro for 2-9 days (typically .4 days) at 37°C with polypeptide (e.g., 5 - 25 ~,g/ml). It maybe desirable to incubate another aliquot of a T
cell sample in the absence of tumor polypeptide to serve as a .control. For :CD4+ T cells, activation is preferably .detected by evaluating proliferation of he T:cells. For .CI~8+ T
cells, activation is preferably detected by evaluating cytolytic activity. A level of proliferation that is at least two fold greater and/or a level of cytolytic activity that is at least 20% greater than in .disease-free patients indicates the presence -of a cancer in the patient.
As noted above, a cancer may also or alternatively, 'be detected based on the level of mI~NA eneodir~g a tumor protein in a biological sample. For example, at least two oligonucleotide primers niay be employed in ,a polyrnerase chain reaction (FCR) based assay to amplify a portion of a tumor cDNA derived from a biological sample, wherein at least one of the oligonucleotide primers, is specif c for (i. e., hybridizes to) a polyriucleotide .encoding the tuiiior protein. The amplified cDNA is then separated and detected .using techniques well =known in the art, such a's gel electrophoresis. Similarly, oligonucleoticle probes than specif cally -hybridize to a polynucleotide emcoc~ing a ttiriior protein may b;e =used in a hybridization assay to detect the presence of polynucleotide encoding the tumor protein in a biological sample.
To permit hybridization under assay conditions, oligonucleotide primers and probes should cori~prise an oligonucleotide sequence-that has at least about 60%, preferably at least about 75% and more preferably at least about 90%, identity to a portion of a polynucleotide encoding a tumor protein of the invention that is at least 10 nucleotides, arid preferably at least 20 nucleotides, in length. Preferably, oligonucleotide pximers and/or probes hybridize to a .polynupleotide encoding a polypeptide described herein under moderately stringent .conditions, as defined above.
Oligoriucleotide primers and/or probes which may be usefully employed in the diagnostic methods described herein preferably are at least 10-4I7 nucleotides in lengt~i.
In a preferred embodiment, the oligonucleo'tide primers compiise at least 10 contiguous -nucleotides, more preferably at least I S contiguous nucleotides, :of a DNA
molecule having a sequence as disclosed herein. Techniques for both PCR based assays .arid hybridization assays are well known in the art (see, for example, Mullis et al., Cold Spring Harbor Symp. Quant. Biol., 51:263, 1987; Erlich ed., PCR TecFtnology, Stockton Press, NY, 1989).

:One preferred assay employs RT-PCR, in which- PCR is applied in conjunction with reverse transcription. Typically, RNA is extracted from a biological sample, such as. biopsy tissue, arid is revexse transcribed to produce cDNA
molecules.
PCR arriplification using at Least one specific primer generates a cDNA
rriolecule, which may .be separated and visualized using, fog example, gel electrophoresis.
Amplification rriay be performed .onbiological sa~riples taken from a test patient and from an lndivi~ual who -is not afflicted with a cancer. Tl~e amplification reaction may be performed on several dilutions of.cI7NA spaririir~g two orders of magnitude. A
two-fold or greater increase in expression in several dilutions of the west patient sample as compared to the same diltitioiis of the non-cancerous sample is typically considered positive.
In another erribodirrient~ the corripositioms described herein may be used :as marl~ers for the progression of cancer. In this embodiment, assays as described above for the diagnosis of a cancer may-be,performed over time, .and the change in the :level of reactive polypeptide(s) or :polynucleotide(s) evaluated. For example, the assays may be performed every 24-72 hot~t~s for a peiiod .of 6. months -to 1 year, and thereafter performed as needed. In general, a cancer is progressing in those patients in whom the level of :polypeptide or polynucleotide detected increases over time. In contrast, the -cancer is :not progressing wheel the level of reactive polypeptide or polynucleotide either rerriains constant or decreases with time.
.Certain in vivo .diagnostic .assays may be performed directly on a tumor.
-One such assay involves contacting tumor cells with a binding agent. The bound binding agent may them be detected directly or indirectly via .a reporter group. Such binding agents may .also. be used in histological applications. Alternatively, polyriucleotide probes may be used within such. applications.
As noted.above, to improve sensitivity, multiple tumor protein markers may be assayed within. a given: sample. It will- be apparent that binding agents specific for different proteins provided herein may be combined within a single assay.
Further, multiple primers or probes may be used concurrently. The selection .of tumor protein markers may be based on routine experiments to determine combinations that results in optirizal sensitivity. In addition, or alternatively, assays for tumor :proteins provided.
hereinmay be.cornbiried with assays. for other known tumor antigens.
The -present iriverition furthex provides .kits for use within any of the above diagnostic methods. Such kits typically :comprise two .or more components necessary for performing ,a diagnostic assay. Components ri~ay be compounds, reagents, containers aridlor equipment. F.or eXample, :one container within a kit may contain a rriorioclonal antibody -or fragment thereof that specifically Binds to a tumor protein. Such antibodies or fragrr~ents may be provided attached to a support material, as desGribed~ above. Orie or more additional containers may enclose elements, such as reagents. or -bt~ffe'rs, .to be used in.the assay. Such kits may also; or altel=riatrvely, contain a detection reagent as described above=tllat contains a reporter group suitable for direct or indirect detection of antibody binding.
Alternatively, a kit may be designed to detect the level of mRNA
encoding a tumor protein iii a biological sample. Such kits generally comprise at least one oligonucleotide probe or primer, as described above, that hybridizes to a polynucleotide encoding a tumor protein. Such an oligonucleotide may be used, for example, within a PCR or hybridization assay. Additional components that may be present within such kits include a second oligonizcleotide andlor .a diagnostic reagent or coil'tainer to facilitate the detection of a polynucleotide encoding a tumor protein.
The follo~uimg Examples are offered by way of illustration and not by way of limitation.

PREPARATION OF LUNG TUMOR-SPECIFIC CDNA SEQUENCES USING
DIFFERENTIAL DISPLAY RT-PCR
This example illustrates tl~e .preparation of cDNA molecules encoding lung tumor-specific polypeptides using a differential display screen.
Tissue samples were prepared from lung tumor and normal tissue of a patient with lung cancer that was confirmed 'by pathology after removal of samples from the patient. Normal RNA ,and tumor RNA was extracted from the samples and mRNA was isolated and converted into cDNA using a (dT)IZAG (SEQ ID NO: 47) anchored 3' primer. Differential display .PCR was then- executed using a randomly chosen primer (S-EQ. ID NO: 48). Amplification conditions were standard buffer containing 1.f mlVl MgCl2; 20 pmol of primer, 500 priiol dNTP and 1 unit of Taq DNA
polymerase (Perkin-Elmer, granchburg, NJ). Forty cfcles of amplification were performed using 94 °C denaturation for 30 seconds, 42 °C
annealing for 1 minute and 72 °C exterisiorl for 30 seconds-. Bands that were repeatedly observed to be specific to. the RNA fingerprint ,pattern of~the tumor were cut out .of a silver stained gel, subcloned into the pGEM-T vector (Profnega, Madison, WI) and sequenced. The isolated 3' sequences are provided in SEQ ID NO: ~1-1.6~
1:0 Cc~iriparison of.these sequences to those in 'the public databases using the BLASTI~ prograti~, revealed ao significant ho 'rnologies to -the sequences provided in SEQ ID IVO: 1-11. To the best- of the inventors' knowledge none of the isolated DNA
sequences have previously been shown to be expressed at a greater .level in human lung tumor tissue -than in norriial lung tissue.

USE OF PATIENT SERA TO IDENTIFY DNA SEQUENCES ENCODING
LUNG TUMOR ANTIGENS
This example illustrates the isolation of cDNA sequences encoding lung tumor antigens by expression screening of lung tumor samples with autologous patient sera.
A human lung tumor directiønal :cDNA .expression library was cotistructed employing .the Lambda ZAP Express expression system (Stratagene, La Jolla, CA). Total =RNA for the library was taken from- a late SLID mouse passaged human squamotis epithelial lung carcinoma and poly A+ :RNA was isolated using the Message Maker kit (Gibco BR:L, Gaithersburg; MD). The resulting library was screened using E. coli-absorbed autologous patient serum, .as described in Sambrook et al., (Molecular .Cloning: A Laboratory Manual, .Cpld 'Spring Harbor Laboratories, Cold Spring Harbor, NY, 1989), with the secondary antibody being goat anti-human IgG-A-1VI (H + L) conjugated with alkaline phosphatase, developed with NBT/BCIP
(Gibco BRL). Positive plaques expressing irivnunoreactive antigens were purified.
Phagemid from the plaques was rescued and- the nucleotide sequences of the clones was determined.
Fifteen clones were isolated, referred to hereinafter as LT86-1 - LT86-15. The isolated cDNA sequences for LT86-1 - LT86-8 and LT86-10 - LT86-15 are provided in SEQ :ID NO: 17-2~ end 26-31, _respectively, with the corresponding predicted amino acid sequences being provided in SEQ ID' NO.: 32-39 and 41-46, respectively. The determined cDNA see~ue~ce for LT86-9 is provided in SEQ ID' NO:
~5, with the corresponding pr,~dicted amino acid sequences from the 3' and 5' ends being provided in SEQ ID' NO: 4Q and =~5, reSpec'tively. These sequences were compared to those in .tl~e -gene 'baizk as described above. Clones LT86-3, LT86-9; LT86-11 - LT86-13 and LT86-15- (SEQ ID' NO: -19, 22-25, 2'7-29 and 31, respectively) were found :to show some homology to previously identified expressed sequence tags (ESTs), with .dories LT86-6, LT86-8, LT86-11, LT86-12 and LT86~15 appearing to be similar or identical to each -other. Clone LT86-3 was found to show some homology with .a 'human transcription repressor. Clones LT86-6, 8, 9, 1l, 12 and 15 were found to show some homology to a yeast RNA -Pol II transcription regulation mediator. Clone LT.86-13 was found to show some horriology with a C. elegans leucine aininopeptic~ase. Clone LT86-9 appears to contain two inserts, with .the 5' sequence ~0 showing homology to the previoixsly .identified ant~sense sequence .of interferon alpha-induced P27, and the 3' sequence -being similar tci LT86-6. Clone LT86-14 (SEQ
ID
NO: 30) was found to show some horiiology to the trithorax gene and has an "RGD"
cell attachment sequence and a beta-Lactamase A site which functions in hydrolysis of penicillin. Clones LT86-1, LT86-2, ~LT$6-4, LT86-5 arid LT86-10 (SEQ ID NOS:
17, 18, 20, 21 and 26, respectively) were found to show homology to previously identified genes. A subsequently determined extended cDNA sequence for LT86-4 is provided in SEQ ID NO: 66, with the corresponding predicted amino acid sequence being provided in SEQ ID NO: 67.
Subsequent studies. led to the isolation of f ve additional clones, referred to as LT86-20, LT86-21, LT86-22, LT86-26 and LT86-2'7. The determined 5' cDNA

sequences far LT86-20; LT86-22, LT86-26 and LT86-27 are provided in SEQ ID NO:
68 and 70-72, respectively, with the determined 3' cDNA sequences for LT86-21 being provided in SEQ II? NO: .69. The corresponding predicted amino -acid sequences far LT86-20, LT86-21, LT86-22, LT$6-26 and- LT86-27 are provided in SEQ. ID NO: 73-77, respectively. LT86-22 anc~ LT8.6-27 were found= to be highly similar to~
each other.
Cofriparisari of these sequences to. those in the ,gene bank as described above, revealed no significant homologies to LT$6-22 arid LT86-27. LT86-20, LT86=21 and LT86-were found to show homology to previously ifentif ed genes.
In further studies, a cDNA expression library was prepared using mRNA
from a lung small cell carcinoma cell line in the laybda ZAP Express expression vector yStratagene), and screened- as described above, with- a pool of tv~o lung small cell caxcirrorr~a- patierit sera. The sera- pool was adsorbed with. E. coli lysate and -human PBM.C lysate was added to the serum to black antibody to p~ateins found in normal tissue. 'Seventy-three clones were isolated. The determined cDNA sequences of these 1S -Tones are provided in SEQ. ID NO: 290-362. The sequences of SEQ TD NO: 289-292, 294, 296-297, 300; 302, 303, 305, 307-315, 317-320, 322-325, 3~7-332, 334, 335, 338-341, 343-352, 354-358, 360.and 362 were found to show some homology to previously isolated genes. The sequences of SEQ ID NO: 293, 295, 298, 299, 301, 304, 306, 316, 321, 326, 333, 336, 337, 342, 353, 359 and 361 were found to show some homology to previously identified ESTs.

USE OF MOUSE ANTISERA TO IDENTIFY DNA SEQUENCES ENCODING
LUNG TUMOR ANTIGENS
This example illustrates the isolation of cIDNA sequences encoding lung tumor antigens by screening of lung tumor -cDNA libraries with mouse anti-tumor sera.
A directional cDNA -lung tumor expression library was prepared as _described above in Example 2. Sera was obtained from SCID mice containing late passaged human squamous cell and adenocarcinoma tumors. These sera were pooled and injected into normal mice to produce anti-lung tumor serum. Approximately 200,000 PFUs were screened from the unamplified library using this antiserum.
Using a goat anti-mouse IgG-A=1~I (H+L) alkaline phosphatase second antibody developed with NBTB'~IP (BR.L Labs.), approximately ~0 positi~Ve plaques were identified.
Phage was purified anal phagemid excised 'for 9 clones with inserts in a pBI~-CMV
vector for expression in prokaryotic or eukaryotic cells.
The determined cI7NA sequences for 7 of the isolated-clones (hereinafter referred to as' a;86S-3, L86S-12, L86S-16, L86S-25, L&6S-36; L868-40 and L86S-46) are provivded in SEQ LD~ NO: 49-55, with the corresponding predicted amino acid sequences being provided in SEQ. ID NQ: 56-62, respectively. The 5' cDNA
sequences for the xemairiirig 2 clones (hereinafter ~refe~ed to as L86S-30 and L86S-41) are provided in, SEQ -ID. N(O: 63 arid 64. L86S-36 and L86S-46 vveie subsequently determined to. represeu~ the same gene. Comparison of these sequences with those in the public .database as described above, revealed rio siguificarit. homologies to clones L86S~30, L86S-36 and L86S-46 (SEQ. ID NO: 63, 53 and 55, respectively). L86S-(SEQ ID NO: 51) was fourid to show some homology to an EST previously identified in .fetal lung arid .germ cell tumor. The remaining clones were found to show at least some degree of homology to previously identified -human genes. Subsequently determined extended.cI~NA sequences for L86S-12, L86S-36 and LB~S-46 are provided in SEQ
ID
NO: 78-80, respectively, with the corresponding .predicted amino acid sequences being provided in SEQ ~I,D NO: 81-83.
Subsequent studies led to the determination of 5 ° cDNA sequences for ari additional mine clones, referred to as L86S-6, L86S-11, L86S-14, L86S-29, L86S-34, L86S-39; L86S-47-, L86S-49 and L86~-~1 (SEQ IID NO: 84-92, respectively). The corresponding predicted amino acid -sequences are provided in SEQ °ID
NO: 93-101, respectively. L86S-30, :L86S-39 and L86S-47 were found to lie similar to each other.
Comparison -of these sequences. with those iri the .gene bank as described above, revealed no significant homologies to L86S-14. L86S-29 was found to show some homology to a previously identified EST. L86S-6, L86S-11, L86S-34, L86S-39, 47, L86S-49' and L86S-51 were found to show some homology to previously identified genes.

In further studies; a directional cDNA library was constructed using a Stratagene kit with ~ Lambda Zap Express vector. Total RNA for the library was isolated from t'?vo. primary squam~us lung turlaors and poly A+.RNA was isolated using an oligo dT column. Antiserum was developed in normal mice using a pool of sera from three SCID mice implanted with human squainous lung carcinomas.
Approximately 700000 PFUs were screened- from. the :unayplified library with E. coli absorbed mouse anti-SCID tumor serum. Positive plaques. were identified as described above. Plia~e was purified and phagemid excised for 180-clones with inserts in apBK-CMV vector for expression in prokaryotic o~ .eukaryotic cells.
The .deterniined. -cDNA seguences for 23 of the isolated clones are provided in SEQ ID NO: 126-14&. .Comparison of these sequences with those in the public database as described above revealed no significant horriologies to the sequence's of SEQ ID NO: 139 and 143-148. The sequences of SEA ID NO: 126-138 and 140-142 were found- to show homology to previously identif ed -.human polynucleotide sequences.

USE OF'MOUSE ANTISERA TO SCREEN LUNG TUMOR LIBRARIES
PREPARED FROM SLID MICE
This .example illustrates the' isolation of cDNA sequences encoding Lung tumor antigens by screening .of lung tumor cDNA libraries prepared from SLID
mice with mouse anti-tumor sera.
A directional- cDNA lpng tumor expression library was prepared using a Stratagene kit with a Lambda Zap -Express vector. Total RNA for-tlie library was taken from a late passaged lung adenocarcinoma grown in SLID mice. Paly A+ RNA was isolated using a Message Maker Kit.(Gibco BRL). Sera was obtained from two SCID
mice implanted with lung adenocarcinomas. These sera were pooled and injected into normal mice to produce anti-lung tumor serum. Approximately 700,000 PFUs were screened from the unamplified library with E. coli-absorbed mouse anti-SLID
tumor serum. Positive plaques were .identified with a goat- anti-mouse IgG-A-M (H+L) alkaline phosphatase second antibody developed with NBT/BCIP (Gibco BRL).
Phage yeas purified and phagemid .excised for 100 clones with insert in a pBK-CMV
vector for -expression in prokaryotic or eul~a~yotic cells.
The determined- S' cDNA s,equerices for 33 of the isolated clones are provided in SEQ ID NO: 149=18~I. The corresponding predicted ayino acid sequences for SEQ ID NO: 149; 150, 152-154, 156-15$ arid 160-181 are.provided in SEQ ID
NO:
182, .183, 185, 1 ~8-193 and 194-215; respectively. The clone of SEQ ID NO:

(refexred to as SAL-25) .was found o~ .contain two op,er! reading frames :(ORFs). The :predicted amino acid sequences encoded .by these ORFs are provided in~ SEQ ID
NO:
1.84 and 185. The clone of SEQ ID NO: 153 (referred to as SAL-50) was found to contain two open reading frames encoding the predicted amino acid sequences of SEQ
ID NO: l'87 and 216. Similarly, the clone of SEQ ID NO: 155 (referred to as SAL-66) was found -to contain two .open reading frarries encoding the predicted ariiino acid sequences of SEQ III NO: 189 .and 190. Comparison of the isolated sequences with those in the public database revealed no significant homologies to the sequences of SEQ
ID NO: 151, 153 and 154. The sequences of SEQ ID NO: 149, 152, 156, 157 and were found to show some homology -to previously .isolated ~Xpress,ed sequence tags (ESTs). The sequences of SEQ ID NO: 150, 155 and 159-181 were found to show homology to sequences previously identified in humans.
Using the procedures described above, =two .directional cDNA libraries (referred to as LT46-90 and LT86-21 ) were prepared fr~W two late ,passaged lung squamous carcinomas grown in SCID mice and screened with sera obtained from SLID
mice implanted with human squamous lung carcinomas. The determined cDNA
sequences -for the isolated clones- are provided in SEQ 'ID NO: 217-237 and 286-289.
SEQ ID NO: 286 was found to be a longer sequence of LT4690-71 (SEQ ID' NO:
237).
Comparison of these sequences with those in the public .databases: revealed no known homologies to the sequences of SEQ ID NO: 219, 220, 225, 226, 287 and 288. The sequences of SEQ ID NO: 218, 221, 222 and 224 were found to show some horriology to previously identif ed sequences of unknown function. The sequence of SEQ ID
NO:
236 was found to show homology to a known mouse mRNA sequence. The sequences of SEQ ID NO: 217, 223, 227-23?, 286 arid 289 showed some homology to -known -human DNA and/or RNA sequences.
In fiuther studies using the techniques :described above, one of the cDNA
libraries described above (LT86-21) was screened with E coli-absorbed mouse anti-s SCID tumor serum. This serum was. obtained from normal mice immunized with a pool of 3 -sera takers frorrr 'SCII~ mice implanted ~?vith hurray. squanious lung carcinomas.
T'he determined cDNA sequences for-vhe isolated clones are provided in SEQ ID
NO:
238-285. Comparison of these sequences with those in the public databases revealed no significant homologies to the sequences of SEQ ID NO: 253, 260, 27T and 285.
The sequences of SEQ ID NO: 249; 250, 256; 266, 276 arid 282 ~v~re foui~c~ to show some horriology to previously isolated expressect~ sequence tags (E~Ts)-. The sequences of SEQ ID NO: 23f-248; 251, 25~, 254, 255, 257-25.9, 261-263, 265, 267-275, 278.-281, 283 arid 28~ were found to show some homology to previously identified DNA or RNA
sequences.
The expression levels of certain of the isolated antigens in lung tumor issues compared to .expression levels in normal tissues was determined by microarray technology. The results of these studies are shown below in Table 2, together with the databank analyses for these sequences.
TABLE Z
Clone vSEQ. Description :LT+F/N SCC+lVIINSqua/ Aden~o/N
ID NO: N-2LT-3 23 8 Unknown 2.2 3.8 3.3 -(KIAA0712 2LT-6 239 Lactate DH 2.3 3.8 4.1 -B

2LT-22 240 Fumarate - 3.0 - -hydratase 2LT-26 242 CGl-39 - - 12:8 -2LT-31 243 ADH7 - - 8.4 2.2 2LT-36. 244 ADH7 - 2.4 2.0 -2LT-42 245 HMG-CoA 2.2 2.6 2.2 -synthase 2LT-54 247 (Mus) ninein - 2.1 - -2LT-55 248 Ubiquitin 2.2 - 2.5 2.0 2LT-57 249 Novel 2.1 2:9- 2.4 -2LT-58 250 Novel 2.3 4.0 2.9 -2LT-59 251 Unknown 2.4 3.0 2.3 2.0 KIAA0.784 2LT 62 X52 Nuc Pore Cmplx-- - - 2.1 ass, pro TPR

2LT-70 256 Unknown - 2.5 2.2 2.1 2LT-73 2'57 Mus - 2.0 - -poly~denylate-binding 2LT-76 259 Trans-Golgi 2.1 - 2.6 -p230 ZLT-85 263 Ribosomal protein- - - 2.1 (L X29.) 2LT-89 265. Unknown - 2.0 - -2LT-98 268 1~!Ielai~oma - - - 2.2 cliff assoc pro 9 2LT-100'269 Mus Collagen - - - 2.1 alpha. UI

2LT-105 271' NY-CO-7 antigen- 3.2 -2LT-108 273 Unknown - 3.1 - -2LT-124 279 ~Galectin-9 2.3 2,7 2.0 -(secreted) 2LT-126 280 Ll element 2.5 - 3.1 -L1.33 p~0 2LT-128 282 Novel (kappa 2.3+ - 20.4 2.5 B'-ras 2) 2LT-133.284 alpha ~I spectrin- 2.3 - -LT+F/N = Lung Tumor plus Fetal tissue over Normal tissues SC+M/N = Lung ~Smal-1-Cell carcinoma plus Metastatic over Normal tissues Squa/N = Squamous lung turrior over Normal tissues, S Aden/N = Adenocarcirlorria over Normal tissues Full-length sequencing studies on :antigen 2LT-128 (SEQ ID NO: 282) resulted in the isolation of the full-length cDNA sequence provided in SEQ ID
NO:
392. This amino acid sequence encoded by this full-length cDNA sequence is provided in SEQ ID NO: 393. This antigen shows 20-fold over-expression in squamous cell carcinoma and 2.5-fold over-expression in -lung adenocarcinoma. This gene has been described as a potential ras oncogene (Fenwick,et al. Scievtce, 287:869-873 2000).

Extended sequence information was obfained for clones 2LT-3 (SEQ ID
N0:238), 2LT-26 (SEQ- ID N0:242), 2LT-57 (SEQ ID'. NO: 249), 2LT-58 (SEQ ID
N0:250), 2LT-98 (SEQ ID N0:268) and 2LT-124 (SEQ ID. N0:279): The extended cDNA sequences. for these clones ire set forth in sEQ ID NOs:428-433, respectively, encoding the polypeptide s'equenees set forkh in SEQ ID NOs: 434-439, respectively.

DETERMINATION OF TISSUE SPECIFICITY Oh LUNG TUMOR POLYPEPTIDES
Using gene specific primers, mRNA.expression levels for representative lung tumor polypeptides were -examined in a variety of normal axid tumor tissues using RT.~PCR.
Briefly; total -RNA was extracted from a variety of normal and tumor tissues using Trizol reagent. First strand synthesis was carried out using 2 p,g of total RNA with Superscript II reverse transcriptase (BRL Life Tech~iologies) at 42°C for one hour. The cDNA was-theri.arnplified by PCR with gene-specific primers. To ensure the semi-quantitative mature of the RT-PCR, (3-actin was used, as an internal control for each of the tissues examined. 1 ~,1 of 1:30 dilution of cDNA was employed to enable the linear range amplification of the (3-actin template and was sensitive enough-to reflect the differences in the initial -copy numbers. Using these corlditioris, the :(3-actin levels were determined for each reverse transcription reaction from each -tissue. DNA
contamination was minimized by DNase treatment and by assuring, a negative PCR
result when using first strand cDNA that was prepared' without- adding reverse transcriptase.
mRNA Expression levels were examined in five .~tifferent types of tumor tissue (lung squamous tumor .fro~ri 3 patients, lung adenocarcinorim, prostate tumor, :colon tumor and lung tumor), .and different normal tissues, including lung from four patients, prostate, brain, kidney, liver, ovary, -skeletal muscle, skin, small intestine, myocardium, retina and testes. L86S-46 was found to be expressed at high levels in lung squamous tumor, colon tumor and prostate tumor, and -was undetectable in the other tissues examined. L86S-5 was found to ~be expressed in the lung tumor samples and in 2 out of 4 normal lung samples, but not in the other normal or tumor tissues tested. L86S-16 was found to-be expressed in all tissues except normal liver and normal stomach. Using real-time PCR, L86S-46 was found to be over-expressed in lung squamous tissue and- noirilal -tonsil, with. expression being Iow or undetectable in all other tissues examined.
E~AlVIPLE 6 ISOLATION-OF DNA SEQUENCES ENCODING LUNG TUMOR ANTIGENS
DNA sequences encoding antigens potentially involved in squainous cell -lung. tumor formation wexe isolated as follows.
A lung tumor directional cDNA expression library was constructed employing the Lambda CAF Express expression system :(Stratagene, La Jolla, CA.).
Total RNA for the library was taken from a pool. of two human' squamous epithelial lung carcinomas and poly A+ RNA was isolated- using oligo-dT cellulose (Gibco BRL, Gaithersburg, MDT. Phagemid were rescued at random and the cDNA sequences of -isolated clones were determined:
The determined cDNA sequence for the clone SLT-Tl is provided in SEQ ID NO: 102, .With the determined 5 ° cDNA sequences for the clones SLT-T2, SLT-T3, SLT-TS, SLT-T7, SLT-~9~ S-LT-T10, SLT-T11 and SLT-T12 being provided .in SEQ ID NO: 103-110 respectively. The corresponding predicted amino acid sequence for SLT-T1, SLT-T2, SLT-T3~ SLT-T10 and SLT-T12 are provided in SEQ
2Q ID NO: 111-115, -respectively. Comparison of the sequences for SLT-T2, SLT-T3, SLT-T5, SLT-T7, SLT-T9 and SLT-T11 with those in the public databases as described above, revealed no significant homologies. The sequences for SLT-T10 and SLT-were found to show some hoW orgy to sequences previously identified in humans.
The sequence of rLT-T1 was determined to show some homology to a -f~A,C ,clone of unknown pretein functibii. The cDNA seguence of SLT-T1 (SEQ
ID
NO: 102) was found to contain a-mutator (MUTT) domain. Such domains are known to function in removal of damaged guanine from DNA that can cause A to G
transversions (see, =for example, el-Deiry, W.S., 1997-Curr. Opin. Oncol. 9:79-87; Okamoto, K. et al.
1996 Int. J. Cancer 65:437-41; Wu, C. et al. 1995 Biochem. Biophys. Res.
Comrnun.
214:1239-45; Porter, D.W. et al. 1996 Chena. Res. Toxicol. 9:1375-81). SLT-Tl may thus be of use in the treatment, by -gene therapy, of lung cancers caused by, or associated with; a disruption in DNA repair.
In fui ther stud.i~s, DNA sequences. -encoding antigens potentially involved in a~enocarcinoya lung tumor formatiyn were isolated as: follows. ~
human lung turrior .directional cDNA eXpression .library was constructed employing the LaiTibda Z~.P -Express expression system (Stratagene; La Jolla, CA). Total RNA
for the library was takeri fro~n° a late SCID mouse passaged human adenocarcinomia and poly A+ RNA was isolated= using the Message Maker :kit (Gibco BRL, Gaithersburg, MD).
Phagemid were rescued at random and the cDNA sequences of isolated clones were determined:
The determined 5' cDNA sequences for five isolated clones (referred to as -SALT,'F3, SALT-T4, SALT-T7, SALT-T8, and SALT-T9) are provided in SEQ ID
NO: 116='120, with the corresponding predicted amino acid sequences being provided in SEQ ID NO: 121-125. SALT-T3 was found -to show 98% identity to the previously identified rhurrian transducin-like enhances protein TLE2. SALT-T4 appears to be the human homologue of the mouse H :beta 58 gene. SALT-T7 was found to have 97%
identity to human 3-mercaptopyruvate sulfurtransferase and SALT-T8 was found to show homology to human interferon-inducible protein 1-8U. SALT-T9. shows approxiiiiately 90% identity to human mucin MtJC SB.
,cDNA sequences encoding antigens potentially involued in syall cell lung carcinoma development were isolated as follows. eDNA expression libraries were constructed with mRNA from the small cell lung carcinoma cell lines NCIH69, NCIH128 and DMS79 .(all available from the American Type Culture Collection, Manassas, VA) .employing the Lambda ZAP Express expression system (Stratagene, La Jolla, CA). Phagemid were rescued at- random and the cDNA sequences of 27 isolated clones were determined. Comparison of the determined cDNA sequences revealed no significant homologies to the sequences of ~EQ ID NO: 372 and 373. The sequences of SEQ ID NO: 364, X69, 377, 379 and 386 showed some homology to previously isolated ESTs. The sequences of the remaining 20 clones showed some homology to previously identified genes. The cDNA sequences of these clones are provided in SEQ ID
NO:

363, 365-368, 370, 371, 374-376, 378, 380-385 and 387-3.89, wherein SEQ ID~
NO:
363, 366-36$; 370 375, 376, 378, 380-382, 384 and 385 .are hill-length sequences.
Comparison of the cDNA sequence of SEQ ID NO: 372 indicated that this clone (referred to as 128'TI) is a novel member of a family of putative seven pass transmembrane proteins. Specifically, using the computer algorithm PSOR'~, the protein was predicted ao -lie a type IIIA plasma membrane seven pass trarismembrane protein. A genemic clone was identified in the ~Genbarik database which contained the predicted N-terminal 58 arlaino acids missing from the amino .acid sequence encoded by SEQ ID NO: 372. The determined full-length cDNA sequence for the 128TI clone is provided in SEQ ID N,O: 390, with the ,corresponding ariiino acid sequence being provided-in SEQ ID NO: 39:1.
The e~pressiorl levels of certain of the isolated antigens in lung tur~ior tissues compared to expression levels in normal tissues was determined by microarray technology. The results of these stud-ies axe shown below in Table 3, together with the databank analyses for these sequences.

Clone SEQ~ Description LT+F/N SCC+MIN Squa/ Adeno/N

ID N

NO

DMS79- 363 STAT-ind inhib- 2.0 - -of T l cytokirie DMS79- 367 Neuronal-cell - 2.2 - -T6 death related DMS79- 369 Novel - 2.2 - -DIVIS79-370 Ubiquitin carrier- 3.9 2.2 -T10 protein DMS79- 371 HPVI6E1 pro - 2.1 - -T11 binding protein 128-T9 378 Elongation - 2.7 - -factor 1 alpha 128T11 380 Malate - 2.3 2.0 -dehyrogenase 128-T12 381 Apurinic/apyrim- 5.4 - -endoW clease NCIH69- 382 Sm-like protein- - 2.4 -T3 CaSm NCIH69- 3 84 Transcription - 2.5 - -T6 factor BTF3a LT+F/N = Lung Turrior plus Fetal :tissue over Normal. tissues SC+M/N = Lung Small Cell carcinoma plus- Metastatic over Normal tissues Squa/N = Squamous lung tumor over Normal tissues Aden/N = Adenocarcinama over Normal tissues SYNTHESIS DF POLYPEPTIDES
Polypeptides may be synthesized on a Perkin Elmer/Applied Biosystems Division 430A peptide synthesizer using F1VIOC chemistry with HPTU (O.-B.enzotriazole-N,N,N',N'-tetramethyluroriizuri heXa~luorophosphat~) activation. A Gly-Cys-Gly sequence may be aftached to the amino terminus of the peptide to provide a~
method of conjugation, -binding to an immobilized surface, -or labeling of the peptide.
Cleavage of the peptides from the solid support may be carried out using the following cleavage mixture: trifluoroacetic acidethanedithiolal~ioanisole:water:phenol (40:1:2:2:3). After cleaving fox 2 hours, the peptides may be precipitated in cold methyl-t-butyl=ether. The peptide pellets may then be dissolved in iwater containing Q.1 % trifluoroacetic acid (TFA} arid lyophilized prior to .purification by C
18 rever se phase HPLC. A gradient of '0%-60% acetonitrile {containing 0.1 % TFA) in water (containing 0.1 % TFA) may be used to elute the peptides. FollovVirig lyophilization ,of the pure fractions, the peptides may be characterized using electrospray or other types pf mass spectrometry and by ammo acid analysis.

ISOLATION AND CHAKACTERIZATION OF DNA SEQUENCES ENCODING LUNG TUMOR
ANTIGENS BY T-CELL EXPRESSION CLONING
Lung turrior antigens may also be identified by T cell eXpression cloning.
One source of tumor specific T cells is from surgically excised tumors from human patients.

A non-small cell lung carcinoma was minced and eiazymatically digested for several hours to release tumor cells and infiltrating lymphocytes -(tumor infiltrating T cells, or TILs). The cells were washed in HBSS buffer and passed .over a Ficoll (100%/75%/HBSS) discontinuous, gradient to separate tumor cells and lymphocytes from hOn-viable cells. Twa bands were harvested from the -interfaces; the upper band at the ~5%/HBSS interface contained. predominantly tumor cells while- the lower band at the 100%/75%/HBSS interface contained a majority of lyW phocytes. The TILs were expanded in ,culture, either in 24-well plates with culture media supplemented with 10 ng/ml IL-7.and 100 U/ml IL-2, or alternatively, 24.-well plates that have been pre-coated with the anti-CD3 monoclorial antibody OKT3. The -resulting TIL cultures were ar?alyzed. by FACS to confirm that a high percentage were CD~+ T.~cells (>90%
of gated population) with oily a sriiall percentage of CD4+ cells.
Iri addition, -non-small .cell lung carcinoma cells were expanded in culture .using standard techniques to est~:blish a tumor cell line (referred to as LT391-06), which was later confirmed to be a lung carcinoma cell line by immunohistochemical analysis. This tumor cell line was transduced with a retroviral.
vector to express human CD80, and characterized by FACS analysis to confirm high expression levels of CD80, class L 1VIHC and class iI MHC molecules.
The ability of the TIL lines to specifically recognize autologous lung tumor was demonstrated by cytokirie release assays (IFN-~y arid TNF-a) as well as 5'Cr release assays. Briefly, TIL cells from day 21 cultures were co-cultured with either autologous or allogeneic tumor cells, EBV-iiW iortalized LCL, :or control cell lines Daudi and K562, and the culture supernatant monitored by ELISA for the presence of cytokiries. The TIL specifically recognized autologous tumor but not allogeneic tumor.
In addition, there was no recognition of EBV-immortalized LCL or the control cell lines, indicating that the TIL lines are tumor specific and are potentially recognizing a tumor antigen presented by autologous MHC molecules.
The characterized tumor-specific TIL lines were expanded to suitable nuiribers for T cell expression cloning using soluble anti-CD3 antibody in culture with irradiated EBV transformed LCLs ,and PBL feeder cells in the presence of 20 LT/ml IL-12f 2. Clones from the expanded TIL lines were generated by standard limiting dilution techniques. Specifically, TIL cells were seeded at 0.5 cells/well in a 96-well U bottom plate and stimulated wi.'th CD-80-transduced autologous, tumor .cells, EBV
transformed LCL, and PBL feeder cells in the presence of 50 U/~nl IL-2. The specificity of these clones fox autologous tumor was confirmed by SICr microcytotoxicity and IFN-y bioassays.
These CTL clones were demonstrated to be HLA-B/C restricted by antibody blocking experiments. A representative CTL clone was tested on a panel of allogeneie -lung .carcinomas and it recognized both autologous tumor and a lung squarnous cell carcinoma (936T), As the only class I 1VIHC molecule shard among these tumors was HLA-Cw1203, this indicated that this -was the restriction element used by the CTL. 'This finding was confirmed by -the vecognition of a number of allogeneic Lung carcinomas transduced with a retroviral vector encoding HLA-CwI203 by the CTL.
PolyA mRNA was prepared from 'a lung tumor cell line referred to as LT391-06 using Message Maker (Life Technologies;-Rockville, MD). The subsequent step's involving cDNA synthesis were performed according to Life Technologies cloning manual (Superscript Plasmid System for cDNA Synthesis and Plasriiid Cloning). ~IVIodifications tp. the protocol were made as follows. At the adapter addition step, EcoRI-Xmi~I adapters (New England Biolabs; Beverly, MA) were substituted.
Size fractionated cDNAs were ligated into the expression vector system HisMax A, B, C (Invitrogen; -Carlsbad, CA) to optimize for protein expression in all three coding frames. Library plasmids were then aliquotted at approximately 100 :CFU/well into a 96-well block for -overnight Liquid amplificatiQri. From these .cultures, glycerol stocks were made and :pooled plasmid was prepared by .autorriated robot (Qiagen;
Valencia, CA). The concentration of the plasmid DNA in .each well of the library plates was determined to be approximately 150 ng/ul. Initial characterization of the cDNA
expression library was performed by randomly sequencing 24 primary transformants arid subjecting the resulting sequences o BLAST searches against available databases.

The determined cDNA sequences are provided in SEQ ID NO: 443-4-80, with the results of the BLAST searches~be'irig provided-iri Table 4.
TABLE ~
CloneSEQ~ID:=NO:GenBank Descriptiow Aa_ccession-55163458; 459 Novel in Gehbai~k 55158' 452 Novel i~zGe~ba~k Hctrizology ao k~iawn sequences vwitH
unknown-function 55153443 444 7018516 H. Sapiens mRNA; cDNA DKFZp434M035 55154.445, 446 6437562 H. Sapiens Chr 22q11 PAC Clone p393 5517'450, 451 2887408 H. sapiens KIAA0417 rinRNA

55165462, 463 3970871 H. Sapiens HRIHFB2122 mRNA

Hoinol-ogy to known segtie~ices with known.
furi~tiori 55155447 7677405 H. Sapiens=F-box protein FBS
(FBS) 55156448, 449 3929584 H. Sapiens EEN pseudogene 55161454, 455 450335Q H. sapiens DNA (cytosine-S-)-methyltransfera.se 1 (DNMT1) 55162456, 457 31220 ' ERI~l mRNA for protein serine/threonine kinase 55164460, 461 6677666 H. sapiens RNA-binding protein (autoantigenic) (RALY) 55166464, 465 3249540 H: sapieris ribonuclease P .protein subunif p40 (Rl'F~40) S 466, 467 7657497 H. Sapiens. renal turiyor antigen S (RAGE) 55168468, 469 2873376 H, sapiens exportin t~riiRNA

SSI69470, 471 3135472 H, sapiens-Cre binding protein-like mRNA

55171474 4759151 H. sapiens sperinine synthase (SMS) 55173476, 668&148 H. sapiens partial mRNA for NICE-3 protein 55174:477, 478 531394 Human transcriptiorial coactivator 55175479 6563201 H. Sapiens translation initiation factor eIF-2b delta subun~t 55176480 298.60 hCENP-Bgene, for centromere autoantigen B .(CENP-B) Homology to Riliosoinal l~rote'iri 55159453 337494 Ribosomal protein L7a (surf 3) large suburiit mRNA

55170472, 473 4506648 H.sapiens mRNA for ribosomal protein L3 Clone SEQ ID NO: GenB:ank Description' Accession 55172 47S 388031 H. Sapiens ribosomal protein For T cell screening, approximately 80 ng of the library plasW id DNA
and. 80 rig of HLA-Cw1203 plasrnid -DNA was mixed with the lipid Fugene according to the manufacturers' instructions and ~transfected~ in duplicate into CQS=T
cells. After incubation at 37 °C for 4,8 hours, the transfection mixture was xeinoved and 10,000 LT391-06 CTL were added~to each well in fresh media containing human serum.
The ability of T cells to recognize an antigen in the library was assessed by =cytokine release aftex .6rhours (TNF-alpha, WEHI bip-assay) or after 24 hours (IFN-gamma, ELISA.). Approximately 2:0 x 105 clones (in plasiriid pools of 100) were screened. °using this systerii iri COS-7 cells. Three plasmid pools were identified (referred to as 14F10, 19A4, andT 20E10) that were recognized by LT391-06 CTL.
Transfectian of these plasmid pools into COS-7 cells led .to production of bath IFN-gamma and TNF-alpha from the LT391-06 CTL at levels significantly above 'background. 'Pools 1.4F10, 19A4 and 20E10 were "broken down" into several hundred individual plasmid DNAs and retested. The sequences of 24 novel clones isolated from pool 14F10 are provided in SEQ Ip NO: 481-511.
One plasmid (3D9). from pool 14F10, ono plasmid from pool 20E10 and S plasmids (2A6, 2E11, Zfl2, 3F4, 3H8) from pool 19A4 wore capable of reconstituting T cell recognition. Sequencing of these plasriiids led to the identification of a 7:8 kB. cDNA insert (referred to as clone 14F 10), a 2.2 kB cDNA insert (referred to as clone 19A4, SEQ ID NQ:44,0), and a clone referred' to as 20E10. The full-length cDNA sequence for 14F 10 is :provided in SEQ ID NO: 44.1. Gione 14F 10 does not contain .tlie first two "G" nucleotides found at the S' end of 19A4, and the 3'-proximal 24 by of 19A4 differ from the corresponding region of 14F1'0 (nucleotides 2145-2165).
2S Furthermore, 3837 by of 3' additional sequence was isolated for clone 14F10. The S' erminal cDNA sequence (337 bp) .of clone 20E10 is provided in SEQ ID NO: 442.
20E10 contains an additional 3 .nucleotides '(as compared to 19A4) at he S'-most end.
The additional sequence from the S' :end of clone 20E10 contains an "ATG" and therefore appears to contain the translational start site of a novel open reading frame.
BLAST search analysis against the ~GenBarik database identified these sequences as having significant homology with a truncated- human cystine/glutamate transporter gene. Unlike the published sequence, however, clones 14F1-0 and 19.A4 contain a unique S' terminus consisting of 1.81 nucleotides. This novel sequence replaces the published. S' -region and results irr the removal of the reported initiating rriethiorline (start ,codon} and an additional two amino acids of the reported transporter protein.
Therefore, the translated product of clones ~lA~FlO and 19A4 is different than the cystine/glutamate .transporter protein. Furthermore, T cell recognition of other lung tumors ;demonstrates that this antigen is expressed by other tumors as v'vell.
The epitope and amino acid sequeriee encoded within clones, 19A4 and 14F10 which reconstitutes T cell recognition of ariti~LT391-06. cells were mapped as follows. Cos-7 cells were transfected with 80 ng/well HLA-Cw1203 along with titrated amounts of cDhTA encoding clone 19A4, a potential open reading frame located in the unique 5' terminus of 19A4, ox the open reading frame frorr~ the cystine/glutamate (Cys--Glu) transporter :gene, cloned into a -etikaryotic expression vector and tested for stimulation of anti-LT391-06 T cells ixr a TNF assay. As a positive control Cos-7 cells were .co-transfected with HLA-Cw1203 and the positive plasmid clone 19A4 described :above-. The Cys-Glu .transporter expression construct was isolated by -PCR
using 5' and 3' primers ~pecif c for the known ORF of the transporter with 19A4 as template. In addition, .each 5 ° primer contained a Kozak translation initiation site and starting methionirle to drive translation of the polypeptide. CTL against LT391-06 .did not recognize transfectants expressing the Cys-Glu transporter construct, but did recognize transfectants expressing 19A4 and the 5' ORF from 19A4.
In subsequent experiinerits, Cos-7 cells were co-transfected with 80 ng/well HLA-Cw1203 along with titrated amounts of DNA of transposition mutants F 10 .and C 12, respectively, and tested. for simulation of anti-LT391-06 T-cells in a TNF
assay. As a positive control, Cos-7 cells were co-transfected with HLA-Cw1203, and clones .of the 5' ORF of 19A4. Transposition mutants F10 and C12 vl~ere obtained by transposon-mediated mutation of .the 14F10 clone and screening for insertion site by sequence analyses. The transposon of -:mutant F10 is inserted approximately 304 by from the 5' EcoRI cloning site of the 14F10 cDNA. This mutation did not disrupt translation -of the T -cell epitope. By contrast, the transposon of mutant C
1,2, which is ins~rted~ approximately 116 by from the 5' EcoRI cloning site of the 14F10 cDNA, was found to interrupt translation of the T .cell eptiope. Thus 'the epitope in-14F10 maps between these 'two trarlsposon insertion sites. Tile amino acid sequence of the region betweeythe-.C12 and F-10 tr~nsposon insertion sites is provided in SEQ ID' NO:
5$6.
series ~f 11 .overlapping 16-mer and= 15-mer peptides for the region slzowri in SEQ ID NO: 586-were prepared and~.tested for stimulation of anti-LT391-0'6 1,0 cells, as deteniiined by cytokirie release .in TNF and IFN-y .assays.
Oilly .the peptide provided in SEQ- ID~ NO: 587 -(corresponding to residues 5-20 -of S~Q ID NO:
586) stimulated cytol~ine release. These studies .demonstr to that the HLA-Cw1203 restricted epitope ofthe L'T391-06 antigen is contained within SEQ IDvNO: 587.

1 S ISOLATI01~ AND CHARACTERIZATION OF DNA SEQUENCES ENCODING
LUNG TUMOR ANTIGENS BY PCR SUBTRACTION
This example describes the isolation and characterization. of cDNA
clones from a P.Cl~ subtracted expression library ,prepared from the human lung tumor cell line LT391-06 described above.
20 Tester poly A mRNA was prepared from the cell line LT391-06 as described above. Driver poly A mRNA was isolated from a human acute .T :cell leukeinia/T lymphocyte cell .line (Jurkat) which is derived from non-lung cells and is not recognized by LT391-06 reactive T cells. 'The subtraction Was performed according to the -rilethod of Cloritech (Palo Alto, CA) with the 'following changes: 1) a second 25 restriction digestion reaction of cDNA was completed using a pool of enzymes (MscI, PvuII, ~StuI and DraI). This was in addition to, and separate from, the Clontecli reconimerided single restriction enzyme digestion with RsaI. Each restriction digest set was treated as a separate library to ensure -.that the -final mixed library contained overlapping fragments. Thus, the epitope recognized by the T cells should be 30 represented on a fragment within the library ,and not destroyed by the presence of a single restriction site within it. 2) The ratio of .driver to tester cDNA was increased in the hybridization ste~ss to increase subtraction stringency. To axlalyze the efficiency of the subtraction, actin. was PCR amplified from dilutioris of subtracted, as well as unsubtracted, PCR samples. The second arilplification step utilized primers that were rriodified from those normally used. Three nested. PC1Z primers were engineered to con°tain a cleavable EcoRI- site (not utilized during cloning) that was in one of three -frames. Thus, secondary ampIi~cation with these priznexs resulted in products that could be ligated directly into the cukaryo'tic expression plasmid pcDNA4His%Max-Topo (Invitrogen). This -result~c~ irl the PCR subtracted and amplified fragments being represented iri-fr~ine ~omewliere within the library. pue to the :mechanics of the subtraction only 5Q% of fragments will be in the correct orieritatian, The complexity and redundancy of tl~e library was characterized by sequencing 9C randomly picked clones from the final pooled PCR subtraction expression library, referred to as LT391-06PCR. These sequences (SEQ ID NO: 512-581) were analyzed by comparison to sequences in publicly available databases (Table 5).

Clone SEQ~ID.l~TOGenBanl~ Description Accession 57235.532 Novel in Gehliartk 57255 54'7 Novel in Ge~batik 57264 554 Novel in Genbai~k Homology to kriowii sequences with unknown function 57215 518 5689540 H. sapiens.mRNA for K,IAAl 102 protein 57223 522 2341006 Human Xq.I3 3' end of PAC-92E23 57227'S24 7022540 H. Sapiens cDNA FLJ10480 fis, clone NT2RP2000126:

57238 535 6807795 H. Sapiens mRNA; cDNA
DKFZp76 ~ G02121 57239 536 5757546 H. sapiens clone DJ0~23F17 57243 539 7023805 H. Sapiens cDNA FLJl 1259 fis, clone 57245 540 4884472 H. Sapiens mRNA; .cDNA DKFZp586O2223 57267 557 6808218 H. sapiens mRNA; cDNA DKFZp434O1519 57268 558 10040400- Sequence 12 from Patent W09954460 CloneS~Q-ID NO: GenBank -Descriptiari.
Accession 57270560 7959775 H. sapiens PROI489 mRNA

57271561 ~500:1~58 H. sapiens mRNA; cDNA DKFZp586B0.918 57281S67 656020. H. sapiens clone RPI 1- 50107 57283569 28~96~ Human mRNA for KIAA0108 gene 57285570 7019813. H, Sapiens cDNA FLJ200Q2 fs, clone ADKA015'7'7 .~H~inology tai known sequences with.
known function 5720'7512 517176. H: sapiens YAP6S mRNA

57210S14 6841233' H. Sapiens HSFC292~ mRNA

57211S15 260609f H~. sapiens Cyr61 protein (CYR61)-mRNA

57212516 33964& Hurnan-thioredoxin (TXN) mRNA

57219519 4504616 H. Sapiens insulin-.like growth facto binding protein 3 (IGFBP3) 57.221520. 72'74241 H. Sapiens novel retinal pigment-epithelial cell protein (NORPEG) S7222S21 18956 Human, plasminogen activator inhibitor- 1 gene 572285~5 4757755 H. sapiens annexin A2 (ANXA2) 57230527 1-80800 Human alpha- 1 collagen type IV gene, exori 57232529 6729061 H. Sapiens clone RPC11- 98D12 from 7q31 57233530 338391 Spermidine/ spermine N1- acetyltrarisferase 57234X31 7305302 H. Sapiens NCK- associ~.ted protein (NCKAP 1 ) 57236533 4929722 H. Sapiens CGI- 127 protein 57242538 4503558 H, Sapiens epithelial membrane . protein 1 (EMP 1 ).
~

57248541 18=3585 . Huinan~ pregnancy- specific beta-glycoprotein c 57250543 4759283 H. Sapiens ~xbiquitin carboxyl-terminal esterase L~ (UCHL1) 57251544 1236321 Human laW inin gamrrta2 chain gene (LAlVIC2) 57253545 213831 H, Sapiens lysyl hydroxylase isoform 2 (PLOD2) 57254546 536897 Human follistatin- related protein precursor mRNA

57257548 339656 Human endothelial-.cell-thrombomodulin 57258549 190467 Human prion protein (PrP) .mRNA

57261551 338031 Human serglycin gene 57262552 178430 Human alphoid DNA (alphoid repetitive CloneSEQ ID.:NO:GenBank Description A ccession sequence) 57265SSS 4S02S62 H. sapiens calpain, large polypeptide (CAPN2) 57266SS6 398163 H. Sapiens mRNA fox insulin-like growth factor binding protein- 3 57269SS9 7262375 H. carboxylesteras~ 2 (intestine, liver) (CE~~) 57272S62 467560' H, sapiens mRNA for cysteine dioxygenase type 1 57274563 482664 H. sapiens atniexin A3 (ANXA3) S727S564.- 22.8'1904. -H. sapiens B:ruton's ty~. kinase (B'TK), alpha.- D- galactosidase A (GLA)-57277565 4557498- H. sapieris C- terrninal~ binding protein 2 (CT~P2) 57282568; 1.89245 Human; NAD( P) H: menadione axidoredttctase mRNA

57287571 28S2S Human mRNA for azriyloid A4 precursor of 57288S72 47S77S5 Alzheimer's disease H. sapieris annexin A_2 (ANXA2) 57289573 5729841 -I-~. sapietis glyoxalase I
(GLO1) mRNA

57290574 -6103642 H. sapiens F- box protein FBX3 mRNA

S729S57'6 182513 Human ferritin L chain mI~NA

57299579 37137 Human mRNA for thrombospondin 57301S80 179682 Human (clorie A12) C4b-,binding protein beta- chain ~

5730258.1 6042205. ~H.
,. sapiens membrane metallo-endopeptidase (neutral endopeptidase,enkephalinase, CALLA, CI710). (1VIME).

57213S17 2665791 ~ H. sapiens.caveolin- 2 mRNA

S72S9SSO 2665791 H. Sapiens caveolin- 2 mRNA

S722SS23 179765 Human caleyclin gene 57229'S26 179765 Human calcyclin gene 57237S34 186962 Human lanTinin B2 chain gene 57249S42 186962 Huizian laminin B2 chain gene 57231S28 4972626 H. Sapiens caveolin 1 (CAVl) gene 57296S77 4972626 H. Sapiens caveolin I (CAV 1 ) gene 57297S78 4972626 H. Sapiens caveolin 1 (CAV1) gene 57240S37 266237 insulin- like growth factor binding protein 3 57292S7S ~ 184522 Human insulin- like growth-factor-binding protein- 3 gene 57263SS3 4504618 I~. Sapiens insulin- like growth factor Clone SEQ ID NO: ~~enBank Description.
Accession binding protein 7 (IGFBP7) 57280 ~6&. 4504618 H. Sapiens insulin- .like growth factor binding protein 7 (IGfBP7) Homology-to RibosomalvProteiri 57209 513 337504 Human. ribosomal protein S24 mRNA

EXAI~~IPLE I0 ISOLATION AND CHARACTERIZATION OF T CELL RECEPTORS FROM T CELL CLONES
SPECIFIC FOR LUNG T'UM -OR ANTIGENS
This exarmple describes the cloning arid sequencing 'of T cell' receptor (TCR) alpha and beta chains frorii a CD8 T cell clone specific for an. antigen expressed by the lung tumor celh line LT391=06: T cells lave, a liriaited lifespan.
Cloning of TCR
chains any subsequent transfer would essentially enable infinite propagation of the' T
cell specificity. :Cloning of tumor antigen TCR .chains allows the transfer -of the specificity into T cells isolated from patients that share TCR MHC-restricting alleles.
such T.cells can there be expanded and used in adoptive transfer techniques to introduce the tumor antigen specificity into .patients carrying tumors that express the antigen (see, for example, Clay et al. J Immunol. 163:507 (1999)).
Cytotoxic T lymphocyte (CTL) clones specific for the lung tumor cell line LT391-06 were generated. Total mRNA fr, oin 2 x 106 cells from 15 such clones was isolated using Trizol reagent and cDNA was synthesized- using Ready-to-Go kits (Phariilacia). To-deternline Va and Vb sequences iri:these clories,.a panel of Va and Vb subtype-specific primers was synthesized and used in RT-PCR reactions with cDNA
generated from each of the clones. The RT-PCR reactions demonstrated that each of the clones expressed 'a common Vb sequence that corresponded to 'the Vbl3 subfamily.
Using cDNA generated from one of the clones (referred o as 1105), the Va sequence expressed was.deterriiined to be Va22. To clone the full TCR alpha and beta chains from clone 1105, -primers were :designed :teat spanned the initiator and terminator-coding TGR -nucleotides. 'Standard 35-cycle ~T PCR reactions, were established using cDNA synthesized from the CTL clone and the primers, with PWO (BMB) as the thermostable polymerase. The resultant speeif c bands (approximately $50~ by for the alpha chain and approximately 950 by for the beta chain) were Iigated into the PCR
blunt vector (Invitrogen). and ransformed into E. coli. E. coli transformed with plasmids containing the full-length alpha and beta ,chains were identified, and large scale preparations of the cor~espondirig plasmids were generated. Plasniids containing full-length TCR alpha .and beta chains were sequenced: The >deterinined cDNA
sequences for the alpha and beta chains are provided in SEQ ID NO: 583 and 582, respectively, with the corresponding arilino acid sequences being provided in SEQ ID
NO: 58 ,4 and 585, respectively.
From tlie. foregoing it will be appreciated. that, although specific embodiments of the invention Have been described herein for pizrpases of illustration, various rriodifications may be made without deviating fraril the spirit and scope of the invention. Accordingly; 'the invention is not limited except as'by the appended claims.

., 1 SEQUENCE LISTING
<110> Coxixa Corporation Reed, Steven G.
Henderson, Robert A.
Z,odes, Michael J.
Fling, Steven P.
Mohamath, Raodoh Algate, Paul A.
Secrist, Heather Indirias, Carol Yoseph Benson, Darin R..
Elliot, Mark Mannion, Jane Kalos, Michael D.
<120> COMPOSITIONS AND METHODS FOR
THE THERAPY AND DTAGNOSIS OF LUNG CANCER
<130> 210121.47501PC
<140> PCT
<141> 2001-03-38 <160> 587 <170> FastSEQ for Windows Version 3.0 <210> 1 <21i> 339 <212> DNA
<213> Homo sapien <400> 1 gtactcagacaggatagtcatcatgtagcacaaagcamatcctgtttctatacttgtagt 60 ttgctctcactcagtggcatratcattactatacagtgtagaatgttrttatgtagcata 120 gatgtggggtctctagcccacagctctstacctttgtctagcactcctgtcctcatacct 180 ragtggcctgtccatcagcatgtttctcatctactttgcttgtccagtccactgtggtcc 240 tcccttgccctctcccttatgtggcagagtggaaccagctgtcctgagacttgagttcaa 300 catctggttcgcccatytgcatgtttgtggtctgagtac 339 <210> 2 <211> 698 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1)...(698) <223> n = A,T,C or G
<400> 2 gtactcagac cacgactgca ttttctccac tgctgacggg tctaatacca gctgcttccc 60 tttcttggag gcagagctng tgaccttgag aaagtgacct gtgaccatca tgtgggtagt 120 gagctgctgc aaggtgtcat gggagctccc acactccatg cactttwaga tctgggactt 180 gcaggcctca ractgccagg tgtagctcgc tccattttgg tagccatagc gsttgttgga 240 ggacaactgcaagttggcgttcttctgagaagaaaaagaatctgcaaaagatcctgtggt 300 tgaatcgggggaacacggccgattgacatcaaaaacgcgtttcttagcccgggtgaccat 360 tttcgaggaaatggttggggactggctccttcaaaggcactttttggttatgttttgttt 420 yaatcatgtkgacgctccaatcttggragggaatcgaangrantcnccnccaaaacatrc 480 stttcagraaccttttgarcatcctcttttttccgtrtcccggmaargcccytttccckg 540 ggctttgaaawyagcctsgttgggttcttaaattaccartccacnwgttggaattccccg 600 ggccccctgcccggktccaaccaattttgggraaaacccccncansccgttkggantgcn 660 acaacntggnntttttcntttcgtgntcccctngaacc 698 <210> 3 <211> X97 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1). .(697) <223> n = A,T,C or G
<400> 3 gtactcagacccccaacctcgaacagccagaagacaggttgtctcctgggccttggacac 60 agccngccaggccattgaagganaagcaaagacgaagcgaaccatctctctccattgtgg 120 gggccaagtagctgcantanccttcagtcccagttgcattgggttaaagagctcatacat 180 actatgtgtnaggggtacagaagcttttcctcatagggcatgagctctccnagagttgac 240 cttttgcctnaacttggggtttctgtggttcataaagttnggatatgtattttttttcaa 300 atggaanaaaatccgtatttggcaaaaagactccagggggatgatactgtccttgccact 360 tacagtccaaangatnttccccaaagaatagacattttttcctctcatcacttctggatg 420 caaaatcttttatttttttcctttctcgcaccnccccagaccccttnnaggttnaaccgc 480 ttcccatctcccccattccacacgatnttgaattngcannncgttgntggtcgggtcccn 540 nccgaaagggtntttttattcggggtnctganttnnnaaccnctnagttgaatccgcggg 600 gcggccnngngggttnnaccatgntgggganaactncccnccgcgnttggaatgccanag 660 ccttgaaanttttcttttggtcgccccccngagattc 697 <210> 4 <211> 712 <212> DNA
<213> Homo sapien <220>
<221> misc feature <222> (1) .-. . (712) <223> n = A,T,C or G
<400> 4 gtactcagacaaccaataggtgtgttyctcanatctgaaacacaaaaagattctagctna 60 taatgttsaatggttgagggtttaagtgatcttggtatgttngatttagcagcgatnggc 120 cgggtgcggtggctcacgcatgtatcccagcactttgggaggccgaggcaggaggatcac 180 ctgaggtcaggagtttgagaccagcctggccgacatggtnaaaccccgtctctactanga 240 atacanaaattagcccgggcatagtggcgcgtgcctrtgacctcsgctactttggggatt 300 ctcctgaggaagaattgcttgaactcagggaagtggargtttgcagtgagcttaaatcaa 360 gccactggcactcccagcctgggktaacagagccamgactctkgccgaaaaaaaaraama 420 cgacggagaanmagntctgttattccatgggaaattkgaatttccttcyttkaaatatct 480 taaaatnggtcctcctwaaaaaagttcggctggggcccgktggctcacattttkttaycc 540 cycccccttttggggarggccaarggccggkttgawtnncccttgaggggccanaactcc 600 agnaaccrgncccgggccarsmgwkgkstrarmccctttccyyccmaraaaawwcsmaaa 660 wwttycccsccygsykggctggkasckgttmyyyyygmtmcsyagcttgctt 712 <210> 5 <2l1> 679 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1)...(679) <223> n = A,T,C or G
<400> 5 gtactcagaccacctcacatgcagggtnagaaacatggagtgtgcggcagcatcctcctc 60 acatccctttgtgagcacggctgctccggaatactgaccatctgggctagcacgacctaa 120 cagagggttctgcaggatgtgctattttaaagcagctgggtgcaacttgtgaaaacggga 180 atctngaagcagaacatgtnatcagcgatggctgggattggtggacaggattgacaggag 240 tatttgaggctctaccaggcctgtctacaggacagcttcatcgaagggacattttttaac 300 ctgttattttanatnccacatatnttttttaatgctnaagcatacaggttgaatttctgg 360 atcgtaactactagtgacttctgaggtttacagttngaatatgttctcnnaggtttatca 420 agttntgttattgatgatnggtaatctacacctctggaagctgtngaatgtgaaaaagat 480 ncntncanctgaccagtttgnagggcactctcttctggnaagnaatccgnccaaaaaaat 540 tgtttcnagggggcntggggggtttaaaaaaatgtttctnttnccntaaaaatgtttacc 600 cnnctattgaaaaaatgggggtcgnggggggcttnaaatccccnanttntgaatnttnta 660 tccggaancttggtttccc 679 <210> 6 <211> 369 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1). .(369) <223> n = A,T,C or G
<400> 6 tcagtccagtcatgggtcctataagagaagtcactctgtgagtttccatggaggaagaaa 60 ~

aagcttcatttctttaccctgcagcaacagcggagggagggagagcctatcttctttgca 120 aattcattaactttgtggttgaagggagcagcgtcngaaactgctttagcacagtgggag 180 gaaaacaaacagattcatctccggaaaccaaaggaaagggtragtgggtttttattagcc 240 agctgtatcctagatggtcaatttccagtggatgaatacaccttacgtacgtttctcttg 300 cttcctacctnggcctgatcagctnggcacttraatcattccgtnggggtwgctgtnaca 360 ctggactga 369 <210> 7 <211> 264 <212> DNA
<213> Homo sapien <220>
<221> misc_feature -<222> (1)...(264) <223> n = A,T,C or G
<400> 7 tgctggatra gggatggggc acgggagcac agatmgactt taactgcccc cacgttntcm 60 aggaaaggat tacaggcgtg agccactgcg cccggcctct tctccacttt cataggttcc 120 agtctctggt tcttctttct cagtttgttg tttttgcttc ttaaatmatg gagatnagaa 180 tgaacactac actcggaatc aggaagccct gcctggcgcc tctgtcacct gtctaggggc 240 ttcttctcac tgagtcatcc agca 264 <210> 8 <211> 280 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1). .(280) <223> n = A,T,C or G
<400>

acctcaactgcccanaacanaactgttgtacaagatttgaggatttaacaatatttcaca 60 tgaaatatttcagacctacgngagggcttaaagacnaattaaatgagcaccngtgtgccc 120 accgccccnattaagaattagagcaagcagtgaggtgaagccttgtccttgcttttaaca 180 tagaaagtgatccaaattcaccaaacttgacttnnggttttgcagtgtggcctcctgatt 240 ctagacnctggcgaaacatttgatgggcaaaaaaaaaaaa 280 <210> 9 <211> 449 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1). .(449) <223> n = A, T, C or G
<400>

tcgtcaactccaggatggctttgaaaatnaatggacacagatctctcctgttttgatrat 60 ntgcagtgctnatgactggctttgcagttnattttgattcaggcaacagatgttcctttt 120 ggttccctgtctcccatgggcgtcatttcatgttgtcctctgccttcccccagatattct 180 aagttcaggacacaagcttctggcccatgcagagcagaggccatgaggggtcacagcatg 240 ggtacgggaggaaacactgggctnacccagatnctggacttgagtcttgcctctgctgct 300 tgctgcacagcttctgtcatggtgctaaacctgtgacctgcctcacaggcttagagcatg 360 cccgtagaagtactctnaactaaratgctttccacaaatgagatggtttcatgaaaactt 420 caaatagagggcctgggcaaaaaaaaaaa 449 <210> 10 <211> 538 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> ( 1 ) . . ( 538 ) <223> n = A,T,C or G
<400>

ttttttttttttcccaaaggcctcaraacactagtcttctaattccaagcagaaagttac 60 atccgccgggatacatgccacttggtttgataaatcaaaatacagcatccttcagatccc 120 tttgctgagcaatacaattatttgtatatgttacttttttttctgtttggctnaaagatt 180 tgatatgagctgaggaaaatgaagccnttactgctatnagatctnatccctttccaccac 240 ctttcagggatnttggcactgcayatattcagaattccccnnagtcgctngtgataaaaa 300 tgtcttcagagatggcagaatatgtttcctttggtacatgttcattaaaaatatacacgt 360 gctcactacgtggatatgtatgtnttgaccgatnacacaggctgatttagggaagagat 420 t aaaagcacacttngaatttattagcctttcaccnagactaanattctgaaattaagaatg 480 S
tattccttgg tcaacaattt tcctcttctc ttagccctct tacattgtan tggactga 538 <210> 11 <211> 543 <2l2> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1). .(543) <223> n = A,T,C or G
<400>

ttttttttttttgcccacagctgccatctttgtgtgataaggccaaccttctatgggaat 60 caaccctcgccatcccagcaaatcccctctctcccttctcatgggagtgccttgtattca 120 tcaggcatctgggacttgatgtgggtntgggatttgaaatcagagcacctnggtctctst 180 caccattctntcacttattagctctnaccttgggtnaatacctgccttagtgtcntaggt 240 acaatatgaatattgtctatttctcagggattgcaatgacnagtnnatnagtgcatgaga 300 gggtaaaaccacagggtactccgctcctccnaagaatggagaattttttctagaagccca 360 natntgcttggaaggttggccaccnagagccnnaatcttcttttatttnccactgaangc 420 ctaagaggnaattctgaactcatccccnnatgacctctcccgaatmagaatatctctggc 480 acttaccatattttcttgccctcttccacttacnaaactcctttattccttaacnggacg 540 aaa 543 <210> 12 <211> 329 <212> DNA
<213> Homo sapien <400>

cgatgacttgggcagtgagtgggcctcctgccaggtggcagggcacagcttagaccaaac 60 ccttggcctcccccctctgcagstacctctgaccaagaaggaaactagcaagcctatgct 120 ggcaagaccataggtggggtgctgggaatcctcggggccggctggcacccactcctggtg 180 ctcaagggagagacccacttgttcagatgcatrggcctcaggcggttcaaggcrgtctta 240 gagccacagagtcaaataaaaatcaattttgagagaccacagcacctgctgctttgatcg 300 tgatgttcaaggcaagttgcaagtcatcg 329 <210> 13 <211> 314 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1). .(314) <223> n = A,T,C or G
<400> 13 cgatgacttgcacccgggagctgtgacagtggcctggaagcagatggcagccccgtcaag 60 gcgggagtggagaccaccaaaccctccaaacagagcaacaactagtacgcggccagcagc 120 tacctgagcctgacgcccgagcagtggaagtcccacagaagctacagctgccaggtcacg 180 catgaagggagcaccgtggagaagacagtggcccctacagaatgttcataggttcccnac 240 tctnaccccacccacgggagcctgganctgcangatcccgggggaagggtctctctcCCC 300 atcccaagtcatcg 314 <210> 14 <211> 691 <212> DNA

<213> Homo sapien <220>
<221> misc feature <222> (1).x.(691) <223> n = A,T,C or G
<400>

cgattacttgcacaatgcanattagaacccaaatgaagggtacaacccagatcttctggc 60 ttccagttcagtgctgctgggtttttcttactaaaccaaaacaatkaagagcatagaagg 120 gaagagaagaataaagtctattttggtctttggtagcchgggtaangagaatgctstcac 180 tctacnagaaaacccnaagtgaacccggctaatcaggaccgtgcttgggaagggagcagg 240 ggcattacctttcaacaccagaggttctttgcCttctctctgcagggactcgargactat 300 gtgaagtggctgggarggcatcactcggcttggttcattggtrttctcatcataaactat 360 natttctttggaaaaagatcctcttgaaagartccttgccttccctacaggaaatcaagt 420 ctaggacagtgatcttgcccctgcttgcastctccgccggctgatcttatcsgscccagt 480 tkatgtgsamcgctccttggatrtkactcttgttttwctccvaggaaggggcytgcmagt 540 ccnwtnaatgamssgggcccttaactccggscrggtnamyncttgsctscrattttgggt 600 ycytcttcytttgsccmggttcktcnaaaccacttngttraattccccggsccgcctkgc 660 nggtycaaccwttttgggaamamcycccccc 691 <210> 15 <211> 355 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1). .(355) <223> n = A,T,C or G
<400> 15 acctgaactgtgtgttgaagagtgatgtcctgctgcctggagctcaagtcactactgatg 60 accgtgcctatgtccgacagctagttncctccatggatgtgactgagaccaatgtcttct 120 tcyaccctcggctcttacctttgacnaagtctcccgttgagagtactaccgaaccaccag 180 cagttcgagcctctnaagagcgtctaagcgatggggatatatatttactggagaatgggc 240 tcaacctcttcctctgggtgggagcaagcgtccagcagggtgttgtccagagccttttca 300 gcgtctcctccttcagtcagatcaccagtggtntgagtgttctgccagttcaggt 355 <210> 16 <211> 522 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1)...(522) <223> n = A,T,C 'or G
<400> 16 tcagtccagtgaggtggaagacttcgaggctcgtgggagccgcttctccaagtctgctga 60 tgagagacagcgcatgctggtgcagcgtanggacgaactcctccagcaagctcgcagacg 120 tttcttgaacaaaagttctgaagatgatgcggcctcagagagcttcctcccctcggaagg 180 tgcgtcctctgaccccgtgaccctncgtcgaangatgctggctgccgccgcggaacggan 240 gcttcagaagcagcagacctcctngcgctcccttgccttcctcagctgcctcctgcgccc 300 tgtgcccggctgactggaggaggcctgtccaattctgcccgccccatggaaaagcgggct 360 tgactgcattgccgctgtatnaaagcatgtggtcttacagtgttnggacngctnatnaat 420 ttnatcctnctntgtaatacttcctatgtgacatttctcttccccttggaaacactgcan 480 attttaactg tgagtttgat ctcttctngt gttactggac tg 522 <210> 17 <211> 317 <212> DNA
<213> Homo sapien <400> 17 gtgtcgcgaattcgcggtggtgctaagaaaaggaagaagaagtcttacaccactcccaag 60 aaggataagcaccagagaaagaaggttcagccggccgtcctgaaatattataaggtggat 120 gagaatggcaaaattagttgccttcgtcgagagtgcccctctgatgaatgtggtgctggg 180 gtgtttatggcaagtcactttgacagacattattgtggcaaatgttgtctgacccactgt 240 ttcaactaaccagaagacaagtaactgtatgagttaattaaagacatgaactaaaaaaaa 300 aaaaaaaaaaactcgag 317 <210> 18 <211> 392 <212> DNA
<213> Homo sapien <400> 18 tggagatttctaatgaggtgaggaagttccgtacattgacagaattgatcctcgatgctc 60 aggaacatgttaaaaatccttacaaaggcaaaaaactcaagaaacacccagacttcccca 120 agaagcccctgaccccttatttccgcttcttcatggagaagcgggccaagtatgcgaaac 180 tccaccctcagatgagcaacctggacctgaccaagattctgtccaagaaatacaaggagc 240 ttccggagaagaagaagatgaaatatgttccggacttccagagaagagaaacaggagttc 300 gagcgaaacctggcccgattcagggaggatcacccccaccttatccagaatgccaagaat 360 cggacatcccagagaagccccaagaccccccg 392 <210> 19 <211> 2624 <212> DNA
<213> Homo sapien <400> 19 gaaacagtgagaaggagattcctgtgctcaatgagctgccagtccccatggtggcccgct 60 acattcgcataaaccctcagtcctggtttgataacgggagcatctgcatgaggatggaga 120 tcttgggctgcccactgccggatcctaataactattatcaccgacgtaatgagatgacca 180 ccacggatgacctggattttaagcaccacaactattaggaaatgcgccagttgatgaagg 240 ttgtcaatgaaatgtgccccaatattaccaggatttacaacattggcaaaagccaccagg 300 gcctgaaattgtatgcggtagagatctctgaccatcctggggaacatgaagttggtgagc 360 ccgagttccactacatcgcaggggcccacggcaatgaggttctgggacgagaactgctgc 420 tgctgctgctgcacttcctctgccaggaatactcggcgcagaacgcacgcatcgtccgct 480 tggtggaggagactcgaatccacattctaccctccctcaatcctgatggctatgagaagg 540 cctatgaaggaggttccgagttgggaggctggtccctgggacgttggacccatgatggca 600 tcgatatcaacaacaactttccggatttaaactcgctgctctgggaggcagaggaccagc 660 agaatgccccaaggaaggtccccaaccactacattgccatccctgagtggtttctgtctg 720 agaatgccacagtggccacagagaccagagccgtcatcgcctggatggagaagatcccgt 780 ttgtgctgggaggcaacctacaggggggtgagctggtcgtggcatacccctatgacatgg 840 tgcggtccctgtggaagacccaggagcacaccccaacacctgatgatcatgtgttccgct 900 ggctggcgtattcctacgcctccactcaccgcctcatgacagatgccaggaggcgagtgt 960 gccacacggaagattttcagaaggaggagggcaccgtcaatggggcttcctggcacacag 1020 tggctggaagtctaaacgatttcagctacctccatacaaactgctttgagctgtccatct 1080 acgtgggctgtgataaatacccacacgagagcgagctgccggaggaatgggagaataacc 1140 gggagtctctgattgtgttcatggagcaggttcatcgaggcatcaaaggcatagtgagag 1200 atttacaagggaaagggatttcaaatgctgtcatctctgtggaaggtgttaaccatgaca 1260 tccggacagccagcgatggggattactggcgtctactgaaccctggcgaatatgtggtca 1320 cagccaaggcggaaggctttatcacttccaccaagaactgcatggttggctatgatatgg.1380 gagctactcggtgtgacttcaccctcacaaagaccaacctggctaggataagagaaatta 1440 tggagacatttgggaagcagcctgtcagcctaccctccaggcgcctgaagctgcggggac 1500 ggaaaaggcggcagcgtgggtgaccctgtcggacacttgagacataccccagaccgtgca 1560 aataaaaatccactccagtagtaactctgtagcaggctttccctgttgttttgactgtaa 1620 ttcaagagacactcaggagcatacctgcatggcttggctgaccccaaaggggagggctgg 1680 tggctcagggtgttttgttttttgttttttgttttttcctttgttctcatttatccaaat 1740 accttgaacagagcagcagagaaaggccggtggcagtgagggaattaattcagtgagtca 1800 gtctgagattctaaaaagggtgcttgaccactggccaggaagggaaatcaggccttcccc 1860 catttgcgtgacattcaagcttcccagtgcatttgcaagtggcacagttgacattgcagc 1920 acccagggaatcctttgccccagatgttatcatttgagatgctcttatgcagcctaagaa 1980 aatccatcctctctggccccaggggacaagccaagctgctatgtacacactcggtgttct 2040 attgacaatagaggcatttattaccaagtgtgcatcgctgagtcctaaat'cagctctgtt 2100 cctttttccaacaaagcttgtcttcctaagagcagacagaagtggagagcacccaagaat 2160 gagtgctgggcagcagaccctgggggagggggcttgctatcccagaaagcccctaaaccc 2220 tttgctgctccattagccctggggtgaggagagccagacatgttaggaggccagagcagt 2280 cagtcagggcatcttggaaaagaccttgaaggaagcaaaccctgggttccttttgctcca 2340 gaatgtgagagctccaagttggccccaatcaggaggggagtaatgatgaacatacagacg 2400 gccacatcttgccaatcaagcatcatctgatgaaaaagaaagcaatcttaggattacctg 2460 ggacacgtcagtctgggagaggtggttgaatcattgtgtaagggaatagtgtatctaatc 2520 tgtgttgatcctgctgccttgttgacctggagagaatgaaacaaacaaacacataaacaa 2580 ataaagcaaatggtaagattaaaaaaaaaaaaaaaaaactcgag 2624 <210> 20 <211> 488 <212> DNA
<213> Homo sapien <400> 20 CtttCaaCCCgCgCtCgCCggctccagcccCgCgCgCCCCCdCCCCttgCCCtCCCggCg 60 gctccgcagggtgaggtggctttgaccccgggttgcccggccagcacgaccgaggaggtg 120 gctggacagctggaggatgaacggagaagccgactgccccacagacctggaaatggccgc 180 ccccagaggccaagaccgttggtcccaggaagacatgctgactttgctggaatgcatgaa 240 gaacaaccttccatccaatgacagctcccagttcaaaaccacccaaacacacatggaccg 300 ggaaaaagttgcattgaaagacttttctggagacatgtgcaagctcaaatgggtcgagat 360 ctctaatgaggtgaggaagttccgtacattgacagaattgatcctcgatactcaggaaca 420 tgtttaaaatccttacaaaggcaaaaaatcaagaaacaccccgacttccccgagaaagcc 480 cctaaccc 488 <210> 21 <211> 391 <212> DNA
<213> Homo sapien <400> 21 atggaattgtggttttctctttgggatcaatggtctcagaaattccagagaagaaagctg 60 tggcgattgctgatgctttgggcaaaatccctcagacagtcctgtggcggtacactggaa 120 cccgaccatcgaatcttgcgaacaacacgatacttgttcagtggctaccccaaaacgatc 180 tgcttggtcacccaatgacccgtgcctttatcacccatgctagttcccatggtgttaatg 240 aaagcatatgcaatggcgttcccatggtgatgatacccttatttggtgatcagatggaca 300 atgcaaagcgcagggagactaagggagctggagtgaccctgaatgttctggagatgactt 360 ctgaagatctagaagatgctctgaagagcag 391 <210> 22 <211> 1320 <212> DNA
<213> Homo sapien <400> 22 aatctgctgggaatttcttgggttgacagctcttggatccctattttgaacagtggtagt 60 gtcctggattacttttcagaaagaagtaatcctttttatgacagaacatgtaataatgaa 120 gtggtcaaaatgcagaggctaacattagaacacttgaatcagatggttggaatcgagtac 180 atccttttgcatgctcaagagcccattcttttcatcattcggaagcaacagcggcagtcc 240 cctgcccaagttatcccactagctgattactatatcattgctggagtgatctatcaggca 300 ccagacttgggatcagttataaactctagagtgcttactgcagtgcatggtattcagtca 360 gcttttgatgaagctatgtcatactgtcgatatcatccttccaaagggtattggtggcac 420 ttcaaagatcatgaagagcaagataaagtcagacctaaagccaaaaggaaagaagaacca 480 agctctatttttcagagacaacgtgtggatgctttacttttagacctcagacaaaaattt 540 ccacccaaatttgtgcagctaaagcctggagaaaagcctgttccagtggatcaaacaaag 600 aaagaggcagaacctataccagaaactgtaaaacctgaggagaaggagaccacaaagaat 660 gtacaacagacagtgagtgctaaaggcccccctgaaaaacggatgagacttcagtgagta 720 ctggacaaaagagaagcctggaagactcctcatgctagttatcatacctcagtactgtgg 780 ctcttgagctttgaagtactttattgtaaccttcttatttgtatggaatgcgcttatttt 840 ttgaaaggatattaggccggatgtggtggctcacgcctgtaatcccagcactttgggagg 900 ccatggcgggtggatcacttgaggtcagaagttcaagaccagcctgaccaatatggtgaa 960 accccgtctctactaaaaatacaaaaattagccgggcgtggtggcgggcgcccatagtcc 1020 cagctactcgggaggctgagacaggagacttgcttgaacccgggaggtggaggttgccct 1080 gagctgatcatcctgctgttgcactccagcttgggcgaaagagcgagactttgtctctat 1140 aaagaaggaaagatattattcccatcatgatttcttgtgaatatttgtaatatgtttttt 1200 gtaacctttcctttcccggacttgagcaacctacacactcacatgtttaatggtagatat 1260 gttttaaagcaagataaaggtattggttttaaaaaaaaaaaaaaaaaaaaaaaactcgag 1320 <210> 23 <211> 633 <212> DNA
<213> Homo sapien <400> 23 ctaagggcagtgaaggtgaaaaccctctcacggtcccagggagggagaaggaaggcatgc 60 tgatgggggttaagccgggggaggacgcatcggggcctgctgaagaccttgtgagaagat 120 ctgagaaagatactgcagctgttgtctccagacagggcagctccctgaacctctttgaag 180 atgtgcagatcacagaaccagaagctgagccagagtccaagtctgaaccgagacctccaa 240 tttcctctccgagggctccccagaccagagctgtcaagccccgacttcatcctgtgaagc 300 caatgaatgccacggccaccaaggttgctaactgcagcttgggaactgccaccatcatcg 360 gtgagaacttgaacaatgaggtcatgatgaagaaatacagcccctcggaccctgcatttg 420 catatgcgcagctgacccacgatgagctgattcagctggtcctcaaacagaaggaaacga 480 taagcaagaaggagttccaggtccgcgagctggaagactacattgacaacctgctcgtca 540 gggtcatggaagaaacccccaatatcctccgcatcccgactcaggttggcaaaaaagcag 600 gaaagatgtaaattagcagaaaaaaaactcgag 633 <210> 24 <211> 1328 <212> DNA
<213> Homo sapien <400> 24 gtaaacgctctcggaattatggcggcggtggatatccgagacaatctgctgggaatttct 60 tgggttgacagctcttggatccctattttgaacagtggtagtgtcctggattacttttca 120 gaaagaagtaatcctttttatgacagaacatgtaataatgaagtggtcaaaatgcagagg 180 ctaacattagaacacttgaatcagatggttggaatcgagtacatccttttgcatgctcaa 240 gagcccattcttttcatcattcggaagcaacagcggcagtcccctgcccaagttatccca 300 ctagctgattactatatcattgctggagtgatctatcaggcaccagacttgggatcagtt 360 ataaactctagagtgcttactgcagtgcatggtattcagtcagcttttgatgaagctatg 420 .

tcatactgtcgatatcatccttccaaagggtattggtggcacttcaaagatcatgaagag 480 caagataaagtcagacctaaagccaaaaggaaagaagaaccaagctctatttttcagaga 540 caacgtgtggatgctttacttttagacctcagacaaaaaatttccacccaaatttgtgca 600 gtggatcaaacaaagaaagaggcagaacctataccagaaactgtaaaacctgaggagaag 660 1~
gagaccacaaagaatgtacaacagacagtgagtgctaaaggcccccctgaaaaacggatg 720 agacttcagtgagtactggacaaaagagaagcctggaagactcctcatgctagttatcat 780 acctcagtactgtggctcttgagctttgaagtactttattgtaaccttcttatttgtatg 840 gaatgcgcttatttttttgaaaggatattaggccggatgtggtggctcacgcctgtaatc 900 ccagcactttgggaggccatggcgggtggatcacttgaggtcagaagttcaagaccagcc 960 tgaccaatatggtgaaaccccgtctctactaaaaatacaaaaattagccgggcgtggtgg 1020 cgggcgcccatagtcccagctactcgggaggctgagacaggagacttgcttgaacccggg 1080 aggtggaggttgccctgagctgattatcatgctgttgcactccagcttgggcgacagagc 1140 gagactttgtctcaaaaaagaagaaaagatattattcccatcatgatttcttgtgaatat 1200 ttgtgatatgtcttctgtaacctttcctctcccggacttgagcaacctacacactcacat 1260 gtttactggtagatatgtttaaaagcaaaataaaggtatttgtataaaaaaaaaaaaaaa 1320 aaactcga 1328 <210> 25 <211> 1758 <212> DNA
<213> Homo sapien <400>

gtttttttttttttttttttaaagagttgcaacaattcatctttatttcttattttcctc 60 tggagatgcagaatttggtatatttcaccccaagtatatttgggatagttggctcctcgc 120 tgggtcaggatggctgggtgccttctcccctggcatggttctcttctctgcagggcgagg 180 ggcagggagctagtaaaacctcgcaatgacagccgcaatggcagacccaatggagcccag 240 gatgaacttggtcaatccggagagtccagttgctcccagtgactgcagagtagccacaag 300 gctgcccgaggcaactccacccccattggcaatggccgccgcggacatcatcttggctgc 360 tatggaggacgaggcgattcccgccgcagtgaagcccatggcactgagtggcggcggtgg 420 atatccgagacaatctgctgggaatttcttgggttgacagctcttggatccctattttga 480 acagtggtagtgtcctggattacttttcagaaagaagtaatcctttttatgacagaacat 540 gtaataatgaagtggtcaaaatgcagaggctaacattagaacacttgaatcagatggttg 600 gaatcgagtacatccttttgcatgctcaagagcccattcttttcatcattcggaagcaac 660 agcggcagtcccctgcccaagttatcccactagctgattactatatcattgctggagtga 720 tctatcaggcaccagacttgggatcagttataaactctagagtgcttactgcagtgcatg 780 gtattcagtcagcttttgatgaagctatgtcatactgtcgatatcatccttccaaagggt 840 attggtggcacttcaaagatcatgaagagcaagataaagtcagacctaaagccaaaagga 900 aagaagaaccaagctctatttttcagagacaacgtgtggatgctttacttttagacctca 960 gacaaaaatttccacccaaatttgtgcagctaaagcctggagaaaagcctgttccagtgg 1020 atcaaacaaagaaagaggcagaacctataccagaaactgtaaaacctgaggagaaggaga 1080 ccacaaagaatgtacaacagacagtgagtgctaaaggcccccctgaaaaacggatgagac 1240 ttcagtgagtactggacaaaagagaagcctggaagactcctcatgctagttatcatacct 1200 cagtactgtggctcttgagctttgaagtactttattgtaaccttcttatt.tgtatggaat1260 gcgcttattttttgaaaggatattaggccggatgtggtggctcacgcctgtaatcccagc 2320 actttgggaggccatggcgggtggatcacttgaggtcagaagttcaagaccagcctgacc 1380 aatatggtgaaaccccgtctctactaaaaatacaaaaattagccgggcgtggtggcgggc 1440 gcccatagtcccagctactcgggaggctgagacaggagacttgcttgaacccgggaggtg 1500 gaggttgccctgagctgattatcatgctgttgcactccagcttgggcgacagagcgagac 1560 tttgtctcaaaaaagaagaaaagatattattcccatcatgatttcttgtgaatatttgtt 1620 atatgtcttctgttacctttcctctcccggaattgagcaacctacacactcacatgttta 1680 ctggtagatatgtttaaaagcaaataaaggtattggtatatattgcttcaaaaaaaaaaa 1740 aaaaaaaaaaaactcgag 1758 <210> 26 <211> 493 <212> DNA
<213> Homo sapien <400> 26 gaggcgagcg gcagggcctg gtggcgagag cgcggctgtc actgcgcccg agcatcccag 60 agctttccga gcggacgagc cggccgtgcc gggcatcccc agcctcgcta ccctcgcagc 120 acacgtcgagccccgcacaggcaagggtccggaacttagcccaaagcacgtttcccctgg180 cagcgcaggagacgcccggccgcgcgccggcgcacgcccccctctcctcctttgttccgg240 gggtcggcggccgctctcctgccagcgtcgggatctcggccccgggaggcgggccgtcgg300 gcgcagccgcgaagattccgttggaactgacgcagagccgagtgcagaagatctgggtgc360 ccgtggaccacaggccctcgttgcccagatcctgtgggccaaagctgacc.aactcccccg420 ccgtcttcgtcatggtgggcctcccccgcccggggcaagacctacttctccacgaaagct480 tactcgctgcctc 493 <210> 27 <211> 1331 <212> DNA
<213> Homo sapien <400> 27 ggtggatatc cgagacaatctgctgggaatttcttgggttgacagctcttggatccctat 60 tttgaacagt ggtagtgtcctggattacttttcagaaagaagtaatcctttttatgacag 120 aacatgtaat aatgaagtggtcaaaatgcagaggctaacattagaacacttgaatcagat 180 ggttggaatc gagtacatccttttgcatgctcaagagcccattcttttcatcattcggaa 240 gcaacagcgg cagtcccctgcacaagttatcccactagctgattactatatcattgctgg 300 agtgatctat caggcaccagacttgggatcagttataaactctagagtgcttactgcagt 360 gcatggtatt cagtcagcttttgatgaagctatgtcatactgtcgatatcatccttccaa 420 agggtattgg tggcacttcaaagatcatgaagagcaagataaagtcagacctaaagccaa 480 aaggaaagaa gaaccaagctctatttttcagagacaacgtgtggatgctttacttttaga 540 cctcagacaa aaatttccacccaaatttgtgcagctaaagcctggagaaaagcctgttcc 600 agtggatcaa acaaagaaagaggcagaacctataccagaaactgtaaaacctgaggagaa 660 ggagaccaca aagaatgtacaacagacagtgagtgctaaaggcccccctgaaaaacggat 720 gagacttcag tgagtactggacaaaagagaagcctggaagactcctcatgctagttatca 780 _ _ tacctca~tactgtggctcttgagctttgaagtactttattgtaaccttcttatttgtat 840 ggaatgcgc t tattttttgaaaggatattaggccggatgtggfggct-cacgcctgtaatc 900 ccagcacttt gggaggccatggcgggtggatcacttgaggtcagaagttcaagaccagcc 960 tgaccaatat ggtgaaaccccgtctctactaaaaatacaaaaattagccgggcgtggtgg 1020 cgggcgccca tagtcccagctactcgggaggctgagacaggagacttgcttcjaacccggg1080 aggtggaggt tgccctgagctgattatcatgctgttgcactccagcttgggcgacagagc 1140 gagactttgt ctcaaaaaaagaagaaaagatattattcccatcatgatttcttgtgaata 1200 tttgttatat gtcttctgtaacctttcctctcccggacttgagcaacctacacactcaca 1260 tgtttactgg tagatatgtttaaaagcaaaataaaggtattggtataaaaaaaaaaaaaa 1320 aaaaactcga g 1331 <210> 28 <211> 1333 <212> DNA
<213> Homo sapien <400> 28 cggcggtggatatccgagacaatctgctgggaatttcttgggttgacagctcttggatcc60 ctattttgaacagtggtagtgtcctggattacttttcagaaagaagtaatcctttttatg120 acagaacatgtaataatgaagtggtcaaaatgcagaggctaacattagaacacttgaatc180 agatggttggaatcgagtacatccttttgcatgctcaagagcccattcttttcatcattc240 ggaagcaacagcggcagtcccctgcccaagttatcccactagctgattactatatcattg300 ctggagtgatctatcaggcaccagacttgggatcagttataaactctagagtgcttactg360 cagtgcatggtattcagtcagcttttgatgaagctatgtcatactgtcgatatcatcctt420 ccaaagggtattggtggcacttcaaagatcatgaagagcaagataaagtcagacctaaag480 ccaaaaggaaagaagaaccaagctctatttttcagagacaacgtgtggatgctttacttt540 tagacctcagacaaaaatttccacccaaatttgtgcagctaaagcctggagaaaagcctg600 ttccagtggatcaaacaaagaaagaggcagaacctataccagaaactgtaaaacctgagg660 agaaggagaccacaaagaatgtacaacagacagtgagtgctaaaggcccccctgaaaaac720 ggatgagacttcagtgagtactggacaaaagagaagcctggaagactcctcatgctagtt780 atcatacctcagtactgtggctcttgagctttgaagtactttattgtaaccttcttattt840 gtatggaatgcgcttattttttgaaaggatattaggccggatgtggtggctcacgcctgt900 aatcccagcactttgggaggccatggcgggtggatcacttgaggtcagaagttcaagacc960 agcctgaccaatatggtgaaaccccgtctctactaaaaatacaaaaattagccgggcgtg1020 gtggcgggcgcccatagtcccagctactcgggaggctgagacaggagacttgcttgaacc1080 cgggaggtggaggttgccctgagctgattatcatgctgttgcactccagcttgggcgaca1140 gagcgagactttgtctcaaaaaagaagaaaagatattattcccatcatgatttcttgtga1200 atatttgtgatatgtcttctgtaacctttcctctcccggacttgagcaacctacacactc1260 acatgtttactggtagatatgtttaaaagcaaaataaaggtatttgtataaaaaaaaaaa1320 aaaaaaactcgag 1333 <210> 29 <211> 813 <212> DNA
<213> Homo sapien <400> 29 ctgagctgca cttcagcgaattcacctcggctgtggctgacatgaagaactccgtggcgg 60 accgagacaa cagccccagctcctgtgctggcctcttcattgcttcacacatcgggtttg 120 actggcccgg ggtctgggtccacctggacatcgctgctccagtgcatgctggcgagcgag 180 ccacaggctt tggggtggctctcctactggctctttttggccgtgcctccgaggacccgc 240 tgctgaacct ggtatccccgctggactgtgaggtggatgcccaggaaggcgacaacatgg 300 ggcgtgactc caagagacggaggctcgtgtgagggctacttcccagctggtgacacaggg 360 ttccttacct cattttgcactgactgattttaagcaattgaaagattaactaactcttaa 420 gatgagtttg gcttctccttctgtgcccag,tggtgacaggagtgagccattcttctctta 480 gaagcagctt aggggcttggtggggtctggagaaaattgtcacagaccccataggtctcc 540 atctgtaagc tctgtcccttgtcctccaccctggtctttagagccacctcaggtcaccct 600 ctgtagtgag tgtacttcctgacccaggcccttgctcaagctggggctccctggggtgtc 660 __ taaccagccc gggtaga~ ~actggctgttagggaccccattctgtgaagcaggagac 720 t cctcacagct cccaccaacccccagttcac_ attaaa~at-g'gccacaacat - 78-0-----ttgaagttga -aaaaaaaaaa aaaaaaaaaaaaaaaaactcgag 813 <210> 30 <211> 1316 <212> DNA
<213> Homo sapien <400> 30 caggcgcccagtcatggcccaagagacagcaccaccgtgtggcccagtctcaaggggtga60 cagtccaatcatagaaaagatggaaaaaaggacatgtgccctgtgccctgaaggccacga120 gtggagtcaaatatacttttcaccatcaggaaatatagttgctcatgaaaactgtttgct180 gtattcatcaggactggtggagtgtgagactcttgatctacgtaatacaattagaaactt240 tgatgtcaaatctgtaaagaaagagatctggagaggaagaagattgaaatgctcattctg300 taacaaaggaggcgccaccgtggggtgtgatttatggttctgtaagaagagttaccacta360 tgtctgtgccaaaaaggaccaagcaattcttcaagttgatggaaaccatggaacttacaa420 attattttgcccagaacattctccagaacaagaagaggccactgaaagtgctgatgaccc480 aagcatgaagaagaagagaggaaaaaacaaacgcctctcatcaggccctcctgcacagcc540 aaaaacgatgaaatgtagtaacgccaaaagacatatgacagaagagcctcatggtcacac600 agatgcagctgtcaaatctccttttcttaagaaatgccaggaagcaggacttcttactga660 actatttgaacacatactagaaaatatggattcagttcatggaagacttgtggatgagac720 tgcctcagagtcggactatgaagggatcgagaccttactgtttgactgtggattatttaa780 agacacactaagaaaattccaagaagtaatcaagagtaaagcttgtgaatgggaagaaag840 gcaaaggcagatgaagcagcagcttgaggcacttgcagacttacaacaaagcttgtgctc900 atttcaagaaaatggggacctggactgctcaagttctacatcaggatccttgctacctcc960 tgaggaccaccagtaaaagctgttcctcaggaaaactggatggggcctccatgttctcca1020 aggatcgaggaagtcttcctgcctaccctgcccaccccagtcaagggcagcaacaccaga1080 gctttgctcagccttaaatggaatcttagagctttctcttgcttctgctactcctacaga1140 tggcctcatcatggtctccactcagtattaataactccatcagcatagagcaaactcaac1200 actgtgcattgcacactgttaccatgggtttatgctcactatcatatcacattgccaata1260 tttagcacac ttaataaatg cttgtcaaaa cccaaaaaaa aaaaaaaaaa ctcgag 1316 <210> 31 <211> 1355 <212> DNA
<213> Homo sapien <400>

cggcggtggatatccgagacaatctgctgggaatttcttgggttgacagctcttggatcc 60 ctattttgaacagtggtagtgtcctggattacttttcagaaagaagtaatcctttttatg 120 acagaacatgtaataatgaagtggtcaaaatgcagaggctaacattagaacacttgaatc 180 agatggttggaatcgagtacatccttttgcatgctcaagagcccattcttttcatcattc 240 ggaagcaacagcggcagtcccctgcccaagttatcccactagctgattactatatcattg 300 ctggagtgatctatcaggcaccagacttgggatcagttataaactctagagtgcttactg 360 cagtgcatggtattcagtcagcttttgatgaagctatgtcatactgtcgatatcatcctt 420 ccaaagggtattggtggcacttcaaagatcatgaagagcaagataaagtcagacctaaag 480 ccaaaaggaaagaagaaccaagctctatttttcagagacaacgtgtggatgctttacttt 540 tagacctcagacaaaaatttccacccaaatttgtgcagctaaagcctggagaaaagcctg 600 ttccagtggatcaaacaaagaaagaggcagaacctataccagaaactgtaaaacctgagg 660 agaaggagaccacaaagaatgtacaacagacagtgagtgctaaaggcccccctgaaaaac 720 ggatgagacttcagtgagtactggacaaaagagaagcctggaagactcctcatgctagtt 780 atcatacctcagtactgtggctcttgagctttgaagtactttattgtaaccttcttattt 840 gtatggaatgcgcttattttttgaaaggatattaggccggatgtggtggctcacgcctgt 900 aatcccagcactttgggaggccatggcgggtggatcacttgaggtcagaagttcaagacc 960 agcctgaccaatatggtgaaaccccgtctctactaaaaatacaaaaattagccgggcgtg 1020 gtggcgggcgcccatagtcccagctactcgggaggctgagacaggagacttgcttgaacc 1080 cgggaggtggaggttgccctgagctgattatcatgctgttgcactccagcttgggcgaca 1140 gaacgagactttgtctcaaaaaaagaagaaaagatattattcccatcatgatttcttgtg 1200 aatatttgttatatgtcttctggtaacctt_ gacttgaagcaacctcacac--1260 tcctctcccg actcacatgtttactggtagatatgttttaaaagcaaaataaaggtatttgtttttccaa 1320 aaaaaaaaaaaaaaaaaaaaaaaaaaaaactcgag 1355 <210> 32 <211> 80 <212> PRT
<213> Homo sapien <400> 32 Val Ser Arg Ile Arg Gly Gly Ala Lys Lys Arg Lys Lys Lys Ser Tyr Thr Thr Pro Lys Lys Asp Lys His Gln Arg Lys Lys Val Gln Pro Ala Val Leu Lys Tyr Tyr Lys Val Asp Glu Asn G1y Lys Tle Ser Cys Leu

35 40 45 Arg Arg Glu Cys Pro Ser Asp Glu Cys Gly Ala Gly Val Phe Met Ala Sex His Phe Asp Arg His Tyr Cys Gly Lys Cys Cys Leu Thr His Cys <210> 33 <211> 130 <212> PRT
<213> Homo sapien <400> 33 Glu Ile Ser Asn Glu Val Arg Lys Phe Arg Thr Leu Thr Glu Leu Ile Leu Asp Ala Gln Glu His Val Lys Asn Pro Tyr Lys Gly Lys Lys Leu Lys Lys His Pro Asp Phe Pro Lys Lys Pro Leu Thr Pro Tyr Phe Arg Phe Phe Met Glu Lys Arg Ala Lys Tyr Ala Lys Leu His Pro Gln Met Ser Asn Leu Asp Leu Thr Lys Ile Leu Ser Lys Lys Tyr Lys Glu Leu Pro G1u Lys Lys Lys Met Lys Tyr Val Pro Asp Phe Gln Arg Arg Glu Thr Gly Val Arg Ala Lys Pro Gly Pro Ile Gln Gly Gly Ser Pro Pro Pro Tyr Pro Glu Cys Gln Glu Ser Asp Ile Pro Glu Lys Pro Gln Asp Pro Pro <210> 34 <211> 506 <212> PRT
<213> Homo sapien r <400> 34 Asn Ser Glu Lys Glu Ile Pro Val Leu Asn Glu Leu Pro Val Pro Met Val Ala Arg Tyr Ile Arg Ile Asn Pro Gln Ser Trp Phe Asp Asn Gly Ser Ile Cys Met Arg Met Glu Ile Leu Gly Cys Pro Leu Pro Asp Pro Asn Asn Tyr Tyr His Arg Arg Asn Glu Met Thr Thr Thr Asp Asp Leu Asp Phe Lys His His Asn Tyr Lys Glu Met Arg Gln Leu Met Lys Val Val Asn Glu Met Cys Pro Asn Ile Thr Arg Ile Tyr Asn Ile G1y Lys Ser His Gln Gly Leu Lys Leu Tyr Ala Val Glu Ile Ser Asp His Pro Gly Glu His Glu Val Gly Glu Pro G1u Phe His Tyr Ile A1a Gly Ala His Gly Asn Glu Val Leu Gly Arg Glu Leu Leu Leu Leu Leu Leu His Phe Leu Cys Gln Glu Tyr Ser Ala Gln Asn Ala Arg Ile Val Arg Leu Val Glu Glu Thr Arg Ile His Ile Leu Pro Ser Leu Asn Pro Asp Gly Tyr G1u Lys Ala Tyr Glu Gly Gly Ser Glu Leu Gly G1y Trp Ser Leu Gly Arg Trp Thr His Asp Gly Ile Asp Ile Asn Asn Asn Phe Pro Asp Leu Asn Ser Leu Leu Trp Glu Ala Glu Asp Gln Gln Asn Ala Pro Arg Lys Val Pro Asn His Tyr I1e Ala Ile Pro Glu Trp Phe Leu Ser Glu Asn Ala Thr Val Ala Thr Glu Thr Arg Ala Val Ile Ala Trp Met Glu Lys Ile Pro Phe Val Leu Gly Gly Asn Leu Gln Gly Gly Glu Leu Val Va1 Ala Tyr Pro Tyr Asp Met Val Arg Ser Leu Trp Lys Thr Gln Glu His Thr Pro Thr Pro Asp Asp His Val Phe Arg Trp Leu AIa Tyr Ser Tyr Ala Ser Thr His Arg Leu Met Thr Asp Ala Arg Arg Arg Val Cys His Thr Glu Asp Phe Gln Lys Glu Glu G1y Thr Val Asn Gly Ala Ser Trp His Thr Val Ala Gly Ser Leu Asn Asp Phe Ser Tyr Leu His Thr Asn Cys Phe Glu Leu Ser Ile Tyr Val Gly Cys Asp Lys Tyr Pro His Glu Ser Glu Leu Pro Glu Glu Trp Glu Asn Asn Arg Glu Ser Leu Ile Val Phe Met G1u Gln Val His Arg Gly Ile Lys Gly Ile Val Arg Asp Leu Gln GIy Lys Gly Ile Ser Asn A1a Val Ile Ser Val Glu Gly Val Asn His Asp Tle Arg Thr Ala Ser Asp Gly Asp Tyr Trp Arg Leu Leu Asn Pro Gly Glu Tyr Val Val Thr Ala Lys Ala Glu Gly Phe Ile Thr Ser Thr Lys Asn Cys Met Val Gly Tyr Asp Met Gly A1a Thr Arg Cys Asp Phe Thr Leu Thr Lys Thr Asn Leu Ala Arg Ile Arg Glu Ile Met Glu Thr Phe Gly Lys Gln Pro Val Sex Leu Pro Ser Arg Arg Leu Lys Leu Arg Gly Arg Lys Arg Arg Gln Arg Gly <210> 35 <211> 96 <212> PRT
<213> Homo sapien <400> 35 Met Asn Gly Glu Ala Asp Cys Pro Thr Asp Leu Glu Met Ala Ala Pro 1 5 l0 15 Arg Gly Gln Asp Arg Trp Ser Gln Glu Asp Met Leu Thr Leu Leu Glu Cys Met Lys Asn Asn Leu Pro Ser Asn Asp Ser Ser Gln Phe Lys Thr.

Thr Gln Thr His Met Asp Arg Glu Lys Val Ala Leu Lys Asp Phe Ser Gly Asp Met Cys Lys Leu Lys Trp Val Glu I1e Ser Asn Glu Val Arg Lys Phe Arg Thr Leu Thr Glu Leu Tle Leu Asp Thr Gln Glu His Val <210> 36 <211> 129 <212> PRT
<213> Homo sapien <400> 36 Gly Ile Val Val Phe Ser Leu Gly Ser Met Val Ser Glu Ile Pro Glu Lys Lys Ala Val Ala Ile A1a Asp Ala Leu Gly Lys Ile Pro Gln Thr Val Leu Trp Arg Tyr Thr Gly Thr Arg Pro Ser Asn Leu Ala Asn Asn Thr Ile Leu Val Gln Trp Leu Pro Gln Asn Asp Leu Leu Gly His Pro Met Thr Arg Ala Phe Ile Thr His Ala Ser Ser His G1y Val Asn Glu Ser Ile Cys Asn Gly Val Pro Met Val Met Ile Pro Leu Phe Gly Asp G1n Met Asp Asn Ala Lys Arg Arg Glu Thr Lys Gly Ala Gly Val Thr Leu Asn Val Leu Glu Met Thr Ser Glu Asp Leu Glu Asp Ala Leu Lys Ser <210> 37 <211> 238 <212> PRT
<213> Homo sapien <400> 37 Asn Leu Leu Gly Tle Ser Trp Val Asp Ser Ser Trp Ile Pro Ile Leu Asn Ser Gly Ser Val Leu Asp Tyr Phe Ser Glu Arg Ser Asn Pro Phe Tyr Asp Arg Thr Cys Asn Asn Glu Val Val Lys Met Gln Arg Leu Thr Leu Glu His Leu Asn Gln Met Val Gly Ile Glu Tyr Ile Leu Leu His Ala Gln G1u Pro Ile Leu Phe I1e Ile Arg Lys Gln Gln Arg Gln Ser Pxo Ala G1n Va1 Ile Pro Leu Ala Asp Tyr Tyr Ile Ile Ala Gly Val Ile Tyr Gln Ala Pro Asp Leu Gly Ser Val I1e Asn Ser Arg Val Leu Thr Ala Val Hi.s Gly Ile Gln Ser Ala Phe Asp Glu Ala Met Ser Tyr Cys Arg Tyr His Pro Ser Lys Gly Tyr Trp Trp His Phe Lys Asp His Glu Glu Gln Asp Lys Val Arg Pro Lys Ala Lys Arg Lys Glu Glu Pro Ser Ser Ile Phe Gln Arg Gln Arg Val Asp Ala Leu Leu Leu Asp Leu Arg Gln Lys Phe Pro Pro Lys Phe Val Gln Leu Lys Pro Gly Glu Lys Pro Val Pro Val Asp Gln Thr Lys Lys Glu Ala Glu Pro I1e Pro G1u Thr Val Lys Pro Glu Glu Lys Glu Thr Thr Lys Asn Val Gln Gln Thr Val Ser Ala Lys Gly Pro Pro Glu Lys Arg Met Arg Leu Gln <210> 38 <211> 202 <212> PRT
<213> Homo sapien <400> 38 Lys Gly Ser Glu Gly Glu Asn Pro Leu Thr Va1 Pro Gly Arg Glu Lys Glu Gly Met Leu Met Gly Val Lys Pro G1y Glu Asp Ala Ser Gly Pro A1a G1u Asp Leu Val Arg Arg Ser Glu Lys Asp Thr Ala Ala Val Val Ser Arg Gln Gly Ser Ser Leu Asn Leu Phe Glu Asp Val Gln Ile Thr Glu Pro Glu Ala Glu Pro Glu Ser Lys Ser Glu Pro Arg Pro Pro Ile Ser Ser Pro Arg Ala Pro Gln Thr Arg A1a Val Lys Pro Arg Leu His Pro Va1 Lys Pro Met Asn Ala Thr Ala Thr Lys Val Ala Asn Cys Ser Leu Gly Thr Ala Thr Ile Ile Gly Glu Asn Leu Asn Asn Glu Val Met Met Lys Lys Tyr Ser Pro Ser Asp Pro Ala Phe Ala Tyr Ala Gln Leu Thr His Asp Glu Leu Ile G1n Leu Val Leu Lys Gln Lys Glu Thr Ile Ser Lys Lys Glu Phe Gln Val Arg Glu Leu Glu Asp Tyr I1e Asp Asn Leu Leu Val Arg Val Met Glu Glu Thr Pro Asn Ile Leu Arg Ile Pro Thr Gln Va1 Gly Lys Lys Ala Gly Lys Met <210> 39 <211> 243 <212> PRT
<213> Homo sapien <400> 39 Va1 Asn Ala Leu Gly Ile Met Ala Ala Val Asp Ile Arg Asp Asn Leu Leu Gly Ile Ser Trp Val Asp Ser Ser Trp Ile Pro Ile Leu Asn Ser Gly Ser Val Leu Asp Tyr Phe Ser Glu Arg Ser Asn Pro Phe Tyr Asp Arg Thr Cys Asn Asn Glu Val Val Lys Met Gln Arg Leu Thr Leu Glu His Leu Asn Gln Met Val Gly Ile Glu Tyr Tle Leu Leu His Ala Gln Glu Pro I1e Leu Phe Ile Ile Arg Lys Gln Gln Arg Gln Ser Pro Ala Gln Val Ile Pro Leu A1a Asp Tyr Tyr Ile Ile Ala Gly Val Ile Tyr Gln Ala Pro Asp Leu Gly Ser Val Tle Asn Ser Arg Val Leu Thr Ala Val His Gly Ile Gln Ser Ala Phe Asp Glu Ala Met Ser Tyr Cys Arg Tyr His Pro Ser Lys Gly Tyr Trp Trp His Phe Lys Asp His Glu Glu Gln Asp Lys Val Arg Pro Lys Ala Lys Arg Lys Glu Glu Pro Ser Ser Ile Phe Gln Arg Gln Arg Val Asp Ala Leu Leu Leu Asp Leu Arg Gln Lys Ile Ser Thr Gln Ile Cys Ala Val Asp Gln Thr Lys Lys Glu Ala Glu Pro Ile Pro G1u Thr Val Lys Pro Glu Glu Lys Glu Thr Thr Lys Asn Val Gln Gln Thr Val Ser Ala Lys Gly Pro Pro Glu Lys Arg Met Arg Leu Gln <210> 40 <211> 245 <212> PRT
<213> Homo sapien <400> 40 Ala Ala Val Asp Ile Arg Asp Asn Leu Leu Gly Tle Ser Trp Val Asp Ser Ser Trp Ile Pro Ile Leu Asn Ser Gly Ser Val Leu Asp Tyr Phe Ser Glu Arg Ser Asn Pro Phe Tyr Asp Arg Thr Cys Asn Asn Glu Val Val Lys Met Gln Arg Leu Thr Leu Glu His Leu Asn Gln Met Val Gly Ile G1u Tyr Ile Leu Leu His Ala Gln Glu Pro Ile Leu Phe Ile Ile Arg Lys Gln Gln Arg Gln Ser Pro Ala Gln Val Ile Pro Leu Ala Asp Tyr Tyr Ile T1e Ala Gly Val Tle Tyr Gln Ala Pro Asp Leu Gly Ser Val Ile Asn Ser Arg Val Leu Thr Ala Val His Gly Ile G1n Ser Ala Phe Asp Glu Ala Met Ser Tyr Cys Arg Tyr His Pro Ser Lys Gly Tyr Trp Trp His Phe Lys Asp His Glu Glu Gln Asp Lys Val Arg Pro Lys Ala Lys Arg Lys Glu Glu Pro Ser Ser Ile Phe Gln Arg G1n Arg Val Asp Ala Leu Leu Leu Asp Leu Arg Gln Lys Phe Pro Pro Lys Phe Val Gln Leu Lys Pro Gly Glu Lys Pro Val Pro Val Asp Gln Thr Lys Lys Glu Ala Glu Pro Ile Pro Glu Thr Val Lys Pro GIu Glu Lys Glu Thr Thr Lys Asn Val Gln Gln Thr Va1 Ser Ala Lys Gly Pro Pro GIu Lys Arg Met Arg Leu Gln <210> 41 <211> 163 <212> PRT
<213> Homo sapien <400> 41 Gly Glu Arg Gln Gly Leu Val Ala Arg Ala Arg Leu Ser Leu Arg Pro Ser Ile Pro Glu Leu Ser Glu Arg Thr Ser Arg Pro Cys Arg Ala Ser Pro Ala Ser Leu Pro Ser G1n His Thr Ser Ser Pro Ala Gln Ala Arg Val Arg Asn Leu Ala Gln Ser Thr Phe Pro Leu Ala Ala Gln Glu Thr Pro Gly Arg Ala Pro Ala His Ala Pro Leu Ser Ser Phe Val Pro Gly Val Gly Gly Arg Ser Pro Ala Ser Val Gly Ile Ser Ala Pro Gly Gly G1y Pro Ser Gly Ala Ala Ala Lys Ile Pro Leu G1u Leu Thr Gln Ser Arg Va1 G1n Lys Ile Trp Val Pro Val Asp His Arg Pro Ser Leu Pro Arg Ser Cys Gly Pro Lys Leu Thr Asn Ser Pro Ala Val Phe Val Met Val G1y Leu Pro Arg Pro Gly Gln Asp Leu Leu Leu His Glu Ser Leu Leu Ala Ala <210> 42 <211> 243 <212> PRT
<213> Homo sapien <400> 42 Val Asp Ile Arg Asp Asn Leu Leu Gly Ile Ser Trp Val Asp Ser Ser Trp Ile Pro Ile Leu Asn Ser Gly Ser Val Leu Asp Tyr Phe Ser Glu Arg Ser Asn Pro Phe Tyr Asp Arg Thr Cys Asn Asn Glu Val Val Lys Met Gln Arg Leu Thr Leu Glu His Leu Asn Gln Met Val Gly Ile Glu Tyr Ile Leu Leu His A1a Gln G1u Pro Ile Leu Phe Ile Ile Arg Lys G1n Gln Arg Gln Ser Pro Ala Gln Val Ile Pro Leu A1a Asp Tyr Tyr Ile Ile Ala Gly Val Ile Tyr Gln Ala Pro Asp Leu Gly Ser Val Ile Asn Ser Arg Va1 Leu Thr Ala Val His Gly Ile G1n Ser Ala Phe Asp Glu Ala Met Ser Tyr Cys Arg Tyr His Pro Ser Lys Gly Tyr Trp Trp His Phe Lys Asp His Glu Glu Gln Asp Lys Val Arg Pro Lys A1a Lys Arg Lys Glu Glu Pro Ser Ser Ile Phe Gln Arg Gln Arg Val Asp Ala Leu Leu Leu Asp Leu Arg Gln Lys Phe Pro Pro Lys Phe Val Gln Leu Lys Pro Gly Glu Lys Pro Val Pro Val Asp Gln Thr Lys Lys Glu Ala G1u Pro I1e Pro Glu Thr Val Lys Pro Glu Glu Lys Glu Thr Thr Lys Asn Val Gln Gln Thr Val Ser Ala Lys Gly Pro Pro Glu Lys Arg Met Arg Leu Gln <210> 43 <211> 244 <212> PRT
<213> Homo sapien <400> 43 Ala Val Asp Ile Arg Asp Asn Leu Leu Gly Ile Ser Trp Va1 Asp Ser Ser Trp Ile Pro Ile Leu Asn Ser Gly Ser Val Leu Asp Tyr Phe Ser Glu Arg Ser Asn Pro Phe Tyr Asp Arg Thr Cys Asn Asn Glu Val Val Lys Met Gln Arg Leu Thr Leu Glu His Leu Asn G1n Met Val G1y Ile G1u Tyr Tle Leu Leu His Ala Gln Glu Pro Ile Leu Phe Ile I1e Arg Lys Gln Gln Arg Gln Ser Pro Ala Gln Val Ile Pro Leu Ala Asp Tyr Tyr Ile Ile Ala Gly Val Ile Tyr Gln Ala Pro Asp Leu Gly Ser Val Ile Asn Ser Arg Val Leu Thr Ala Va1 His Gly I1e Gln Ser A1a Phe Asp Glu Ala Met Ser Tyr Cys Arg Tyr His Pro Ser Lys Gly Tyr Trp Trp His Phe Lys Asp His Glu Glu Gln Asp Lys Val Arg Pro Lys Ala Lys Arg Lys G1u Glu Pro Ser Ser Ile Phe Gln Arg Gln Arg Val Asp Ala Leu Leu Leu Asp Leu Arg Gln Lys Phe Pro Pro Lys Phe Val G1n Leu Lys Pro Gly Glu Lys Pro Val Pro Val Asp Gln Thr Lys Lys Glu Ala Glu Pro Ile Pro Glu Thr Val Lys Pro Glu Glu Lys Glu Thr Thr Lys Asn Val Gln G1n Thr Val Ser Ala Lys Gly Pro Pro Glu Lys Arg Met Arg Leu Gln <210> 44 <211> 109 <212> PRT
<213> Homo sapien <400> 44 Glu Leu His Phe Ser Glu Phe Thr Ser Ala Val Ala Asp Met Lys Asn Ser Val Ala Asp Arg Asp Asn Ser Pro Ser Ser Cys Ala G1y Leu Phe Ile Ala Ser His Ile Gly Phe Asp Trp Pro Gly Val Trp Val His Leu Asp I1e Ala Ala Pro Va1 His Ala Gly Glu Arg Ala Thr Gly Phe Gly Val Ala Leu Leu Leu Ala Leu Phe GIy Arg Ala Ser G1u Asp Pro Leu Leu Asn Leu Val Ser Pro Leu Asp Cys Glu Val Asp Ala Gln Glu Gly Asp Asn Met Gly Arg Asp Ser Lys Arg Arg Arg Leu Val <210> 45 <211> 324 <212> PRT
<213> Homo sapien <400> 45 Arg Arg Pro Va1 Met Ala Gln Glu Thr Ala Pro Pro Cys Gly Pro Val Ser Arg Gly Asp Ser Pro Ile Ile Glu Lys Met Glu Lys Arg Thr Cys Ala Leu Cys Pro Glu Gly His Glu Trp Ser Gln Ile Tyr Phe Ser Pro Ser Gly Asn Tle Val Ala His Glu Asn Cys Leu Leu Tyr Ser Ser Gly Leu Val Glu Cys Glu Thr Leu Asp Leu Arg Asn Thr Ile Arg Asn Phe Asp Va1 Lys Ser Val Lys Lys Glu Ile Trp Arg Gly Arg Arg Leu Lys Cys Ser Phe Cys Asn Lys Gly G1y Ala Thr Val Gly Cys Asp Leu Trp Phe Cys Lys Lys Ser Tyr His Tyr Val Cys Ala Lys Lys Asp Gln Ala 115 120 125 , Ile Leu Gln Val Asp Gly Asn His Gly Thr Tyr Lys Leu Phe Cys Pro Glu His Ser Pro G1u Gln Glu Glu Ala Thr Glu Ser Ala Asp Asp Pro Ser Met Lys Lys Lys Arg Gly Lys Asn Lys Arg Leu Ser Ser Gly Pro Pro Ala Gln Pro Lys Thr Met Lys Cys Ser Asn A1a Lys Arg His Met Thr G1u Glu Pro His Gly His Thr Asp A1a Ala Val Lys Ser Pro Phe l95 200 205 Leu Lys Lys Cys Gln Glu Ala Gly Leu Leu Thr Glu Leu Phe Glu His Ile Leu G1u Asn Met Asp Ser Val His Gly Arg Leu Val Asp Glu Thr Ala Ser Glu Ser Asp Tyr Glu Gly Ile Glu Thr°Leu Leu Phe Asp Cys G1y Leu Phe Lys Asp Thr Leu Arg Lys Phe Gln Glu Val Ile Lys Ser Lys Ala Cys Glu Trp Glu Glu Arg Gln Arg Gln Met Lys Gln Gln Leu Glu Ala Leu Ala Asp Leu Gln Gln Ser Leu Cys Ser Phe Gln Glu Asn Gly Asp Leu Asp Cys Ser Ser Ser Thr Ser Gly Ser Leu Leu Pro Pro Glu Asp His Gln <210> 46 <211> 244 <212> PRT
<213> Homo sapien <400> 46 Ala Val Asp Ile Arg Asp Asn Leu Leu Gly Ile Ser Trp Val Asp Ser Ser Trp Ile Pro Ile Leu Asn Ser Gly Ser Val Leu Asp Tyr Phe Ser Glu Arg Ser Asn Pro Phe Tyr Asp Arg Thr Cys Asn Asn Glu Val Val Lys Met Gln Arg Leu Thr Leu Glu His Leu Asn Gln Met Val Gly Ile Glu Tyr Ile Leu Leu His Ala Gln Glu Pro Ile Leu Phe Ile Tle Arg Lys Gln Gln Arg Gln Ser Pro Ala Gln Val Ile Pro Leu Ala Asp Tyr Tyr Ile Ile Ala Gly Val Ile Tyr Gln Ala Pro Asp Leu G1y Ser Val Tle Asn Ser Arg Val Leu Thr Ala Val His Gly Tle Gln Ser Ala Phe Asp Glu Ala Met Ser Tyr Cys Arg Tyr His Pro Ser Lys Gly Tyr Trp Trp His Phe Lys Asp His Glu Glu Gln Asp Lys Val Arg Pro Lys Ala Lys Arg Lys Glu Glu Pro Ser Ser Ile Phe Gln Arg Gln Arg Val Asp Ala Leu Leu Leu Asp Leu Arg Gln Lys Phe Pro Pro Lys Phe Val Gln Leu Lys Pro Gly Glu Lys Pro Val Pro Val Asp Gln Thr Lys Lys Glu Ala Glu Pro Ile Pro Glu Thr Val Lys Pro Glu Glu Lys Glu Thr Thr Lys Asn Va1 G1n Gln Thr Val Ser Ala Lys Gly Pro Pro Glu Lys Arg Met Arg Leu Gln <210> 47 <211> 14 <212> DNA
<213> Homo sapien <400> 47 tttttttttt ttag 14 <210> 48 <211> 10 <212> DNA
<213> Homo sapien <400> 48 cttcaacctc 10 <210> 49 <211> 496 <212> DNA
<213> Homo sapien <400> 49 gcaccatgta ccgagcactt cggctcctcg cgcgctcgcg tcccctcgtg cgggctccag 60 ccgcagcctt agcttcggct cccggcttgg gtggcgcggc cgtgccctcg ttttggcctc 120 cgaacgcggc tcgaatggca agccaaaatt ccttccggat agaatatgat acctttggtg 180 aactaaaggt gccaaatgat aagtattatg gcgcccagac cgtgagatct acgatgaact 240 ttaagattgg aggtgtgaca gaacgcatgc caaccccagt tattaaagct tttggcatct 300 tgaagcgagc ggccgctgaa gtaaaccagg attatggtct tgatccaaag attgctaatg 360 caataatgaa ggcagcagat gaggtagctg aaggtaaatt aaatgatcat tttcctctcg 420 tggtatggca gactggatca ggaactcaga caaatatgaa tgtaaatgaa gtcattagcc 480 aatagagcaa ttgaaa 496 <210> 50 <211> 499 <212> DNA
<213> Homo sapien <400> 50 agaaaaagtctatgtttgcagaaatacagatccaagacaaagacaggatgggcactgctg 60 gaaaagttattaaatgcaaagcagctgtgctttgggagcagaagcaacccttctccattg 120 aggaaatagaagttgccccaccaaagactaaagaagttcgcattaagattttggccacag 180 gaatctgtcgcacagatgaccatgtgataaaaggaacaatggtgtccaagtttccagtga 240 ttgtgggacatgaggcaactgggattgtagagagcattggagaaggagtgactacagtga 300 aaccaggtgacaaagtcatccctctctttctgccacaatgtagagaatgcaatgcttgtc 360 gcaacccagatggcaacctttgcattaggagcgatattactggtcgtggagtactggctg 420 atggcaccaccagatttacatgcaagggcgaaccagtccaccacttcatgaacaccagta 480 catttaccgagtacacagt 499 <210> 51 <211> 887 <212> DNA
<213> Homo sapien <400> 51 gagtctgagcagaaaggaaaagcagccttggcagccacgttagaggaatacaaagccaca 60 gtggccagtgaccagatagagatgaatcgcctgaaggctcagctggagaatgaaaagcag 120 aaagtggcagagctgtattctatccataactctggagacaaatctgatattcaggacctc 180 ctggagagtgtcaggctggacaaagaaaaagcagagactttggctagtagcttgcaggaa 240 gatctggctcatacccgaaatgatgccaatcgattacaggatgccattgctaaggtagag 300 gatgaataccgagccttccaagaagaagctaagaaacaaattgaagatttgaatatgacg 360 ttagaaaaattaagatcagacctggatgaaaaagaaacagaaaggagtgacatgaaagaa 420 accatctttgaacttgaagatgaagtagaacaacatcgtgctgtgaaacttcatgacaac 480 ctcattatttctgatctagagaatacagttaaaaaactccaggaccaaaagcacgacatg 540 gaaagagaaataaagacactccacagaagacttcgggaagaatctgcggaatggcggcag 600 tttcaggctgatctccagactgcagtagtcattgcaaatgacattaaatctgaagcccaa 660 gaggagattggtgatctaaagcgccggttacatgaggctcaagaaaaaaatgagaaactc 720 acaaaagaattggaggaaataaagtcacgcaagcaagaggaggagcgaggcgggtataca 780 attacatgaatgccgttgagagagatttggcagccttaaggcagggaatgggactgagta 840 gaaggtcctcgacttcctcagagccaactcctacagtaaaaaccctc 887 <210> 52 <211> 491 <212> DNA
<213> Homo sapien <400>

ggcacgagcttttccaaaaatcatgctgctcctttctctaaagttcttacattttataga 60 aaggaacctttcactcttgaggcctactacagctctcctcaggatttgccctatccagat 120 cctgctatagctcagttttcagttcagaaagtcactcctcagtctgatggctccagttca 180 aaagtgaaagtcaaagttcgagtaaatgtccatggcattttcagtgtgtccagtgcatct 240 ttagtggaggttcacaagtctgaggaaaatgaggagccaatggaaacagatcagaatgca 300 aaggaggaagagaagatgcaagtggaccaggaggaaccacatgttgaagagcaacagcag 360 cagacaccaggcagaaaataaggcagagtctgaagaaatggagacctctcaagctggatc 420 caaggataaaaagatggaccaaccaccccaagccaagaaggcaaaagtgaagaccagtac 480 tgtggacctgg 491 <210> 53 <211> 787 <212> DNA
<213> Homo sapien <400> 53 aagcagttgagtaggcagaaaaaagaacctcttcattaaggattaaaatgtataggccag 60 cacgtgtaacttcgacttcaagatttctgaatccatatgtagtatgtttcattgtcgtcg 120 caggggtagtgatcctggcagtcaccatagctctacttgtttactttttagcttttgatc 180 aaaaatcttacttttataggagcagttttcaactcctaaatgttgaatataatagtcagt 240 taaattcaccagctacacaggaatacaggactttgagtggaagaattgaatctctgatta 300 ctaaaacattcaaagaatcaaatttaagaaatcagttcatcagagctcatgttgccaaac 360 tgaggcaagatggtagtggtgtgagagcggatgttgtcatgaaatttcaattcactagaa 420 ataacaatggagcatcaatgaaaagcagaattgagtctgttttacgacaaatgctgaata 480 actctggaaacctggaaataaacccttcaactgagataacatcacttactgaccaggctg 540 cagcaaattggcttattaatgaatgtggggccggtccagacctaataacattgtctgagc 600 agagaatccttggaggcactgaggctgaggagggaagctggccgtggcaagtcagtctgc 660 ggctcaataatgcccaccactgtggaggcagcctgatcaataacatgtggatcctgacag 720 cagctcactgcttcagaagcaactctaatcctcgtgactggattgccacgtctggtattt 780 ccacaac 787 <210> 54 <211> 386 <212> DNA
<213> Homo sapien <400> 54 ggcattttcagtgtgtccagtgcatctttagtggaggttcacaagtctgaggaaaatgag 60 gagccaatggaaacagatcagaatgcaaaggaggaagagaagatgcaagtggaccaggag 120 gaaccacatgttgaagagcaacagcagcagacaccagcagaaaataaggcagagtctgaa 180 gaaatggagacctctcaagctggatccaaggataaaaagatggaccaaccaccccaagcc 240 aagaaggcaaaagtgaagaccagtactgtggacctgccaatcgagaatcagctattatgg 300 cagatagacagagagatgctcaacttgtacattgaaaatgagggtaagatgatcatgcag 360 gataaactggagaaggagcggaatga 386 <210> 55 <211> 1462 <212> DNA
<213> Homo sapien <400> 55 aagcagttgagtaggcagaaaaaagaacctcttcattaaggattaaaatgtataggccag 60 cacgtgtaacttcgacttcaagatttctgaatccatatgtagtatgtttcattgtcgtcg 120 caggggtagtgatcctggcagtcaccatagctctacttgtttactttttagcttttgatc 180 aaaaatcttacttttataggagcagttttcaactcctaaatgttgaatataatagtcagt 240 taaattcaccagctacacaggaatacaggactttgagtggaagaattgaatctctgatta 300 ctaaaacattcaaagaatcaaatttaagaaatcagttcatcagagctcatgttgccaaac 360 tgaggcaagatggtagtggtgtgagagcggatgttgtcatgaaatttcaattcactagaa 420 ataacaatggagcatcaatgaaaagcagaattgagtctgttttacgacaaatgctgaata 480 actctggaaacctggaaataaacccttcaactgagataacatcacttactgaccaggctg 540 cagcaaattggcttattaatgaatgtggggccggtccagacctaataacattgtctgagc 600 agagaatccttggaggcactgaggctgaggagggaagctggccgtggcaagtcagtctgc 660 ggctcaataatgcccaccactgtggaggcagcctgatcaataacatgtggatcctgacag 720 cagctcactgcttcagaagcaactctaatcctcgtgactggattgccacgtctggtattt 780 ccacaacatttcctaaactaagaatgagagtaagaaatattttaattcataacaattata 840 aatctgcaactcatgaaaatgacattgcacttgtgagaCttgagaacagtgtcaccttta 900 ccaaagatatccatagtgtgtgtctcccagctgctacccagaatattccacctggctcta 960 ~$
ctgcttatgtaacaggatggggcgctcaagaatatgctggccacacagttccagagctaa 1020 ggcaaggacaggtcagaataataagtaatgatgtatgtaatgcaccacatagttataatg 1080 gagccatcttgtctggaatgctgtgtgctggagtacctcaaggtggagtggacgcatgtc 1140 agggtgactctggtggcccactagtacaagaagactcacggcggctttggtttattgtgg 1200 ggatagtaagctggggagatcagtgtggcctgccggataagccaggagtgtatactcgag 1260 tgacagcatacattgactggattaggcaacaaactgggatctagtgcaacaagtgcatcc 1320 ctgttgcaaagtctgtatgcaggtgtgcctgtcttaaattccaaagctttacatttcaac 1380 tgaaaaagaaactagaaatgtcctaatttaacatcttgttacataaatatggtttaacaa 1440 aaaaaaaaaaaaaaaactcgag 1462 <210> 56 <211> 159 <212> PRT
<213> Homo sapien <400> 56 Thr Met Tyr Arg Ala ~eu Arg Leu Leu Ala Arg Ser Arg Pro Leu Val 1 ~ 5 10 15 Arg Ala Pro Ala A1a Ala Leu A1a Ser Ala Pro Gly Leu Gly Gly Ala Ala Val Pro Ser Phe Trp Pro Pro Asn Ala Ala Arg Met Ala Ser G1n Asn Ser Phe Arg Ile Glu Tyr Asp Thr Phe Gly Glu Leu Lys Val Pro Asn Asp Lys Tyr Tyr Gly Ala Gln Thr Val Arg Ser Thr Met Asn Phe Lys Ile Gly Gly Val Thr Glu Arg Met Pro Thr Pro Val Ile Lys Ala Phe Gly Ile Leu Lys Arg Ala Ala Ala G1u Val Asn Gln Asp Tyr Gly Leu Asp Pro Lys Tle Ala Asn Ala Ile Met Lys Ala Ala Asp Glu Va1 1l5 120 125 Ala G1u Gly Lys Leu Asn Asp His Phe Pro Leu Val Val Trp Gln Thr Gly Ser Gly Thr Gln Thr Asn Met Asn Val Asn G1u Val Ile Ser <210> 57 <211> 165 <212> PRT
<213> Homo sapien <400> 57 Lys Lys Ser Met Phe Ala Glu Ile Gln Ile Gln Asp Lys Asp Arg Met 1 5 10 , 15 Gly Thr Ala Gly Lys Val Tle Lys Cys Lys Ala Ala Val Leu Trp Glu Gln Lys Gln Pro Phe Ser Ile Glu Glu Ile Glu Val Ala Pro Pro Lys Thr Lys Glu Val Arg Ile Lys Ile Leu Ala Thr Gly Ile Cys Arg Thr Asp Asp His Val T1e Lys Gly Thr Met Val Ser Lys Phe Pro Val Ile Val Gly His Glu Ala Thr Gly Ile Val Glu Ser Ile G1y Glu G1y Val Thr Thr Val Lys Fro Gly Asp Lys Val Ile Pro Leu Phe Leu Pro Gln Cys Arg Glu Cys Asn Ala Cys Arg Asn Pro Asp Gly Asn Leu Cys Ile Arg Ser Asp Ile Thr Gly Arg Gly Val Leu Ala Asp Gly Thr Thr Arg Phe Thr Cys Lys Gly G1u Pro Val His His Phe Met Asn Thr Ser Thr Phe Thr Glu Tyr Thr <210> 58 <211> 259 <212> PRT
<213> Homo sapien <400> 58 Glu Ser Glu Gln Lys Gly Lys Ala Ala Leu Ala Ala Thr Leu Glu Glu Tyr Lys Ala Thr Val Ala Ser Asp Gln Ile Glu Met Asn Arg Leu Lys Ala Gln Leu Glu Asn Glu Lys Gln Lys Val Ala Glu Leu Tyr Ser Ile His Asn Ser Gly Asp Lys Ser Asp Ile G1n Asp Leu Leu Glu Ser Val Arg Leu Asp Lys Glu Lys Ala Glu Thr Leu Ala Ser Ser Leu Gln Glu Asp Leu Ala His Thr Arg Asn Asp Ala Asn Arg Leu Gln Asp Ala Ile Ala Lys Val Glu Asp Glu Tyr Arg Ala Phe Gln Glu Glu Ala Lys Lys Gln Ile G1u Asp Leu Asn Met Thr Leu Glu Lys Leu Arg Ser Asp Leu Asp Glu Lys G1u Thr G1u Arg Ser Asp Met Lys Glu Thr Ile Phe Glu Leu Glu Asp Glu Val Glu Gln His Arg Ala Val Lys Leu His Asp Asn 145 150 l55 160 Leu Ile Tle Ser Asp Leu G1u Asn Thr Val Lys Lys Leu Gln Asp Gln Lys His Asp Met Glu Arg Glu I1e Lys Thr Leu His Arg Arg Leu Arg Glu Glu Ser Ala Glu Trp Arg Gln Phe Gln Ala Asp Leu Gln Thr Ala Val Val Ile Ala Asn Asp Ile Lys Ser Glu Ala Gln Glu Glu Ile Gly Asp Leu Lys Arg Arg Leu His Glu Ala Gln G1u Lys Asn Glu Lys Leu Thr Lys Glu Leu Glu Glu Ile Lys Ser Arg Lys Gln Glu Glu Glu Arg Gly Gly Tyr <210> 59 <211> 125 <212> PRT
<213> Homo sapien <400> 59 Gly Thr Ser Phe Ser Lys Asn His Ala Ala Pro Phe Ser Lys Val Leu Thr Phe Tyr Arg Lys Glu Pro Phe Thr Leu Glu Ala Tyr Tyr Ser Ser 20 25 . 30 Pro Gln Asp Leu Pro Tyr Pro Asp Pro Ala Ile Ala Gln Phe Ser Val G1n Lys Val Thr Pro Gln Ser Asp Gly Ser Ser Ser Lys Val Lys Val Lys Val Arg Val Asn Val His Gly Ile Phe Ser Val Ser Ser A1a Ser Leu Va1 Glu Val His Lys Ser Glu Glu Asn Glu Glu Pro Met G1u Thr Asp Gln Asn Ala Lys Glu Glu Glu Lys Met Gln Val Asp Gln Glu Glu Pro His Val Glu Glu Gln Gln G1n Gln Thr Pro Gly Arg <210> 60 <211> 246 <212> PRT
<213> Homo sapien <400> 60 Met Tyr Arg Pro Ala Arg Val Thr Ser Thr Ser Arg Phe Leu Asn Pro Tyr Val Val Cys Phe Ile Val Val Ala Gly Va1 Val Ile Leu Ala Val Thr Ile Ala Leu Leu Val Tyr Phe Leu Ala Phe Asp Gln Lys Ser Tyr Phe Tyr Arg Ser Ser Phe Gln Leu Leu Asn Val G1u Tyr Asn Ser Gln Leu Asn Ser Pro Ala Thr Gln Glu Tyr Arg Thr Leu Ser Gly Arg Ile Glu Ser Leu T1e Thr Lys Thr Phe Lys Glu Ser Asn Leu Arg Asn Gln Phe Ile Arg Ala His Val Ala Lys Leu Arg Gln Asp Gly Ser G1y Val Arg A1a Asp Val Val Met Lys Phe Gln Phe Thr Arg Asn Asn Asn Gly Ala Ser Met Lys Ser Arg Ile Glu Ser Val Leu Arg Gln Met Leu Asn Asn Ser Gly Asn Leu Glu Ile Asn Pro Ser Thr Glu Ile Thr Ser Leu Thr Asp Gln Ala Ala Ala Asn Trp Leu Ile Asn Glu Cys Gly A1a Gly Pro Asp Leu Ile Thr Leu Ser Glu Gln Ar_g Tle Leu Gly G1y Thr Glu Ala Glu Glu Gly Ser Trp Pro Trp Gln Val Ser Leu Arg Leu Asn Asn Ala His His Cys Gly Gly Ser Leu I1e Asn Asn Met Trp Ile Leu Thr Ala Ala His Cys Phe Arg Ser Asn Ser Asn Pro Arg Asp Trp Tle Ala Thr Ser G1y Tle Ser Thr <210> 61 <211> 128 <212> PRT
<213> Homo sapien 2$
<400> 61 Gly Ile Phe Ser Val Ser Ser Ala Ser Leu Val Glu Val His Lys Ser 2 5 l0 15 G1u Glu Asn Glu Glu Pro Met Glu Thr Asp Gln Asn Ala Lys Glu Glu Glu Lys Met Gln Val Asp Gln Glu Glu Pro His Val Glu Glu Gln Gln Gln Gln Thr Pro Ala Glu Asn Lys Ala G1u Ser Glu Glu Met G1u Thr Ser Gln Ala Gly Ser Lys Asp Lys Lys Met Asp Gln Pro Pro G1n Ala Lys Lys Ala Lys Val Lys Thr Ser Thr Val Asp Leu Pro I1e Glu Asn Gln Leu Leu Trp Gln Ile Asp Arg Glu Met Leu Asn Leu Tyr Ile Glu Asn Glu Gly Lys Met Ile Met Gln Asp Lys Leu Glu Lys Glu Arg Asn <210> 62 <211> 418 <212> PRT
<213> Homo sapien <400> 62 Met Tyr Arg Pro Ala Arg Val Thr Ser Thr Ser Arg Phe Leu Asn Pro Tyr Va1 Val Cys Phe Ile Val Val Ala Gly Va1 Val Ile Leu Ala Val Thr Ile Ala Leu Leu Val Tyr Phe Leu Ala Phe Asp Gln Lys Ser Tyr Phe Tyr Arg Ser Ser Phe G1n Leu Leu Asn Val G1u Tyr Asn Ser Gln Leu Asn Ser Pr.o Ala Thr Gln Glu Tyr Arg Thr Leu Ser Gly Arg Ile Glu Ser Leu I1e Thr Lys Thr Phe Lys Glu Ser Asn Leu Arg Asn Gln Phe Ile Arg Ala His Val Ala Lys Leu Arg Gln Asp Gly Ser Gly Val Arg Ala Asp Val Val Met Lys Phe Gln Phe Thr Arg Asn Asn Asn Gly Ala Ser Met Lys Ser Arg Ile Glu Ser Val Leu Arg Gln Met Leu Asn Asn Ser Gly Asn Leu Glu Ile Asn Pro Ser Thr Glu Ile Thr Ser Leu Thr Asp Gln Ala Ala Ala Asn Trp Leu Ile Asn Glu Cys Gly Ala Gly Pro Asp Leu Ile Thr Leu Ser Glu Gln Arg Ile Leu Gly Gly Thr Glu Ala Glu Glu Gly Ser Trp Pro Trp Gln Val Ser Leu Arg Leu Asn Asn Ala His His Cys Gly G1y Ser Leu Ile Asn Asn Met Trp Ile Leu Thr Ala Ala His Cys Phe Arg Ser Asn Ser Asn Fro Arg Asp.Trp Ile Ala Thr Ser Gly Tle Ser Thr Thr Phe Pro Lys Leu Arg Met Arg Val Arg Asn Ile Leu Ile His Asn Asn Tyr Lys Ser Ala Thr His Glu Asn Asp Ile Ala Leu Val Arg Leu Glu Asn Ser Val Thr Phe Thr Lys Asp Ile His Ser Val Cys Leu Pro Ala Ala Thr Gln Asn Ile Pro Pro Gly Ser Thr Ala Tyr Val Thr Gly Trp G1y Ala Gln Glu Tyr Ala Gly His Thr Val Pro Glu Leu Arg Gln Gly Gln Val Arg Ile Tle Ser Asn Asp Val Cys Asn Ala Pro His Ser Tyr Asn Gly Ala Ile Leu Ser Gly Met Leu Cys Ala Gly Va1 Pro Gln Gly Gly Val Asp Ala Cys Gln Gly Asp Ser Gly Gly Pro Leu Val Gln Glu Asp Ser Arg Arg Leu Trp Phe Ile Val Gly Ile Val Ser Trp Gly Asp Gln Cys Gly Leu Pro Asp Lys Pro Gly Val Tyr Thr Arg Val Thr Ala Tyr Ile Asp Trp Ile Arg Gln Gln Thr Gly Ile <210> 63 <211> 776 <212> DNA
<213> Homo sapien <400> 63 cacagatggtgatagaggaatccatcttgcagtcagataaagccctcactgatagagaga 60 aggcagtagcagtggatcgggccaagaaggaggcagctgagaaggaacaggaacttttaa 120 aacagaaatt acaggagcagccagcaacagatggaggctcaagataagagtcgcaaggaa 180 aactagccaactgaaggagaagctgcagatggagagagaacacctactgagagagcagat 240 tatgatgttggagcacacgcagaaggtccaaaatgattggcttcatgaaggatttaagaa 300 gaagtatgaggagatgaatgcagagataagtcaatttaaacgtatgattgatactacaaa 360 aaatgatgatactccctggattgcacgaaccttggacaaccttgccgatgagctaactgc 420 aatattgtctgctcctgctaaattaattggtcatggtgtcaaaggtgtgagctcactctt 480 taaaaagcataagctccccttttaaggatattatagattgtacatatatgctttggacta 540 tttttgatctgtatgtttttcattttcattcagcaagttttttttttttttcagagtctt 600 actctgttgcccaggctggagtacagtggtgcaatctcagctcactgcaacctctgcctc 660 ctgggttcaagagattcacctgcctcagccccctagtagctgggattataggtgtacacc 720 accacacccagctaatttttgtatttttagtagagatggggtttcactatgttggc 776 <210> 64 <211> 160 <212> DNA
<213> Homo sapien <400> 64 gcagcgctct cggttgcagt acccactgga aggacttagg cgctcgcgtg gacaccgcaa 60 gcccctcagt agcctcggcc caagaggcct gctttccact cgctagcccc gccgggggtc 120 cgtgtcctgt ctcggtggcc ggacccgggc ccgagcccga 160 <210> 65 <211> 72 <212> PRT
<213> Homo sapien <400> 65 Leu Ser A1a Met Gly Phe Thr Ala Ala Gly Ile Ala Ser Ser Ser Ile Ala Ala Lys Met Met Ser Ala Ala Ala Ile Ala Asn Gly Gly Gly Val Ala Ser Gly Ser Leu Val Ala Thr Leu Gln Ser Leu Gly Ala Thr Gly Leu Ser Gly Leu Thr Lys Phe Ile Leu Gly Ser Ile Gly Ser Ala Ile Ala Ala Val Tle A1a Arg Phe Tyr <210> 66 <211> 2581 <212> DNA
<213> Homo sapien <400> 66 ctttcaacccgcgctcgccggctccagccccgcgcgcccccaccccttgccctcccggcg 60 gctccgcagggtgaggtggctttgaccccgggttgcccggccagcacgaccgaggaggtg 120 gctggacagctggaggatgaacggagaagccgactgccccacagacctggaaatggccgc 180 ccccaaaggccaagaccgttggtcccaggaagacatgctgactttgctggaatgcatgaa 240 gaacaaccttccatccaatgacagctccaagttcaaaaccaccgaatcacacatggactg 300 gg~aaaagtagcatttaaagacttttctggagacatgtgcaagctcaaatgggtggagat 360 ttctaatgaggtgaggaagttccgtacattgacagaattgatcctcgatgctcaggaaca 420 tgttaaaaatccttacaaaggcaaaaaactcaagaaacacccagacttcccaaagaagcc 480 cctgaccccttatttccgcttcttcatggagaagcgggccaagtatgcgaaactccaccc 540 tgagatgagcaacctggacctaaccaagattctgtccaagaaatacaaggagcttccgga 600 gaagaagaagatgaaatatattcaggacttccagagagagaaacaggagttcgagcgaaa 660 cctggcccgattcagggaggatcaccccgacctaatccagaatgccaagaaatcggacat 720 cccagagaagcccaaaaccccccagcagctgtggtacacccacgagaagaaggtgtatct 780 caaagtgcggccagatgccactacgaaggaggtgaaggactccctggggaagcagtggtc 840 tcagctctcggacaaaaagaggctgaaatggattcataaggccctggagcagcggaagga 900 gtacgaggagatcatgagagactatatccagaagcacccagagctgaacatcagtgagga 960 gggtatcaccaagtccaccctcaccaaggccgaacgccagctcaaggacaagtttgacgg 1020 gcgacccaCCaagccacctccgaacagctactcgctgtactgcgCagagctcatggccaa 1080 catgaaggacgtgcccagcacagagcgcatggtgctgtgcagccagcagtggaagctgct 1140 gtcccagaaggagaaggacgcctatcacaagaagtgtgatcagaaaaagaaagattacga 1200 ggtggagctgctccgtttcctcgagagcctgcctgaggaggagcagcagcgggtcttggg 1250 ggaagagaagatgctgaacatcaacaagaagcaggccaccagccccgcctccaagaagcc 1320 agcccaggaagggggcaagggcggctccgagaagcccaagcggcccgtgtcggccatgtt 1380 catcttctcggaggagaaacggcggcagctgcaggaggagcggcctgagctctccgagag 1440 cgagctgacccgcctgctggcccgaatgtggaacgacctgtctgagaagaagaaggccaa 1500 gtacaaggcccgagaggcggcgctcaaggctcagtcggagaggaagcccggcggggagcg 1560 cgaggaacggggcaagctgcccgagtcccccaaaagagctgaggagatctggcaacagag 1620 cgttatcggcgactacctggcccgcttcaagaatgaccgggtgaaggccttgaaagccat 1680 ggaaatgacctggaataacatggaaaagaaggagaaactgatgtggattaagaaggcagc 1740 cgaagaccaaaagcgatatgagagagagctgagtgagatgcgggcacctccagctgctac 1800 aaattcttccaagaagatgaaattccagggagaacccaagaagcctcccatgaacggtta 1860 ccagaagttctcccaggagctgctgtccaatgg'ggagctgaaccacctgccgctgaagga 1920 gcgcatggtggagatcggcagtcgctggcagcgcatctcccagagccagaaggagcacta 1980 caaaaagctggccgaggagcagcaaaagcagtacaaggtgcacctggacctctgggttaa 2040 gagcctgtctccccaggaccgtgcagcatataaagagtacatctccaataaacgtaagag 2100 catgaccaagctgcgaggcccaaaccccaaatccagccggactactctgcagtccaagtc 2160 ggagtccgaggaggatgatgaagaggatgaggatgacgaggacgaggatgaagaagagga 2220 agatgatgagaatggggactcctctgaagatggcggcgactcctctgagtccagcagcga 2280 ggacgagagcgaggatggggatgagaatgaagaggatgacgaggacgaagacgacgacga 2340 ggatgacgatgaggatgaagataatgagtccgagggcagcagctccagctcctcctcctt 2400 aggggactcctcagactttgactccaactgaggcttagccccaccccaggggagccaggg 2460 agagcccaggagctcccctccccaactgaccacctttgtttcttccccatgttctgtccc 2520 ttgcccccct ggcctccccc actttctttc tttctttaaa aaaaaaaaaa aaaaactcga 2580 g 2581 <210> 67 <211> 764 <212> PRT
<213> Homo sapien <400> 67 Met Asn Gly Glu Ala Asp Cys Pro Thr Asp Leu Glu Met Ala Ala Pro Lys Gly Gln Asp Arg Trp Ser Gln Glu Asp Met Leu Thr Leu Leu Glu Cys Met Lys Asn Asn Leu Pro Ser Asn Asp Ser Ser Lys Phe Lys Thr Thr Glu Ser His Met Asp Trp Glu Lys Val Ala Phe Lys Asp Phe Ser Gly Asp Met Cys Lys Leu Lys Trp Val Glu Ile Ser Asn Glu Val Arg Lys Phe Arg Thr Leu Thr Glu Leu Ile Leu Asp Ala Gln Glu His Val Lys Asn Pro Tyr Lys Gly Lys Lys Leu Lys Lys His Pro Asp Phe Pro Lys Lys Pro Leu Thr Pro Tyr Phe Arg Phe Phe Met Glu Lys Arg Ala Lys Tyr Ala Lys Leu His Pro Glu Met Ser Asn Leu Asp Leu Thr Lys Ile Leu Ser Lys Lys Tyr Lys Glu Leu Pro Glu Lys Lys Lys Met Lys Tyr Ile Gln Asp Phe Gln Arg Glu Lys Gln Glu Phe Glu Arg Asn Leu Ala Arg Phe Arg Glu Asp His Pro Asp Leu Ile Gln Asn Ala Lys Lys Ser Asp Ile Pro Glu Lys Pro Lys Thr Pro Gln Gln Leu Trp Tyr Thr His Glu Lys Lys Val Tyr Leu Lys Val Arg Pro Asp Ala Thr Thr Lys Glu Val Lys Asp Ser Leu Gly Lys Gln Trp Ser Gln Leu Ser Asp Lys Lys Arg Leu Lys Trp Ile His Lys A1a Leu Glu Gln Arg Lys Glu Tyr G1u Glu Ile Met Arg Asp Tyr Ile Gln Lys His Pro Glu Leu Asn Ile Ser Glu Glu Gly Ile Thr Lys Ser Thr Leu Thr Lys Ala Glu Arg Gln Leu Lys Asp Lys Phe Asp Gly Arg Pro Thr Lys Pro Pro Pro Asn Ser Tyr Ser Leu Tyr Cys Ala Glu Leu Met Ala Asn Met Lys Asp Val Pro Ser Thr Glu Arg Met Va1 Leu Cys Ser Gln Gln Trp Lys Leu Leu Ser G1n Lys Glu Lys Asp Ala Tyr His Lys Lys Cys Asp Gln Lys Lys Lys Asp Tyr Glu Val Glu Leu Leu Arg Phe Leu Glu Ser Leu Pro Glu Glu Glu Gln Gln Arg Val Leu Gly Glu Glu Lys Met Leu Asn Ile Asn Lys Lys Gln Ala Thr Ser Pro Ala Ser Lys Lys Pro Ala Gln Glu Gly Gly gagcctgtctccccaggaccgtgcagcatataaagagtacatctccaataaacgta Lys Gly Gly Ser Glu Lys Pro Lys Arg Pro Val Ser Ala Met Phe Ile Phe Ser Glu Glu Lys Arg Arg G1n Leu Gln Glu Glu Arg Pro Glu Leu Ser Glu Ser Glu Leu Thr Arg Leu Leu Ala Arg Met Trp Asn Asp Leu Ser Glu Lys Lys Lys Ala Lys Tyr Lys Ala Arg Glu Ala Ala Leu Lys Ala Gln Ser Glu Arg Lys Pro Gly Gly Glu Arg Glu Glu Arg Gly Lys Leu Pro Glu Ser Pro Lys Arg Ala Glu Glu I1e Trp Gln Gln Ser Val Ile Gly Asp Tyr Leu Ala Arg Phe Lys Asn Asp Arg Va1 Lys Ala Leu Lys Ala Met Glu Met Thr Trp Asn Asn Met Glu Lys Lys Glu Lys Leu Met Trp Ile Lys Lys Ala A1a Glu Asp Gln Lys Arg Tyr Glu Arg Glu Leu Ser Glu Met Arg Ala Pro Pro Ala Ala Thr Asn Ser Ser Lys Lys Met Lys Phe Gln Gly Glu Pro Lys Lys Pro Pro Met Asn Gly Tyr Gln Lys Phe Ser Gln Glu Leu Leu Ser Asn Gly Glu Leu Asn His Leu Pro Leu Lys Glu Arg Met Val Glu Ile Gly Ser Arg Trp Gln Arg Ile Ser Gln Ser Gln Lys Glu His Tyr Lys Lys Leu Ala Glu Glu Gln Gln Lys G1n Tyr Lys Val His Leu Asp Leu Trp Va1 Lys Ser Leu Ser Pro Gln Asp Arg Ala Ala Tyr Lys Glu Tyr Ile Ser Asn Lys Arg Lys Ser Met Thr Lys Leu Arg Gly Pro Asn Pro Lys Ser Ser Arg Thr Thr Leu Gln Ser Lys Ser Glu Ser Glu Glu Asp Asp Glu Glu Asp Glu Asp Asp Glu Asp Glu Asp Glu G1u Glu Glu Asp Asp Glu Asn Gly Asp Ser Ser Glu Asp Gly Gly Asp Ser Ser G1u Ser Ser Ser Glu Asp Glu Ser Glu Asp Gly Asp G1u Asn Glu Glu Asp Asp Glu Asp Glu Asp Asp Asp Glu Asp Asp Asp Glu Asp Glu Asp Asn Glu Ser Glu Gly Ser Ser Ser Ser Ser Ser Ser Leu Gly Asp Ser Ser Asp Phe Asp Ser Asn <210> 68 <211> 434 <212> DNA
<213> Homo sapien <400> 68 ctaagatgct ggatgctgaa gacatcgtcg gaactgcccg gccagatgag aaagccatta 60 tgacttatgt gtctagcttc tatcatgcct tctctggagc ccagaaggca gaaacagcag 120 ccaatcgcat ctgcaaagtg ttggcggtca atcaagagaa cgagcagctt atggaagact 180 atgagaagct ggccagtgat ctgttggagt ggatccgccg caccatccca tggctggaga 240 atcgggtgcc tgagaacacc atgcatgcca tgcagcagaa gctggaggac ttccgagact 300 atagacgcct gcacaagccg cccaaggtgc aggagaagtg ccagctggag atcaacttta 360 acacgctgca gaccaaactg cggctcagca accggcctgc cttcatgccc tccgagggca 420 ggatggtctc ggat 434 <2i0> 69 <211> 244 <212> DNA
<213> Homo sapien <400> 69 aggcagcatgctcgttgagagtcatcaccactccctaatctcaagtaCgcagggacacaa 60 acactgcggaaggccgcagggtcctctgcctaggaaaaccagagacctttgttcacttgt 120 ttatgtgctgaccttccctccactattgtcctgtgaccctgccaaatccccctttgtgag 180 aaacacccaagaatgatcaataaaaaataaattaatttaggaaaaaaaaaaaaaaaaact 240 cgag 244 <210> 70 <2i1> 437 <212> DNA
<213> Homo sapien <400> 70 ctgggacgggagcgtccagcgggactcgaaccccagatgtgaaggcgtttctggaaagtc 60 cttggtccctggatccagcgtcggccagcccagagcccgtgccgcacatccttgcgtcct 120 ccaggcagtgggaccccgcgagctgcacgtccctgggcacggacaagtgtgaggcactgt 180 tggggctgtgccaggtgcggggtgggctgccccctttctcagaaccttccagcctggtgc 240 cgtggcccccaggccggagtcttcctaaggctgtgaggccacccctgtcctggcctccgt 300 tctcgcagcagcagaccttgcccgtgatgagcggggaggcccttggctggctgggccagg 360 ctggttccctggccatgggggctgcacctctgggggagccagccaaggaggaccccatgc 420 tggcgcaggaagccggg 437 <210> 7l <211> 271 <212> DNA
<213> Homo sapien <400> 71 gcgcagagttctgtcgtccaccatcgagtgaggaagagagcattggttcccctgagatag 60 aagagatggctctcttcagtgcccagtctccatacattaacccgatcatcccctttactg 120 gaccaatccaaggagggctgcaggagggacttcaggtgaccctccaggggactaccgaga 180 gttttgcacaaaagtttgtggtgaacttttcagaacagcttcaatggagatgacttggcc 240 ttccacttcaaccccggttatgaggaaggag 271 <210> 72 <211> 290 <212> DNA
<213> Homo sapien <400> 72 ccgagcccta cccggaggtc tccagaatcc ccaccgtcag gggatgcaac ggctccctgt 60 ctggtgccct ctcctgctgc gaggactcgg cccagggctc gggcccgccc aaggccccta 120 cggtggccga gggtcccagc tcctgccttc ggcggaacgt gatcagcgag agggagcgca 180 ggaagcggat gtcgttgagc tgtgagcgtc tgcgggccct gctgccccag ttcgatggcc 240 ggcgggagga catggcctcg gtcctggaga tgtctgttgc aattcctgcg 290 <210> 73 <221> 144 <212> PRT
<213> Homo sapien <400> 73 Lys Met Leu Asp Ala Glu Asp Tle Val G1y Thr Ala Arg Pro Asp Glu Lys Ala Ile Met Thr Tyr Val Ser Ser Phe Tyr His Ala Phe Ser Gly Ala Gln Lys Ala Glu Thr Ala Ala Asn Arg Ile Cys Lys Val Leu Ala Val Asn Gln Glu Asn Glu Gln Leu Met Glu Asp Tyr G1u Lys Leu Ala Ser Asp Leu Leu Glu Trp Ile Arg Arg Thr Ile Pro Trp Leu Glu Asn Arg Val Pro Glu Asn Thr Met His Ala Met Gln Gln Lys Leu Glu Asp Phe Arg Asp Tyr Arg Arg Leu His Lys Pro Pro Lys Val Gln Glu Lys Cys Gln Leu Glu Ile Asn Phe Asn Thr Leu G1n Thr Lys Leu Arg Leu Ser Asn Arg Pro Ala Phe Met Pro Ser Glu Gly Arg Met Val Ser Asp <210> 74 <211> 64 <212> PRT
<213> Homo sapien <400> 74 Gly Ser Met Leu Val Glu Ser His His His Ser Leu Tle Ser Ser Thr Gln Gly His Lys His Cys Gly Arg Pro Gln fly Pro Leu Pro Arg Lys Thr Arg Asp Leu Cys Ser Leu Val Tyr Val Leu Thr Phe Pro Pro Leu Leu Ser Cys Asp Pro Ala Lys Ser Pro Phe Val Arg Asn Thr G1n Glu <210> 75 <211> 145 <212> PRT
<213> Homo sapien <400> 75 G1y Thr Gly Ala Ser Ser G1y Thr Arg Thr Pro Asp Val Lys Ala Phe Leu Glu Ser Pro Trp Ser Leu Asp Pro Ala Ser Ala Ser Pro Glu Pro Val Pro His Ile Leu Ala Ser Ser Arg Gln Trp Asp Pro Ala Ser Cys Thr Ser Leu Gly Thr Asp Lys Cys Glu Ala Leu Leu Gly Leu Cys Gln Val Arg Gly Gly Leu Pro Pro Phe Ser Glu Pro Ser Ser Leu Val Pro Trp Pro Pro Gly Arg Ser Leu Pro Lys Ala Val Arg Pro Pro Leu Ser Trp Pro Pro Phe Sex Gln G1n Gln Thr Leu Pro Val Met Ser Gly Glu 100 7.05 110 Ala Leu Gly Trp Leu Gly Gln Ala Gly Ser Leu Ala Met Gly Ala Ala Pro Leu Gly Glu Pro Ala Lys Glu Asp Pro Met Leu Ala Gln Glu Ala Gly <210> 76 <211> 69 <212> PRT
<213> Homo sapien <400> 76 Ala Glu Phe Cys Arg Pro Pro Ser Ser Glu Glu Glu Ser Ile Gly Ser Pro Glu Ile Glu Glu Met Ala Leu Phe Ser A1a Gln Ser Pro Tyr Ile Asn Pro Ile Ile Pro Phe Thr Gly Pro Ile Gln Gly Gly Leu Gln Glu Gly Leu Gln Val Thr Leu Gln Gly Thr Thr Glu Ser Phe Ala Gln Lys Phe Va1 Val Asn Phe <210> 77 <211> 96 <212> PRT
<213> Homo sapien <400> 77 Glu Pro Tyr Pro Glu Val Ser Arg T1e Pro Thr Val Arg Gly Cys Asn l 5 10 15 Gly Ser Leu Ser Gly Ala Leu Ser Cys Cys Glu Asp Ser Ala G1n Gly Ser Gly Pro Pro Lys Ala Pro Thr Val Ala G1u Gly Pro Ser Ser Cys Leu Arg Arg Asn Val Ile Ser Glu Arg Glu Arg Arg Lys Arg Met Ser Leu Ser Cys Glu Arg Leu Arg Ala Leu Leu Pro Gln Phe Asp Gly Arg Arg Glu Asp Met Ala Ser Val Leu Glu Met Ser Val Ala Ile Pro Ala <210> 78 <211> 2076 <212> DNA
<213> Homo sapien <400>

agaaaaagtctatgtttgcagaaatacagatccaagacaaagacaggatgggcactgctg 60 gaaaagttattaaatgcaaagcagctgtgctttgggagcagaagcaacccttctccattg 120 aggaaatagaagttgccccaccaaagactaaagaagttcgcattaagattttggccacag 180 gaatctgtcgcacagatgaccatgtgataaaaggaacaatggtgtccaagtttccagtga 240 ttgtgggacatgaggcaactgggattgtagagagcattggagaaggagtgactacagtga 300 aaccaggtgacaaagtcatccctctctttctgccacaatgtagagaatgcaatgcttgtc 360 gcaacccagatggcaacctttgcattaggagcgatattactggtcgtggagtactggctg 420 atggcaccaccagatttacatgcaagggcaaaccagtccaccacttcatgaacaccagta 480 catttaccgagtacacagtggtggatg~atcttctgttgctaagattgatgatgcagctc 540

36 ctcctgagaaagtctgtttaattggctgtgggttttccactggatatggcgctgctgtta 600 aaactggcaaggtcaaacctggttccacttgcgtcgtctttggcctgagaggagttggcc 660 tgtcagtcatcatgggctgtaagtcagctggtgcatctaggatcattgggattgacctca 720 acaaagacaaatttgagaaggccatggctgtaggtgccactgagtgtatcagtcccaagg 780 actctaccaaacccatcagtgaggtgctgtcagaaatgacaggcaacaacgtgggataca 840 cctttgaagttattgggcatcttgaaaccatgattgatgccctggcatcctgccacatga 900 actatgggaccagcgtggttgtaggagttcctccatcagccaagatgctcacctatgacc 960 cgatgttgctcttcactggacgcacatggaagggatgtgtctttggaggtttgaaaagca 1020 gagatgatgtcccaaaactagtgactgagttcctggcaaagaaatttgacctggaccagt 1080 tgataactcatgtcttaccatttaaaaaaatcagtgaaggatttgagctgctcaattcag 1140 gacaaagcattcgaacggtcctgacgttttgagatccaaagtggcaggaggtctgtgttg 1200 tcatggtgaactggagtttctcttgtgagagttccctcatctgaaatcatgtatctgtct 1260 cacaaatacaagcataagtagaagatttgttgaagacatagaacccttataaagaattat 1320 taacctttataaacatttaaagtcttgtgagcacctgggaattagtataataacaatgtt 1380 aatatttttgatttacattttgtaaggctataattgtatcttttaagaaaacatacactt 1440 ggatttctatgttgaaatggagatttttaagagttttaaccagctgctgcagatatatat 1500 ctcaaaacagatatagcgtataaagatatagtaaatgcatctcctagagtaatattcact 1560 taacacattgaaactattattttttagatttgaatataaatgtattttttaaacacttgt 1620 tatgagttaacttggattacattttgaaatcagttcattccatgatgcatattactggat 1680 tagattaagaaagacagaaaagattaagggacgggcacatttttcaacgattaagaatca 1740 tcattacataacttggtgaaactgaaaaagtatatcatatgggtacacaaggctatttgc 1800 cagcatatattaatattttagaaaatattccttttgtaatactgaatataaacatagagc 1860 tagaatcatattatcatacttatcataatgttcaatttgatacagtagaattgcaagtcc 1920 ttaagtccctattcactgtgcttagtagtgactccatttaataaaaagtgtttttagttt 1980 ttaacaactacactgatgtatttatatatatttataacatgttaaaaatttttaaggaaa 2040 ttaaaaattatataaaaaaaaaaaaaaaaactcgag 2076 <210> 79 <211> 2790 <212> DNA
<213> Homo sapien <400> 79 aagcagttgagtaggcagaaaaaagaacctcttcattaaggattaaaatgtataggccag 60 cacgtgtaacttcgacttcaagatttctgaatccatatgtagtatgtttcattgtcgtcg 120 caggggtagtgatcctggcagtcaccatagctctacttgtttactttttagcttttgatc 180 aaaaatcttacttttataggagcagttttcaactcctaaatgttgaatataatagtcagt 240 taaattcaccagctacacaggaatacaggactttgagtggaagaattgaatctctgatta 300 ctaaaacattcaaagaatcaaatttaagaaatcagttcatcagagctcatgttgccaaac 360 tgaggcaagatggtagtggtgtgagagcggatgttgtcatgaaatttcaattcactagaa 420 ataacaatggagcatcaatgaaaagcagaattgagtctgttttacgacaaatgctgaata 480 actctggaaacctggaaataaacccttcaactgagataacatcacttactgaccaggctg 540 cagcaaattggcttattaatgaatgtggggccggtccagacctaataacattgtctgagc 600 agagaatccttggaggcactgaggctgaggagggaagctggccgtggcaagtcagtctgc 660 ggctcaataatgcccaccactgtggaggcagcctgatcaataacatgtggatcctgacag 720 cagctcactgcttcagaagcaactctaatcctcgtgactggattgccacgtctggtattt 780 ccacaacatttcctaaactaagaatgagagtaagaaatattttaattcataacaattata 840 aatctgcaactcatgaaaatgacattgcacttgtgagacttgagaacagtgtcaccttta 900 ccaaagatatccatagtgtgtgtctcccagctgctacccagaatattccacctggctcta 960 ctgcttatgtaacaggatggggcgctcaagaatatgctggccacacagttccagagctaa 1020 ggcaaggacaggtcagaataataagtaatgatgtatgtaatgcaccacatagttataatg 1080 gagccatcttgtctggaatgctgtgtgctggagtacctcaaggtggagtggacgcatgtc 1140 agggtgactctggtggcccactagtacaagaagactcacggcggctttggtttattgtgg 1200 ggatagtaagctggggagatcagtgtggcctgccggataagccaggagtgtatactcgag 1260 tgacagcctaccttgactggattaggcaacaaactgggatctagtgcaacaagtgcatcc 2320 ctgttgcaaagtctgtatgcaggtgtgcctgtcttaaattccaaagctttacatttcaac 1380 tgaaaaagaaactagaaatgtcctaatttaacatcttgttacataaatatggtttaacaa 1440 acactgtttaacctttctttattattaaaggttttctattttctccagagaactatatga 1500

37 atgttgcatagtactgtggctgtgtaacagaagaaacacactaaactaattacaaagtta 1560 acaatttcattacagttgtgctaaatgcccgtagtgagaagaacaggaaccttgagcatg 1620 tatagtagaggaacctgcacaggtctgatgggtcagaggggtcttctctgggtttcactg 1680 aggatgagaagtaagcaaactgtggaaacatgcaaaggaaaaagtgatagaataatattc 1740 aagacaaaaagaacagtatgaggcaagagaaatagtatgtatttaaaatttttggttact 1800 caatatcttatacttagtatgagtcctaaaattaaaaatgtgaaactgttgtactatacg 1860 tataacctaaccttaattattctgtaagaacatgcttccataggaaatagtggataattt 1920 tcagctatttaaggcaaaagctaaaatagttcactcctcaactgagacccaaagaattat 1980 agatatttttcatgatgacccatgaaaaatatcactcatctacataaaggagagactata 2040 tctattttatagagaagctaagaaatatacctacacaaacttgtcaggtgctttacaact 2100 acatagtactttttaacaacaaaataataattttaagaatgaaaaatttaatcatcggga 2160 agaacgtcccactacagacttcctatcactggcagttatatttttgagcgtaaaagggtc 2220 gtcaaacgctaaatctaagtaatgaattgaaagtttaaagagggggaagagttggtttgc 2280 aaaggaaaagtttaaatagcttaatatcaatagaatgatcctgaagacagaaaaaacttt 2340 gtCaCtCttCCt CtCtCattttCtttCt Ct CtCCCCCCttCtCdtaCaCatgCCECCC 2400 Ct cgaccaaagaatataatgtaaattaaatccactaaaatgtaatggcatgaaaatctctgt 2460 agtctgaatcactaatattcctgagtttttatgagctcctagtacagctaaagtttgcct 2520 atgcatgatcatctatgcgtcagagcttcctccttctacaagctaactccctgcatctgg 2580 gcatcaggactgctccatacatttgctgaaaacttcttgtatttcctgatgtaaaattgt 2640 gcaaacacctacaataaagccatctacttttagggaaagggagttgaaaatgcaaccaac 2700 tcttggcgaactgtacaaacaaatctttgctatactttatttcaaataaattctttttga 2760 aatgaaaaaaaaaaaaaaaaaaaactcgag 2790 <210> 80 <211> 1460 <212> DNA
<213> Homo sapien <400>

ctcaaagcagttgagtaggcagaaaaaagaacctcttcattaaggattaaaatgtatagg 60 ccagcacgtgtaacttcgacttcaagatttctgaatccatatgtagtatgtttcattgtc 120 gtcgcaggggtagtgatcctggcagtcaccatagctctacttgtttactttttagctttt 180 gatcaaaaatcttacttttataggagcagttttcaactcctaaatgttgaatataatagt 240 cagttaaattcaccagctacacaggaatacaggactttgagtggaagaattgaatctctg 300 attactaaaacattcaaagaatcaaatttaagaaatcagttcatcagagctcatgttgcc 360 aaactgaggcaagatggtagtggtgtgagagcggatgttgtcatgaaatttcaattcact 420 agaaataacaatggagcatcaatgaaaagcagaattgagtctgttttacgacaaatgctg 480 aataactctggaaacctggaaataaacccttcaactgagataacatcacttactgaccag 540 gctgcagcaaattggcttattaatgaatgtggggccggtccagacctaataacattgtct 600 gagcagagaatccttggaggcactgaggctgaggagggaagctggccgtggcaagtcagt 660 ctgcggctcaataatgcccaccactgtggaggcagcctgatcaataacatgtggatcctg 720 acagcagctcactgcttcagaagcaactctaatcctcgtgactggattgccacgtctggt 780 atttccacaacatttcctaaactaagaatgagagtaagaaatattttaattcataacaat 840 tataaatctgcaactcatgaaaatgacattgcacttgtgagacttgagaacagtgtcacc 900 tttaccaaagatatccatagtgtgtgtctcccagctgctacccagaatattccacctggc 960 tctactgcttatgtaacaggatggggcgctcaagaatatgctggccacacagttccagag 1020 ctaaggcaaggacaggtcagaataataagtaatgatgtatgtaatgcaccacatagttat 1080 aatggagccatcttgtctggaatgctgtgtgctggagtacctcaaggtggagtggacgca 1140 tgtcagggtgactctggtggcccactagtacaagaagactcacggcggctttggtttatt 1200 gtggggatagtaagctggggagatcagtgtggcctgccggataagccaggagtgtatact 1260 cgagtgacagcctaccttgactggattaggcaacaaactgggatctagtgcaacaagtgc 1320 atccctgttgcaaagtctgtatgcaggtgtgcctgtcttaaattccaaagctttacattt 1380 caactgaaaaagaaactagaaatgtcctaatttaacatcttgttacataaatatggttta 1440 acaaaaaaaaaaaaaaaaaa 1460 <210> 81 <211> 386 <212> PRT

38 <213> Homo sapien <400> 81 Met Phe Ala Glu Ile GIn Ile Gln Asp Lys Asp Arg Met Gly Thr Ala Gly Lys Va1 Ile Lys Cys Lys Ala Ala Val Leu Trp Glu Gln Lys Gln Pro Phe Ser Ile Glu Glu Ile Glu Val Ala Pro Pro Lys Thr Lys Glu Val Arg I1e Lys Ile Leu Ala Thr Gly Ile Cys Arg Thr Asp Asp His Val Ile Lys Gly Thr Met Val Sex Lys Phe Pro.Val Ile Val Gly His Glu Ala Thr Gly Ile Val Glu Sex Ile Gly Glu Gly Val Thr Thr Val Lys Pro Gly Asp Lys Val T1e Pro Leu Phe Leu Pro Gln Cys Arg G1u Cys Asn Ala Cys Arg Asn Pro Asp GIy Asn Leu Cys Ile Arg Ser Asp Ile Thr Gly Arg Gly Val Leu Ala Asp Gly Thr Thr Arg Phe Thr Cys Lys Gly Lys Pro Val His His Phe Met Asn Thr Ser Thr Phe Thr Glu Tyr Thr Val Val Asp Glu Ser Ser Val A1a Lys Ile Asp Asp Ala Ala Pro Pro G1u Lys Val Cys Leu Ile G1y Cys Gly Phe Sex Thr Gly Tyr G1y Ala Ala Val Lys Thr Gly Lys Val Lys Pro Gly Ser Thr Cys Val Val Phe Gly Leu Arg Gly Val Gly Leu Ser Val Ile Met G1y Cys Lys 210 2l5 220 Ser A1a Gly Ala Ser Arg Ile Tle Gly Ile Asp Leu Asn Lys Asp Lys Phe Glu Lys Ala Met A1a Val Gly A1a Thr Glu Cys Ile Ser Pro Lys Asp Ser Thr Lys Pro Ile Ser Glu Val Leu Ser Glu Met Thr Gly Asn Asn Val Gly Tyr Thr Phe G1u Val Ile Gly His Leu Glu Thr Met Ile Asp Ala Leu Ala Ser Cys His Met Asn Tyr Gly Thr Ser Va1 Val Val Gly Va1 Pro Pro Ser Ala Lys Met Leu Thr Tyr Asp Pro Met Leu Leu Phe Thr Gly Arg Thr Trp Lys Gly Cys Val Phe Gly G1y Leu Lys Ser Arg Asp Asp Val Pro Lys Leu Val Thr G1u Phe Leu Ala Lys Lys Phe Asp Leu Asp Gln Leu Ile Thr His Val Leu Pro Phe Lys Lys Ile Ser Glu Gly Phe G1u Leu Leu Asn Ser Gly Gln Ser Ile Arg Thr Va1 Leu Thr Phe <210> 82 <211> 418 <212> PRT
<213> Homo sapien

39 <400> 82 Met Tyr Arg Pro Ala Arg Val Thr Ser Thr Ser Arg Phe Leu Asn Pro Tyr Val Val Cys Phe Ile Val Val A1a Gly Val Val Ile Leu Ala Val Thr I1e Ala Leu Leu Val Tyr Phe Leu Ala Phe Asp Gln Lys Ser Tyr Phe Tyr Arg Ser Ser Phe Gln Leu Leu Asn Val Glu Tyr Asn Ser Gln Leu Asn Ser Pro Ala Thr Gln Glu Tyr Arg Thr Leu Ser Gly Arg Ile 65 70 75 80 .
Glu Ser Leu Ile Thr Lys Thr Phe Lys Glu Ser Asn Leu Arg Asn Gln Phe T1e Arg Ala His Val Ala Lys Leu Arg Gln Asp Gly Ser Gly Val Arg Ala Asp Val Val Met Lys Phe Gln Phe Thr Arg Asn Asn Asn G1y 115 l20 125 Ala Ser Met Lys Ser Arg Ile Glu Ser Va1 Leu Arg Gln Met Leu Asn Asn Ser Gly Asn Leu Glu Ile Asn Pro Ser Thr Glu Ile Thr Ser Leu Thr Asp Gln Ala Ala Ala Asn Trp Leu Ile Asn G1u Cys Gly Ala Gly Pro Asp Leu Ile Thr Leu Ser Glu Gln Arg Ile Leu G1y Gly Thr Glu Ala Glu Glu G1y Ser Trp Pro Trp Gln Val Ser Leu Arg Leu Asn Asn Ala His His Cys Gly Gly Ser Leu Ile Asn Asn Met Trp Ile Leu Thr Ala A1a His Cys Phe Arg Ser Asn Ser Asn Pro Arg Asp Trp I1e Ala Thr Ser Gly T1e Ser Thr Thr Phe Pro Lys Leu Arg Met Arg Val Arg Asn Ile Leu Tle His Asn Asn Tyr Lys Sex Ala Thr His Glu Asn Asp Ile Ala Leu Val Arg Leu Glu Asn Ser Va1 Thr Phe Thr Lys Asp Ile His Ser Val Cys Leu Pro Ala Ala Thr Gln Asn Tle Pro Pro Gly Ser Thr Ala Tyr Val Thr Gly Trp Gly Ala Gln Glu Tyr Ala Gly His Thr Val Pro Glu Leu Arg Gln Gly Gln Val Arg Ile Ile Ser Asn Asp Val Cys Asn Ala Pro His Ser Tyr Asn Gly Ala I1e Leu Ser Gly Met Leu Cys Ala Gly Val Pro Gln Gly Gly Val Asp Ala Cys G1n Gly Asp Ser Gly Gly Pro Leu Val Gln Glu Asp Ser Arg Arg Leu Trp Phe Ile Val Gly Ile Val Sex Trp Gly Asp Gln Cys Gly Leu Pro Asp Lys Pro Gly Val Tyr Thr Arg Val Thr Ala Tyr Leu Asp Trp Ile Arg G1n Gln Thr Gly Ile <210> 83 <211> 418 <212> PRT
<213> Homo sapien <400> 83 Met Tyr Arg Pro Ala Arg Val Thr Ser Thr Ser Arg Phe Leu Asn Pro Tyr Val Val Cys Phe Ile Val Val Ala Gly Va1 Val Ile Leu Ala Val Thr Ile Ala Leu Leu Val Tyr Phe Leu Ala Phe Asp Gln Lys Ser Tyr Phe Tyr Arg Ser Ser Phe Gln Leu Leu Asn Val Glu Tyr Asn Ser Gln Leu Asn Ser Pro Ala Thr Gln Glu Tyr Arg Thr Leu Ser Gly Arg Ile Glu Ser Leu Tle Thr Lys Thr Phe Lys Glu Ser Asn Leu Arg Asn Gln Phe Ile Arg Ala His Val A1a Lys Leu Arg G1n Asp Gly Ser Gly Val Arg Ala Asp Val Val Met Lys Phe Gln Phe Thr Arg Asn Asn Asn Gly Ala Ser Met Lys Ser Arg Ile Glu Ser Val Leu Arg Gln Met Leu Asn Asn Ser Gly Asn Leu Glu Ile Asn Pro Ser Thr Glu Ile Thr Ser Leu Thr Asp Gln Ala Ala A1a Asn Trp Leu Tle Asn Glu Cys Gly A1a Gly Pro Asp Leu Ile Thr Leu Ser Glu Gln Arg Ile Leu Gly Gly Thr Glu Ala Glu Glu Gly Ser Trp Pro Trp Gln Val Ser Leu Arg Leu Asn Asn Ala His His Cys Gly Gly Ser Leu I1e Asn Asn Met Trp Ile Leu Thr Ala Ala His Cys Phe Arg Ser Asn Ser Asn Pro Arg Asp Trp Ile Ala Thr Ser Gly Ile Ser Thr Thr Phe Pro Lys Leu Arg Met Arg Val Arg Asn Ile Leu Ile His Asn Asn Tyr Lys Ser Ala Thr His Glu Asn Asp Tle Ala Leu Val Arg Leu Glu Asn Ser Val Thr Phe Thr Lys Asp Ile His Ser Va1 Cys Leu Pro Ala Ala Thr Gln Asn Ile Pro Pro Gly Ser Thr A1a Tyr Val Thr Gly Trp Gly Ala Gln Glu Tyr Ala Gly His Thr Val Pro Glu Leu Arg Gln Gly Gln Val Arg Ile Ile Ser Asn Asp Val Cys Asn Ala Pro His Ser Tyr Asn Gly Ala Ile Leu Sex Gly Met Leu Cys Ala Gly Val Pro Gln Gly Gly Val Asp A1a Cys Gln Gly Asp Ser G1y Gly Pro Leu Val Gln Glu Asp Ser Arg Arg Leu Trp Phe Ile Val Gly Ile Va1 Ser Trp Gly Asp Gln Cys Gly Leu Pro Asp Lys Pro Gly Val Tyr Thr Arg Val Thr Ala Tyr Leu Asp Trp Ile Arg Gln Gln Thr G1y Ile <210> 84 <211> 489 <212> DNA
<213> Homo sapien <400> 84 aaaagggtaagcttgatgattaccaggaacgaatgaacaaaggggaaaggcttaatcaag 60 atcagctggatgccgtttctaagtaccaggaagtcacaaataatttggagtttgcaaaag 120 aattacagaggagtttcatggCactaagtcaagatattcagaaaacaataaagaagacag 7.80 cacgtcgggagcagcttatgagagaagaagctgaacagaaacgtttaaaaactgtacttg 240 agctacagtatgttttggacaaattgggagatgatgaagtgcggactgacctgaaacaag 300 gtttgaatggagtgccaatattgtccgaagaggagttgtcattgttggatgaattctata 360 agctagtagaccctgaacgggacatgagcttgaggttgaatgaacagtatgaacatgcct 420 ccattcacctgtgggacctgctggaagggaaggaaaaacctgtatgtggaaccacctata 480 aagttctaa 489 <210> 85 <211> 304 <2I2> DNA
<213> Homo sapien <400> 85 gggacctggaggaggccacgctgcagcatgaagccacagcagccaccctgaggaagaagc 60 acgcggacagcgtggccgagctcggggagcagatcgacaacctgcagcgggtgaagcaga 120 agctggagaaggagaagagcgagatgaagatggagatcgatgacctcgcttgtaacatgg 180 aggtcatctccaaatctaagggaaaccttgagaagatgtgccgcacactggaggaccaag 240 tgagtgagctgaagacccaggaggaggaacagcagcggctgatcaatgaactgactgcgc 300 agag 304 <210> 86 <211> 296 <212> DNA
<213> Homo sapien <400> 86 gaaaatccttcctttgaatgggaatctccaagcagttgaattgggcgaaaaaagaacctc 60 ttccttaaggattaaaatgtttagggcaacacgtgttacttccacttccagatttctgaa 120 tccatatgttgtatgtttccttgtcctcccaggggttgtgatcctggcagtccccatagc 180 tctacttgtttactttttagcttttgatcaaaaatcttacttttattggagcaattttcc 240 actcccaaatgttgaatataatagtccgtttaattcccccgcttcaccgggaattc 296 <210> 87 <211> 904 <212> DNA
<213> Homo sapien <400>

gtgtccaggaaacgattcatgaacataacaagcttgctgcaaattcagatcatctcatgc 60 agattcaaaaatgtgagttggtcttgatccacacctacccagttggtgaagacagccttg 120 tatctgatcgttctaaaaaagagttgtccccggttttaaccagtgaagttcatagtgttc 180 gtgcaggacggcatcttgctaccaaattgaatattttagtacagcaacattttgacttgg 240 cttcaactactattacaaatattccaatgaaggaagaacagcatgctaacacatctgcca 300 attatgatgtggagctacttcatcacaaagatgcacatgtagatttcctgaaaagtggtg 360 attcgcatctaggtggcggcagtcgagaaggctcgtttaaagaaacaataacattaaagt 420 ggtgtacaccaaggacaaataacattgaattacactattgtactggagcttatcggattt 480 cacctgtagatgtaaatagtagaccttcctcctgccttactaattttcttctaaatggtc 540 gttctgttttattggaacaaccacgaaagtcaggttctaaagtcattagtcatatgctta 600 gtagccatggaggagagatttttttgcacgtccttagcagttctcgatccattctagaag 660 atccaccttcaattagtgaaggatgtggaggaagagttacagactaccggattacagatt 720 ttggtgaatttatgaggggaaaacagattaactccttttctacaccccagatataaaatc 780 gatggaagtcttgaggtccctttggaaccgagccaaaagatcagttaaaaaaacataccc 840 gttactggcctatgatttcaaaaacccaccatttttaacatgcaagcggtagttccgtta 900 acca 904 <210> 88 <211> 387 <212> DNA
<213> Homo sapien <400> 88 cgtctctcccccagtttgccgttcacccggagcgctcgggacttgccgatagtggtgacg 60 gcggcaacatgtctgtggctttcgcggccccgaggcagcgaggcaagggggagatcactc 120 ccgctgcgattcagaagatgttggatgacaataaccatcttattcagtgtataatggact 180 ctcagaataaaggaaagacctcagagtgttctcagtatcagcagatgttgcacacaaact 240 tggtataccttgctacaatagcagattctaatcaaaatatgcagtctcttttaccagcac 300 cacccacacagaatatgcctatgggtcctggagggatgaatcagagcgggcctcccccac 360 ctccacgctctcacaacatgccttcaa 387 <210> 89 <211> 481 <212> DNA
<213> Homo sapien <400> 89 tgttcttggacctgcggtgctatagagcaggctcttctaggttggcagttgccatggaat 60 ctggacccaaaatgttggcccccgtttgcctggtggaaaataacaatgagcagctattgg 120 tgaaccagcaagctatacagattcttgaaaagatttctcagccagtggtggtggtggcca 180 ttgtaggactgtaccgtacagggaaatcctacttgatgaaccatctggcaggacagaatc 240 atggcttccctctgggctccacggtgcagtctgaaaccaagggcatctggatgtggtgcg 300 tgccccacccatccaagccaaaccacaccctggtccttctggacaccgaaggtctgggcg 360 atgtggaaaagggtgaccctaagaatgactcctggatctttgccctggctgtgctcctgt 420 gcagcacctttgtctacaacagcatgagcaccatcaaccaccaggccctggagcagctgc 480 a 481 <210> 90 <211> 491 <212> DNA
<213> Homo sapien <400>

tgaaaactgttcttggacctgcggtgctatagagcaggttggcagttgccatggaatctg 60 gacccaaaatgttggcccccgtttgcctggtggaaaataacaatgagcagctattggtga 120 accagcaagctatacagattcttgaaaagatttctcagccagtggtggtggtggccattg 180 taggactgtaccgtacagggaaatcctacttgatgaaccatctggcaggacagaatcatg 240 gcttccctctgggctccacggtgcagtctgaaaccaagggcatctggatgtggtgcgtgc 300 cccacccatccaagccaaaccacaccctggtccttctggacaccgaaggtctgggcgatg 360 tggaaaagggtgaccctaagaatgactcctggatctttgccctggctgtgctcctgtgca 420 gcacctttgtctacaacagcatgagcaccatcaaccaccaagccctggagcagctgcatt 480 atgtgacggac 491 <210> 91 <211> 488 <2l2> DNA
<213> Homo sapien <400> 91 ttcgacagtcagccgcatcttcttttgcgtcgccagccgagccacatcgctcagacacca 60 tggggaaggtgaaggtcggagtcaacggatttggtcgtattgggcgcctggtcaccaggg 120 ctgcttttaactctggtaaagtggatattgttgccatcaatgaccccttcattgacctca 180 actacatggtttacatgttccaatatgattccacccatggcaaattccatggcaccgtcg 240 aggctgagaacgggaagcttgtcatcaatggaaatcccatcaccatcttccaggagcgag 300 atccctccaaaatcaagtggggcgatgctggcgctgagtacgtcgtggagtccactggcg 360 tcttcaccaccatggagaaggctggggctcatttgcaggggggagccaaaagggtcatca 420 tctctgcccctctgctgatgccccatgttcgtcatgggtgtgaaccatgagaagtatgac 480 acagcctc 488 <210> 92 <211> 384 <212> DNA
<213> Homo sapien <400> 92 gacagtcagccgcatcttcttttgcgtcgccagccgagccacatcgctcagacaccatgg 60 ggaaggtgaaggtcggagtcaacggatttggtcgtattgggcgcctggtcaccagggctg 120 cttttaactctggtaaagtggatattgttgccatcaatgaccccttcattgacctcaact 180 acatggtttacatgttccaatatgattccacccatggcaaattccatggcaccgtcgagg 240 ctgagaacgggaagcttgtcatcaatggaaatcccatcaccatcttccaggagcgagatc 300 cctccaaaatcaagtggggcgatactggcgctgagtacgtcgtggagtccactggcgtct 360 tcaccaccatggagaaggctgggg 384 <210> 93 <211> 162 <212> PRT
<213> Homo sapien <400> 93 Lys G1y Lys Leu Asp Asp Tyr Gln Glu Arg Met Asn Lys Gly Glu Arg Leu Asn Gln Asp Gln Leu Asp Ala Val Ser Lys Tyr Gln Glu Val Thr Asn Asn Leu Glu Phe Ala Lys Glu Leu Gln Arg Ser Phe Met Ala Leu Ser Gln Asp Ile Gln Lys Thr Ile Lys Lys Thr Ala Arg Arg Glu Gln Leu Met Arg Glu Glu Ala Glu Gln Lys Arg Leu Lys Thr Val Leu Glu Leu G1n Tyr Val Leu Asp Lys Leu Gly Asp Asp Glu Val Arg Thr Asp Leu Lys Gln Gly Leu Asn Gly Val Pro Ile Leu Ser Glu Glu Glu Leu 100 105 l10 Ser Leu Leu Asp Glu Phe Tyr Lys Leu Val Asp Pro Glu Arg Asp Met Ser Leu Arg Leu Asn Glu Gln Tyr Glu His Ala Ser Ile His Leu Trp Asp Leu Leu Glu Gly Lys Glu Lys Pro Val Cys Gly Thr Thr Tyr Lys Val Leu <210> 94 <211> 100 <212> PRT

<213> Homo sapien <400> 94 Asp Leu Glu Glu Ala Thr Leu Gln His Glu Ala Thr Ala Ala Thr Leu Arg Lys Lys His Ala Asp Ser Val Ala Glu Leu Gly Glu Gln Ile Asp Asn Leu Gln Arg Val Lys Gln Lys Leu Glu Lys Glu Lys Ser Glu Met Lys Met Glu Ile Asp Asp Leu Ala Cys Asn Met Glu Val Ile Ser Lys Ser Lys Gly Asn Leu Glu Lys Met Cys Arg Thr Leu G1u Asp Gln Val Ser Glu Leu Lys Thr Gln Glu Glu Glu Gln G1n Arg Leu Ile Asn Glu Leu Thr Ala Gln <210> 95 <211> 99 <212> PRT
<213> Homo sapien <400> 95 .
Lys Ile Leu Pro Leu Asn Gly Asn Leu G1n Ala Val Glu Leu Gly Glu l 5 10 15 Lys Arg Thr Ser Ser Leu Arg Ile Lys Met Phe Arg Ala Thr Arg Val Thr Ser Thr Ser Arg Phe Leu Asn Pro Tyr Val Va1 Cys Phe Leu Val Leu Pro Gly Val Val Ile Leu Ala Val Pro Ile Ala Leu Leu Val Tyr Phe Leu Ala Phe Asp Gln Lys Ser Tyr Phe Tyr Trp Ser Asn Phe Pro Leu Pro Asn Val Glu Tyr Asn Ser Pro Phe Asn Ser Pro Ala Ser Pro G1y Ile Pro <210> 96 <211> 257 <2I2> PRT
<213> Homo sapien <400> 96 Val G1n Glu Thr Ile His Glu His Asn Lys Leu Ala Ala Asn Ser Asp His Leu Met Gln Ile Gln Lys Cys G1u Leu Val Leu Ile His Thr Tyr Pro Val Gly Glu Asp Ser Leu Val Ser Asp Arg Ser Lys Lys Glu Leu Ser Pro Val Leu Thr Ser Glu Val His Ser Val Arg A1a Gly Arg His Leu Ala Thr Lys Leu Asn Ile Leu Val Gln Gln His Phe Asp Leu Ala Ser Thr Thr Ile Thr Asn Ile Pro Met Lys Glu Glu Gln His Ala Asn Thr Ser Ala Asn Tyr Asp Val Glu Leu Leu His His Lys Asp Ala His Val Asp Phe Leu Lys Ser Gly Asp Ser His Leu Gly Gly Gly Ser Arg 1l5 120 125 Glu Gly Ser Phe Lys Glu Thr Ile Thr Leu Lys Trp Cys Thr Pro Arg Thr Asn Asn Ile Glu Leu His Tyr Cys Thr Gly Ala Tyr Arg Ile Ser Pro Val Asp Val Asn Ser Arg Pro Ser Ser Cys Leu Thr Asn Phe Leu Leu Asn Gly Arg Ser Val Leu Leu Glu Gln Pro Arg Lys Ser Gly Ser , Lys Val Ile Ser His Met Leu Ser Ser His Gly Gly Glu Ile Phe Leu His Val Leu Ser Ser Ser Arg Ser Ile Leu Glu Asp Pro Pro Ser Ile Ser Glu Gly Cys Gly Gly Arg Val Thr Asp Tyr Arg Ile Thr Asp. Phe Gly Glu Phe Met Arg Gly Lys Gln Ile Asn Ser Phe Ser Thr Pro Gln Ile <210> 97 <211> 128 <212> PRT
<213> Homo sapien <400> 97 Ser Leu Pro Gln Phe Ala Val His Pro Glu Arg Ser Gly Leu Ala Asp Ser Gly Asp Gly Gly Asn Met Ser Val Ala Phe Ala Ala Pro Arg Gln Arg Gly Lys G1y Glu I1e Thr Pro Ala Ala Ile Gln Lys Met Leu'Asp Asp Asn Asn His Leu Ile Gln Cys Ile Met Asp Ser Gln Asn Lys Gly Lys Thr Ser G1u Cys Ser Gln Tyr Gln Gln Met Leu His Thr Asn Leu Val Tyr Leu Ala Thr Ile Ala Asp Ser Asn Gln Asn Met Gln Ser Leu Leu Pro Ala Pro Pro Thr Gln Asn Met Pro Met Gly Pro Gly Gly Met Asn Gln Ser Gly Pro Pro Pro Pro Pro Arg Ser His Asn Met Pro Ser <210> 98 <211> 159 <212> PRT
<213> Homo sapien <400> 98 Phe Leu Asp Leu Arg Cys Tyr Arg Ala Gly Ser Ser Arg Leu Ala Val Ala Met Glu Ser Gly Pro Lys Met Leu Ala Pro Val Cys Leu Val Glu Asn Asn Asn Glu Gln Leu Leu Val Asn Gln Gln Ala Ile Gln Ile Leu Glu Lys Ile Ser Gln Pro Val Val Val Val Ala Ile Val Gly Leu Tyr Arg Thr Gly Lys Ser Tyr Leu Met Asn His Leu Ala Gly Gln Asn His Gly Phe Pro Leu Gly Ser Thr Val G1n Ser Glu Thr Lys Gly Ile Trp Met Trp Cys Va1 Pro His Pro Ser Lys Pro Asn His Thr Leu Val Leu Leu Asp Thr Glu Gly Leu Gly Asp Val Glu Lys Gly Asp Pro Lys Asn 1.15 120 125 Asp Ser Trp Ile Phe Ala Leu Ala Val Leu Leu Cys Ser Thr Phe Val Tyr Asn Ser Met Ser Thr Ile Asn His Gln Ala Leu Glu Gln Leu <210> 99 <211> 147 <212> PRT
<213> Homo sapien <400> 99 Met Glu Ser Gly Pro Lys Met Leu Ala Pro Val Cys Leu Val Glu Asn Asn Asn Glu Gln Leu Leu Val Asn GIn Gln A1a Ile Gln Ile Leu Glu Lys Ile Ser Gln Pro Val Val Val Val Ala Ile Val Gly Leu Tyr Arg Thr Gly Lys Ser Tyr Leu Met Asn His Leu Ala Gly Gln Asn His Gly Phe Pro Leu Gly Ser Thr Val Gln Ser Glu Thr Lys Gly Ile Trp Met Trp Cys Val Pro His Pro Ser Lys Pro Asn His Thr Leu Val Leu Leu Asp Thr Glu Gly Leu G1y Asp Val Glu Lys G1y Asp Pro Lys Asn Asp Ser Trp Tle Phe Ala Leu Ala Val Leu Leu Cys Ser Thr Phe Val Tyr Asn Ser Met Ser Thr Ile Asn His Gln Ala Leu Glu Gln Leu His Tyr Val Thr Asp <210> 100 <211> 124 <212> PRT
<213> Homo sapien <400> 100 Met Gly Lys Val Lys Val Gly Val Asn Gly Phe Gly Arg Ile Gly Arg Leu Val Thr Arg A1a Ala Phe Asn Ser Gly Lys Val Asp Ile Val Ala Ile Asn Asp Pro Phe Tle Asp Leu Asn Tyr Nlet Val Tyr Met Phe Gln Tyr Asp Ser Thr His Gly Lys Phe His G1y Thr Val Glu Ala Glu Asn Gly Lys Leu Val Ile Asn Gly Asn Pro Ile Thr Ile Phe Gln Glu Arg Asp Pro Ser Lys Ile Lys Trp Gly Asp A1a Gly Ala Glu Tyr Val Val Glu Ser Thr Gly Val Phe Thr Thr Met Glu Lys Ala Gly Ala His Leu Gln Gly Gly Ala Lys Arg Val Ile Ile Ser Ala Pro <210> 101 <211> 127 <212> PRT
<213> Homo sapien <400> 101 Gln Ser Ala Ala Ser Ser Phe Ala Ser Pro Ala G1u Pro His Arg Ser Asp Thr Met Gly Lys Val Lys Val Gly Val Asn G1y Phe Gly Arg Ile Gly Arg Leu Val Thr Arg Ala Ala Phe Asn Ser Gly Lys Val Asp Ile Val Ala Ile Asn Asp Pro Phe Ile Asp Leu Asn Tyr Met Val Tyr Met Phe Gln Tyr Asp Ser Thr His Gly Lys Phe His Gly Thr Val Glu Ala Glu Asn Gly Lys Leu Val Ile Asn Gly Asn Pro Ile Thr Ile Phe Gln Glu Arg Asp Pro Ser Lys Ile Lys Trp Gly Asp Thr Gly Ala Glu Tyr Va1 Val Glu Ser Thr Gly Val Phe Thr Thr Met Glu Lys Ala Gly <210> 102 <211> 1225 <212> DNA
<213> Homo sapien <400>

atggcggcgcggtcgtcgtcgggggtggcggcggcagagggggcggcggccctggcggca 60 gcggagacggcagccgtgacggtggcagcggcggcgcgggacctgggcctgggggaatga 120 ggcggccgcggcgggccagcggcggagccgtgtagcggagaagctccccctccctgcttc 180 ccttggccgagccgggggcgcgcgcgcacgcggccgtccagagcgggctccccacccctc 240 gactcctgcgacccgcaccgcacccccacccgggcccggaggatgatgaagctcaagtcg 300 aaccagacccgcacctacgacggcgacggctacaagaagcgggccgcatgcctgtgtttc 360 cgcagcgagagcgaggaggaggtgctactcgtgagcagtagtcgccatccagacagatgg 420 attgtccctggaggaggcatggagcccgaggaggagccaagtgtggcagcagttcgtgaa 480 gtctgtgaggaggctggagtaaaagggacattgggaagattagttggaatttttgagaac 540 caggagaggaagcacaggacgtatgtctatgtgctcattgtcactgaagtgctggaagac 600 tgggaagattcagttaacattggaaggaagagggaatggtttaaaatagaagacgccata 660 aaagtgctgcagtatcacaaacccgtgcaggcatcatattttgaaacattgaggcaaggc 720 tactcagccaacaatggcaccccagtcgtggccaccacatactcggtttctgctcagagc 780 tcgatgtcaggcatcagatgactgaagacttcctgtaagagaaatggaaattggaaacta 840 gactgaagtgcaaatcttccctctcaccctggctctttccacttctcacaggcctcctct 900 ttcaaataaggcatggtgggcagcaaagaaagggtgtattgataatgttgctgtttggtg 960 ttaagtgatggggctttttcttctgtttttattgagggtgggggttgggtgtgtaatttg 2020 taagtacttttgtgcatgatctgtccctccctcttcccacccctgcagtcctctgaagag 1080 aggccaacagccttcccctgccttggattctgaagtgttcctgtttgtcttatcctggcc 1140 ctggccagacgttttctttgatttttaattttttttttttattaaaagataccagtatga 1200 gaaaaaaaaaaaaaaaaaactcgag 1225 <210> 103 <211> 741 <212> DNA
<213> Homo sapien <400> 103 agaaacctcaatcggattcagcaaaggaatggtgttattatcactacataccaaatgtta 60 atcaataactggcagcaactttcaagctttaggggccaagagtttgtgtgggactatgtc 120 atcctcgatgaagcacataaaataaaaacctcatctactaagtcagcaatatgtgctcgt 180 gctattcctgcaagtaatcgcctcctcctcacaggaaccccaatccagaataatttacaa 240 gaactatggtccctatttgattttgcttgtcaagggtccctgctgggaacattaaaaact 300 tttaagatggagtatgaaaatcctattactagagcaagagagaaggatgctaccccagga 360 gaaaaagccttgggatttaaaatatctgaaaacttaatggcaatcataaaaccctatttt 420 ctcaggaggactaaagaagacgtacagaagaaaaagtcaagcaacccagaggccagactt 480 aatgaaaagaatccagatgttgatgccatttgtgaaatgccttccctttccaggagaaat 540 gatttaattatttggatacgacttgtgcctttacaagaagaaatatacaggaaatttgtg 600 tctttagatcatatcaaggagttgctaatggagacgcgctcacctttggctgagctaggt 660 gtcttaaagaagctgtgtgatcatcctaggctgctgtctgcacgggcttgttgtttgcta 720 aatcttgggacattctctgct 741 <210> 104 <211> 321 <212> DNA
<213> Homo sapien <400> 104 ttgctctgcgtcatcaaagacaccaaactgctgtgctataaaagttccaaggaccagcag 60 cctcagatggaactgccactccaaggctgtaacattacgtacatcccgaaagacagcaaa 120 aagaagaagcacgagctgaagattactcagcagggcacggacccgcttgttctcgccgtc 7.80 cagagcaaggaacaggccgagcagtggctgaaggtgatcaaagaagcctacagtggttgt 240 agtggc.cccgtggattcagagtgtcctcctccaccaagctccccggtgcacaaggcagaa 300 ctggagaagaaactgtcttca 321 <210> 105 <211> 389 <212> DNA
<213> Homo sapien <400> 105 cagcactggccacactataaaattcaggttcagaaaaacagggtaagtcacagacagcaa 60 cgcttccagcatttattttctttgcacccatgggcaatttgagaaaatttacctttagaa 120 cgaactctgttaaaggtacagacagtacaatactttttattcagaaggtttctgcataaa 180 ggtgatagtcttttgacttaatatattattgtctcctgccttgtgtttctggaatgaatg 240 aaggtcattatttagaagataatctgggttgtatttgtgtcgtcagattgaattttcatt 300 gcacatgctacttaatgtctttaccaaataataacaaagggaaagaaaaccaaatataga 360 tgtataataaggaaaagctggcctataga 389 <210> 106 <211> 446 <212> DNA
<213> Homo sapien <400> 106 gccacatttgccctggtcatagtttaaacaccaggtcctgtgtcacatctttttggtgcc 60 acaagtatcactccattgttcagagagtaatgtattagttctgcccaattcattcttcac 120 ttttatttcttccatttcattagcatttatatcagctcaagaagttaaggttagaaaatt 180 ttccacttcaaattttcagtacagaaatgtgctgtgatgtttgacaagactatttcatag 240 taagtgagttaatgtttattggcctctgctctcctctgtgtcagacctaggaagcctgag 300 gattacttagttgttctgtctctgggtccacaggcagaatttggcccatccaaagactgg 360 ccaagtgcca aaaaaaggcc tgattaggcc ctgaaattca gtgaaattct gcctgaagaa 420 acctcttatt gaatttgaaa accata 446 <210> 107 <211> 467 <212> DNA
<213> Homo sapien <400> 107 ccgccgctgccgtcgccttcctgggattggagtctcgagctttcttcgttcgttcgccgg 60 cgggttcgcgcccttctcgcgcctcggggctgcgaggctggggaaggggttggagggggc 120 tgttgatcgccgcgtttaagttgcgctcggggcggccatgtcggccggcgaggtcgagcg 180 cctagtgtcggagctgagcggcgggaccggaggggatgaggaggaagagtggctctatgg 240 cgatgaagatgaagttgaaaggccagaagaagaaaatgccagtgctaatcctccatctgg 3d0 aattgaagatgaaactgctgaaaatggtgtaccaaaaccgaaagtgactgagaccgaaga 360 tgatagtgatagtgacagcgatgatgatgaagatgatgtgcatgtcactataggagacat 420 taaaacgggagcaccacagtatgggagttatggtacagcacctgtaa 467 <210> 108 <211> 491 <212> DNA
<213> Homo sapien <400> 108 gaaagatacaacttccccaacccaaacccgtttgtggaggacgacatggataagaatgaa 60 atcgcctctgttgcgtaccgttaccgcaggtggaagcttggagatgatattgaccttatt 120 gtccgttgtgagcacgatggcgtcatgactggagccaacggggaagtgtccttcatcaac 180 atcaagacactcaatgagtgggattccaggcactgtaatggcgttgactggcgtcagaag 240 ctggactctcagcgaggggctgtcattgccacggagctgaagaacaacagctacaagttg 300 gcccggtggacctgctgtgctttgctggctggatctgagtacctcaagcttggttatgtg 360 tctcggtaccacgtgaaagactcctcacgccacgtcatcctaggcacccagcagttcaag 420 cctaatgagtttgccagccagatcaacctgagcgtggagaatgcctgaggcattttacgc 480 tgcgtcattga 491 <210> 109 <211> 489 <212> DNA
<213> Homo sapien <400> 109 ctcagatagtactgaaccctttatcaactatgttttttcagtctgacaaccaaggcggct 60 actaagtgactaaggggcaggtagtatacagtgtggataagcaggacaaaggggtgattc 120 acatcccaggcaggacagagcaggagatcatgagatttcatcactcaggatggcttgtga 180 tttattttattttattctttttttt~ttttgagatggagtctcactcttgcccaggctgga 240 gtgcagtggtgcgatcttggctcactgcaacctctgcctcctgggttcaagcagttctcc 300 tgcctcagcctcccaagtagctgggattacaggcgtccgccaccatgcccagccaatttt 360 tgtacttttagtagagatggggtttcaccatgttggccaggctggtctcgaactccfgac 420 ctcaggtgatccactcgcctcggcctcccaaagtgctgggattataggcatgcgccacca 480 tgcccgggc 489 <210> 110 <211> 391 <212> DNA
<213> Homo sapien <400> 110 gcggagtccg ctggctgacc cgagcgctgg tctccgccgg gaaccctggg gcatggagag 60 gtctgagtac ctcggccgcg gcgcacgctg catcgcggag ccaggctgcc gctgtcccag 220 SO
tggagttccaggagcaccacctgagtgaggtgcagaatatggcatctgaggagaagctgg 180 agcaggtgctgagttccatgaaggagaacaaagtggccatcattggaaagattcataccc 240 cgatggagtataagggggagctagcctcctatgatatgcggctgaggcgtaagttggact 300 tatttgccaacgtaatccatgtgaagtcacttcctgggtatatgactcggcacaacaatc 360 tagacctggtgatcattcgagagcagacaga 391 <210> 111 <211> 172 <212> PRT
<213> Homo sapien <400> 111 Met Met Lys Leu Lys Ser Asn Gln Thr Arg Thr Tyr Asp G1y Asp Gly Tyr Lys Lys Arg Ala Ala Cys Leu Cys Phe Arg Ser Glu Ser Glu Glu Glu Val Leu Leu Val Ser Ser Ser Arg His Pro Asp Arg Trp Ile Val Pro Gly Gly Gly Met Glu Pro Glu Glu Glu Pro Ser Val Ala Ala Val Arg Glu Val Cys Glu Glu Ala Gly Val Lys Gly Thr Leu Gly Arg Leu Val Gly Ile Phe Glu Asn Gln Glu Arg Lys His Arg Thr Tyr Val Tyr Val Leu Ile Val Thr Glu Val Leu Glu Asp Trp Glu Asp Ser Val Asn Ile Gly Arg Lys Arg Glu Trp Phe Lys I1e Glu Asp Ala Ile Lys Val Leu G1n Tyr His Lys Pro Val Gln Ala Ser Tyr Phe Glu Thr Leu Arg Gln Gly Tyr Ser Ala Asn Asn Gly Thr Fro Val Val Ala Thr Thr Tyr Ser Val Ser Ala Gln Ser Ser Met Ser Gly Tle Arg <210> 112 <21l> 247 <212> PRT
<213> Homo sapien <400> 112 Arg Asn Leu Asn Arg Ile Gln Gln Arg Asn Gly Val Ile Ile Thr Thr Tyr Gln Met Leu Tle Asn Asn Trp G1n Gln Leu Ser Ser Phe Arg G1y Gln Glu Phe Val Trp Asp Tyr Va1 Ile Leu Asp Glu Ala His Lys Ile Lys Thr Ser Ser Thr Lys Ser Ala Ile Cys Ala Arg Ala Ile Pro Ala Ser Asn Arg Leu Leu Leu Thr Gly Thr Pro Ile Gln Asn Asn Leu Gln Glu Leu Trp Ser Leu Phe Asp Phe Ala Cys Gln Gly Ser Leu Leu Gly Thr Leu Lys Thr Phe Lys Met Glu Tyr Glu Asn Pro Ile Thr Arg Ala Arg Glu Lys Asp Ala Thr Pro Gly Glu Lys Ala Leu Gly Phe Lys Ile Ser Glu Asn Leu Met Ala Ile Ile Lys Pro Tyr Phe Leu Arg Arg Thr SI

Lys Glu Asp Val Gln Lys Lys Lys Ser Ser Asn Pro Glu Ala Arg Leu Asn Glu Lys Asn Pro Asp Val Asp Ala Ile Cys Glu Met Pro Ser Leu Ser Arg Arg Asn Asp Leu Ile Ile Trp Ile Arg Leu Val Pro Leu Gln Glu Glu Ile Tyr Arg Lys Phe Val Ser Leu Asp His Tle Lys Glu Leu Leu Met Glu Thr Arg Ser Pro Leu Ala G1u Leu Gly Val Leu Lys Lys Leu Cys Asp His Pro Arg Leu Leu Ser Ala Arg Ala Cys Cys Leu Leu Asn Leu Gly Thr Phe Sex Ala <210> 113 <211> 107 <212> PRT
<213> Homo sapien <400> 113 Leu Leu Cys Val Ile Lys Asp Thr Lys Leu Leu Cys Tyr Lys Ser Ser Lys Asp Gln Gln Pro Gln Met Glu Leu Pro Leu Gln Gly Cys Asn Ile Thr Tyr Ile Pro Lys Asp Ser Lys Lys Lys Lys His G1u Leu Lys Ile Thr Gln Gln Gly Thr Asp Pro Leu Val Leu Ala Val Gln Ser Lys Glu Gln A1a Glu Gln Trp Leu Lys Val Ile Lys Glu Ala Tyr Ser Gly Cys Ser Gly Pro Val Asp Ser Glu Cys Pro Pro Pro Pro Ser Ser Pro Val His Lys Ala G1u Leu Glu Lys Lys Leu Ser Ser <210> 114 <211> 155 <212> PRT
<213> Homo sapien <400> 114 Glu Arg Tyr Asn Phe Pro Asn Pro Asn Pro Phe Val G1u Asp Asp Met Asp Lys Asn Glu Ile Ala Ser Val Ala Tyr Arg Tyr Arg Arg Trp Lys Leu Gly Asp Asp Ile Asp Leu Ile Va1 Arg Cys Glu His Asp Gly Val Met Thr Gly Ala Asn Gly Glu Val Ser Phe Ile Asn Ile Lys Thr Leu Asn Glu Trp Asp Ser Arg His Cys Asn Gly Val Asp Trp Arg Gln Lys Leu Asp Ser Gln Arg Gly Ala Val Ile Ala Thr Glu Leu Lys Asn Asn Ser Tyr Lys Leu Ala Arg Trp Thr Cys Cys Ala Leu Leu Ala Gly Ser Glu Tyr Leu Lys Leu Gly Tyr Val Ser Arg Tyr His Val Lys Asp Ser Ser Arg His Val Ile Leu Gly Thr Gln Gln Phe Lys Pro Asn Glu Phe Ala Ser Gln Ile Asn Leu Ser Va1 Glu Asn Ala <210> 115 <211> 129 <212> PRT
<213> Homo sapien <400> 115 ' Gly Val Arg Trp Leu Thr Arg Ala Leu Val Ser Ala Gly Asn Pro Gly Ala Trp Arg Gly Leu Ser Thr Ser Ala Ala Ala His Ala Ala Ser Arg Ser Gln Ala Ala Ala Val Pro Val Glu Phe Gln G1u His His Leu Ser Glu Val Gln Asn Met Ala Ser Glu Glu Lys Leu Glu Gln Val Leu Ser Ser Met Lys G1u Asn Lys Va1 Ala Ile Ile Gly Lys Ile His Thr Pro 65 70 ~ 75 80 Met Glu Tyr Lys Gly Glu Leu Ala Ser Tyr Asp Met Arg Leu Arg Arg Lys Leu Asp Leu Phe Ala Asn Val Ile His Val Lys Ser Leu Pro Gly Tyr Met Thr Arg His Asn Asn Leu Asp Leu Val Ile Ile Arg Glu Gln Thr <210> 116 <211> 550 <212> DNA
<213> Homo sapien <400> 116 gaattcggcaccagcctcagagccccccagcccggctaccaccccctgcggaaaggtacc 60 catctgcattcctgcccgtcgggacctggtggacagtccagcctccttggcctctagcct 120 tggctcaccgctgcctagagccaaggagctcatcctgaatgaccttcccgccagcactcc 180 tgCCtCCaaatcctgtgactCCtCCCCgCCCCaggaCgCttCCaCCCCCaggcccagctc 240 ggccagtcacctctgccagcttgctgccaagccagcaccttccacggacagcgtcgccct 300 gaggagccccctgactctgtccagtcccttcaccacgtccttcagcctgggctcccacag 360 CaCtCtCaaCggagaCCtCtCCgtgCCCagCtCCtaCgtCagCCtCCaCCtgtCCCCCCa 420 ggtcagcagctctgtggtgtacggacgctcccccgtgatggcatttgagtctcatcccca 480 tctccgagggtcatccgtctcttcctccctacccagcatccctgggggaaagccggccta 540 ctccttccac 550 <210> 117 <211> 154 <212> DNA
<213> Homo sapien <400> 117 ttctgaggga aagccgagtg gagtgggcga cccggcggcg gtgacaatga gttttcttgg 60 aggctttttt ggtcccattt gtgagattga tgttgccctt aatgatgggg aaaccaggaa 120 aatggcagaa atgaaaactg aggatggcaa agta 154 <210> 118 <211> 449 <212> DNA
<213> Homo sapien <400> 118 gaattcggcaccagggcccgcagcccgagtgtcgccgccatggcttcgccgcagctctgc 60 cgcgcgctggtgtcggcgcaatgggtggcggaggcgctgcgggccccgcgcgctgggcag 120 cctctgcagctgctggacgcctcctggtacctgccgaagctggggcgcgacgcgcgacgc 180 gagttcgaggagcgccacatcccgggcgccgctttcttcgacatcgaccagtgcagcgac 240 cgcacctcgccctacgaccacatgctgcccggggccgagcatttcgcggagtacgcaggc 300 cgcctgggcgtgggcgcggccacccacgtcgtgatctacgacgccagcgaccagggcctc 360 tactccgccccgcgcgtctggtggatgttccgcgccttcggccaccacgccgtgtcactg 420 cttgatggcggcctccgccactggctgcg 449 <210> 119 <211> 642 <212> DNA
<213> Homo sapien <400> 119 gaattcggcacgagcagtaacccgaCCgccgctggtcttcgctggacaccatgaatcaca 60 ctgtccaaaccttcttctctcctgtcaacagtggccagccccccaactatgagatgctca 120 aggaggagcacgaggtggctgtgctgggggcgccccacaaccctgctcccccgacgtcca 180 ccgtgatccacatccgcagcgagacctccgtgcccgaccatgtcgtctggtccctgttca 240 acaccctcttcatgaacccctgctgcctgggcttcatagcattcgcctactccgtgaagt 300 ctagggacaggaagatggttggcgacgtgaccggggcccaggcctatgcctccaccgcca 360 agtgcctgaacatctgggccctgattctgggcatcctcatgaccattctgctcatcgtca 420 tcccagtgctgatcttccaggcctatggatagatcaggaggcatcactgaggccaggagc 480 tctgcccatgacctgtatcccacgtactccaacttccattcctcgccctgcccccggagc 540 cgagtcctgtatcagccctttatcctcacacgcttttctacaatggcattcaataaagtg 600 cacgtgtttctggtgaaaaaaaaaaaaaaaaaaaaactcgag 642 <210> 120 <211> 603 <212> DNA
<213> Homo sapien <400>

gaattcggcacgagccacaacagccactacgactgcatccactggatccacggccacccc 60 gtcctccaccccgggaacagctccccctcccaaagtgctgaccagcccggccaccacacc 120 catgtccaccatgtccacaatccacacctcctctactccagagaccacccacacctccac 180 agtgctgaccaccacagccaccatgacaagggccaccaattccacggccacaccctcctc 240 cactctggggacgacccggatcctcactgagctgaccacaacagccactacaactgcagc 300 cactggatccaCggCCdCCCtgtCCtCCaCCCCagggaCCacctggatcctcacagagcc 360 gagcactatagccaccgtgatggtgcccaccggttccacggccaccgcctcctccactct 420 gggaacagctcaCacccccaaagtggtgaccaccatggccactatgcccacagccactgc 480 ctccacggttcccagctcgtccaccgtggggaccacccgcacccctgcagtgctccccag 540 cagcctgccaaccttcagcgtgtccactgtgtcctcctcagtcctcaccaccctgagacc 600 cac 603 <210> 121 <211> 178 <212> PRT
<213> Homo sapien <400> 121 Ser Glu Pro Pro Ser Pro Ala Thr Thr Pro Cys Gly hys Val Pro Ile Cys Ile Pro Ala Arg Arg Asp Leu Val Asp Ser Pro A1a Ser Leu Ala 20 25 ' 30 Sex Ser Leu Gly Ser Pro Leu Pro Arg Ala Lys Glu Leu Ile Leu Asn Asp Leu Pro Ala Sex Thr Pro Ala Ser Lys Ser Cys Asp Ser Ser Pro Pro Gln Asp A1a Ser Thr Pro Arg Pro Ser Ser Ala Ser His Leu Cys Gln Leu Ala Ala Lys Pro Ala Pro Ser Thr Asp Ser Val Ala Leu Arg Ser Pro Leu Thr Leu Ser Ser Pro Phe Thr Thr Ser Phe Ser Leu Gly Ser His Ser Thr Leu Asn Gly Asp Leu Ser Val Pro Ser Ser Tyr Val Ser Leu His Leu Ser Pro Gln Val Ser Sex Ser Val Val Tyr Gly Arg Ser Pro Val Met Ala Phe Glu Ser His Pro His~Leu Arg Gly Ser Ser Val Ser Ser Ser Leu Pro Ser Ile Pro Gly Gly Lys Pro Ala Tyr Ser Phe His <210> 122 <211> 36 <212> PRT
<213> Homo sapien <400> 122 Met Ser Phe Leu Gly Gly Phe Phe Gly Pro Ile Cys Glu Ile Asp Val 1 5 10 . 15 Ala Leu Asn Asp Gly Glu Thr Arg Lys Met A1a Glu Met Lys Thr Glu Asp Gly Lys Va1 <210> 123 <211> 136 <212> PRT
<213> Homo sapien <400> 123 Met Ala Ser Pro Gln Leu Cys Arg A1a Leu Val Ser Ala Gln Trp Val Ala Glu Ala Leu Arg Ala Pro Arg Ala Gly Gln Pro Leu Gln Leu Leu Asp Ala Ser Trp Tyr Leu Pro Lys Leu Gly Arg Asp Ala Arg Arg G1u Phe Glu Glu Arg His Ile Pro Gly Ala Ala Phe Phe Asp T1e Asp Gln Cys Ser Asp Arg Thr Ser Pro Tyr Asp His Met Leu Pro Gly Ala Glu His Phe Ala Glu Tyr Ala Gly Arg Leu Gly Val Gly Ala Ala Thr His Val Val Ile Tyr Asp Ala Ser Asp Gln Gly Leu Tyr Ser A1a Pro Arg Val Trp Trp Met Phe Arg Ala Phe Gly His His Ala Val Ser Leu Leu SS

Asp Gly Gly Leu Arg His Trp Leu <210> l24 <211> 7.33 <212> PRT
<213> Homo sapien <400> 124 Met Asn His Thr Val Gln Thr Phe Phe Ser Pro Val Asn Ser Gly Gln Pro Pro Asn Tyr Glu Met Leu Lys Glu Glu His Glu Val Ala Val Leu Gly Ala Pro His Asn Pro Ala Pro Pro Thr Ser Thr Val Ile His Tle Arg Ser Glu Thr Ser Val Pro Asp His Val Val Trp Ser Leu Phe Asn Thr Leu Phe Met Asn Pro Cys Cys Leu Gly Phe Tle Ala Phe Ala Tyr Ser Val Lys Ser Arg Asp Arg Lys Met Val Gly Asp Val Thr Gly Ala Gln Ala Tyr Ala Ser Thr Ala Lys Cys Leu Asn Tle Trp Ala Leu Ile Leu Gly Ile Leu Met Thr I1e Leu Leu Ile Va1 I1e Pro Val Leu Ile Phe Gln Ala Tyr Gly <210> 125 <211> 195 <212> PRT
<213> Homo sapien <400> 125 Thr Thr A1a Thr Thr Thr Ala Ser Thr Gly Ser Thr Ala Thr Pro Ser Ser Thr Pro Gly Thr Ala Pro Pro Pro Lys Val Leu Thr Ser Pro Ala Thr Thr Pro Met Ser Thr Met Ser Thr Ile His Thr Ser Ser Thr Pro Glu Thr Thr His Thr Ser Thr Val Leu Thr Thr Thr Ala Thr Met Thr Arg Ala Thr Asn Ser Thr Ala Thr Pro Ser Ser Thr Leu Gly Thr Thr Arg Ile Leu Thr Glu Leu Thr Thr Thr Ala Thr Thr Thr Ala Ala Thr Gly Ser Thr Ala Thr Leu Ser Ser Thr Pro Gly Thr Thr Trp Ile Leu Thr Glu Pro Ser Thr Ile A1a Thr Val Met Val Pro Thr Gly Ser Thr Ala Thr Ala Ser Ser Thr Leu Gly Thr Ala His Thr Pro Lys Val Val Thr Thr Met Ala Thr Met Pro Thr Ala Thr Ala Ser Thr Val Pro Ser 145 150 155 ~ 160 Ser Ser Thr Val Gly Thr Thr Arg Thr Pro Ala Val Leu Pro Ser Ser Leu Pro Thr Phe Ser Val Ser Thr Val Ser Ser Ser Val Leu Thr Thr I,eu Arg Pro <210> 126 <211> 509 <212> DNA
<213> Homo sapien <400>

gaattcggcacgagccaagtaccccctgaggaatctgcagcctgcatctgagtacaccgt 60 atccctcgtggccataaagggcaaccaagagagccccaaagccactggagtctttaccac 120 actgcagcctgggagctctattccaccttacaacaccgaggtgactgagaccaccattgt 180 gatcacatggacgcctgctccaagaattggttttaagctgggtgtacgaccaagccaggg 240 aggagaggcaccacgagaagtgacttcagactcaggaagcatcgttgtgtccggcttgac 300 tccaggagtagaatacgtctacaccatccaagtcctgagagatggacaggaaagagatgc 360 gccaattgtaaacaaagtggtgacaccattgtctccaccaacaaacttgcatctggaggc 420 aaaccctgacactggagtgctcacagtctcctggagaggagcaccaccccagacattact 480 gggtatagaattaccacaacccctacaaa 509 <210> 127 <211> 500 a <212> DNA
<213> Homo sapien <400>

gaattcggcacgagccactgatgtccggggagtcagccaggagCttggggaagggaagcg 60 cgcccccggggccggtcccggagggctcgatccgcatctacagcatgaggttctgcccgt 120 ttgctgagaggacgcgtctagtcctgaaggccaagggaatcaggcatgaagtcatcaata 180 tcaacctgaaaaataagcctgagtggttctttaagaaaaatccctttggtctggtgccag 240 ttctggaaaacagtcagggtcagctgatctacgagtctgccatcacctgtgagtacctgg 300 atgaagcatacccagggaagaagctgttgccggatgacccctatgagaaagcttgccaga 360 agatgatcttagagttgttttctaaggtgccatccttggtaggaagctttattagaagcc 420 aaaataaagaagactatgctggcctaaaagaagaatttcgtaaagaatttaccaagctag 480 aggaggttctgactaataag 500 <210> 128 <211> 500 <212> DNA
<213> Homo sapien <400>

agctttcctctgctgccgctcggtcacgcttgtgcccgaaggaggaaacagtgacagacc 60 tggagactgcagttctctatccttcacacagctctttcaccatgcctggatcacttcctt 120 tgaatgcagaagcttgctggccaaaagatgtgggaattgttgcccttgagatctattttc 180 cttctcaatatgttgatcaagcagagttggaaaaatatgatggtgtagatgctggaaagt 240 ataccattggcttgggccaggccaagatgggcttctgcacagatagagaagatattaact 300 ctctttgcatgactgtggttcagaatcttatggagagaaataacctttcctatgattgca 360 ttgggcggctggaagttggaacagagacaatcatcgacaaatcaaagtctgtgaagacta 420 atttgatgcagctgtttgaagagtctgggaatacagatatagaaggaatcgacacaacta 480 atgcatgctatggaggcaca 500 <210> 129 <211> 497 <212> DNA
<213> Homo sapien <400> 129 gaattcggcacgagcagaggtctccagagccttctctctcctgtgcaaaatggcaactct 60 taaggaaaaactcattgcaccagttgcggaagaagaggcaacagttccaaacaataagat 120 cactgtagtgggtgttggacaagttggtatggcgtgtgctatcagcattctgggaaagtc 180 tctggctgatgaacttgctcttgtggatgttttggaagataagcttaaaggagaaatgat 240 ggatctgcagcatgggagcttatttcttcagacacctaaaattgtggcagataaagatta 300 ttctgtgaccgccaattctaagattgtagtggtaactgcaggagtccgtcagcaagaagg 360 ggagagtcggctcaatctggtgcagagaaatgttaatgtcttcaaattcattattcctca 420 gatcgtcaagtacagtcctgattgcatcataattgtggtttccaacccagtggacattct 480 tacgtatgttacctgga 497 <210> 130 <211> 383 <212> DNA
<213> Homo sapien <400> 130 gaattcggcacgagggccgcggctgccgactgggtcccctgccgctgtcgccaccatggc 60 tccgcaccgccccgcgcccgcgctgctttgcgcgctgtccctggcgctgtgcgcgctgtc 120 gctgcccgtccgcgcggccactgcgtcgcggggggcgtcccaggcgggggcgccccaggg 180 gcgggtgcccgaggcgcggcccaacagcatggtggtggaacaccccgagttcctcaaggc 240 agggaaggagcctggcctgcagatctggcgtgtggagaaagttcgatctggtggcccgtg 300 cccaccaacctttatggagacttcttcacgggcgacgcctacgtcatcctgaagacagtg 360 cagcttaagaacggaaaatcttg 383 <210> 131 <211> 509 <212> DNA
<213> Homo sapien <400> 131 gaattcggcacgagagtcagccgcatcttcttttgcgtcgccagccgagccacatcgctc 60 agacaccatggggaaggtgaaggtcggagtcaacggatttggtcgtattgggcgcctggt 120 caccagggctgcttttaactctggtaaagtggatattgttgccatcaatgaccccttcat 180 tgacctcaactacatggtttacatgttccaatatgattccacccatggcaaattccatgg 240 caccgtcaaggctgagaacgggaagcttgtcatcaatggaaatcccatcaccatcttcca 300 ggagcgagatccctccaaaatcaagtggggcgatgctggcgctgagtacgtcgtggagtc 360 Cactggccgtcttcaccaccatggagaaggctggggctcatttgcaggggggagccaaaa 420 gggtcatcatctctgccccctctgctgacgcccccatgttcgtcatgggtgtgaaccatg 480 agaagtatgacaacagcctcaagatcatc 509 <210> 132 <211> 357 <212> DNA
<2l3> Homo sapien <400> 132 gaattcggcacgagtaagaagaagcccctagaccacagctccacaccatggactggacct 60 ggaggatcctcttcttggtggcagcagcaacaggtgcccactcccaggtgcaactggtgc 120 aatctgggtctgagttgaagaagcctggggcctcagtgaaggtttcctgcaaggcttctg 180 gacacatcttcagtatctatggtttgaattgggtgcgacaggcccctggtcaaggccttg 240 agtggatgggatggatcaaagtcgacactgcgaacccaacgtatgcccagggcttcacag 300 gacgatttgtcttctccctggacacctctgtcagcacggcatatctgcagatcagca 357 <210> 133 <2I1> 468 <212> DNA
<213> Homo sapien <400> 133 gaattcggcacgaggcgccccgaaccgtcctcctgctgctctcggcggccctggccctga 60 ccgagacctgggccggctcccactccatgaggtatttcgacaccgccatgtcccggcccg 120 gccgcggggagccccgcttcatctcagtgggctacgtggacgacacgcagttcgtgaggt 180 tcgacagcgacgccgcgagtccgagagaggagccgcgggcgccgtggatagagcaggagg 240 ggccggagtattgggaccggaacacacagatcttcaagaccaacacacagactgaccgag 300 agagcctgcggaacctgcgcggctactacaaccagagcgaggccgggtctcacaccctcc 360 agagcatgtacggctgcgacgtggggccggacgggcgcctcctccgcgggcataaccagt 420 acgcctacgacggcaaggattacatcgccctgaacgaggacctgcgct 468 <210> 134 <211> 214 <212> DNA
<213> Homo sapien <400> 134 gaattcggca cgagctgcgt cctgctgagc tctgttctct ccagcacctc ccaacccact 60 agtgcctggt tctcttgctc caccaggaac aagccaccat gtctcgccag tcaagtgtgt 120 ccttccggag cgggggcagt cgtagcttca gcaccgcctc tgccatcacc ccgtctgtct 180 cccgcaccag cttcacctcc gtgtcccggt ccgg 214 <210> 135 <211> 355 <212> DNA
<213> Homo sapien <400> 135 gaattcggca cgaggtgaac aggacccgtc gccatgggcc gtgtgatccg tggacagagg 60 aagggcgccg ggtctgtgtt ccgcgcgcac gtgaagcacc gtaaaggcgc tgcgcgcctg 120 cgcgccgtgg atttcgctga gcggcacggc tacatcaagg gcatcgtcaa ggacatcatc 180 cacgacccgg gccgcggcgc gcccctcgcc aaggtggtct tccgggatcc gtatcggttt 240 aagaagcgga cggagctgtt cattgccgcc gagggcattc acacgggcca gtttgtgtat 300 tgcggcaaga aggcccagct caacattggc aatgtgctcc ctgtgggcac catgc 355 <210> 136 <211> 242 <212> DNA
<213> Homo sapien <400> 136 gaattcggcacgagccagctcctaaccgcgagtgatccgccagcctccgcctcccgaggt 60 gcccggattgcagacggagtctccttcactcagtgctcaatggtgcccaggctggagtgc 120 agtggtgtgatctcggctcgctacaacatccacctcccagCagCCtgCCttggCCtCCCa 180 aagtgccgagattgcagctctctgcccggccgccacccctgtctgggaagtgaggatgct 240 gt 242 <210> l37 <211> 424 <212> DNA
<213> Homo sapien <400> 137 gaattcggca cgagcccaga tcccgaggtc cgacagcgcc cggcccagat ccccacgcct 60 gccaggagca agccgagagc cagccggccg gcgcactccg actccgagca gtctctgtcc 120 ttcgacccga gccccgcgcc ctttccggga cccctgcccc gcgggcagcg ctgccaacct 180 gccggccatg gagaccccgt cccagcggcg cgccacccgc agcggggcgc aggccagctc 240 cactccgctg tcgcccaccc gcatcacccg gctgcaggag aaggaggacc tgcaggagct 300 caatgatcgc ttggcggtct acatcgaccg tgtgcgctcg ctggaaacgg agaacgcagg 360 gctgcgcctt cgcatcaccg agtctgaaga ggtggtcagc cgcgaggtgt ccggcatcaa 420 ggcc 424 <210> 138 <211> 448 <212> DNA
<213> Homo sapien <400> 138 gaattcggcacgagcctgtgttccaggagccgaatcagaaatgtcatcctcaggcacgcc 60 agacttacctgtcctactcaccgatttgaagattcaatatactaagatcttcataaacaa 120 tgaatggcatgattcagtgagtggcaagaaatttcctgtctttaatcctgcaactgagga 180 ggagctctgccaggtagaagaaggagataaggaggatgttgacaaggcagtgaaggccgc 240 aagacaggcttttcagattggatccccgtggcgtactatggatgcttccgagagggggcg 300 actattatacaagttggctgatttaatcgaaagagatcgtctgctgctggccgacaatgg 360 agtcaatgaatggtggaaaactctattccaatgcatatctgaatgatttagcaggctgca 420 tcaaaacattgcgctactgtgcaggttg 448 <2I0> 139 <211> 510 <212> DNA
<213> Homo sapien <400> 139 gaattcggcacgaggttccgtgcagctcacggagaagcgaatggacaaagtcggcaagta 60 ccccaaggagctgcgcaagtgctgcgaggacggcatgcgggagaaccccatgaggttctc 120 gtgccagcgccggacccgtttcatctccctggcgaggcgtgcaagaaggtcttcctggac 180 tgctgcaactacatcacagagctgcggcggcagcacgcgcgggccagccacctggcctgc 240 caggagtaacctggatgaggacatcattgcagaagagaacatcgtttcccgaagtgagtt 300 cccagagagctggctgtggaacgttgaggacttgaaagagccaccgaaaaatggaatctc 360 tacgaagctcatgaatatatttttgaaagactccatcaccacgtgggagattctggctgt 420 gagcatgtcggacaagaaagggatctgtgtggcagaccccttcgaggtcacagtaatgca 480 ggacttcttcatcgacctgcggctacccta 510 <210> 140 <211> 360 <212> DNA
<213> Homo sapien <400> 140 gaattcggcacgagcggtaactaccccggctgcgcacagctcggcgctccttcccgctcc 60 ctcacacaccggcctcagcccgcaccggcagtagaagatggtgaaagaaacaacttacta 120 cgatgttttgggggtcaaacccaatgctactcaggaagaattgaaaaaggcttataggaa 180 actggctttgaagtaccatcctgataagaacccaaatgaaggagagaagtttaaacagat 240 ttctcaagcttacgaagttctctctgatgcaaagaaaagggaattatatgacaaaggagg 300 agaacaggcaattaaagagggtggagcaggtggcggttttggctcccccatggacatctt 360 <210> 141 <211> 483 <212> DNA
<213> Homo sapien <400> 141 gaattcggcacgagagcagaggctgatctttgctggaaaacagctggaagatgggctgca 60 ccctgtctgactacaacatccagaaagagtccaccctgcacctggtgctccgtctcagag 120 gtgggatgcaaatcttcgtgaagacactcactggcaagaccatcacccttgaggtggagc 180 ccagtgacaccatcgagaacgtcaaagcaaagatccaggacaaggaaggcattcctcctg 240 accagcagaggttgatctttgccggaaagcagctggaagatgggcgcaccctgtctgact 300 acaacatcca gaaagagtct accctgcacc tggtgctccg tctcagaggt gggatgcaga 360 tcttcgtgaa gaccctgact ggtaagacca tcaccctcga ggtggagccc agtgacacca 420 tcgagaatgt caaggcaaag atccaagata aggaaggcat tcctcctgat cagcagaggt 480 tga 483 <210> 142 <211> 500 <212> DNA
<213> Homo sapien <400>

gaattcggcacgaggcggcgacgaccgccgggagcgtgtgcagcggcggcggcggaagtg 60 gccggcgagcccggtccccgccggcaccatgcttcccttgtcactgctgaagacggctca 120 gaatcaccccatgttggtggagctgaaaaatggggagacgtacaatggacacctggtgag 180 ctgcgacaactggatgaacattaacctgcgagaagtcatctgcacgtccagggacgggga 240 caagttctggcggatgcccgagtgctacatccgcggcagcaccatcaagtacctgcgcat 300 ccccgacgagatcatcgacatggtcaaggaggaggtggtggccaagggccgcggccgcgg 360 aggcctgcagcagcagaagcagcagaaaggccgcggcatgggcggcgctggccgaggtgt 420 gtttggtggccggggccgaggtgggatcccgggcacaggcagaagccagccagagaagaa 480 gcctggcagacaggcgggca 500 <210> 143 <211> 400 <212> DNA
<213> Homo sapien <400>

gaattcggcacgagctcggatgtcagcaggcgtcccaacccagcaggaactggctcaatt 60 ctcagaagaaagcgatcggccccgaggcaggaaggccggctccggtgcagggcgcgccgc 120 ctgcgggctgcttcgggccagggtcgacccgagggccagcgcaagcagcggcaacaggag 180 cgccaggaggacatgaggctctgcctgcagtcagcaacttggaatattcagacttcagac 240 cagcatcacagattataaccctccgtaaatcatctgcatcccagctcccatcaaaagcca 300 gcctgaaggacccatggacacgtgactccagtgttctcaacaacatcttagatcaagttg 360 gtttgcacaacatttgcatctacttgggacaaagcaagaa 400 <210> 144 <211> 243 <212> DNA
<213> Homo sapien <400>

gaattcggcacgagccagct cctaaccgcgagtgatccgccagcctccgcctcccgaggt 60 gcccggattgcagacggagt ctccttcactcagtgctcaatggtgcccaggctggagtgc 120 agtggtgtgatctcggctcg ctacaacatccacctcccagcagcctgccttggcctccca 180 aagtgccgagattgcagcct ctgcccggccgtcaccccgtctgggaagtgaggagcgttt 240 ctg 243 <210> 145 <211> 450 <212> DNA
<213> Homo sapien <400> 145 gaattcggca cgaggacagc aggaccgtgg aggccgcggc aggggtggca gtggtggcgg 60 cggcggcggc ggcggtggtg gttacaaccg cagcagtggt ggctatgaac ccagaggtcg 120 tggaggtggc cgtggaggca gaggtggcat gggcggaagt gaccgtggtg gcttcaataa 180 atttggtggc cctcgggacc aaggatcacg tcatgactcc gaacaggata attcagacaa 240 caacaccatc tttgtgcaag gcctgggtga gaatgttaca attgagtctg tggctgatta 300 cttcaagcag attggtatta ttaagacaaa caagaaaacg ggacagccca tgattaattt 360 gtacacagac agggaaactg gcaagctgaa gggagaggca acggtctctt ttgatgaccc 420 accttcagct aaagcagcct attgactggt . 450 <210> 146 <211> 451 <212> DNA
<213> Homo sapien <400> 146 gaattcggcacgagccatcgagtccctgcctttcgacttgcagagaaatgtctcgctgat 60 gcgggagatcgacgcgaaataccaagagatcctgaaggagctagacgagtgctacgagcg 120 cttcagtcgcgagacagacggggcgcagaagcggcggatgctgcactgtgtgcagcgcgc 180 gctgatccgcaccaggagctgggcgacgagaagatccagatcgtgagccagatggtggag 240 ctggtggagaaccgcacgcggcaggtggacagccacgtggagctgttcgaggcgcagcag 300 gagctgggcgacacagcgggcaacagcggcaaggctggcgcggacaggcccaaaggcgag 360 gcggcagcgcaggctgacaagcccaacagcaagcgctcacggcggcagcgcaacaacgag 420 aaccgtgagaacgcgtccagcaaccacgacc 451 <210> 147 <211> 400 <212> DNA
<213> Homo sapien <400> 147 gaattcggcacgagctcggatgtcagcaggcgtcccaacccagcaggaac tggctcaatt60 ctcagaagaaagcgatcggccccgaggcaggaaggccggctccggtgcag ggcgcgccgc120 ctgcgggctgcttcgggccagggtcgacccgagggccagcgcaagcagcg gcaacaggag280 cgccaggaggacatgaggctctgcctgcagtcagcaacttggaatattca gacttcagac240 cagcatcacagattataaccctccgtaaatcatctgcatcccagctccca tcaaaagcca300 gcctgaaggacccatggacacgtgactccagtgttctcaacaacatctta gatcaagttg360 gtttgcacaacatttgcatctacttgggacaaagcaagaa 400 <210> 148 <211> 503 <212> DNA
<213> Homo sapien <400> 148 aaaagaattcggcacgagcggcgccgctcatccccctctcccagcagattcccactggaa 60 attcgttgtatgaatcttattacaagcaggtcgatccggcatacacagggagggtggggg 120 cgagtgaagctgcgctttttctaaagaagtctggcctctcggacattatccttgggaaga 180 tatgggacttggccgatccagaaggtaaagggttcttggacaaacagggtttctatgttg 240 cactgagactggtggcctgtgcacagagtggccatgaagttaccttgagcaatctgaatt 300 tgagcatgccaccgcctaaatttcacgacaccagcagccctctgatggtcacaccgccct 360 ctgcagaggcccactgggctgtgagggtggaagaaaaggccaaatttgatgggatttttg 420 aaagcctcttgcccatcaatggtttgctctctggagacaaagtcaagccagtcctcatga 480 actcaaagctgcctcttgatgtc 503 <210> 149 <211> 1061 <212> DNA
<213> Homo sapien <400> 149 gaattcggca cgaggccttt tccagcaacc ccaaggtcca ggtggaggcc atcgaagggg 60 gagccctgca gaagctgctg gtcatcctgg ccacggagca gccgctcact gcaaagaaga 120 aggtcctgtt tgcactgtgc tccctgctgc gccacttccc ctatgcccag cggcagttcc 180 tgaagctcggggggctgcaggtcctgaggaccctggtgcaggagaagggcacggaggtgc 240 tcgccgtgcgcgtggtcacactgctctacgacctggtcacggagaagatgttcgccgagg 300 aggaggctgagctgacccaggagatgtccccagagaagctgcagcagtatcgccaggtac 360 acctcctgccaggcctgtgggaacagggctggtgcgagatcacggcccacctcctggcgc 420 tgcccgagcatgatgcccgtgagaaggtgctgcagacactgggcgtcctcctgaccacct 480 gccgggaccgctaccgtcaggacccccagctcggcaggacactggccagcctgcaggctg 540 agtaccaggtgctggccagcctggagctgcaggatggtgaggacgagggctacttccagg 600 agctgctgggctctgtcaacagcttgctgaaggagctgagatgaggccccacaccagtac 660 tggactgggatgccgctagtgaggctgaggggtgccagcgtgggtgggcttctcaggcag 720 gaggacatcttggcagtgctggcttggccattaaatggaaacctgaaggccatcctcttt 780 ctgctgtgtgtctgtgtagactgggcacagccctgtggccggggggtcaggtgagtggtt 840 gggtgatgggctctgctgacgtgcagggctcagcccagggcatccaggaacaggctccag 900 ggcaggaacctgggcccaggagttgcaagtctctgcttcttaccaagcagcagctctgta 960 ccttgggaagtcgcttaattgctctgagcttgtttcctcatctgtcaggagtgccattaa 1020 aggagaaaaatcacgtaaaaaaaaaaaaaaaaaaactcgag 1061 <210> 150 <211> 781 <212> DNA
<213> Homo sapien <400> 150 gaattcggcacgagaaatggcggcaggggtcgaagcggcagccgaagtggcggcgacaga 60 acccaaaatggaggaagagagcggcgcgccctgcgtgccgagcggcaacggagctccggg 120 cccgaagggtgaagaacgacctactcagaatgagaagaggaaggagaaaaacataaaaag 180 aggaggcaatcgctttgagccatattccaacccaactaaaagatacagagccttcattac 240 aaatataccttttgatgtgaaatggcagtcacttaaagacctggttaaagaaaaagttgg 300 tgaggtaacatacgtggagctattaatggacgctgaaggaaagtcaaggggatgtgctgt 360 tgttgaattcaagatggaggagagcatgaaaaaagctgctgaagttctaaacaagcatag 420 tctgagtggaaggccactgaaagtcaaggaagatcctgatggtgaacatgcaaggagagc 480 aatgcaaaaggctggaagacttggaagcacagtatttgtagcaaatctggattataaagt 540 tggctggaagaaactgaaggaagtatttagtatggctggtgtggtggtccgagcagacat 600 tctggaagataaagatgggaaaagtcgtggaataggcattgtgacttttgaacagtccat 660 tgaagctgtgcaagcaatatctatgtttaatggccagttgctgtttgatagaccgatgca 720 cgtcaagatggatgagagggctttaccaaagggagacttttttcctcctgaacgccacag 780 c 781 <210> 151 <211> 3275 <212> DNA
<213> Homo sapien <400> 151 cttaagtggatcctgcatcaggagggagcagacaccggagaaagaaaaacaagttgtgct 60 gtttgaggaagcaagttggacctgcactccagcctgtggagatgaacctaggactgtgat 120 tctgctatccagtatgttggctgaccacaggctcaaactggaggattataaggatcgcct 180 gaaaagtggagagcatcttaatccagaccagttggaagctgtagagaaatatgaagaagt 240 gctacataatttggaatttgccaaggagcttcaaaaaaccttttctgggttgagcctaga 300 tctactaaaagcgcaaaagaaggcccagagaagggagcacatgctaaaacttgaggctga 360 gaagaaaaagcttcgaactatacttcaagttcagtatgtattgcagaacttgacacagga 420 gcacgtacaaaaagacttcaaagggggtttgaatggtgcagtgtatttgccttcaaaaga 480 acttgactacctcattaagttttcaaaactgacctgccctgaaagaaatgaaagtctgag 540 acaaacacttgaaggatctactgtctaaattgctgaactcaggctattttgaaagtatcc 600 cagttcccaaaaatgccaaggaaaaggaagtaccactggaggaagaaatgctaatacaat 660 cagagaaaaaaacacaattatcgaagactgaatctgtcaaagagtcagagtctctaatgg 720 aatttgcccagccagagatacaaccacaagagtttcttaacagacgctatatgacagaag 780 tagattattcaaacaaacaaggcgaagagcaaccttgggaagcagattatgctagaaaac 840 caaatctcccaaaacgttgggatatgcttactgaaccagatggtcaagagaagaaacagg 900 agtcctttaagtcctgggaggcttctggtaagcaccaggaggtatccaagcctgcagttt 960 ccttagaacagaggaaacaagacacctcaaaactcaggtctactctgccggaagagcaga 1020 agaagcaggagatctccaaatccaagccatctcctagccagtggaagcaagatacaccta 1080 aatccaaagcagggtatgttcaagaggaacaaaagaaacaggagacaccaaagctgtggc 1140 cagttcagctgcagaaagaacaagatccaaagaagcaaactccaaagtcttggacacctt 1200 ccatgcagagcgaacagaacaccaccaagtcatggaccactcccatgtgtgaagaacagg 1260 attcaaaacagccagagactccaaaatcctgggaaaacaatgttgagagtcaaaaacact 1320 ctttaacatcacagtcacagatttctccaaagtcctggggagtagctacagcaagcctca 1380 taccaaatgaccagctgctgcccaggaagttgaacacagaacccaaagatgtgcctaagc 1440 ctgtgcatcagcctgtaggttcttcctctacccttccgaaggatccagtattgaggaaag 1500 aaaaactgcaggatctgatgactcagattcaaggaacttgtaactttatgcaagagtctg 1560 ttcttgactttgacaaaccttcaagtgcaattccaacgtcacaaccgccttcagctactc 1620 caggtagccccgtagcatctaaagaacaaaatctgtccagtcaaagtgattttcttcaag 1680 agccgttacaggtatttaacgttaatgcacctctgcctccacgaaaagaacaagaaataa 1740 aagaatccccttattcacctggctacaatcaaagttttaccacagcaagtacacaaacac 1800 caccccagtgccaactgccatctatacatgtagaacaaactgtccattctcaagagactg 1860 cagcaaattatcatcctgatggaactattcaagtaagcaatggtagccttgccttttacc 1920 cagcacagacgaatgtgtttcccagacctactcagccatttgtcaatagccggggatctg 1980 ttagaggatgtactcgtggtgggagattaataaccaattcctatcggtcccctggtggtt 2040 ataaaggttttgatacttatagaggactcccttcaatttccaatggaaattatagccagc 2100 tgcagttccaagctagagagtattctggagcaccttattcccaaagggataatttccagc 2160 agtgttataagcgaggagggacatctggtggtccacgagcaaattcgagagcagggtgga 2220 gtgattcttctcaggtgagcagcccagaaagagacaacgaaacctttaacagtggtgact 2280 ctggacaaggagactcccgtagcatgacccctgtggatgtgccagtgacaaatccagcag 2340 ccaccatactgccagtacacgtctaccctctgcctcagcagatgcgagttgccttctcag 2400 cagccagaacctctaatctggcccctggaactttagaccaacctattgtgtttgatcttc 2460 ttctgaacaacttaggagaaacttttgatcttcagcttggtagatttaattgcccagtga 2520 atggcacttacgttttcatttttcacatgctaaagctggcagtgaatgtgccactgtatg 2580 tcaacctcatgaagaatgaagaggtcttggtatcagcctatgccaatgatggtgctccag 2640 accatgaaactgctagcaatcatgcaattcttcagctcttccagggagaccagatatggt 2700 tacgtctgcacaggggagcaatttatggaagtagctggaaatattctacgttttcaggct 2760 atcttctttatcaagattgaaagtcagtacagtattgacaataaaaggatggtgttctaa 2820 ttagtgggattgaaggaaaagtagtctttgccctcatgactgattggtttaggaaaatgt 2880 ttttgttcctagagggaggaggtccttacttttttgttttccttcctgaggtgaaaaatc 2940 aagctgaatgacaattagcactaatctggcactttataaattgtgatgtagcctcgctag 3000 tcaagctgtgaatgtatattgtttgcacttaatccttaactgtattaacgttcagcttac 3060 taaactgactgcctcaagtccaggcaagttacaatgccttgttgtgcctcaataaaaaag 3120 ttacatgcaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa 3180 aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa 3240 aaaaaaaaaaaaaaaaaaaaaaaaaaaaactcgag 3275 <210> 152 <211> 2179 <212> DIVA
<213> Homo sapien <900> 152 gaattcggcaCcaggcactattaaatgtgaggcagcctccatctactacaacatttgtgc 60 tgaatcaaataaatcatcttccacccttgggatctacaattgtaatgactaaaacaccac 120 ctgtaacaaccaacaggcaaaccatcactttaactaagtttatccagactactgcaagca 180 cacgcccgtcagtctcagcaccaacagtacgaaatgccatgacctctgcaccttcaaaag 240 accaagttcagcttaaagatctactgaaaaataatagtcttaatgaactgatgaaactaa 300 agccacctgctaatattgctcagccagtagcaacagcagctactgatgtaagcaatggta 360 cagtaaagaaagagtcttctaataaagaaggagctagaatgtggataaacgacatgaaga 420 tgaggagtttttccccaaccatgaaggttcctgttgtaaaagaagatgatgaaccagagg,480 aagaagatgaagaagaaatgggtcatgcagaaacctatgcagaatacatgccaataaaat 540 taaaaattggcctacgtcatccagatgctgtagtggaaaccagctctttatccagtgtta 600 ctcctcctgatgtttggtacaaaacatccatttctgaggaaaccattgataatggctggt 660 tatcagcattgcagcttgaggcaattacatatgcagcccagcaacatgaaactttcctac720 ctaatggagatcgtgctggcttcttaataggtgatggtgccggtgtaggaaaaggaagga780 cgatagcaggaatcatctatgaaaattatttgttgagtagaaaacgagcattgtggttta840 gtgtttcaaatgacttaaagtatgatgctgaaagagatttaagggatattggagcaaaaa900 acattttggttcattcgttaaataagtttaaatacggaaaaatttcttccaaacataatg960 ggagtgtgaaaaagggtgttatttttgctacttactcttcacttattggtgaaa,gccagt1020 ctggcggcaagtataaaactaggttaaaacaacttctgcattggtgcggtgatgacttcg1080 atggagtgatagtgtttgatgagtgtcataaagccaaaaacttatgtcctgttggttctt1140 caaagccaaccaagacaggcttagcagttttagagcttcagaacaaattgccaaaagcca1200 gagttgtttatgctagtgcaactggtgcttctgaaccacgcaacatggcctatatgaacc1260 gtcttggcatatggggtgagggtactccatttagagaattcagtgattttattcaagcag1320 tagaacggagaggagttggtgccatggaaatagttgctatggatatgaagcttagaggaa1380 tgtacattgctcgacaactgagctttactggagtgaccttcaaaattgaggaagttcttc1440 tttctcagagctacgttaaaatgtataacaaagctgtcaagctgtgggtcattgccagag1500 agcggtttcagcaagctgcagatctgattgatgctgagcaacgaatgaagaagtccatgt1560 ggggtcagttctggtctgctcaccagaggttcttcaaatacttatgcatagcatccaaag1620 ttaaaagggttgtgcaactagctcgagaggaaatcaagaatggaaaatgtgttgtaattg2680 gtctgcagtctacaggagaagctagaacattagaagctttggaagagggcgggggagaat1740 tgaatgattttgtttcaactgccaaaggtgtgttgcagtcactcattgaaaaacattttc1800 ctgctccagacaggaaaaaactttatagtttactaggaatcgatttgacagctccaagta1860 acaacagttcgccaagagatagtccttgtaaagaaaataaaataaagaagcggaaaggtg1920 aagaaataactcgagaagccaaaaaagcacgaaaagtaggtggccttactggtagcagtt1980 ctgacgacagtggaagtgaatctgatgcctctgataatgaagaaagtgactatgagagct2040 ctaaaaacatgagttctggagatgatgacgatttcaacccatttttagatgagtctaatg2100 aggatgatgaaaatgatccctggttaattaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa2160 aaaaaaaaaaaaactcgag 2179 <210> 153 <211> 2109 <212> DNA
<213> Homo sapien <400> 153 cagagagccccaggcatcgaggagaaggcggcggagaatggggccctggggtcccccgag60 agagaagagaaagtgctggagaatggggagctgacacccccaaggagggaggagaaagcg120 ctggagaatggggagctgaggtccccagaggccggggagaaggtgctggtgaatgggggc180 ctgacacccccaaagagcgaggacaaggtgtcagagaatgggggcctga,gattccccagg240 aacacggagaggccaccagagactgggccttggagagccccagggccctgggagaagacg300 cccgagagttggggtccagcccccacgatcggggagccagccccagagacctctctggag360 agagcccctgcacccagcgcagtggtctcctcccggaacggcggggagacagcccctggc420 ccccttggcccagcccccaagaacgggacgctggaacccgggaccgagaggagagccccc480 gagactgggggggcgccgagagccccaggggctgggaggctggacctcgggagtgggggc540 cgagccccagtgggcacggggacggcccccggcggcggccccggaagcggcgtggacgca600 aaggccggatgggtagacaacacgaggccgcagccaccgccgccaccgctgccaccgcca660 ccggaggcacagccgaggaggctggagccagcgcccccgagagccaggccggaggtggcc720 cccgagggagagcccggggccccagacagcagggccggcggagacacggcactcagcgga780 gacggggacccccccaagcccgagaggaagggccccgagatgccacgactattcttggac840 ttgggaccccctcaggggaacagcgagcagatcaaagccaggctctcccggctctcgctg900 gcgctgccgccgctcacgctcacgccattcccggggccgggcccgcggcggcccccgtgg960 gagggcgcggacgccggggcggctggcggggaggccggcggggcgggagcgccggggccg1020 gcggaggaggacggggaggacgaggacgaggacgaggaggaggacgaggaggcggcggcg2080 ccgggcgcggcggcggggccgcggggccccgggagggcgcgagcagccccggtgcccgtc1140 gtggtgagcagcgccgacgcggacgcggcccgcccgctgcgggggctgctcaagtctccg1200 cgcggggccgacgagccagaggacagcgagctggagaggaagcgcaagatggtctccttc1260 cacggggacgtgaccgtctacctcttcgaccaggagacgccaaccaacgagctgagcgtc1320 caggccccccccgagggggacacggacccgtcaacgcctccagcgcccccgacacctccc1380 caccccgccacccccggagatgggtttcccagcaacgacagcggctttggaggcagtttc1440 gagtgggcggaggatttccccctcetcccccctccaggccccccgctgtgcttctcccgc1500 ttctccgtctcgcctgcgctggagaccccggggccacccgcccgggcccccgacgcccgg1560 cccgcaggccccgtggagaattgattccccgaagacccgaccccgctgcaccctcagaag1620 aggggttgagaatggaatcctctgtggatgacggcgccactgccaccaccgcagacgccg1680 cctctggggaggcccccgaggctgggccctccccctcccactcccctaccatgtgccaaa1740 cgggaggccccgggcccccgcccccccagccccccagatggctcccctgacccccctgac1800 cccctcggagccaaatgaggcaggaatccccccgcccctccatagagagccgcctttctc1860 ggaactgaactgaactcttttgggcctggagcccctcgacacagcggaggtccctcctca1920 cccactcctggcccaagacaggggccgcaggcttcggggacccggaccccccatttcgcg1980 tctcccctttccctccccagcccggcccctggaggggcctctggttcaaaccttcgcgtg2040 gcattttcacattatttaaaaaagacaaaaacaactttttggaggaaaaaaaaaaaaaaa2100 aaactcgag 2109 <210> 154 <211> 1411 <212> DNA
<213> Homo sapien <400> 154 gaattcggcaccaggggagatgaggaagttcgatgttcctagcatggagtctacccttaa60 ccagccagccatgctagagacgttatactcagatccacattaccgagcccatttccccaa120 cccaagacctgatacaaataaggatgtatacaaagtattgccagaatccaagaaggcacc180 gggcagtggtgcagtatttgagaggaacggaccacatgctagcagtagtggggtgctccc240 tttgggactccagcctgcgcctggactttccaagtcactatcctctcaggtgtggcaacc300 aagtcctgacccttggcatcctggagaacaatcctgtgaactcagtacttgtcgacagca360.

gttggaattgatccgtttacagatggagcaaatgcagcttcagaacggagccatgtgtca420 ccatcctgctgctttcgctccattactgcccaccctagagccagcacagtggctcagcat480 cctgaacagtaacgagcatctcctgaaggagaaggagctcctcattgacaagcaaaggaa540 gcatatctctcagctggagcagaaagtgcgagagagtgaactgcaagtccacagtgccct600 tttgggccgccctgccccctttggggatgtctgcttattgaggctacaggagttgcagcg660 agagaacactttcttacgggcacagtttgcacagaagacagaagccctgagcaaggaga.a720 gatggagcttgaaaagaaactctctgcatctgaagttgaaattcagctcattagggagtc780 tctaaaagtgacactacagaagcattcggaggaggggaagaaacaggaggaaagggtcaa840 aggtcgtgataaacatatcaataatttgaaaaagaaatgtcagaaggaatcagagcagaa900 ccgggagaagcagcagcgtattgaaaccttggagcgctatctagctgacctgcccaccct960 agaagaccatcagaaacagacggagcagcttaaggacgctgaattaaagaacacagaact1020 gcaagagagagtggctgagctggagactttgctggaggacacccaggcaacctgcagaga1080 gaaggaggttcagctggaaagtctgagacaaagagaagcagacctctcctctgctagaca1190 taggtaatgccctgtgtacttgggggaaggagggagttcggttctggtgctctgttaact1200 cttgtgtgttcaacagtgttcatttcaagttcctttcttctaagagctttgtgttctttg1260 aattgaaagtcacttatggccgggtgtggtggcgcacacctttaatcccagcacttggga1320 gtcagaggcaggctaatttctgagtttcaggacagccagggctatacagagaaaccctgt1380 ctcaaacaaaaaaaaaaaaaaaaaactcgag 1411 <210> 155 <211> 678 <212> DNA
<213> Homo sapien <400> 155 ctggagtgaagggagctagtggtaaagggagctggtggaggggtggcggcaggggtaagg 60 ggcaggggacaccctctagacggagagcgggctccgaggtcctggctggccctcggtgcg 120 cccgcccctgtgttggtcccacaatccctggcaatgagaggccagggtttattggacaga 180 gtcagttgtggggttcagagggtcagcaatcaatcaatcctccgaatccagagatttaga 240 cccagtcgtccgtattaggactggaggggggtcaataggttcagtgtttgagatgccaag 300 ggaacctgtcttttgatttggggttcaacatacagagttcaggtacctgcaggaatttgc 360 ccccctaggcacagggggtggtctttaccattttcgagaccagatcctggctgggagccc 420 cgaggcattcttcgtgctcaatgctgatgtctgctccgacttccccttgagtgctatgtt 480 ggaagcccaccgacgccagcgtcaccctttcttactccttggcactacggctaacaggac 540 gcaatccctc aactacggct gcatcgttga gaatccacag acacacgagg tattgcacta 600 tgtggagaaa cccagcacat ttatcagtga catcatcaac tgcggcacct acctcttttc 660 tcctgaagcc ttgaagcc 678 <210> 156 <211> 2668 <212> DNA
<213> Homo sapien <400>

gggaaggcggctgcgctgctgggcgggggcgggagctggagccggagctggagccggggc 60 cggggcccgggtcagcgcttgagccgggagaagagtttgagatcgtggaccgaagccagc 120 tgcccggcccaggcgacctgcggagcgcaacgaggccgcgggcggccgagggctggtcgg 180 cgcccatcctgaccctggCacgcagggccaccgggaacctgtcggcgagctgcgggagcg 240 cgctgcgcgcggccgcggggctgggcggcggggacagcggggacggcacggcgcgcgcag 300 cttctaagtgccagatgatggaggagcgtgccaacctgatgcacatgatgaaactcagca ,360 tcaaggtgttgctccagtcggctctgagcctgggccgcagcctggatgcggaccatgccc 420 ccttgcagcagttctttgtagtgatggagcactgcctcaaacatgggctgaaagttaaga 480 agagttttattggccaaaataaatcattctttggtcctttggagctggtggagaaacttt 540 gtccagaagcatcagatatagcgactagtgtcagaaatcttccagaattaaagacagctg 600 tgggaagaggccgagcgtggctttatcttgcactcatgcaaaagaaactggcagattatc 660 tgaaagtgcttatagacaataaacatctcttaagcgagttctatgagcctgaggctttaa 720 tgatggaggaagaagggatggtgattgttggtctgctggtgggactcaatgttctcgatg 780 ccaatctctgcttgaaaggagaagacttggattctcaggttggagtaatagatttttccc 840 tctaccttaaggatgtgcaggatcttgatggtggcaaggagcatgaaagaattactgatg 900 tccttgatcaaaaaaattatgtggaagaacttaaccggcacttgagctgcacagttgggg 960 atcttcaaaccaagatagatggcttggaaaagactaactcaaagcttcaagaagagcttt 1020 cagctgcaacagaccgaatttgctcacttcaagaagaacagcagcagttaagagaacaaa 1080 atgaattaattcgagaaagaagtgaaaagagtgtagagataacaaaacaggataccaaag 1140 ttgagctggagacttacaagcaaactcggcaaggtctggatgaaatgtacagtgatgtgt 1200 ggaagcagctaaaagaggagaagaaagtccggttggaactggaaaaagaactggagttac 1260 aaattggaatgaaaaccgaaatggaaattgcaatgaagttactggaaaaggacacccacg 1320 agaagcaggacacactagttgccctccgccagcagctggaagaagtcaaagcgattaatt 1380 tacagatgtttcacaaagctcagaatgcagagagcagtttgcagcagaagaatgaagcca 1440 tcacatcctttgaaggaaaaaccaaccaagttatgtccagcatgaaacaaatggaagaaa 1500 ggttgcagcactcggagcgggcgaggcagggggctgaggagcggagccacaagctgcagc 1560 aggagctgggcgggaggatcggcgccctgcagctgcagctctcccagctgcacgagcaat 1620 gctcaagcctggagaaagaattgaaatcagaaaaagagcaaagacaggctcttcagcgcg 1680 aattacagcacgagaaagacacttcctctctactcaggatggagctgcaa~caagtggaag1740 gactgaaaaaggagttgcgggagcttcaggacgagaaggcagagctgcagaagatctgcg 1800 aggagcaggaacaagccctccaggaaatgggcctgcacctcagccagtccaagctgaaga 1860 tggaagatataaaagaagtgaaccaggcactgaagggccacgcctggctgaaagatgacg 1920 aagcgacacactgtaggcagtgtgagaaggagttctccatttcccggagaaagcaccact 1980 gccggaactgtggccacatcttctgcaacacctgctccagcaacgagctggccctgccct 2040 cctaccccaagccggtgcgagtgtgcgacagctgccacaccctgctcctgcagcgctgct 2100 cctccacggcctcctgaacgtccgtcctcaggagcacagcctcacggacagtgccaaacc 2160 ctgtgggtctccaggggcttgggaaatgtgttctttcccaagagtatcaaaggaaagaat 2220 caaatttcttgcccggtcactggcactccagaagacagcgtgccggaaccggcagctctc 2280 acctttctgtgacttgttcggaattaactcctctggatggaaacttccatcttacttggt 2340 tacatcacggctctggttcagatacaacttcatgattttgctactatcatttttcacttt 2400 tcaaagaatttaacctattttacagcagttcagttctgctagtgagtagttttcctctcc 2460 taccttccttctaaaaacctgattcatgcacagcgtttgacacacatggagtctgccagt 2520 gtgccttctctgcttcagacaagagatctgccatttcatgcccttgtgactacctatcat 2580 tggccctgcaataaaatcatttatttttcaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa 2640 aaaaaaaaaaaaaaaaaaaaaactcgag 2668 <210> 157 <211> 2313 <212> DNA
<213> Homo sapien <400> 157 gaattcggcaccaggccgggcgggcgcctcagccatggccctgcgcaaggaactgctcaa 60 gtccatctggtacgcctttaccgcgctggacgtggagaagagtggcaaagtctccaagtc 120 ccagctcaaggtgctgtcccacaacctgtacacggtcctgcacatcccccatgaccccgt 180 ggccctggaggaacacttccgagatgatgatgacggccctgtgtccagccagggatacat 240 gccctacctcaacaagtacatcctggacaaggtggaggagggggcttttgttaaagagca 300 ctttgatgagctgtgctggacgctgacggccaagaagaactatcgggcagatagcaacgg 360 gaacagtatgctctccaatcaggatgccttccgcctctggtgcctcttcaacttcctgtc 420 tgaggacaagtaccctctgatcatggttcctgatgaggtggaatacctgctgaaaaaggt 480 actcagcagcatgagcttggaggtgagcttgggtgagctggaggagcttctggcccagga 540 ggcccaggtggcccagaccaccggggggctcagcgtctggcagttcctggagctcttcaa 600 ttcgggccgctgcctgcggggcgtgggccgggacaccctcagcatggccatccacgaggt 660 ctaccaggagctcatccaagatgtcctgaagcagggctacctgtggaagcgagggcacct 720 gagaaggaactgggccgaacgctg.gttccagctgcagcccagctgcctctgctactttgg 780 gagtgaagagtgcaaagagaaaaggggcattatcccgctggatgcacactgctgcgtgga 840 ggtgctgccagaccgcgacggaaagcgctgcatgttctgtgtgaagacagccacccgcac 900 gtatgagatgagcgcctcagacacgcgccagcgccaggagtggacagctgccatccagat 960 ggcgatccggctgcaggccgaggggaagacgtccctacacaaggacctgaagcagaaacg 1020 gcgcgagcagcgggagcagcgggagcggcgccgggcggccaaggaagaggagctgctgcg 1080 gctgcagcagctgcaggaggagaaggagcggaagctgcaggagctggagctgctgcagga 1140 ggcgcagcggcaggccgagcggctgctgcaggaggaggaggaacggcgccgcagccagca 1200 ccgcgagctgcagcaggcgctcgagggccaactgcgcgaggcggagcaggcccgggcctc 1260 catgcaggctgagatggagctgaaggaggaggaggctgcccggcagcggcagcgcatcaa 1320 ggagctggaggagatgcagcagcggttgcaggaggccctgcaactagaggtgaaagctcg 1380 gcgagatgaagaatctgtgcgaatcgctcagaccagactgctggaagaggaggaagagaa 1440 gctgaagcagttgatgcagctgaaggaggagcaggagcgctacatcgaacgggcgcagca 1500 ggagaaggaagagctgcagcaggagatggcacagcagagccgctccctgcagcaggccca 1560 gcagcagctggaggaggtgcggcagaaccggcagagggctgacgaggatgtggaggctgc 1620 ccagagaaaactgcgccaggccagcaccaacgtgaaacactggaatgtccagatgaaccg 1680 gctgatgcatccaattgagcctggagataagcgtccggtcacaagcagctccttctcagg 1740 cttccagccccctctgcttgcccaccgtgactcctccctaaagcgcctgacccgctgggg 1800 atcccagggcaacaggaccccctcgcccaacagcaatgagcagcagaagtccctcaatgg 1860 tggggatgaggctcctgccccggcttccacccctcaggaagataaactggatccagcacc 1920 agaaaattagcctctcttagccccttgttcttcccaatgtcatatccaccaggacctggc 1980 cacagctggcctgtgggtgatcccagctcttactaggagagggagctgaggtcctggtgc 2040 caggggcccaggccctccaaccataaacagtccaggatggaacctggttcacccttcata 2100 ccagctccaagccccagaccatgggagctgtctgggatgttgatccttgagaacttggcc 2160 ctgtgctttagacccaaggacccgattcctgggctaggaaagagagaacaagcaagccgg 2220 ggctacctgcccccaggtggccaccaagttgtggaagcacatttctaaataaaaactgct 2280 cttagaatgaaaaaaaaaaaaaaaaaactcgag 2313 <210> 158 <211> 2114 <212> DNA
<213> Homo sapien <400> 158 gaattcggcacgaggaagaactcgcctctgttgagtgtaagtagccaaacaataaccaag 60 gagaataacagaaatgtccatttggagcactcagagcagaatcctggttcatcagcaggt 120 gacacctcagcagcgcaccaggtggttttaggagaaaacttgatagccacagccctttgt 180 ctttctggcagtgggtctcagtctgatttgaaggatgtggccagcacagcaggagaggag 240 ggggacacaagccttcgggagagcctccatccagtcactcggtctcttaaggcagggtgc 300 catactaagcagcttgcctccaggaattgctctgaagagaaatccccacaaacctccatc 360 ctaaaggaaggtaacagggacacaagcttggatttccgacctgtagtgtctccagcaaat 420 ggggttgaaggagtcCgagtggatcaggatgatgatcaagatagctcttccctgaagctt 480 tctcagaacattgctgtacagactgactttaagacagctgattcagaggtaaacacagat540 caagatattgaaaagaatttggataaaatgatgacagagagaaccctgttgaaagagcgt600 taccaggaggtcctggacaaacagaggcaagtggagaatcagctccaagtgcaattaaag660 cagcttcagcaaaggagagaagaggaaatgaagaatcaccaggagatattaaaggctatt720 caggatgtgacaataaagcgggaagaaacaaagaagaagatagagaaagagaagaaggag780 tttttgcagaaggagcaggatctgaaagctgaaattgagaagctttgtgagaagggcaga840 agagaggtgtgggaaatggaactggatagactcaagaatcaggatggcgaaataaatagg900 aacattatggaagagactgaacgggcctggaaggcagagatcttatcactagagagccgg960 aaagagttactggtactgaaactagaagaagcagaaaaaga.ggcagaattgcaccttact1020 tacctcaagtcaactcccccaacactggagacagttcgttccaaacaggagtgggagacg1080 agactgaatggagttcggataatgaaaaagaatgttcgtgaccaatttaatagtcatatc1140 cagttagtgaggaacggagccaagctgagcagccttcctcaaatccctactcccacttta1200 cctccacccccatcagagacagacttcatgcttcaggtgtttcaacccagtccctctctg1260 gctcctcggatgcccttctccattgggcaggtcacaatgcccatggttatgcccagtgca1320 gatccccgctccttgtctttcccaatcctgaaccctgccctttcccagcccagccagcct1380 tcctcaccccttcctggctcccatggcagaaatagccctggcttgggttcccttgtcagc1440 cctggtgccgaattcggcacgaggtaccactggtctgtgtgctagaggagggtgttgcca2500 tagaaccagtggccacagttgtggtggtggtggtcagcactgtgggggtgtgggtggtcc1560 ccgggacggaggagggggtcaccgtgaagccactggttgtgggtgtggtggttgtgctga1620 tccacactggaggcgtgcgtgccgtccctgggctgaaggagggggtgactgtgaagcccg1680 tggttgtggtagtcggcactttggtagtgtgagctgttcctggggtggaagagggggtgg1740 ccacagagccggtggccctggttgtggtggccgtggtggtaagcactgtggaggtgtggg1800 cagtctctggagtggaggagggtgtggctgtggacatggtggccgtgggtgtggtggtct1860 gtgataggcgggtccaggtggtgcccagggaggaggaggggatggctgtaaagctggtag1920 ctgtgggtgtggtggctgtgcttctcagtgctggaagggcggttgcagtccctggactgg1980 agaagggagtggctttggagctggtgactgtgggtgtcgtggccgtggtgctcacatgtg2040 gggtgccagcagttgcctgggtggaggaggcggtggccgtggatccggtgggcaccgtca2100 cgggagtacttcta 2114 <210> 159 <211> 278 <212> DNA
<213> Homo sapien <400> 159 gaattcggcacaggtaactttgcctggggtatttaaaaaaaaaaaaaaaa aaaaaaaaag60 tcaaatatctgagtactaatttcctgaaaagtatgttccgatagatgaac agatcattaa120 tgcagaatgagaatcactcctaaaataggtaatggtaaaaattaaattga caattacctc180 tctctatgcagaaggaaatatcacctatatgacatcatcatcatctattg atacttgctg240 gcagtgctaataatggttttaatgccaatttgtaagaa 278 <210> 160 <211> 848 <212> DNA
<213> Homo sapien <400> 160 gaattcggcacgagccccagaggagctcggcctgcgctgcgccacgatgtccggggagtc 60 agccaggagcttggggaagggaagcgcgcccccggggccggtcccggagggctcgatccg 120 catctacagcatgaggttctgcccgtttgctgagaggacgcgtctagtcctgaaggccaa 180 gggaatcaggcatgaagtcatcaatatcaacctgaaaaataagcctgagtggttctttaa 240 gaaaaatccctttggtctggtgccagttctggaaaacagtcagggtcagctgatctacga 300 gtctgccatcacctgtgagtacctggatgaagcatacccagggaagaagctgttgccgga 360 tgacccctatgagaaagcttgccagaagatgatcttagagttgttttctaaggtgccatc 420 cttggtaggaagctttattagaagccaaaataaagaagactatgctggcctaaaagaaga 980 atttcgtaaagaatttaccaagctagaggaggttctgactaataagaagacgaccttctt 540 tggtggcaattctatctctatgattgattacctcatctggccctggtttgaacggctgga 600 agcaatgaagttaaatgagtgtgtagaccacactccaaaactgaaactgtggatggcagc 660 catgaaggaa gatcccacag tctcagccct gcttactagt gagaaagact ggcaaggttt 720 cctagagctc tacttacaga acagccctga ggcctgtgac tatgggctct gaagggggca 780 ggagtcagca ataaagctat gtctgatatt ttccttcact aaaaaaaaaa aaaaaaaaaa 840 aactcgag 848 <210> 161 <211> 432 <212> DNA
<213> Homo sapien <400> 161 gaattcggcacgagggcagaccaagatcctggaggaggacctggaacagatcaagctgtc 60 cttgagagagcgaggccgggagctgaccactcagaggcagctgatgcaggaacgggcaga 120 ggaagggaagggcccaagtaaagcacagcgcgggagcctagagcacatgaagctgatcct 180 gcgtgataaggagaaggaggtggaatgtcagcaggagcatatccatgaactccaggagct 240 caaagaccagctggagcagcagctccagggcctgcacaggaaggtaggtgagaccagcct 300 cctcctgtcccagcgagagcaggaaatagtggtcctgcagcagcaactgcaggaagccag 360 ggaacaaggggagctgaaggagcagtcacttcagagtcaactggatgaggcccagagagc 420 cctagcccagag 432 <210> 162 <211> 433 <212> DNA
<213> Homo sapien <400> 162 gattcggcacgagccggagctgggttgctcctgctcccgtctccaagtcctggtacctcc 60 ttcaagctgggagagggctctagtccctggttctgaacactctggggttctcgggtgcag 120 gccgccatgagcaaacggaaggcgccgcaggagactctcaacgggggaatcaccgacatg 180 ctcacagaactcgcaaactttgagaagaacgtgagccaagctatccacaagtacaatgct 240 tacagaaaagcagcatctgttatagcaaaatacccacacaaaataaagagtggagctgaa 300 gctaagaaattgcctggagtaggaacaaaaattgctgaaaagattgatgagtttttagca 360 actggaaaattacgtaaactggaaaagattcggcaggatgatacgagttcatccatcaat 420 ttcctgactcgag 433 <210> 163 <211> 432 <212> DNA
<213> Homo sapien <400> 163 gaattcggcaccagatgaggccaacgaggtgacggacagcgcgtacatgggctccgagag 60 cacctacagtgagtgtgagaccttcacggacgaggacaccagcaccctggtgcaccctga 120 gctgcaacctgaaggggacgcagacagtgccggcggctcggccgtgccctctgagtgcct 180 ggacgccatggaggagcccgaccatggtgccctgctgctgctcccaggcaggcctcaccc 240 ccatggccagtctgtcatcacggtgatcgggggcgaggagcactttgaggactacggtga 300 aggcagtgaggcggagctgtccccagagaccctatgcaacgggcagctgggctgcagtga 360 ccccgctttcctcacgcccagtccgacaaagcggctctccagcaagaaggtggcaaggta 420 cctgcaccagtc 432 <210> 164 <211> 395 <212> DNA
<213> Homo sapien <400> 164 gacacttgaa tcatgggtga cgttaaaaat tttctgtatg cctggtgtgg caaaaggaag 60 atgaccccat cctatgaaat tagagcagtg gggaacaaaa acaggcagaa attcatgtgt 120 gaggttcaggtggaaggttataattacactggcatgggaaattccaccaataaaaaagat 180 gcacaaagcaatgctgccagagactttgttaactatttggttcgaataaatgaaataaag 240 agtgaagaagttccagcttttggggtagcatctccgcccccacttactgatactcctgac 300 actacagcaaatgctgaaggcatcttgttgacatcgaatatgactttgataataaatacc 360 ggttcctgaaaaaaaaaaaaaaaaaaaaactcgag 395 <210> 165 <211> 503 <212> DNA
<213> Homo sapien <400> 165 gaattcggcaccaggaacgctcggtgagaggcggaggagcggtaactaccccggttgcgc 60 acagctcggcgctccttcccgctccctcacacaccggcctcagcccgcaccggcagtaga 120 agatggtgaaagaaacaacttactacgatgttttgggggtcaaacccaatgctactcagg 180 aagaattgaaaaaggcttataggaaactggccttgaagtaccatcctgataagaacccaa 240 atgaaggagagaagtttaaacagatttctcaagcttacgaagttctctctgatgcaaaga 300 aaagggaattatatgacaaaggaggagaacaggcaattaaagagggtggagcaggtggcg 360 gttttggctcccccatggacatctttgatatgttttttggaggaggaggaaggatgcaga 420 gagaaaggagaggtaaaaatgttgtacatcagctctcagtaaccctagaagacttatata 480 atggtgcaacaagaaaactgget 503 <210> 166 <211> 893 <212> DNA
<213> Homo sapien <400> 166 gaattcggcacgagaggaacttctcttgacgagaagagagaccaaggaggccaagcaggg 60 gctgggccagaggtgccaacatggggaaactgaggctcggctcggaagggtgagagtgag 120 actacatctcaaaaaaaaaaaaaaaaaaaaaaaagaaagaaaagaaaagaaaaaagaaag 180 aacggaagtagttgtaggtagtggtatggtggtatgagtctgttttctgttacttataac 240 aacaacaacaacaaaaaacgctgaaactgggtaatttataaagaaaaggaaaaaaagcag 300 aaaaaaatcaggaagaagagaaaggaaaagaagacaaataaatgaaatttatgtattaca 360 gttctgaaggctgagacatcccaggtcaagggtccacacttggcgagggctttcttgctg 420 gtggagactctttgtggagtcctgggacagtgcagaaggatcacgcctccctaccgctcc 480 aagcccagccctcagccatggcatgccccctggatcaggccattggcctcctcgtggcca 540 tcttccacaagtactccggcagggagggtgacaagcacaccctgagcaagaaggagctga 600 aggagctgatccagaaggagctcaccattggctcgaagctgcaggatgctgaaattgcaa 660 ggctgatggaagacttggaccggaacaaggaccaggaggtgaacttccaggagtatgtca 720 ccttcctgggggccttggctttgatctacaatgaagccctcaagggctgaaaataaatag 780 ggaagatggagacaccctctgggggtcctctctgagtcaaatccagtggtgggtaattgt 840 acaataaattttttttggtcaaatttaaaaaaaaaaaaaaaaaaaaactcgag 893 <210> 167 <211> 549 <212> DNA
<213> Homo sapien <400> 167 gaattcggcacgagcccagatcccgaggtccgacagcgcccggcccagatccccacgcct 60 gccaggagcaagccgagagccagccggccggcgcactccgactccgagcagtctctgtcc 120 ttcgacccgagccccgcgccctttccgggacccctgccccgcgggcagcgctgccaacct 180 gccggccatggagaccccgtcccagcggcgcgccacccgcagcggggcgcaggccagctc 240 cactccgctgtcgcccacccgcatcacccggctgcaggagaaggaggacctgcaggagct 300 caatgatcgcttggcggtctacatcgaccgtgtgcgctcgctggaaacggagaacgcagg 360 gctgcgccttcgcatcaccgagtctgaagaggtggtcagccgcgaggtgtccggcatcaa 420 ggccgcctacgaggccgagctcggggatgcccgcaagacccttgactcagtagccaagga 480 gcgcgcccgc ctgcagctgg agctgagcaa agtgcgtgaa gagtttaagg agctgaaagc 540 gcgcaatac 549 <210> 168 <211> 547 <212> DNA
<213> Homo sapien <400> 168 gaattcggcacgagatggcggcaggggtcgaagcggcggcggaggtggcggcgacggaga 60 tcaaaatggaggaagagagcggcgcgcccggcgtgccgagcggcaacggggctccgggcc 120 ctaagggtgaaggagaacgacctgctcagaatgagaagaggaaggagaaaaacataaaaa 180 gaggaggcaatcgctttgagccatatgccaatccaactaaaagatacagagccttcatta 240 caaacataccttttgatgtgaaatggcagtcacttaaagacctggttaaagaaaaagttg 300 gtgaggtaacatacgtggagctcttaatggacgctgaaggaaagtcaaggggatgtgctg 360 ttgttgaattcaagatggaagagagcatgaaaaaagctgcggaagtcctaaacaagcata 420 gtctgagcggaagaccactgaaagtcaaagaagatcctgatggtgaacatgccaggagag 480 caatgcaaaaggctggaagacttggaagcacagtatttgtagcaaatctggattataaag 540 ttggctg 547 <210> 169 <211> 547 <212> DNA
<213> Homo sapien <400> 169 gaattcggcaccaggagtccgactgtgctcgctgctcagcgccgcacccggaagatgagg 60 ctcgccgtgggagccctgctggtctgcgccgtcctggggctgtgtctggctgtccctgat 120 aaaactgtgagatggtgtgcagtgtcggagcatgaggccactaagtgccagagtttccgc 180 gaccatatgaaaagcgtcattccatccgatggtcccagtgttgcttgtgtgaagaaagcc 240 tcctaccttgattgcatcagggccattgcggcaaacgaagcggatgctgtgacactggat 300 gcaggtttggtgtatgatgcttacctggctcccaataacctgaagcctgtggtggcagag 360 ttctatgggtcaaaagaggatccacagactttctattatgctgttgctgtggtgaagaag 420 gatagtggcttccagatgaaccagcttcgaggcaagaagtcctgccacacgggtctaggc 480 aggtccgctgggtggaacatccccataggcttactttactgtgacttacctgagccacgt 540 aaacctc 547 <210> 170 <211> 838 <212> DNA
<213> Homo sapien <400> 170 gaattcggcaccagaggagctcggcctgcgctgcgccacgatgtccggggagtcagccag 60 gagcttggggaagggaagcgcgcccccggggccggtcccggagggctcgatccgcatcta 120 cagcatgaggttctgcccgtttgctgagaggacgcgtctagtcctgaaggccaagggaat 180 caggcatgaagtcatcaatatcaacctgaaaaataagcctgagtggttctttaagaaaaa 240 tccctttggtctggtgccag'ttctggaaaacagtcagggtcagctgatctacgagtctgc 300 catcacctgtgagtacctggatgaagcatacccagggaagaagctgttgccggatgaccc 360 ctatgagaaagcttgccagaagatgatcttagagttgttttctaaggtgccatccttggt 420 aggaagctttattagaagccaaaataaagaagactatgatggcctaaaagaagaatttcg 480 taaagaatttaccaagctagaggaggttctgactaataagaagacgaccttctttggtgg 540 caattctatctctatgattgattacctcatctggccctggtttgaacggctggaagcaat 600 gaagttaaatgagtgtgtaga'ccacactccaaaactgaaactgtggatggcagccatgaa 660 ggaagatcccacagtctcagccctgcttactagtgagaaagactggcaaggtttcctaga 720 gctctacttacagaacagccctgaggcctgtgactatgggctctgaagggggcaggagtc 780 agcaataaagctatgtctgatattttccttcactaaaaaaaaaaaaaaaaaactcgag 838 <210> 171 <211> 547 <212> DNA
<213> Homo sapien <400>

gaattcggcaccagcgggatttgggtcgcagttcttgtttgtggattgctgtgatcgtca 60 cttgacaatgcagatcttcgtgaagactctgactggtaagaccatcaccctcgaggttga 120 gcccagtgacaccatcgagaatgtcaaggcaaagatccaagataaggaaggcatccctcc 180 tgaccagcagaggctgatctttgctggaaaacagctggaagatgggcgcaccctgtctga 240 ctacaacatccagaaagagtccaccctgcacctggtgctccgtctcagaggtgggatgca 300 aatcttcgtgaagacactcactggcaagaccatcacccttgaggtcgagcccagtgacac 360 catcgagaacgtcaaagcaaagatccaggacaaggaaggcattcctcctgaccagcagag 420 gttgatctttgccggaaagcagctggaagatgggcgcaccctgtctgactacaacatcca 480 gaaagagtctaccctgcacctggtgctccgtctcagaggtgggatgcagatcttcgtgaa 540 gaccctg <210> 172 <211> 608 <212> DNA
<213> Homo sapien <400>

gaattcggcaccagagacttctccctctgaggcctgcgcacccctcctcatcagcctgtc 60 ' caccctcatctacaatggtgccctgccatgtcagtgcaaccctcaaggttcactgagttc 120 tgagtgcaaccctcatggtggtcagtgcctgtgcaagcctggagtggttgggcgccgctg 180 tgacctctgtgcccctggctactatggctttggccccacaggctgtcaaggcgcttgcct 240 gggctgccgtgatcacacagggggtgagcactgtgaaaggtgcattgctggtttccacgg 300 ggacccacggctgccatatgggggccagtgccggccctgtccctgtcctgaaggccctgg 360 gagccaacggcactttgctacttcttgccaccaggatgaatattcccagcagattgtgtg 420 ccactgccgggcaggctatacggggctgcgatgtgaagcttgtgcccctgggcactttgg 480 ggacccatcaaggccaggtggccggtgccaactgtgtgagtgcagtgggaacattgaccc 540 aatggatcctgatgcctgtgacccccacacggggcaatgcctgcgctgtttacaccacac 600 agagggtc <210> 173 <211> 543 <212> DNA
<213> Homo sapien <400>

gaattcggcaccagagatcatccgccagcagggtctggcctcctacgactacgtgcgccg 60 ccgcctcacggctgaggacctgttcgaggctcggatcatctctctcgagacctacaacct 120 gctccgggagggcaccaggagcctccgtgaggctctcgaggcggagtccgcctggtgcta 180 cctctatggcacgggctccgtggctggtgtctacctgcccggttccaggcagacactgag 240 catctaccaggctctcaagaaagggctgctgagtgccgaggtggcccgcctgctgctgga 300 ggcacaggcagccacaggcttcctgctggacccggtgaagggggaacggctgactgtgga 360 tgaagctgtgcggaagggcctcgtggggcccgaactgcacgaccgcctgctctcggctga 420 gcgggcggtcaccggctaccgtgacccctacaccgagcagaccatctcgctcttccaggc 480 catgaagaaggaactgatccctactgaggaggccctgcggctgtggatgcccagctggcc 540 acc 543 <210> 174 <211> 548 <212> DNA
<213> Homo sapien <400> 174 gaattcggcacgagaaatggcggcaggggtcgaagcggcggcggaggtggcggcgacgga 60 gatcaaaatggaggaagagagcggcgcgcccggcgtgccgagcggcaacggggctccggg 120 ccctaagggtgaaggagaacgacctgctcagaatgagaagaggaaggagaaaaacataaa 180 aagaggaggcaatcgctttgagccatatgccaatccaactaaaagatacagagccttcat 240 tacaaacataccttttgatgtgaaatggcagtcacttaaagacctggttaaagaaaaagt 300 tggtgaggtaacatacgtggagctcttaatggacgctgaaggaaagtcaaggggatgtgc 360 tgttgttgaattcaagatggaagagagcatgaaaaaagctgcggaagtcctaaacaagca 420 tagtctgagcggaagaccactgaaagtcaaagaagatcctgatggtgaacatgccaggag 480 agcaatgcaaaaggtgatggctacgactggtgggatgggtatgggaccaggtggcccagg 540 aatgatta 548 <210> 175 <211> 604 <212> DNA
<213> Homo sapien <400> 175 gaattcggcaccagaggacctccaggacatgttcatcgtccataccatcgaggagattga 60 gggcctgatctcagcccatgaccagttcaagtccaccctgccggacgccgatagggagcg 120 cgaggccatcctggccatccacaaggaggcccagaggatcgctgagagcaaccacatcaa 180 gctgtcgggcagcaacccctacaccaccgtcaccccgcaaatcatcaactccaagtggga 240 gaaggtgcagcagctggtgccaaaacgggaccatgccctcctggaggagcagagcaagca 300 gcagtccaacgagcacctgcgccgccagttcgccagccaggccaatgttgtggggccctg 360 gatccagaccaagatggaggagatcgggcgcatctccattgagatgaacgggaccctgga 420 ggaccagctgagccacctgaagcagtatgaacgcagcatcgtggactacaagcccaacct 480 ggacctgctggagcagcagcaccagcttatccaggaggccctcatcttcgacaacaagca 540 caccaactataccatggagcacatccgcgtgggctgggagcagctgctcaccaccattgc 600 ccgg 604 <210> 176 <211> 486 <212> DNA
<213> Homo sapien <400> 176 gaattcggcaccagccaagctcactattgaatccacgccgttcaatgtcgcagaggggaa 60 ggaggttcttctactcgcccacaacctgccccagaatcgtattggttacagctggtacaa 120 aggcgaaagagtggatggcaacagtctaattgtaggatatgtaataggaactcaacaagc 180 taccccagggcccgcatacagtggtcgagagacaatataccccaatgcatccctgctgat 240 ccagaacgtcacccagaatgacacaggattctataccctacaagtcataaagtcagatct 300 tgtgaatgaagaagcaaccggacagttccatgtatacccggagctgcccaagccctccat 360 ctccagcaacaactccaaccccgtggaggacaaggatgctgtggccttcacctgtgaacc 420 tgaggttcagaacacaacctacctgtggtgggtaaatggtcagagcctcccggtcagtcc 480 caaggc 486 <210> 177 <211> 387 <212> DNA
<213> Homo sapien <400> 177 gaattcggcaccagggacagcagaccagacagtcacagcagccttgacaaaacgttcctg 60 gaactcaagctcttctccacagaggaggacagagcagacagcagagaccatggagtctcc 120 ctcggcccctccccacagatggtgcatcccctggcagaggctcctgctcacagcctcact 180 tctaaccttctggaacccgcccaccactgccaagctcactattgaatccacgccgttcaa 240 tgtcgcagaggggaaggaggtgcttctacttgtccacaatctgccccagcatctttttgg 300 ctacagctggtacaaaggtgaaagagtggatggcaaccgtcaaattataggatatgtaat 360 aggaactcaacaagctaccccagggcc 387 <210> 178 <211> 440 <212> DNA
<213> Homo sapien <400>

gaattcggcacgaggagaagcagaaaaacaaggaatttagccagactttagaaaatgaga 60 aaaataccttactgagtcagatatcaacaaaggatggtgaactaaaaatgcttcaggagg 120 aagtaaccaaaatgaacctgttaaatcagcaaatccaagaagaactctctagagttacca 180 aactaaaggagacagcagaagaagagaaagatgatttggaagagaggcttatgaatcaat 240 tagcagaacttaatggaagcattgggaattactgtcaggatgttacagatgcccaaataa 300 aaaatgagctattggaatctgaaatgaagaaccttaaaaagtgtgtgagtgaattggaag 360 aagaaaagcagcagttagtcaaggaaaaaactaaggtggaatcagaaatacgaaaggaat 420 atttggagaaaatacaaggt 440 <210> 179 <211> 443 <212> DNA
<213> Homo sapien <400>

gaattcggcaccagcggggggctacggcggcggctacggcggcgtcctgaccgcgtccga 60 cgggctgctggcgggcaacgagaagctaaccatgcagaacctcaacgaccgcctggcctc 120 ctacctggacaaggtgcgcgccctggaggcggccaacggcgagctagaggtgaagatccg 180 cgactggtaccagaagcaggggcctgggccctcccgcgactacagccactactacacgac 240 catccaggacctgcgggacaagattcttggtgccaccattgagaactccaggattgtcct 300 gcagatcgacaacgcccgtctggctgcagatgacttccgaaccaagtttgagacggaaca 360 ggctctgcgcatgagcgtggaggccgacatcaacggcctgcgcagggtgctggatgagct 420 gaccctggccaggaccgacctgg 443 <210> 180 <211> 403 <212> DNA
<213> Homo sapien <400>

gaattcggcacgaggttatgagagtcgacttcaatgttcctatgaagaacaaccagataa 60 caaacaaccagaggattaaggctgctgtcccaagcatcaaattctgcttggacaatggag 120 ccaagtcggtagtccttatgagccacctaggccggcctgatggtgtgcccatgcctgaca 180 agtactccttagagccagttgctgtagaactcagatctctgctgggcaaggatgttctgt 240 tcttgaaggactgtgtaggcccagaagtggagaaagcctgtgccaacccagctgctgggt 300 ctgtcatcctgctggagaacctccgctttcatgtggaggaagaagggaagggaaaagatg 360 cttctgggaacaaggttaaagccgagccagccaaaatagaagc 403 <210> 181 <211> 493 <212> DNA
<213> Homo sapien <400>

gaattcggcaccagcagaggtctccagagccttctctctcctgtgcaaaatggcaactct 60 taaggaaaaactcattgcaccagttgcggaagaagaggcaacagttccaaacaataagat 120 cactgtagtgggtgttggacaagttggtatggcgtgtgctatcagcattctgggaaagtc 180 tctggctgatgaacttgctcttgtggatgttttggaagataagcttaaaggagaaatgat 240 ggatctgcagcatgggagcttatttcttcagacacctaaaattgtggcagataaagatta 300 ttctgtgaccgccaattctaagattgtagtggtaactgcaggagtccgtcagcaagaagg 360 ggagagtcggctcaatctggtgcagagaaatgttaatgtcttcaaattcattattcctca 420 gatcgtcaag tacagtcctg attgcatcat aattgtggtt tccaacccag tggacattct 480 tacgtatgtt acc 493 <210> 182 <211> 209 <212> PRT
<213> Homo sapien <400> 182 Ala Phe Ser Ser Asn Pro Lys Val Gln Val Glu Ala Ile Glu Gly G1y Ala Leu Gln Lys Leu Leu Val Ile Leu Ala Thr Glu Gln Pro Leu Thr Ala Lys Lys Lys Val Leu Phe Ala Leu Cys Ser Leu Leu Arg His Phe Pro Tyr Ala Gln Arg Gln Phe Leu Lys Leu Gly Gly Leu Gln Val Leu Arg Thr Leu Val Gln G1u Lys Gly Thr Glu Val Leu Ala Val Arg Val Val Thr Leu Leu Tyr Asp Leu Val Thr Glu Lys Met Phe Ala Glu Glu 90 ' 95 Glu Ala Glu Leu Thr Gln Glu Met Ser Pro Glu Lys Leu Gln Gln Tyr Arg Gln Val His Leu Leu Pro Gly Leu Trp Glu Gln G1y Trp Cys Glu Ile Thr Ala His Leu Leu Ala Leu Pro Glu His Asp Ala Arg Glu Lys Val Leu Gln Thr Leu Gly Val Leu Leu Thr Thr Cys Arg Asp Arg Tyr Arg Gln Asp Pro Gln Leu Gly Arg Thr Leu Ala Ser Leu Gln Ala Glu Tyr Gln Val Leu Ala Ser Leu G1u Leu Gln Asp Gly Glu Asp Glu Gly Tyr Phe Gln Glu Leu Leu Gly Ser Val Asn Ser Leu Leu Lys Glu Leu Arg <210> 183 <211> 255 <212> PRT
<213> Homo sapien <400> 183 Met Ala Ala Gly Val Glu A1a Ala Ala Glu Va1 Ala Ala Thr Glu Pro Lys Met Glu Glu Glu Ser Gly Ala Pro Cys Val Pro Ser Gly Asn Gly A1a Pro Gly Pro Lys Gly Glu Glu Arg Pro Thr Gln Asn Glu Lys Arg Lys Glu Lys Asn I1e Lys Arg G1y Gly Asn Arg Phe Glu Pro Tyr Ser Asn Pro Thr Lys Arg Tyr Arg Ala Phe Ile Thr Asn Ile Pro Phe Asp Val Lys Trp Gln Ser Leu Lys Asp Leu Val Lys Glu Lys Val G1y Glu Val Thr Tyr Va1 Glu Leu Leu Met Asp Ala Glu Gly Lys Ser Arg Gly 100 ~ 105 110 Cys Ala Val Val Glu Phe Lys Met Glu Glu Ser Met Lys Lys Ala Ala Glu Va1 Leu Asn Lys His Ser Leu Ser Gly Arg Pro Leu Lys Val Lys Glu Asp Pro Asp Gly Glu His Ala Arg Arg Ala Met Gln Lys Ala Gly Arg Leu Gly Ser Thr Val Phe Val Ala Asn Leu Asp Tyr Lys Val Gly Trp Lys Lys Leu Lys Glu Val Phe Ser Met Ala Gly Val Val Val Arg Ala Asp Ile Leu Glu Asp Lys Asp G1y Lys Ser Arg Gly Ile Gly Tle Val Thr Phe Glu Gln Ser Ile G1u Ala Val G1n A1a I1e Ser Met Phe Asn Gly Gln Leu Leu Phe Asp Arg Pro Met His Val Lys Met Asp Glu Arg Ala Leu Pro Lys Gly Asp Phe Phe Pro Pro Glu Arg His Ser <210> 184 <211> 188 <212> PRT
<213> Homo sapien <400> 184 Leu Ser Gly Ser Cys Ile Arg Arg Glu Gln Thr Pro Glu Lys Glu Lys Gln Val Val Leu Phe Glu Glu Ala Ser Trp Thr Cys Thr Pro Ala Cys Gly Asp Glu Pro Arg Thr Val Ile Leu Leu Ser Ser Met Leu Ala Asp His Arg Leu Lys Leu Glu Asp Tyr Lys Asp Arg Leu Lys Ser Gly Glu His Leu Asn Pro Asp G1n Leu Glu Ala Val GIu Lys Tyr Glu Glu Val Leu His Asn Leu Glu Phe Ala Lys Glu Leu Gln Lys Thr Phe Ser Gly Leu Ser Leu Asp Leu Leu Lys Ala Gln Lys Lys Ala Gln Arg Arg Glu His Met Leu Lys Leu Glu Ala Glu Lys Lys Lys Leu Arg Thr Ile Leu Gln Val Gln Tyr Val Leu G1n Asn Leu Thr Gln Glu His Val Gln Lys Asp Phe Lys Gly Gly Leu Asn Gly Ala Val Tyr Leu Pro Ser Lys Glu Leu Asp Tyr Leu Ile Lys Phe Ser Lys Leu Thr Cys Pro Glu Arg Asn Glu Ser Leu Arg Gln Thr Leu Glu Gly Ser Thr Val <210> 185 <211> 746 <212> PRT
<213> Homo sapien <400> 185 Asp Lys His Leu Lys Asp Leu Leu Ser Lys Leu Leu Asn Ser Gly Tyr Phe Glu Ser Ile Pro Val Pro Lys Asn Ala Lys Glu Lys Glu Val Pro Leu Glu Glu Glu Met Leu Ile Gln Ser Glu Lys Lys Thr Gln Leu Ser Lys Thr Glu Ser Val Lys Glu Ser Glu Ser Leu Met Glu Phe Ala Gln Pro Glu Ile Gln Pxo Gln Glu Phe Leu Asn Arg Arg Tyr Met Thr Glu Val Asp Tyr Ser Asn Lys Gln Gly Glu Glu Gln Pro Trp Glu Ala Asp Tyr Ala Arg Lys Pro Asn Leu Pro Lys Arg Trp Asp Met Leu Thr Glu Pro Asp Gly G1n Glu Lys Lys Gln Glu Sex Phe Lys Ser Trp Glu Ala Ser Gly Lys His Gln Glu Val Ser Lys Pro Ala Val Ser Leu Glu Gln Arg Lys Gln Asp Thr Ser Lys Leu Arg Ser Thr Leu Pro Glu Glu Gln Lys Lys Gln Glu Ile Ser Lys Ser Lys Pro Ser Pro Ser Gln Trp Lys Gln Asp Thr Pro Lys Ser Lys Ala G1y Tyr Va1 Gln Glu Glu Gln Lys Lys Gln Glu Thr Pro Lys Leu Trp Pro Val Gln Leu Gln Lys Glu Gln Asp Pro Lys Lys Gln Thr Pro Lys Ser Trp Thr Pro Ser Met G1n Ser Glu Gln Asn Thr Thr Lys Ser Trp Thr Thr Pro Met Cys Glu Glu Gln Asp Ser Lys G1n Pro Glu Thr Pro Lys Ser Trp Glu Asn Asn Val Glu Ser Gln Lys His Ser Leu Thr Ser Gln Ser Gln Ile Ser Pro Lys Ser Trp Gly Val Ala Thr Ala Ser Leu Ile Pro Asn Asp Gln Leu Leu Pro Arg Lys Leu Asn Thr Glu Pro Lys Asp Val Pro Lys Pro Val His Gln Pro Val Gly Ser Ser Ser Thr Leu Pro Lys Asp Pro Val Leu Arg Lys Glu Lys Leu Gln Asp Leu Met Thr Gln Ile Gln Gly Thr Cys Asn Phe Met Gln Glu Ser Val Leu Asp Phe Asp Lys Pro Ser Ser Ala Ile Pro Thr Ser Gln Pro Pro Ser Ala Thr Pro Gly Ser Pro Val Ala Ser Lys Glu Gln Asn Leu Ser Ser Gln Ser Asp Phe Leu Gln GIu Pro Leu Gln 370 375 ' 380 Val Phe Asn Val Asn Ala Pro Leu Pro Pro Arg Lys Glu G1n Glu Tle Lys Glu Ser Pro Tyr Ser Pro Gly Tyr Asn Gln Ser Phe Thr Thr A1a Ser Thr Gln Thr Pro Pro Gln Cys Gln Leu Pro Ser Tle His Val Glu Gln Thr Val His Ser Gln Glu Thr Ala Ala Asn Tyr His Pro Asp Gly Thr Ile Gln Val Ser Asn Gly Ser Leu Ala Phe Tyr Pro Ala Gln Thr Asn Val Phe Pro Arg Pro Thr Gln Pro Phe Val Asn Ser Arg Gly Ser Val Arg Gly Cys Thr Arg Gly Gly Arg Leu Ile Thr Asn Ser Tyr Arg Ser Pro Gly Gly Tyr Lys Gly Phe Asp Thr Tyr Arg Gly Leu Pro Ser Ile Ser Asn Gly Asn Tyr Ser Gln Leu Gln Phe Gln Ala Arg Glu Tyr Ser Gly Ala Pro Tyr Ser Gln Arg Asp Asn Phe Gln Gln Cys Tyr Lys Arg Gly Gly Thr Ser Gly Gly Pro Arg Ala Asn Ser Arg Ala Gly Trp Ser Asp Ser Ser Gln Val Ser Ser Pro Glu Arg Asp Asn Glu Thr Phe Asn Ser Gly Asp Ser Gly Gln Gly Asp Ser Arg Ser Met Thr Pro Val Asp Val Pro Val Thr Asn Pro Ala Ala Thr Ile Leu Pro Val His Va1 Tyr Pro Leu Pro Gln Gln Met Arg Val Ala Phe Ser Ala Ala Arg Thr 610 615 ~ 620 Ser Asn Leu Ala Pro Gly Thr Leu Asp Gln Pro Ile Val Phe Asp Leu Leu Leu Asn Asn Leu Gly Glu Thr Phe Asp Leu Gln Leu Gly Arg Phe Asn Cys Pro Val Asn Gly Thr Tyr Va1 Phe Ile Phe His Met Leu Lys Leu Ala Val Asn Val Pro Leu Tyr Val Asn Leu Met Lys Asn G1u Glu Val Leu Val Ser Ala Tyr Ala Asn Asp Gly Ala Pro Asp His Glu Thr Ala Ser Asn His Ala Ile Leu Gln Leu Phe Gln.Gly Asp Gln Ile Trp Leu Arg Leu His Arg Gly Ala Ile Tyr Gly Ser Ser Trp Lys Tyr Ser Thr Phe Ser Gly Tyr Leu Leu Tyr Gln Asp <210> 186 <211> 705 <212> PRT
<213> Homo sapien <400> 186 Ala Leu Leu Asn Val Arg Gln Pro Pro Ser Thr Thr Thr Phe Val Leu Asn Gln Ile Asn His Leu Pro Pro Leu Gly Ser Thr I1e Va1 Met Thr Lys Thr Pro Pro Val Thr Thr Asn Arg Gln Thr Ile Thr Leu Thr Lys Phe Ile Gln Thr Thr A1a Ser Thr Arg Pro Ser Val Ser Ala Pro Thr Va1 Arg Asn Ala Met Thr Ser Ala Pro Ser Lys Asp Gln Val Gln Leu Lys Asp Leu Leu Lys Asn Asn Ser Leu Asn Glu Leu Met Lys Leu Lys Pro Pro Ala Asn Ile Ala Gln Pro Val Ala Thr Ala Ala Thr Asp Val Ser Asn Gly Thr Val Lys Lys Glu Ser Ser Asn Lys Glu Gly Ala Arg Met Trp Ile Asn Asp Met Lys Met Arg Ser Phe Ser Pro Thr Met Lys Val Pro Val Val Lys Glu Asp Asp Glu Pro Glu Glu Glu Asp Glu Glu Glu Met Gly His A1a Glu Thr Tyr Ala G1u Tyr Met Pro Ile Lys Leu 165 170 ~ 175 Lys Ile Gly Leu Arg His Pro Asp Ala Val Val Glu Thr Ser Ser Leu Ser Ser Val Thr Pro Pro Asp Val Trp Tyr Lys Thr Ser Ile Ser Glu Glu Thr Ile Asp Asn Gly Trp Leu Ser Ala Leu Gln Leu Glu Ala Ile Thr Tyr Ala Ala Gln Gln His Glu Thr Phe Leu Pro Asn Gly Asp Arg Ala Gly Phe Leu Ile Gly Asp G1y Ala Gly Val Gly Lys Gly Arg Thr Ile Ala G1y Ile Ile Tyr Glu Asn Tyr Leu Leu Ser Arg Lys Arg Ala Leu Trp Phe Ser Val Ser Asn Asp Leu Lys Tyr Asp Ala Glu Arg Asp Leu Arg Asp Ile Gly Ala Lys Asn Ile Leu Val His Ser Leu Asn Lys Phe Lys Tyr Gly Lys Ile Ser Ser Lys His Asn Gly Ser Val Lys Lys 305 , 310 315 320 Gly Val Ile Phe Ala Thr Tyr Ser Ser Leu Ile Gly Glu Ser Gln Ser Gly Gly Lys Tyr Lys Thr Arg Leu Lys Gln Leu Leu His Trp Cys Gly Asp Asp Phe Asp Gly Val Ile Val Phe Asp Glu Cys His Lys Ala Lys Asn Leu Cys Pro Val Gly Ser Ser Lys Pro Thr Lys Thr Gly Leu Ala Val Leu Glu Leu Gln Asn Lys Leu Pro Lys Ala Arg Val Val Tyr Ala Ser Ala Thr G1y Ala Ser Glu Pro Arg Asn Met Ala Tyr Met Asn Arg Leu Gly Ile Trp Gly Glu Gly Thr Pro Phe Arg Glu Phe Ser Asp Phe Ile Gln Ala Val Glu Arg Arg Gly Val Gly Ala Met Glu Ile Val Ala 435 ° 440 445 Met Asp Met Lys Leu Arg Gly Met Tyr Ile Ala Arg Gln Leu Sex Phe Thr Gly Val Thr Phe Lys Ile Glu Glu Val Leu Leu Ser Gln Ser Tyr Val Lys Met Tyr Asn Lys Ala Val Lys Leu Trp Va1 Ile Ala Arg Glu Arg Phe Gln Gln Ala Ala Asp Leu Ile Asp Ala Glu Gln Arg Met Lys Lys Ser Met Trp Gly Gln Phe Trp Ser Ala His Gln Arg Phe Phe Lys Tyr Leu Cys Ile Ala Ser Lys Val Lys Arg Val Val Gln Leu Ala Arg Glu Glu Ile Lys Asn Gly Lys Cys Val Val Ile Gly Leu Gln Ser Thr 545 ~ 550 555 560 Gly Glu Ala Arg Thr Leu Glu Ala Leu Glu Glu Gly Gly Gly Glu Leu Asn Asp Phe Val Ser Thr Ala Lys Gly Val Leu Gln Ser Leu Ile Glu Lys His Phe Pro Ala Pro Asp Arg Lys Lys Leu Tyr Ser Leu Leu Gly Ile Asp Leu Thr Ala Pro Ser Asn Asn Ser Ser Pro Arg Asp Ser Pro Cys Lys Glu Asn Lys Ile Lys Lys Arg Lys Gly Glu Glu Ile Thr Arg Glu Ala Lys Lys Ala Arg Lys Val Gly Gly Leu Thr Gly Ser Ser Ser Asp Asp Ser Gly Ser Glu Ser Asp Ala Sex Asp Asn Glu Glu Ser Asp Tyr Glu Ser Ser Lys Asn Met Ser Ser G1y Asp Asp Asp Asp Phe Asn Pro Phe Leu Asp Glu Ser Asn Glu Asp Asp Glu Asn Asp Pro Trp Leu Ile <210> 187 <211> 595 <212> PRT
<213> Homo sapien <400> 187 Glu Ser Pro Arg His Arg Gly Glu Gly Gly Gly Glu Trp G1y Pro Gly Val Pro Arg Glu Arg Arg Glu Ser Ala Gly Glu Trp Gly Ala Asp Thr Pro Lys Glu Gly Gly Glu Ser Ala Gly Glu Trp Gly Ala Glu Val Pro Arg Gly Arg Gly Glu Gly Ala Gly Glu Trp Gly Pro Asp Thr Pro Lys Glu Arg Gly Gln Gly Val Arg G1u Trp Gly Pro Glu Ile Pro Gln Glu His Gly Glu Ala Thr Arg Asp Trp Ala Leu Glu Ser Pro Arg A1a Leu Gly Glu Asp Ala Arg Glu Leu Gly Ser Ser Pro His Asp Arg Gly Ala . 100 105 110 Ser Pro Arg Asp Leu Ser Gly Glu Ser Pro Cys Thr Gln Arg Ser Gly Leu Leu Pro G1u Arg Arg Gly Asp Ser Pro Trp Pro Pro Trp Pro Ser Pro Gln Glu Arg Asp Ala Gly Thr Arg Asp Arg Glu Glu Ser Pro Arg Asp Trp Gly Gly Ala Glu Ser Pro Arg Gly Trp Glu A1a Gly Pro Arg Glu Trp Gly Pro Ser Pro Ser Gly His Gly Asp Gly Pro Arg Arg Arg Pro Arg Lys Arg Arg Gly Arg Lys Gly Arg Met Gly Arg Gln His Glu Ala A1a Ala Thr Ala Ala Thr A1a Ala Thr Ala Thr Gly Gly Thr Ala Glu Glu Ala Gly A1a Sex A1a Pro Glu Ser Gln Ala Gly Gly Gly Pro Arg Gly Arg Ala Arg Gly Pro Arg Gln Gln Gly Arg Arg Arg~His Gly Thr Gln Arg Arg Arg Gly Pro Pro Gln Ala Arg Glu Glu Gly Pro Arg Asp Ala Thr Thr Ile Leu Gly Leu Gly Thr Pro Ser Gly Glu Gln Arg Ala Asp Gln Ser Gln Ala Leu Pro Ala Leu Ala Gly Ala Ala Ala Ala His Ala His Ala Tle Pro Gly Ala Gly Pro Ala Ala Ala Pro Val G1y 305 ~ 310 315 320 Gly Arg Gly Arg Arg Gly Gly Trp Arg Gly G1y Arg Arg Gly Gly Ser Ala Gly Ala Gly Gly Gly Gly Arg Gly Gly Arg Gly Arg Gly Arg Gly Gly Gly Arg Gly Gly Gly Gly Ala Gly Arg Gly Gly Gly Ala Ala Gly.

Pro Arg Glu Gly Ala Ser Ser Pro Gly Ala Arg Arg Gly Glu Gln Arg Arg Arg Gly Arg Gly Pro Pro Ala Ala Gly Ala Ala Gln Val Ser Ala Arg Gly Arg Arg Ala Arg Gly Gln Arg Ala Gly Glu Glu Ala G1n Asp Gly Leu Leu Pro Arg Gly Arg Asp Arg Leu Pro Leu Arg Pro Gly Asp Ala Asn Gln Arg Ala Glu Arg Pro Gly Pro Pro Arg Gly G1y His Gly Pro Val Asn Ala Ser Ser Ala Pro Asp Thr Ser Pro Pro Arg His Pro Arg Arg Trp Val Ser Gln Gln Arg Gln Arg Leu Trp Arg G1n Phe Arg Val Gly Gly Gly Phe Pro Pro Pro Pro Pro Ser Arg Pro Pro Ala Val Leu Leu Pro Leu Leu Arg Leu Ala Cys Ala Gly Asp Pro Gly Ala Thr Arg Pro G1y Pro Arg Arg Pro Ala Arg Arg Pro Arg Gly Glu Leu Ile Pro Arg Arg Pro Asp Pro Ala Ala Pro Ser Glu Glu Gly Leu Arg Met Glu Ser Ser Val Asp Asp Gly Ala Thr Ala Thr Thr Ala Asp Ala Ala Sex Gly Glu Ala Pro Glu Ala Gly Pro Ser Pro Ser His Ser Pro Thr Met Cys Gln Thr Gly Gly Pro Gly Pro Pro Pro Pro Gln Pro Pro Arg Trp Leu Pro <210> 188 <211> 376 <212> PRT
<213> Homo sapien <400> 188 Glu Met Arg Lys Phe Asp Va1 Pro Ser Met Glu Ser Thr Leu Asn Gln Pro A1a Met Leu Glu Thr Leu Tyr Ser Asp Pro His Tyr Arg Ala His Phe Pro Asn Pro Arg Pro Asp Thr Asn Lys Asp Val Tyr Lys Val Leu 35 40 45 ' Pro Glu Ser Lys Lys Ala Pro Gly Ser Gly Ala Val Phe Glu Arg Asn Gly Pro His Ala Ser Ser Ser Gly Val Leu Pro Leu G1y Leu Gln Pro Ala Pro Gly Leu Ser Lys Ser Leu Ser Ser Gln Val Trp Gln Pro Ser Pro Asp Pro Trp His Pro Gly Glu G1n Ser Cys Glu Leu Ser Thr Cys Arg Gln Gln Leu Glu Leu Ile Arg Leu Gln Met Glu Gln Met Gln Leu Gln Asn Gly Ala Met Cys His His Pro A1a Ala Phe Ala Pro Leu Leu Pro Thr Leu Glu Pro Ala Gln Trp Leu Ser Ile Leu Asn Ser Asn Glu His Leu Leu Lys Glu Lys Glu Leu Leu Ile Asp Lys Gln Arg Lys His Ile Ser Gln Leu Glu Gln Lys Val Arg Glu Ser Glu Leu Gln Val His Ser Ala Leu Leu Gly Arg Pro Ala Pro Phe Gly Asp Va1 Cys Leu Leu Arg Leu Gln Glu Leu Gln Arg Glu Asn Thr Phe Leu Arg Ala Gln Phe Ala Gln Lys Thr Glu Ala Leu Ser Lys Glu Lys Met Glu Leu Glu Lys Lys Leu Ser Ala Ser Glu Val Glu Ile Gln Leu Ile Arg Glu Ser Leu Lys Val Thr Leu Gln Lys His Ser Glu G1u Gly Lys Lys Gln Glu Glu Arg Va1 Lys Gly Arg Asp Lys His Ile Asn Asn Leu Lys Lys Lys Cys Gln Lys Glu Ser Glu Gln Asn Arg Glu Lys Gln Gln Arg Ile Glu Thr Leu Glu Arg Tyr Leu Ala Asp Leu Pro Thr Leu Glu Asp His Gln Lys Gln Thr Glu Gln Leu Lys Asp Ala Glu Leu Lys Asn Thr Glu Leu Gln Glu Arg Val Ala Glu Leu Glu Thr Leu Leu Glu Asp Thr Gln Ala Thr Cys Arg Glu Lys Glu Va1 Gln Leu G1u Ser Leu Arg Gln Arg Glu Ala Asp Leu Ser Ser Ala Arg His Arg <210> 189 <211> 160 <212> PRT
<213> Homo sapien <400> 189 Met Leu Glu Ala His Arg Arg Gln Arg His Pro Phe Leu Leu Leu Gly Thr Thr Ala Asn Arg Thr Gln Ser Leu Asn Tyr Gly Cys Ile Va1 Glu Asn Pro Gln Thr His Glu Val Leu His Tyr Val Glu Lys Pro Ser Thr Phe Ile Ser Asp Ile Ile Asn Cys Gly Ile Tyr Leu Phe Ser Pro Glu Ala Leu Lys Pro Leu Arg Asp Val Phe Gln Arg Asn Gln Gln Asp Gly 65 70 . 75 80 G1n Leu Glu Asp Sex Pro Gly Leu Trp Pro Gly Ala Gly Thr Ile Arg Leu Glu Gln Asp Val Phe Ser Ala Leu Ala Gly Gln Gly Gln Ile Tyr Val His Leu Thr Asp Gly Ile'Trp Ser Gln I1e Lys Ser Ala Gly Ser Ala Leu Tyr Ala Ser Arg Leu Tyr Leu Ser Arg Tyr Gln Asp Thr His Pro Glu Arg Leu Ala Lys His Thr Pro Gly Gly Pro Trp T.le Arg Gly <210> 190 <211> 146 <212> PRT
<213> Homo sapien <400> 190 Met Asp Pro Arg Ala Ser Leu Leu Leu Leu Gly Asn Val Tyr Ile His Pro Thr Ala Lys Val Ala Pro Ser Ala Val Leu Gly Pro Asn Val Ser Tle Gly Lys Gly Val Thr Val Gly Glu Gly Val Arg Leu Arg Glu Ser Ile Val Leu His Gly Ala Thr Leu Gln Glu His Thr Cys Val Leu His Ser Ile Val Gly Trp Gly Ser Thr Val Gly Arg Trp Ala Arg Val Glu Gly Thr Pro Ser Asp Pro Asn Pro Asn Asp Pro Arg Ala Arg Met Asp Ser Glu Ser Leu Phe Lys Asp Gly Lys Leu Leu Pro Ala Ile Thr Ile Leu Gly Cys Arg Val Arg Ile Pro Ala GIu Val Leu Ile Leu Asn Ser Ile Va1 Leu Pro His Lys Glu Leu Ser Arg Ser Phe Thr Asn Gln Ile T1e Leu <210> 191 <221> 704 <212> PRT
<213> Homo sapien <400> 191 Glu Gly Gly Cys A1a Ala Gly Arg Gly Arg Glu Leu Glu Pro Glu Leu G1u Pro Gly Pro Gly Pro Gly Sex Ala Leu Glu Pro Gly Glu Glu Phe Glu I1e Val Asp Arg Ser Gln Leu Pro G1y Pro Gly Asp Leu Arg Ser Ala Thr Arg Pro Arg A1a Ala Glu Gly Trp Ser Ala Pro Ile Leu Thr Leu Ala Arg Arg Ala Thr Gly Asn Leu Ser Ala Ser Cys Gly Ser Ala Leu Arg Ala Ala Ala Gly Leu G1y G1y Gly Asp Ser Gly Asp Gly Thr Ala Arg Ala Ala Ser Lys Cys Gln Met Met Glu Glu Arg Ala Asn Leu Met His Met Met Lys Leu Ser Ile Lys Val Leu Leu Gln Ser A1a Leu Ser Leu Gly Arg Ser Leu Asp Ala Asp His Ala Pro Leu G1n Gln Phe Phe Val Val Met Glu His Cys Leu Lys His Gly Leu Lys Va1 Lys Lys Ser Phe Ile Gly Gln Asn Lys Ser Phe Phe Gly Pro Leu Glu Leu Val Glu Lys Leu Cys Pro Glu Ala Ser Asp Ile Ala Thr Ser Val Arg Asn Leu Pro Glu Leu Lys Thr Ala Val Gly Arg Gly Arg Ala Trp Leu Tyr Leu Ala Leu Met Gln Lys Lys Leu Ala Asp Tyr Leu Lys Val Leu Ile Asp Asn Lys His Leu Leu Ser Glu Phe Tyr G1u Pro Glu Ala Leu Met Met Glu Glu G1u Gly Met Val Ile Val Gly Leu Leu Val Gly Leu Asn Val Leu Asp Ala Asn Leu Cys Leu Lys Gly G1u Asp Leu Asp Ser Gln Val Gly Va1 Ile Asp Phe Ser Leu Tyr Leu Lys Asp Val Gln Asp Leu Asp Gly Gly Lys Glu His Glu Arg Ile Thr Asp Val Leu Asp Gln Lys Asn Tyr Val Glu Glu Leu Asn Arg His Leu Ser Cys Thr Val Gly Asp Leu Gln Thr Lys Ile Asp Gly Leu Glu Lys Thr Asn Ser Lys Leu Gln Glu Glu Leu Ser Ala Ala Thr Asp Arg Ile Cys Ser Leu Gln Glu Glu Gln Gln Gln Leu Arg Glu Gln Asn Glu Leu Ile Arg Glu Arg Ser Glu Lys Ser Val Glu Ile Thr Lys Gln Asp Thr Lys Val Glu Leu Glu Thr Tyr Lys Gln Thr Arg Gln Gly Leu Asp G1u Met Tyr Ser Asp Val Trp Lys Gln Leu Lys Glu Glu Lys Lys Val Arg Leu Glu Leu Glu Lys Glu Leu Glu Leu G1n Ile G1y Met Lys Thr Glu Met Glu Ile Ala Met Lys Leu Leu Glu Lys Asp Thr His G1u Lys Gln Asp Thr Leu Val Ala Leu Arg Gln Gln Leu Glu Glu Val Lys Ala Ile Asn Leu Gln Met Phe His Lys Ala Gln Asn Ala Glu Ser Ser Leu Gln Gln Lys Asn Glu Ala Ile Thr Ser Phe Glu Gly Lys Thr Asn Gln Val Met Ser Ser Met Lys G1n Met Glu Glu Arg Leu Gln His Ser Glu Arg Ala Arg Gln Gly Ala Glu Glu Arg Ser His Lys Leu Gln Gln G1u Leu Gly Gly Arg Tle Gly Ala Leu Gln Leu Gln Leu Ser Gln Leu His Glu,Gln Cys Ser Ser Leu Glu Lys G1u Leu Lys Ser Glu Lys Glu Gln Arg Gln Ala Leu Gln Arg Glu Leu Gln His Glu Lys Asp Thr Ser Ser Leu Leu Arg Met Glu Leu Gln Gln Val Glu Gly Leu Lys Lys Glu Leu Arg Glu Leu Gln Asp G1u Lys Ala Glu Leu Gln Lys Ile Cys Glu Glu Gln Glu Gln Ala Leu Gln Glu Met Gly Leu His Leu Ser Gln Ser Lys Leu Lys Met Glu Asp Ile Lys Glu Val Asn Gln Ala Leu Lys Gly His Ala Trp Leu Lys Asp Asp Glu Ala Thr His Cys Arg Gln Cys Glu Lys G1u Phe Ser Ile Ser Arg Arg Lys His His Cys Arg Asn Cys Gly His Ile Phe Cys Asn Thr Cys Ser Ser Asn Glu Leu Ala Leu Pro Ser Tyr Pro Lys Pro Va1 Arg Va1 Cys Asp Ser Cys His Thr Leu Leu Leu Gln Arg Cys Ser Ser Thr Ala Ser <210> 192 <211> 331 <212> PRT
<213> Homo sapien <400> 192 Arg Ala Gly A1a Ser Ala Met Ala Leu Arg Lys Glu Leu Leu Lys Ser Ile Trp Tyr Ala Phe Thr Ala Leu Asp Val G1u Lys Ser Gly Lys Val Ser Lys Ser Gln Leu Lys Val Leu Ser His Asn Leu Tyr Thr Val Leu His Ile Pro His Asp Pro Val Ala Leu Glu Glu His Phe Arg Asp Asp Asp Asp Gly Pro Val Ser Ser Gln Gly Tyr Met Pro Tyr Leu Asn Lys Tyr Ile Leu Asp Lys Val Glu Glu Gly Ala Phe Val Lys Glu His Phe Asp Glu Leu Cys Trp Thr Leu Thr Ala Lys Lys Asn Tyr Arg Ala Asp Ser Asn Gly Asn Ser Met Leu Ser Asn Gln Asp Ala Phe Arg Leu Trp Cys Leu Phe Asn Phe Leu Ser Glu Asp Lys Tyr Pro Leu Ile Met Val Pro Asp Glu Val Glu Tyr Leu Leu Lys Lys Val Leu Ser Ser Met Ser Leu Glu Val Ser Leu Gly Glu Leu Glu Glu Leu Leu Ala Gln Glu Ala 165 l70 175 Gln Val Ala Gln Thr Thr Gly Gly Leu Ser Va1 Trp Gln Phe Leu Glu Leu Phe Asn Ser G1y Arg Cys Leu Arg Gly Val Gly Arg Asp Thr Leu Ser Met Ala Ile His Glu Val Tyr Gln Glu Leu Ile Gln Asp Val Leu Lys Gln Gly Tyr Leu Trp Lys Arg Gly His Leu Arg Arg Asn Trp Ala Glu Arg Trp Phe Gln Leu Gln Pro Ser Cys Leu Cys Tyr Phe G1y Ser Glu Glu Cys Lys Glu Lys Arg Gly Tle Ile Pro Leu Asp Ala His Cys Cys Val Glu Val Leu Pro Asp Arg Asp Gly Lys Arg Cys Met Phe Cys Val Lys Thr Ala Thr Arg Thr Tyr Glu Met Ser Ala Ser Asp Thr Arg Gln Arg Gln Glu Trp Thr Ala Ala Ile Gln Met Ala I1e Arg Leu Gln Ala Glu Gly Lys Thr Ser Leu His Lys Asp Leu <210> 193 <211> 475 <212> PRT
<213> Homo sapien <400> 193 Lys Asn Ser Pro Leu Leu Ser Val Ser Ser Gln Thr Ile Thr Lys Glu Asn Asn Arg Asn Val His Leu Glu His Ser Glu Gln Asn Pro Gly Ser Ser Ala Gly Asp Thr Ser Ala Ala His Gln Val Val Leu Gly Glu Asn Leu Ile Ala Thr Ala Leu Cys Leu Ser Gly Ser Gly Ser Gln Ser Asp Leu Lys Asp Val Ala Ser Thr Ala Gly Glu Glu Gly Asp Thr Ser Leu Arg Glu Ser Leu His Pro Val Thr Arg Ser Leu Lys Ala Gly Cys His Thr Lys G1n Leu Ala Ser Arg Asn Cys Ser Glu Glu Lys Ser Pro G1n Thr Ser Ile Leu Lys Glu Gly Asn Arg Asp Thr Ser Leu Asp Phe Arg Pro Val Val Ser Pro Ala Asn Gly Val Glu Gly Val Arg Val Asp Gln Asp Asp Asp Gln Asp Ser Ser Ser Leu Lys Leu Ser Gln Asn I1e Ala Val Gln Thr Asp Phe Lys Thr Ala Asp Ser Glu Val Asn Thr Asp Gln Asp Ile G1u Lys Asn Leu Asp Lys Met Met Thr Glu Arg Thr Leu Leu Lys G1u Arg Tyr Gln Glu Val Leu Asp Lys Gln Arg Gln Val Glu Asn Gln Leu Gln Val G1n Leu Lys Gln Leu Gln Gln Arg Arg Glu Glu Glu Met Lys Asn His Gln Glu Ile Leu Lys Ala Ile Gln Asp Val Thr Ile Lys Arg Glu Glu Thr Lys Lys Lys Ile Glu Lys Glu Lys Lys Glu Phe Leu Gln Lys Glu Gln Asp Leu Lys Ala Glu Ile Glu Lys Leu Cys Glu Lys Gly Arg Arg Glu Val Trp Glu Met Glu Leu Asp Arg Leu Lys Asn Gln Asp Gly Glu Ile Asn Arg Asn Ile Met Glu Glu Thr Glu Arg Ala Trp Lys Ala Glu Ile Leu Ser Leu Glu Ser Arg Lys Glu Leu Leu Val Leu Lys Leu Glu Glu Ala Glu Lys G1u Ala Glu Leu His Leu Thr Tyr Leu Lys Ser Thr Pro Pro Thr Leu Glu Thr Val Arg Ser Lys Gln G1u Trp Glu Thr Arg Leu Asn Gly Val Arg Ile Met Lys Lys Asn Val Arg 355 360 ' 365 Asp Gln Phe Asn Sex His Ile Gln Leu Val Arg Asn Gly Ala Lys Leu 8~
Ser Ser Leu Pro Gln Ile Pro Thr Pro Thr Leu Pro Pro Pro Pro Ser Glu Thr Asp Phe Met Leu Gln Va1 Phe Gln Pro Ser Pro Ser Leu A1a Pro Arg Met Pro Phe Ser Ile Gly Gln Val Thr Met Pro Met Val Met Pro Ser Ala Asp Pro Arg Ser Leu Ser Phe Pro Ile Leu Asn Pro Ala Leu Ser G1n Pro Ser Gln Pro Ser Ser Pro Leu Pro Gly Ser His Gly Arg Asn Ser Pro Gly Leu Gly Ser Leu Val Ser <210> 194 <211> 241 <212> PRT
<213> Homo sapien <400> 194 Met Ser Gly Glu Ser A1a Arg Ser Leu Gly Lys Gly Ser Ala Pro Pro Gly Pro Val Pro Glu Gly Ser Ile Arg Ile Tyr Ser Met Arg Phe Cys Pro Phe Ala Glu Arg Thr Arg Leu Val Leu Lys Ala Lys Gly Ile Arg His Glu Val Ile Asn Ile Asn Leu Lys Asn Lys Pro Glu Trp Phe Phe Lys Lys Asn Pro Phe Gly Leu Va1 Pro Val Leu Glu Asn Ser Gln Gly Gln Leu Ile Tyr G1u Ser Ala Tle Thr Cys Glu Tyr Leu Asp Glu Ala Tyr Pro Gly Lys Lys Leu Leu Pro Asp Asp Pro Tyr Glu Lys Ala Cys l00 105 110 G1n Lys Met Ile Leu Glu Leu Phe Ser Lys Val Pro Ser Leu Val Gly Ser Phe Ile Arg Ser Gln Asn Lys Glu Asp Tyr Ala Gly Leu Lys G1u Glu Phe Arg Lys Glu Phe Thr Lys Leu Glu Glu Val Leu Thr Asn Lys Lys Thr Thr Phe Phe Gly Gly Asn Ser Ile Ser Met Ile Asp Tyr Leu Ile Trp Pro Trp Phe Glu Arg Leu Glu Ala Met Lys Leu Asn Glu Cys Val Asp His Thr Pro Lys Leu Lys Leu Trp Met Ala Ala Met Lys G1u Asp Pro Thr Val Ser Ala Leu Leu Thr Ser Glu Lys Asp Trp Gln Gly 210 215 , 220 Phe Leu Glu Leu Tyr Leu Gln Asn Ser Pro Glu Ala Cys Asp Tyr Gly Leu <210> 195 <21l> 138 <212> PRT
<213> Homo sapien <400> 195 Gln Thr Lys Ile Leu Glu Glu Asp Leu Glu Gln Ile Lys Leu Ser Leu Arg Glu Arg Gly Arg Glu Leu Thr Thr Gln Arg Gln Leu Met Gln Glu Arg A1a Glu Glu Gly Lys Gly Pro Ser Lys Ala Gln Arg Gly Ser Leu Glu His Met Lys Leu Ile Leu Arg Asp Lys Glu Lys Glu Val Glu Cys Gln Gln Glu His Ile His Glu Leu Gln Glu Leu Lys Asp Gln Leu Glu Gln Gln Leu Gln Gly Leu His Arg Lys Val Gly Glu Thr Ser Leu Leu Leu Ser Gln Arg Glu Gln Glu Ile Val Val Leu Gln Gln Gln Leu Gln Glu Ala Arg Glu Gln Gly Glu Leu Lys Glu Gln Ser Leu Gln Ser Gln Leu Asp Glu Ala Gln Arg Ala Leu Ala Gln <220> 196 <211> 102 <212> PRT
<213> Homo sapien <400> 196 Met Ser Lys Arg Lys A1a Pro Gln Glu Thr Leu Asn G1y Gly Ile Thr Asp Met Leu Thr Glu Leu Ala Asn Phe Glu Lys Asn Val Ser Gln Ala I1e His Lys Tyr Asn Ala Tyr Arg Lys Ala A1a Ser Val Ile Ala Lys Tyr Pro His Lys Ile Lys Ser Gly Ala Glu Ala Lys Lys Leu Pro Gly Val Gly Thr Lys Ile Ala GluiLys Ile Asp Glu Phe Leu Ala Thr Gly Lys Leu Arg Lys Leu Glu Lys Ile Arg Gln Asp Asp Thr Ser Sex Ser Ile Asn Phe Leu Thr Arg <210> 197 <211> 138 <212> PRT
<213> Homo sapien <400> 197 Glu Ala Asn Glu Val Thr Asp Ser Ala Tyr Met Gly Ser Glu Ser Thr Tyr Ser Glu Cys Glu Thr Phe Thr Asp Glu Asp Thr Ser Thr Leu Val His Pro Glu Leu Gln Pro Glu Gly Asp Ala Asp Ser Ala Gly Gly Ser Ala Val Pro Ser G1u Cys Leu Asp Ala Met Glu Glu Pro Asp His Gly Ala Leu Leu Leu Leu Pro Gly Arg Pro His Pro His Gly Gln Ser Val Ile Thr Val Ile Gly Gly Glu Glu His Phe Glu Asp Tyr Gly Glu Gly Ser Glu Ala Glu Leu Ser Pro Glu Thr Leu Cys Asn G1y G1n Leu Gly Cys Ser Asp Pro Ala Phe Leu Thr Pro Ser Pro Thr Lys Arg Leu Ser Ser Lys Lys Val Ala Arg Tyr Leu His Gln <210> 198 <211> 100 <212> PRT
<213> Homo sapien <400> 198 Met Gly Asp Val Lys Asn Phe Leu Tyr Ala Trp Cys Gly Lys Arg Lys Met Thr Pro Ser Tyr G1u I1e Arg Ala Val G1y Asn Lys Asn Arg G1n Lys Phe Met Cys Glu Val Gln Val Glu Gly Tyr Asn Tyr Thr Gly Met Gly Asn Ser Thr Asn Lys Lys Asp Ala Gln Ser Asn Ala Ala Arg Asp 50 ' 55 60 Phe Val Asn Tyr Leu Va1 Arg Ile Asn Glu Ile Lys Ser Glu Glu Val Pro Ala Phe Gly Val Ala Ser Pro Pro Pro Leu Thr Asp Thr Pro Asp Thr Thr Ala Asn <210> 199 <211> 127 <212> PRT
<213> Homo sapien <400> 199 Met Val Lys Glu Thr Thr Tyr Tyr Asp Val Leu Gly Val Lys Pro Asn Ala Thr G1n Glu Glu Leu Lys Lys Ala Tyr Arg Lys Leu Ala Leu Lys Tyr His Pro Asp Lys Asn Pro Asn Glu Gly Glu Lys Phe Lys Gln Ile Ser Gln Ala Tyr Glu Val Leu Ser Asp A1a Lys Lys Arg Glu Leu Tyr Asp Lys Gly Gly Glu Gln A1a Ile Lys Glu Gly Gly Ala Gly Gly Gly Phe Gly Sex Pro Met Asp Ile Phe Asp Met Phe Phe Gly Gly Gly Gly Arg Met Gln Arg Glu Arg Arg G1y Lys Asn Val Val His Gln Leu Sex Val Thr Leu Glu Asp Leu Tyr Asn G1y A1a Thr Arg Lys Leu Ala <210> 200 <211> 90 <212> PRT
<213> Homo sapien <400> 200 Met Ala Cys Pro Leu Asp Gln Ala Ile Gly Leu Leu Va1 Ala Ile Phe His Lys Tyr Ser Gly Arg Glu Gly Asp Lys His Thr Leu Ser Lys Lys G1u Leu Lys Glu Leu Ile Gln Lys Glu Leu Thr Ile Gly Ser Lys Leu Gln Asp Ala Glu Ile Ala Arg Leu Met Glu Asp Leu Asp Arg Asn Lys Asp Gln Glu Val Asn Phe Gln Glu Tyr Val Thr Phe Leu Gly Ala Leu Ala Leu Ile Tyr Asn Glu Ala Leu Lys Gly <210> 201 <211> 120 <212> PRT
<213> Homo sapien <400> 201 Met Glu Thr Pro Ser Gln Arg Arg Ala Thr Arg Ser Gly Ala Gln Ala Ser Ser Thr Pro Leu Ser Pro Thr Arg Ile Thr Arg Leu Gln Glu Lys Glu Asp Leu Gln Glu Leu Asn Asp Arg Leu Ala Val Tyr Ile Asp Arg Val Arg Ser Leu Glu Thr Glu Asn Ala Gly Leu Arg Leu Arg Ile Thr Glu Ser Glu Glu Val Val Ser Arg Glu Val Ser G1y Ile Lys Ala Ala Tyr Glu Ala Glu Leu Gly Asp Ala Arg Lys Thr Leu Asp Ser Val Ala Lys Glu Arg Ala Arg Leu Gln Leu Glu Leu Ser Lys Val Arg Glu Glu Phe Lys Glu Leu Lys Ala Arg Asn , <210> 202 <211> 177 <212> PRT
<213> Homo sapien <400> 202 Met A1a Ala Gly Val Glu Ala Ala Ala Glu Val Ala Ala Thr Glu Ile Lys Met Glu Glu G1u Ser Gly Ala Pro Gly Val Pro Ser Gly Asn Gly Ala Pro Gly Pro Lys Gly Glu G1y Glu Arg Pro Ala Gln Asn Glu Lys Arg Lys Glu Lys Asn Ile Lys Arg Gly Gly Asn Arg Phe Glu Pro Tyr Ala Asn Pro Thr Lys Arg Tyr Arg Ala Phe Ile Thr Asn I1e Pro Phe Asp Val Lys Trp G1n Ser Leu Lys Asp Leu Val Lys Glu Lys Val Gly Glu Val Thr Tyr Val Glu Leu Leu Met Asp Ala Glu Gly Lys Ser Arg 100 105 l10 Gly Cys Ala Val Val Glu Phe Lys Met Glu G1u Ser Met Lys Lys Ala 115 1.20 125 Ala Glu Val Leu Asn Lys His Ser Leu Ser G1y Arg Pro Leu Lys Val Lys G1u Asp Pro Asp Gly Glu His Ala Arg Arg Ala Met Gln Lys Ala Gly Arg Leu Gly Ser Thr Val Phe Val Ala Asn Leu Asp Tyr Lys Val Gly <210> 203 <211> 164 <212> PRT
<213> Homo sapien <400> 203 Met Arg Leu Ala Val Gly Ala Leu Leu Val Cys Ala Val Leu Gly Leu Cys Leu Ala Val Pro Asp Lys Thr Val Arg Trp Cys Ala Val Ser Glu His Glu Ala Thr Lys Cys Gln Ser Phe Arg Asp His Met Lys Ser Val Ile Pro Ser Asp Gly Pro Ser Val Ala Cys Val Lys Lys Ala Ser Tyr Leu Asp Cys Ile Arg Ala Ile Ala Ala Asn Glu Ala Asp Ala Val Thr Leu Asp Ala Gly Leu Val Tyr Asp Ala Tyr Leu Ala Pro Asn Asn Leu Lys Pro Val Val Ala Glu Phe Tyr Gly Ser Lys Glu Asp Pro Gln Thr Phe Tyr Tyr Ala Val Ala Val Val Lys Lys Asp Ser Gly Phe Gln Met 115 l20 125 Asn Gln Leu Arg Gly Lys Lys Ser Cys His Thr G1y Leu Gly Arg Ser Ala Gly Trp Asn Ile Pro Ile Gly Leu Leu Tyr Cys Asp Leu Pro Glu Pro Arg Lys Pro <210> 204 <211> 241 <212> PRT
<213> Homo sapien <400> 204 Met Ser Gly Glu Ser Ala Arg Ser Leu Gly Lys Gly Ser A1a Pro Pro Gly Pro VaI Pro Glu Gly Ser Ile Arg Ile Tyr Ser Met Arg Phe Cys Pro Phe Ala Glu Arg Thr Arg Leu Val Leu Lys A1a Lys Gly Ile Arg His Glu Val Ile Asn Ile Asn Leu Lys Asn Lys Pro Glu Trp Phe Phe Lys Lys Asn Pro Phe Gly Leu Val Pro Val Leu Glu Asn Ser Gln Gly Gln Leu Ile Tyr Glu Ser Ala Ile Thr Cys Glu Tyr Leu Asp Glu Ala Tyr Pro Gly Lys Lys Leu Leu Pro Asp Asp Pro Tyr Glu Lys Ala Cys Gln Lys Met Ile Leu Glu Leu Phe Ser Lys Val Pro Ser Leu Val Gly Ser Phe Ile Arg Ser Gln Asn Lys Glu Asp Tyr Asp Gly Leu Lys Glu Glu Phe Arg Lys G1u Phe Thr Lys Leu Glu Glu Val Leu Thr Asn Lys Lys Thr Thr Phe Phe Gly Gly Asn Ser Ile Ser Met Tle Asp Tyr Leu Tle Trp Pro Trp Phe Glu Arg Leu Glu Ala Met Lys Leu Asn Glu Cys Val Asp His Thr Pro Lys Leu Lys Leu Trp Met Ala Ala Met Lys Glu Asp Pro Thr Val Ser Ala Leu Leu Thr Ser Glu Lys Asp Trp Gln Gly Phe Leu Glu Leu Tyr Leu G1n Asn Ser Pro Glu Ala Cys Asp Tyr Gly Leu <210> 205 <21l> 160 <212> PRT
<213> Homo sapien <400> 205 Met G1n Tle Phe Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Tle Glu Asn Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pxo Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Sex Asp Tyr Asn Ile Gln Lys G1u Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly G1y Met Gln Tle Phe Va1 Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Tle Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly Met Gln Ile Phe Val Lys Thr Leu <210> 206 <211> 197 <212> PRT
<213> Homo sapien <400> 206 Thr Ser Pro Ser Glu Ala Cys Ala Pro Leu Leu Ile Ser Leu Ser Thr Leu Ile Tyr Asn Gly Ala Leu Pro Cys Gln Cys Asn Pro Gln Gly Ser Leu Ser Ser Glu Cys Asn Pro His Gly Gly Gln Cys Leu Cys hys Pro Gly Val Val Gly Arg Arg Cys Asp Leu Cys Ala Pro Gly Tyr Tyr Gly Phe Gly Pro Thr Gly Cys Gln Gly Ala Cys Leu Gly Cys Arg Asp His Thr Gly Gly Glu His Cys Glu Arg Cys Ile Ala Gly Phe His Gly Asp Pro Arg Leu Pro Tyr Gly Gly Gln Cys Arg Pro Cys Pro Cys Pro Glu Gly Pro Gly Ser Gln Arg His Phe Ala Thr Ser Cys His Gln Asp Glu Tyr Ser Gln Gln T1e Val Cys His Cys Arg A1a Gly Tyr Thr Gly Leu Arg Cys Glu Ala Cys Ala Pro Gly His Phe Gly Asp Pro Ser Arg Pro 145 150 155 l60 Gly Gly Arg Cys Gln Leu Cys Glu Cys Ser Gly Asn Ile Asp Pro Met Asp Pro Asp Ala Cys Asp Pro His Thr Gly Gln Cys Leu Arg Cys Leu His His Thr Glu Gly <210> 207 <211> 175 <212> PRT
<213> Homo sapien <400> 207 Ile Ile Arg Gln Gln Gly Leu Ala Ser Tyr Asp Tyr Val Arg Arg Arg l 5 20 15 Leu Thr Ala Glu Asp Leu Phe Glu Ala Arg Ile Tle Ser Leu Glu Thr Tyr Asn Leu Leu Arg Glu Gly Thr Arg Ser Leu Arg Glu Ala Leu Glu Ala Glu Ser Ala Trp Cys Tyr Leu Tyr Gly Thr Gly Ser Val Ala Gly Val Tyr Leu Pro Gly Ser Arg G1n Thr Leu Ser Tle Tyr G1n Ala Leu 65 70 75 $0 Lys Lys Gly Leu Leu Ser Ala Glu Val Ala Arg Leu Leu Leu Glu Ala G1n Ala Ala Thr Gly Phe Leu Leu Asp Pro Va1 Lys Gly Glu Arg Leu Thr Val Asp G1u Ala Val Arg Lys Gly Leu Val G1y Pro Glu Leu His 115 120 , 125 Asp Arg Leu Leu Ser Ala Glu Arg Ala Val Thr Gly Tyr Arg Asp Pro Tyr Thr Glu Gln Thr Ile Ser Leu Phe Gln Ala Met Lys Lys Glu Leu Ile Pro Thr Glu Glu Ala Leu Arg Leu Trp Met Pro Ser Trp Pro <210> 208 <211> 177 <212> PRT
<213> Homo sapien <400> 208 Met Ala Ala Gly Val Glu Ala Ala Ala Glu Val Ala Ala Thr Glu Ile Lys Met Glu Glu Glu Ser Gly Ala Pro Gly Val Pro Ser Gly Asn G1y Ala Pro Gly Pro Lys Gly Glu Gly Glu Arg Pro Ala Gln Asn Glu Lys Arg Lys Glu Lys Asn Ile Lys Arg Gly Gly Asn Arg Phe Glu Pro Tyr Ala Asn Pro Thr Lys Arg Tyr Arg Ala Phe Ile Thr Asn Ile Pro Phe Asp Val Lys Trp Gln Ser Leu Lys Asp Leu Val Lys Glu Lys Val Gly Glu Val Thr Tyr Val Glu Leu Leu Met Asp Ala Glu Gly Lys Ser Arg Gly Cys Ala Val Val Glu Phe Lys Met Glu Glu Sex Met Lys Lys Ala Ala Glu Val Leu Asn Lys His Ser Leu Ser Gly Arg Pro Leu Lys Val Lys Glu Asp Pro Asp Gly Glu His Ala Arg Arg Ala Met Gln Lys Val Met Ala Thr Thr Gly Gly Met Gly Met Gly Pro Gly Gly Pro Gly Met Ile <210> 209 <211> 196 <212> PRT
<213> Homo sapien <400> 209 Asp Leu Gln Asp Met Phe Tle Va1 His Thr Ile G1u G1u Ile Glu Gly Leu Ile Ser Ala His Asp Gln Phe Lys Ser Thr Leu Pro Asp Ala Asp Arg Glu Arg Glu Ala Ile Leu Ala Il~e His Lys Glu Ala Gln Arg Ile Ala Glu Ser Asn His Ile Lys Leu Ser Gly Ser Asn Pro Tyr Thr Thr Val Thr Pro Gln I1e Ile Asn Ser Lys Trp Glu Lys Val Gln Gln Leu Val Pro Lys Arg Asp His Ala Leu Leu Glu Glu Gln Ser Lys Gln Gln Ser Asn Glu His Leu Arg Arg Gln Phe Ala Ser Gln Ala Asn Val Val 100 105 ~ 110 Gly Pro Trp Ile Gln Thr Lys Met G1u Glu Ile Gly Arg I1e Ser Ile Glu Met Asn Gly Thr Leu Glu Asp Gln Leu Ser His Leu Lys Gln Tyr Glu Arg Ser Ile Val Asp Tyr Lys Pro Asn Leu Asp Leu Leu Glu Gln 145 7:50 155 160 Gln His Gln Leu Ile Gln Glu Ala Leu Ile Phe Asp Asn Lys His Thr Asn Tyr Thr Met Glu His Ile Arg Val Gly Trp Glu Gln Leu Leu Thr Thr Tle A1a Arg <210> 210 <211> 156 <212> PRT

<213> Homo sapien <400> 210 Lys Leu Thr Ile Glu Ser Thr Pro Phe Asn Val Ala Glu Gly Lys Glu Val Leu Leu Leu Ala His Asn Leu Pro Gln Asn Arg Ile Gly Tyr Ser Trp Tyr Lys Gly Glu Arg Val Asp Gly Asn Ser Leu Ile Va1 Gly Tyr Val Ile Gly Thr Gln Gln Ala Thr Pro Gly Pro Ala Tyr Ser Gly Arg Glu Thr Tle Tyr Pro Asn Ala Ser Leu Leu Ile Gln Asn Val Thr Gln Asn Asp Thr Gly Phe Tyr Thr Leu Gln Val Tle Lys Ser Asp Leu Val Asn Glu Glu Ala Thr Gly Gln Phe His Val Tyr Pro Glu Leu Pro Lys Pro Ser Tle Ser Ser Asn Asn Ser Asn Pro Val Glu Asp Lys Asp Ala Val Ala Phe Thr Cys Glu Pro Glu Val Gln Asn Thr Thr Tyr Leu Trp Trp Val Asn Gly Gln Ser Leu Pro Val Ser Pro Lys <210> 211 <211> 92 <212> PRT
<213> Homo sapien <400> 211 Met G1u Ser Pro Ser Ala Pro Pro His Arg Trp Cys Ile Pro Trp Gln Arg Leu Leu Leu Thr Ala Ser Leu Leu Thr Phe Trp Asn Pro Pro Thr Thr Ala Lys Leu Thr Ile Glu Ser Thr Pro Phe Asn Val Ala G1u Gly Lys Glu Va1 Leu Leu Leu Val His Asn Leu Pro Gln His Leu Phe Gly Tyr Ser Trp Tyr Lys Gly Glu Arg Val Asp Gly Asn Arg Gln Ile Ile Gly Tyr Val Ile Gly Thr Gln Gln Ala Thr Pro Gly <210> 212 <211> 142 <212> PRT
<213> Homo sapien <400> 212 Glu Lys Gln Lys Asn Lys Glu Phe Ser Gln Thr Leu Glu Asn Glu Lys Asn Thr Leu Leu Ser Gln Ile Ser Thr Lys Asp Gly Glu Leu Lys Met Leu Gln Glu Glu Val Thr Lys Met Asn Leu Leu Asn G1n Gln Ile G1n Glu Glu Leu Ser Arg Val Thr Lys Leu Lys Glu Thr Ala Glu Glu Glu Lys Asp Asp Leu Glu Glu Arg Leu Met Asn Gln Leu Ala Glu Leu Asn Gly Ser Ile Gly Asn Tyr Cys Gln Asp Val Thr Asp Ala Gln I1e Lys Asn Glu Leu Leu Glu Ser Glu Met Lys Asn Leu Lys Lys Cys Val Ser Glu Leu Glu Glu Glu Lys Gln Gln Leu Val Lys Glu Lys Thr Lys Val Glu Ser Glu Ile Arg Lys Glu Tyr Leu Glu Lys I1e Gln Gly <210> 213 <211> 142 <212> PRT
<213> Homo sapien <400> 213 Gly Gly Tyr G1y Gly Gly Tyr Gly Gly Val Leu Thr A1a Ser Asp Gly Leu Leu Ala G1y Asn Glu Lys Leu Thr Met Gln Asn Leu Asn Asp Arg Leu Ala Ser Tyr Leu Asp Lys Val Arg A1a Leu Glu A1a Ala Asn G1y Glu Leu Glu Val Lys Tle Arg Asp Trp Tyr Gln Lys Gln Gly Pro Gly Pro Ser Arg Asp Tyr Ser His Tyr Tyr Thr Thr Ile Gln Asp Leu Arg Asp Lys Ile Leu G1y Ala Thr Ile Glu Asn Ser Arg Ile Val Leu Gln Ile Asp Asn Ala Arg Leu Ala Ala Asp Asp Phe Arg Thr Lys Phe Glu Thr Glu Gln Ala Leu Arg Met Ser Val Glu Ala Asp I1e Asn Gly Leu Arg Arg Val Leu Asp Glu Leu Thr Leu Ala Arg Thr Asp Leu <210> 214 <211> 129 <212> PRT
<213> Homo sapien <400> 214 Val Met Arg Val Asp Phe Asn Val Pro Met Lys Asn Asn Gln Ile Thr Asn Asn Gln Arg Ile Lys Ala Ala Val Pro Ser I1e Lys Phe Cys Leu Asp Asn Gly Ala Lys Ser Val Val Leu Met Ser His Leu Gly Arg Pro Asp Gly Val Pro Met Pro Asp Lys Tyr Ser Leu Glu Pro Val Ala Val Glu Leu Arg Ser Leu Leu Gly Lys Asp Va1 Leu Phe Leu Lys Asp Cys Val Gly Pro Glu Val Glu Lys Ala Cys Ala Asn Pro Ala Ala Gly Ser Val Ile Leu Leu Glu Asn Leu Arg Phe His Val Glu Glu Glu Gly Lys Gly Lys Asp Ala Ser Gly Asn Lys Val Lys Ala Glu Pro Ala Lys Ile Glu <210> 215 <211> 148 <212> PRT
<213> Homo sapien <400> 215 Met Ala Thr Leu Lys Glu Lys Leu Ile Ala Pro Val Ala Glu Glu Glu Ala Thr Val Pro Asn Asn Lys Ile Thr Val Val Gly Val Gly Gln Val Gly Met Ala Cys Ala Iley Ser Ile Leu Gly Lys Ser Leu Ala Asp Glu Leu Ala Leu Val Asp Val Leu Glu Asp Lys Leu Lys Gly Glu Met Met Asp Leu Gln His Gly Ser Leu Phe Leu Gln Thr Pro Lys Ile Val Ala Asp Lys Asp Tyr Ser Val Thr Ala Asn Ser Lys Ile Val Val Val Thr Ala Gly Val Arg Gln G1n Glu Gly Glu Ser Arg Leu Asn Leu Val G1n Arg Asn Val Asn Val Phe Lys Phe Ile Ile Pro Gln Ile Val Lys Tyr Ser Pro Asp Cys Ile Ile Ile Val Val Ser Asn Pro Val Asp Ile Leu Thr Tyr Val Thr <210> 216 <211> 527 <212> PRT
<213> Homo sapien <400> 216 Gln Arg Ala Pro Gly Ile Glu Glu Lys Ala Ala Glu Asn Gly Ala Leu 1 5 10 l5 Gly Ser Pro Glu Arg Glu Glu Lys Val Leu Glu Asn Gly Glu Leu Thr Pro Pro Arg Arg Glu Glu Lys Ala Leu Glu Asn Gly Glu Leu Arg Ser Pro Glu Ala Gly Glu Lys Val Leu Val Asn Gly Gly Leu Thr Pro Pro Lys Ser Glu Asp Lys Val Ser Glu Asn Gly Gly Leu Arg Phe Pro Arg Asn Thr Glu Arg Pro Pro Glu Thr Gly Pro Trp Arg Ala Pro Gly Pro Trp G1u Lys Thr Pro Glu Ser Trp Gly Pro Ala Pro Thr Ile Gly Glu Pro A1a Pro Glu Thr Ser Leu G1u Arg Ala Pro Ala Pro Ser Ala Val Val Ser Ser Arg Asn Gly Gly Glu Thr Ala Pro Gly Pro Leu Gly Pro Ala Pro Lys Asn Gly Thr Leu Glu Pro Gly Thr Glu Arg Arg Ala Pro Glu Thr Gly Gly Ala Pro Arg Ala Pro Gly Ala Gly Arg Leu Asp Leu Gly Ser Gly Gly Arg Ala Pro Val Gly Thr G1y Thr Ala Pro Gly Gly Gly Pro Gly Ser Gly Val Asp Ala Lys Ala Gly Trp Val Asp Asn Thr Arg Pro Gln Pro Pro Pro Pro Pro Leu Pro Pro Pro Pro Glu Ala Gln Pro Arg Arg Leu Glu Pro Ala Pro Pro Arg Ala Arg Pro Glu Val Ala Pro Glu Gly Glu Pro Gly Ala Pro Asp Ser Arg Ala G1y Gly Asp Thr Ala Leu Ser Gly Asp Gly Asp Pro Pro Lys Pro Glu Arg Lys Gly Pro Glu Met Pro Arg Leu Phe Leu Asp Leu Gly Pro Pro Gln GIy Asn Ser Glu Gln Ile Lys Ala Arg Leu Ser Arg Leu Ser Leu Ala Leu Pro Pro Leu Thr Leu Thr Pro Phe Pro G1y Pro Gly Pro Arg Arg Pro Pro Trp GIu Gly Ala Asp Ala Gly Ala Ala Gly Gly Glu Ala Gly Gly Ala Gly Ala Pro Gly Pro Ala Glu Glu Asp G1y Glu Asp Glu Asp Glu Asp Glu Glu Glu Asp Glu Glu Ala Ala Ala Pro Gly Ala Ala Ala Gly Pro Arg Gly Pro G1y Arg Ala Arg Ala Ala Pro Val Pro Val Val Val Ser Ser Ala Asp Ala Asp Ala Ala Arg Pro Leu Arg Gly Leu Leu Lys Ser Pro Arg Gly Ala Asp Glu Pro Glu Asp Ser Glu Leu Glu Arg Lys Arg Lys 405 410 47.5 Met Val Ser Phe His Gly Asp Val Thr Val Tyr Leu Phe Asp Gln Glu Thr Pro Thr Asn Glu Leu Ser Val Gln Ala Pro Pro Glu Gly Asp Thr Asp Pro Ser Thr Pro Pro Ala Pro Pro Thr Pro Pro His Pro Ala Thr Pro Gly Asp Gly Phe Pro Ser Asn Asp Ser Gly Phe Gly Gly Ser Phe Glu Trp Ala Glu Asp Phe Pro Leu Leu Pro Pro Pro Gly Pro Pro Leu Cys Phe Ser Arg Phe Ser Val Ser Pro Ala Leu Glu Thr Pro Gly Pro Pro Ala Arg Ala Pro Asp Ala Arg Pro Ala Gly Pro Val Glu Asn <210> 217 <211> 466 <212> DNA
<213> Homo sapien <400> 217 gaatggtgcctgtcctgctgtctctgctgctgcttctgggtcctgctgtcccccaggaga 60 accaagatggtcgttactctctgacctatatctacactgggctgtccaagcatgttgaag 120 acgtccccgcgtttcaggcccttggctcactcaatgacctccagttctttagatacaaca 180 gtaaagacaggaagtctcagcccatgggactctggagacaggtggaaggaatggaggatt 240 ggaagcaggacagccaacttcagaaggccagggaggacatctttatggagaccctgaaag 300 acatcgtggagtattacaacgacagtaacgggtctcacgtattgcagggaaggtttggtt 360 gtgagatcgagaataacagaagcagcggagcattctggaaatattactatgatggaaagg 420 actacattgaattcaacaaagaaatcccagcctgggtccccttcga 466 <210> 218 <211> 381 <212> DNA
<213> Homo sapien <400>

gagtttccttcgcaagttcatgtggggtaccttcccaggctgcctggctgaccagctggt 60 tttaaagcgccggggtaaccagttggagatctgtgccgtggtcctgaggcagttgtctcc 120 acacaagtactacttcctcgtgggctacagtgaaactttgctgtcctacttttacaaatg 180 tcctgtgcgactccacctccaaactgtgccctcaaaggttgtgtataagtacctctagaa 240 caatccccttttttccatcaagctgtagcctgcagagaatggaaacgtgggaaaggaatg 300 gtatgtgggggaaatgcatcccctcagaggactgaggcatagtctctcatctgctattga 360 ataaagaccttctatcttgta 381 <210> 219 <21I> 1293 <212> DNA
<213> Homo sapien <400> 219 gaggggaggcgcatggcggggatggcgctggcgcgggcctggaagcagatgtcctggttc60 tactaccagtacctgctggtcacggcgctctacatgctggagccctgggagcggacggtg120 ttcaattccatgctggtttccattgtggggatggcactatacacaggatacgtcttcatg180 ccccagcacatcatggcgatattgcactactttgaaatcgtacaatgaccaagatgcgac240 caggatcagaggttccttggggaagacccaccctacgaagttggaatgagaccatcagat300 gtgataagaaactcttctagatgtcaacataaccaaccttataaagactaaaattcatga360 gtagaacaggaaaatcatcctgactcatgtgttgtgttctttatttttaattttcaaaga420 ggctcttgtatagcagtttttgtctattttaacattgtagtcatttgtactttgatatca480 gtattttcttaacctttgtgactgtttcaatattacccccgtgaaagcttttcttaatgt540 aactttgagtacattttaattgccttctatttttaaaactcaaaatcattagttgggctt600 tactgttcttgctattgtatggcatatacatctgcctggatatatttctactcttgacca660 aagttttgtaaagaacaatataagatttcgggtaggggtatggggagggaagatatttta720 ttgagaactacttaacaaaagatttatctgtaagcttgaactcaggagtacagttttagc780 tatctagactctaacagcttttgctttaaaattattaaagtgtttcttaatgaaaaagaa840 aagatcttgctaaagttaaaataaggaacatttCaccttttaaatatttaattcttatgt900 ggacttatttccagaaaactttggtgataattcttgagacaaaaggtggttaagtagcat960 tattatgtaatgcttatataccatagagtttttaatagaagagaaatccatttcctccga1020 gggtcactattaacaatgtacttccttaaatttagtttaatgattgtaatgggtgctgca1080 tttgcacattgcattaagttatgatgagacgaattgttgttaaaaattatagcaaaaaga1140 aatgtaaacttggttaaaatcctttcactctttgtattgttttttttaaggtttttattc1200 cttaaatgtaaaatgactacctaattttttgatgtaaatacattaaattcaaagagaaaa1260 aaaatcaaaaaaaaaaaaaaaaaaaaactcgag 1293 <210> 220 <211> 983 <212> DNA
<213> Homo sapien <400> 220 caggttattctgatcctgccgcctgtcttccctgtaagagtggagcctcgaggtgtacct 60 taaagtgaccggaatgttagagatgcaatttgcagagctggggcaaggaagggctccttg 120 tcactgtagttactttccttgcagtggccaaatgcccaataagaaggaatacatgaccac 180 tgctgtggggagtcagcaggtgcgtgatgcagctggccacactccatccacggccatgac 240 ataaaacagacaagaagtaaggctggactgtaacacctcaaggcctgctccagtgaccca 300 ctttcttcagagaggctctaccacacacacaaccaccttccaaatttacactcagatcac 360 tacaccatgtctcccaagttaaaacatgtatccacctagactttaaatgtgctttgtaac 420 tgttgatggcactgtacagagggccaaagtatttcccatcagatagcatttttctgaacc 480 1~~
catgcctcttgggacgagatcacaggacttgacccatcatcaaataggaccaggtgacct 540 acagagacatcacaatgatggcttcctacagtcaagtccatttccaataatgctctcatc 600 taagagaacccatgaaccttatttgaatcctggttcaaacaaaaaccttaaattatttat 660 gagacaattataaacttgatagattttgatgtgtgaaggtatttatgaatatttttagtc 720 agtgatggtatactgttaaggaaaaggttcatattttagggacaaaggctgaaacattta 780 tggacagagtgatatgatatctgggatttgttttaggatgaagtgggagggaggaaatga 840 atggaaatagtgttgaaacagtattggccacgagtcagctattgtgtgctaagacgctcc 900 tcacaccagtctactctgtatgtgtttgaatatctctgtaataaacttaacaaggaaaaa 960 aaaaaaaaaaaaaaaaactcgag 983 <210> 221 <211> 373 <2l2> DNA
<213> Homo sapien <400> 221 cattttatgggttaattttttattaaatagcaataagatacttttataactcaataaaat 60 tattcaatgatacattcggaaaataaatgtataaaatatgaaaaagtactaaaaagcatt 120 tttcagtacttttaggtaagattaatccaactaaacactagcatatgttatacagtaata 180 ataaggggaaaatacaataatgttgagaaagcaaactcaaagcatagatcaatgaaaaaa 240 ttgagaaatggacataaatgatttagtatttttaaagagagtgaaaaatcattattttat 300 gcttttgtgtagcgttagatgaattaaataacatatgcacatatagctttgcgatacaaa 360 tttccagaccata 373 <210> 222 <211> 544 <212> DNA
<213> Homo sapien <400> 222 cagagatgctgctgctacaaaggatcggtgtaagcagttaacccaggaaatgatgacaga 60 gaaagaaagaagcaatgtggttataacaaggatgaaagatcgaattggaacattagaaaa 120 ggaacataatgtatttcaaaacaaaatacatgtcagttatcaagagactcaacagatgca 180 gatgaagtttcagcaagttcgtgagcagatggaggcagagatagctcacttgaagcagga 240 aaatggtatactgagagatgcagtcagcaacactacaaatcaactggaaagcaagcagtc 300 tgcagaactaaataaactacgccaggattatgctaggttggtgaatgagctgactgagaa 360 aacaggaaagctacagcaagaggaagtccaaaagaagaatgctgagcaagcagctactca 420 gttgaaggttcaactacaagaagctgagagaaggtgggaagaagttcagagctacatcag 480 gaagagaacagcggaacatgaggcagcacagctagatttacagagtaaatttgtggccaa 540 agaa 544 <210> 223 .
<211> 316 <212> DNA
<213> Homo sapien <400> 223 gaggcaagggatatgctttagtgcctattatagttaattcttcaactccaaagtctaaaa 60 cagttgaatctgctgaaggaaaatctgaagaagtaaatgaaacattagttatacccactg 120 aggaagcagaaatggaagaaagtggacgaagtgcaactcctgttaactgtgaacagcctg 180 atatcttggtttcttctacaccaataaatgaaggacagactgtgttagacaaggtggctg 240 agcagtgtgaacctgctgaaagtcagccagaagcacttctgagaggaagatgtttgcaag 300 gtaactctaacagttg 316 <210> 224 <211> 1583 <212> DNA
<213> Homo sapien <400> 224 cagaccacgtctgccctcgccgctctagccctgcgccccagcccggccgcggcacctccg 60 cctcgccgccgctaggtcggccggctccgcccggctgccgcctaggatgaatatcatgga 120 cttcaacgtgaagaagctggcggccgacgcaggcaccttcctcagtcgcgccgtgcagtt 180 cacagaagaaaagcttggccaggctgagaagacagaattggatgctcacttagagaacct 240 ccttagcaaagctgaatgtaccaaaatatggacagaaaaaataatgaaacaaactgaagt 300 gttattgcagccaaatccaaatgccaggatagaagaatttgtttatgagaaactggatag 360 aaaagctccaagtcgtataaacaacccagaacttttgggacaatatatgattgatgcagg 420 gactgagtttggcccaggaacagcttatggtaatgcccttattaaatgtggagaaaccca 480 aaaaagaattggaacagcagacagagaactgattcaaacgtcagccttaaattttcttac 540 tcctttaagaaactttatagaaggagattacaaaacaattgctaaagaaaggaaactatt 600 gcaaaataagagactggatttggatgctgcaaaaacgagactaaaaaaggcaaaagctgc 660 agaaactagaaattcatctgaacaggaattaagaataactcaaagtgaatttgatcgtca 720 agcagagattaccagacttctgctagagggaatcagcagtacacatgcccatcaccttcg 780 ctgtctgaatgactttgtagaagcccagatgacttactatgcacagtgttaccagtatat 840 gttggacctccagaaacaactgggaagttttccatccaattatcttagtaacaacaatca 900 gacttctgtgacacctgtaccatcagttttaccaaatgcgattggttcttctgccatggc 960 ttcaacaagtggcctagtaatcacctctccttccaacctcagtgaccttaaggagtgtag 1020 tggcagcagaaaggccagggttctctatgattatgatgcagcaaacagtactgaattatc 1080 acttctggcagatgaggtgatcactgtgttcagtgttgttggaatggattcagactggct 1240 aatgggggaaaggggaaaccagaagggcaaggtgccaattacctacttagaactgctcaa 1200 ttaagtaggtggactatggaaaggttgcccatcatgactttgtatttatatacaattaac 1260 tctaaataaagcaggttaagtatcttccatgttaatgtgttaagagactgaaaataccag 1320 ccatcagaaactggcctttttgccaataaagttgcatggtaaatatttcattacagaatt 1380 tatgttagagctttcatgccaagaatgttttcttacaaaattctctttttattgaggttt 1440 cactaataagcagcttctacttttgagcctcaacttaaagcagaactgttttttactgga 1500 tttttcattaacagcaagcttttttttttatgtaaaataaatctattgtgaattgaaaaa 1560 aaaaaaaaaaaaaaaaactcgag 1583 <210> 225 <211> 491 <212> DNA
<213> Homo sapien <400>

gaacaacatcatcttgaatcactagatagactcttgacggaaagcaaaggggaaatgaaa 60 aaggaaaatatgaagaaagatgaagctttaaaagcattacagaaccaagtatctgaagaa 120 acaatcaaggttaggcaactagattcagcattggaaatttgtaaggaagaacttgtcttg 180 catttgaatcaattggaaggaaataaggaaaagtttgaaaaacagttaaagaagaaatct 240 gaagaggtatattgtttacagaaagagctaaagataaaaaatcacagtcttcaagagact 300 tctgagcaaaacgttattctacagcatactcttcagcaacagcagcaaatgttacaacaa 360 gagacaattagaaatggagagctagaagatactcaaactaaacttgaaaaacaggtgtca 420 aaactggaacaagaacttcaaaaacaaagggaaagttcagctgaaaagttgagaaaaatg 480 gaggagaaatg 491 <210> 226 <211> 483 <212> DNA
<213> Homo sapien <400> 226 cagccgcacgccgcggagcaggggctcggaggtcccgggattacggtgctcgagcacgct 60 ggtgggaaaggacccgggacttgaacagtgttgtgcggcgccatgcaggtctccagcctc 120 aatgaggtgaagatttacagcctcagctgcggcaagtcccttcctgagtggctttctgat 180 aggaagaagagagcgctacagaagaaagatgtagatgtccgtaggagaattgaacttatt 240 caggactttgaaatgcctactgtgtgtaccactattaaggtgtcaaaagatggacagtac 300 attttagcaactggaacatataaacctcgggttcgatgttatgacacctatcaattatcc 360 ttgaagtttg aaaggtgttt agattcagaa gttgtcacct ttgaaatttt gtctgatgac 420 tactcaaaga ttgtcttctt acataatgat agatacattg aatttcattc gcaatcaggt 480 ttt 483 <210> 227 <2l1> 486 <212> DNA
<213> Homo sapien <400> 227 gagcctcgctaagctccgactctgggcggcaccgggcgtcccacgatgccgaagaacaag 60 aagcggaacactccccaccgcggtagcagtgctggcggcggcgggtcaggagcagccgca 120 gcgacggcggcgacagcaggtggccagcatcgaaatgttcagccttttagtgatgaagat 180 gcatcaattgaaacagtgagccattgcagtggttatagcgatccttccagttttgctgaa 240 gatggaccagaagtccttgatgaggaaggaaetcaagaagacctagagtacaagttgaag 300 ggattaattgacctaaccctggataagagtgcgaagacaaggcaagcagctcttgaaggt 360 attaaaaatgcactggcttcaaaaatgctgtatgaatttattctggaaaggagaatgact 420 ttaactgatagcattgaacgctgcctgaaaaaaggtaagagtgatgagcaacgtgcagct 480 gcagcg 486 <210> 228 <211> 494 <212> DNA
<213> Homo sapien <400> 228 gaggccaggactccgggaatgcgagcaggccccttattctcccagtggcctcggtctgtc 60 cccacagcggcccggtcagggttgcccgagccccaaggcggggggcggcaccggggtgct 120 gaaagggacagaatgctttgacctccaagctgttttaaatctagtagataagccagatcc 180 tgtgttgccataagcccttggcccacatttaagtgggaatgcagctagcttggatgtctg 240 aaactttgtaagcgccttctgtctgaatcctgaacacaggcaccaagactactgaagaag 300 ctcgtcattcttgtgcagggatagccacacaagcaaacatgtttgcaaaacttgaaagaa 360 agaaaattgcagaaagaagacttgctgttcttaagaggcccaggaaggtgctacttagga 420 atcccaccggcttgtgaagcaagggaatcaagtttgccttcaatggggaacttgacttca 480 ggaaaatgaacttt 494 <210> 229 <211> 465 <212> DNA
<213> Homo sapien <400> 229 gtcagagagctggtataacctcctgttggacatgcagaaccgactcaataaggtcatcaa 60 aagcgtgggcaagattgagcactccttctggagatcctttcacactgagcgaaagacaga 120 accagccacaggcttcatcgatggtgatctgattgaaagtttcctagatatcagccgccc 180 taagatgcaggaggttgtggcaaacttgcagtatgatgatggcagtggtatgaagcggga 240 ggcaactgcagatgacctcatcaaagtcgtggaggaactaactcggatccattagccaag 300 gacaggatctcttttcctgaccctcctaaaggcgttgccctcctatcctcccttccttgc 360 ccacccttggtttctttggcatgggaaggttttccttaaccacttgccctagagccacca 420 gtgaccttgtgtggaaacagggttttttttacttaaaacagttCa 465 <210> 230 <211> 495 <212> DNA
<213> Homo sapien <400> 230 caggggaaag ggtgtttggc cttgaccagc cactgctgac ctcaatctca gacctacaga 60 tggtgaatatctccctgcgagtgttgtctcgacccaatgctcaggagcttcctagcatgt 120 accagcgcctagggctggactacgaggaacgagtgttgccgtccattgtcaacgaggtgc 180 tcaagagtgtggtggccaagttcaatgcctcacagctgatcacccagcgggcccaggtat 240 ccctgttgatccgccgggagctgacagaaagggccaaaggacttcagcctcatcctggat 300 gatgtggccatcacagacttgagctttagccgagaagtacacaagctgcctgtaagaaac 360 ccaaccaagtggggtgaattccaaaaacccgtgggggtgaagggcttcttaagaatgcaa 420 ggaaggaggaaaagaattccatggggggggggttccttaacccaggaacaggggtttccc 480 ttgaatttttttcca 495 <210> 231 <211> 498 <212> DNA
<213> Homo sapien <400>

ggcagcttctgagaccagggttgctccgtccgtgctccgcctcgccatgacttcctacag 60 ctatcgccagtcgtcggccacgtcgtccttcggaggcctgggcggcggctccgtgcgttt 120 tgggccgggggtcgcttttcgcgcgcccagcattcacgggggctccggcggccgcggcgt 180 atccgtgtcctccgcccgctttgtgtcctcgtcctcctcggggggctacggcggcggcta 240 cggcggcgtcctgaccgcgtccgacgggctgctggcgggcaacgagaagctaaccatgca 300 gaacctcaacgaccgcctgcctcCtacctggacaaagtgcgcgccctggaagcgggcaac 360 ggcgaacttagaggtgaaagaatcccgcgaactggtaccaaaaacaaggggcctggggcc 420 ttccgcgacttacagccaacttactacaccgaacattcaagaacttgcgggaacaaaaat 480 ttttggtgccacccattt 498 <210> 232 <211> 465 <212> DNA
<213> Homo sapien <400> 232 caggccggccgagtaggaaagctggaggcgcgggtggggaacatgtctgagtcggagctc 60 ggcaggaagtgggaccggtgtctggcggatgcggtcgtgaagataggtactggttttgga 120 ttaggaattgttttctcacttaccttctttaaaagaagaatgtggccattagccttcggt 180 tctggcatgggattaggaatggcttattccaactgtcagcatgatttccaggctccatat 240 cttctacatggaaaatatgtcaaagagcaggagcagtgacttcacctgagaacatcccag 300 cgggaggacaagagaaaatcatgtttattcctcaggaatacttgaagtgccctggagtaa 360 actgccattcttctgtaacaatggtatcagtaatgctttaaactccagcacctggttatg 420 catttgaaacccaagtctggttcttggtttggattttctctctgg 465 <2I0> 233 <211> 366 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1). .(366) <223> n = A,T,C or G
<400>

cagtaaaaaaggttatgttttattaattgctggacaaccgtgggaaaacaaataagcaat 60 tgacaccaccaaattcttat,tacattcaanataaaanatttattcacaccacaaaaagat 120 aatcacaacaaaatatacactaacttaaaaaacaaaagattatagtgacataaaatgtta 180 tattctctttttaagtgggtaaaagtattttgtttgcttctacataaatttctattcatg 240 ananaataacaaatattaaaatacagtgatagtttgcatttcttctatagaatgaacata 300 gacataaccctgaagcttttagtttacagggagtttccatgaagccacaaactaaactaa 360 ttatca 366 <210> 234 <211> 379 <2l2> DNA
<213> Homo sapien <400> 234 gagggcagccctcctacctgcgcacgtggtgccgccgctgctgcctcccgctcgccctga 60 acccagtgcctgcagccatggctcccggccagctcgccttatttagtgtctctgacaaaa 120 ccggccttgtggaatttgcaagaaacctgaccgctcttggtttgaatctggtcgcttccg 180 gagggactgcaaaagctctcagggatgctggtctggcagtcacagatgtctctgagttga 240 cgggatttctgaaatgttggggggacgtgtgaaaactttgcatcctgcacgatcccatgc 300 tggaatcctagctcctaatattcagaagataatgcttgacatgcgccacacttgattcaa ,360 tcttataacaattgttgcc 379 <210> 235 <211> 406 <212> DNA
<213> Homo sapien <400> 235 caggctgcaccatgtaccccaccttcagtttaaaagaaaaaaaaaatccccttcactcct 60 actgggaggtgggacccctttcattttcagttttgctcatctagggaaaataaggctttg 120 gtttccagtttaattgtttttgaccttctaaaatgtttttatgttagcactgatagttgg 180 cattactgttgttaagcactgtgttccagaccgtgtctgacttagtgtaacctaggagat 240 tttatagttttattttaatgaaaccctgattgacgcacagcagtggggagaacagcgtct 300 tttacctgtcaccgaagccaggaagccccgtttgtaagcgtgtgttgtggtgctttattg 360 tacatcctccagtggcgttctttttactctaatgttcttttggttt 406 <210> 236 <211> 278 <212> DNA
<213> Homo sapien <400> 236 gagattagcacctgtgaacaatgcgttctctgatgacactctgagcatggaccaacgcct 60 tcttaagctaattctgcaaaatcacatattgaaagtaaaagttggccttagcgacctcta 120 caatggacagatactggaaaccattggaggcaaacaactccgagtctttgtgtatcggac 180 ggctatctgcatagaaaactcatgcatggtgagaggaagcaagcagggaaggaacggtgc 240 cattcacatattccgagagatcatccaaccagcagaat 278 <210> 237 <211> 322 <212> DNA
<213> Homo sapien <400> 237 cagggccgtggcggaggaggagcgctgcacggtggagcgtcgggccgacctcacctacgc 60 ggagttcgtgcagcagtacgtgcgcccctgatcgcggaggtcgcgtcctgttcaccggcc 120 cgtctgccccgaccgcccaaggccgccttcccctgacctcgcgcgcacgcgtggggctgg 180 ggcggcgaggctggcggtccggcctggccgcgactctgcccttctttccagaggttccgg 240 gccctgtgctcccgcgacaggttgctggcttcgtttggggacagagtggtccggtgagca 300 ccgccaacacctactcctacct 322 <210> 238 <211> 613 <212> DNA

<213> Homo sapiens <220>
<221> misc_feature <222> (399) <223> n=A,T,C or G
<400> 238 gaattcggca ccagccttct tggatcagga ccagt ctcca ccccgtttct acagtggaga 60 tcagcctcct tcttatcttg gtgcaagtgt ggataaactc catcaccctt tagaatttgc 120 agacaaatct cccacacctc ctaatttacc tagcgataaa atctaccctc cttctgggtc 180 ccccgaagag aataccagca cagccaccat gacttacatg acaactactc cagcaacagc 240 ccaaatgagc accaaggaag ccagctggga tgtggctgaa caacccacca ctgctgattt 300 tgctgctgcc acacttcagc gcacgcacag aactaatcgt ccccttcccc ctccgccttc 360 ccagagatct gcagagcagc caccagttgt ggggcaggna caagcagcaa ccaatatagg 420 attaaataat tcccacaagg ttcaaggagt agttccagtt ccagagaggc cacctgaacc 480 tcgagccatg gatgaccctg cgtctgcctt catcagtgac agtggtgctg ctgctgctca 540 gtgtcccatg gctacagctg tccagccagg cctgcctgag aaagtgcggg acggtgcccg 600 ggtcccgctg ctg <210> 239 <211> 613 <212> DNA
<213> Homo Sapiens <400> 239 gaattcggca ccaggggaca ctggtgctga gctggatgat gatcagcact ggtctgacag 60 cccgtcggat gctgacagag agctgcgttt gccgtgccca gctgaggggg aagcagagct 120 ggagctgagg gtgtcggaag atgaggagaa gctgcccgcc tcaccgaagc accaagagag 180 aggtccctcc caagccacca gccccatccg gtctccccag gaatcagctc ttctgttcat 240 tCCagtCCaC dgCCCCtCaa CagaggggCC ccaactccca cctgtccctg CCgCCdCCCa 300 ggagaaatca cctgaggagc gccttttccc tgagcctttg ctccccaaag agaagcccaa 360 agctgatgcc ccctcggatc tgaaagctgt gcactctccc atccgatcac agccagtgac 420 cctgccagaa gctaggactc ctgtctcacc agggagcccg cagccccagc cacccgtggc 480 ggcctccacg cccccacc~a gcgaggtctc cagagccttc tctctcctgt gcaaaatggc 540 aactcttaag gaaaaactca ttgcaccagt tgcggaagaa gaggcaacag ttccaaacaa 600 taagatcact gta 613 <210> 240 <211> 585 <212> DNA
<213> Homo Sapiens <400> 240 gaattcggca cgaggtgaga tctacgatga actttaagat tggaggtgtg acagaacgca 60 tgccaacccc agttattaaa gcttttggca tcttgaagcg agcggccgct gaagtaaacc 120 aggattatgg tcttgatcca aagattgcta atgcaataat gaaggcagca gatgaggtag 180 ctgaaggtaa attaaatgat cattttcctc tcgtggtatg gcagactgga tcaggaactc 240 agacaaatat gaatgtaaat gaagtcatta gcaatagagc aattgaaatg ttaggaggtg 300 aacttggcag caagatacct gtgcatccca acgatcatgt taataaaagc cagagctcaa 360 atgatacttt tcccacagca atgcacattg ctgctgcaat agaagttcat gaagtactgt 420 taccaggact acagaagtta catgatgctc ttgatgcaaa atccaaagag tttgcacaga 480 tcatcaagat tggacgtact catactcagg atgctgttcc acttactctt gggcaggaat 540 ttagtggtta tgttcaacaa gtaaaatatg caatgacaag aataa 585 <210> 241 <2l1> 566 <212> DNA

<213> Homo Sapiens <400> 241 gaattcggca ccaggcgagc tgcacctcga ggtgaaggcc tcactgatga acgatgactt 60 cgagaagatc aagaactggc agaaggaagc ctttcacaag cagatgatgg gcggcttcaa 120 ggagaccaag gaagctgagg acggctttcg gaaggcacag aagccctggg ccaagaagct 180 gaaagaggta gaagcagcaa agaaagccca ccatgcagcg tgcaaagagg agaagctggc 240 tatctcacga gaagccaaca gcaaggcaga cccatccctc aaccctgaac agctcaagaa 300 attgcaagac aaaatagaaa agtgcaagca agatgttctt aagaccaaag agaagtatga 360 gaagtccctg aaggaactcg accagggcac accccagtac atggagaaca tggagcaggt 420 gtttgagcag tgccagcagt tcgaggagaa acgccttcgc ttcttccggg aggttctgct 9$0 ggaggttcag aagcacctag acctgtccaa tgtggctggc tacaaagcca tttaccatga 540 cctggagcag agcatcagag cagctg 566 <210> 242 <211> 556 <212> DNA
<213> Homo Sapiens <400> 242 gaattcggca cgagcaaagg tgaagcagga catgcctccg cccgggggct atgggcccat 60 cgactacaaa cggaacttgc cgcgtcgagg actgtcgggc tacagcatgc tggccatagg 120 gattggaacc ctgatctacg ggcactggag cataatgaag tggaaccgtg agcgcaggcg 180 cctacaaatc gaggacttcg aggctcgcat cgcgctgttg ccactgttac aggcagaaac 240 cgaccggagg accttgcaga tgcttcggga gaacctggag gaggaggcca tcatcatgaa 300 ggacgtgccc gactggaagg tgggggagtc tgtgttccac acaacccgct gggtgccccc 360 cttgatcggg gagctgtacg ggctgcgcac cacagaggag gctctccatg ccagccacgg 420 CttCatgtgg tacacgtagg ccctgtgccc tccggccacc tggatccctg CCCCtCCCCa 480 ctgggacgga ataaatgctc tgcagacctg gaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 540 aaaaaaaaaa ctcgag 556 <210> 293 <211> 591 <212> DNA
<213> Homo Sapiens <400> 243 gtctatgttt gcagaaatac agatccaaga caaagacagg atgggcactg ctggaaaagt 60 tattaaatgc aaagcagctg tgctttggga gcagaagcaa cccttctcca ttgaggaaat 120 agaagttgcc ccaccaaaga ctaaagaagt tcgcattaag attttggcca caggaatctg 180 tcgcacagat gaccatgtga taaaaggaac aatggtgtcc aagtttccag tgattgtggg 240 acatgaggca actgggattg.tagagagcat tggagaagga gtgactacag tgaaaccagg 300 tgacaaagtc atccctctct ttctgccaca atgtagagaa tgcaatgctt gtcgcaaccc 360 agatggcaac ctttgcatta ggagcgatat tactggtcgt ggagtactgg ctgatggcac 420 caccagattt acatgcaagg gcaaaccagt ccaccacttc atgaacacca gtacatttac 480 cgagtacaca gtggtggatg aatcttctgt tgctaagatt gatgatgcag ctcctcctga 540 gaaagtctgt ttaattggct gtgggttttc cactggatat ggcgctgctg t 591 <210> 244 <211> 594 <212> DNA
<213> Homo Sapiens <400> 244 gaattcggca cgagaacaga gtgaactgag catcagtcag aaaaagtcta tgtttgcaga 60 aatacagatc caagacaaag acaggatggg cactgctgga aaagttatta aatgcaaagc 120 agctgtgctt tgggagcaga agcaaccctt ctccattgag gaaatagaag ttgccccacc 180 aaagactaaa gaagttcgca ttaagatttt ggccacagga atctgtcgca cagatgacca 240 tgtgataaaa ggaacaatgg tgtccaagtt tccagtgatt gtgggacatg aggcaactgg 300 gattgtagag agcattggag aaggagtgac tacagtgaaa ccaggtgaca aagtcatccc 360 tctctttctg ccacaatgta.gagaatgcaa tgcttgtcgc aacccagatg gcaacctttg 420 cattaggagc gatattactg gtcgtggagt actggctgat ggcaccacca gatttacatg 480 caagggcaaa ccagtccacc acttcatgaa caccagtaca tttaccgagt acacagtggt 540 ggatgaatct tctgttgcta agattgat ga tgcagctcct cctgagaaag tctg 594 <210> 245 <211> 615 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <222> (105) <223> n=A,T,C or G
<400> 245 gtccctttcc tctgctgccg ctcggtcacg cttgtgcccg aaggaggaaa cagtgacaga 60 cctggagact gcagttctct atccttccac agctctttca ccatnctgga tcacttcctt 120 tgaatgcaga agcttgctgg ccaaaagatg tgggaattgt tgcccttgag atctattttc 180 cttctcaata tgttgatcaa gcagagttgg aaaaatatga tggtgtagat gctggaaagt 240 ataccattgg cttgggccag gccaagatgg gcttctgcac agatagagaa gatattaact 300 ctctttgcat gactgtggtt cagaatctta tggagagaaa taacctttcc tatgattgca 360 ttgggcggct ggaagttgga acagagacaa tcatcgacaa atcaaagtct gtgaagacta 420 atttgatgca gctgtttgaa' gagtctggga atacagatat agaaggaatc gacacaacta 480 atgcatgcta tggaggcaca gctgctgtct tcaatgcttg ttaactggat tgagtccagc 540 tcttgggatg gacggtatgc cctggtaagt tgcaggagat attgctgtat atgccacagg 600 aaatgctaga cctac 615 <210> 246 <211> 546 <212> DNA
<213> Homo sapiens <400> 246 gaattcggca ccaggctgcc tcccgctcgc cctgaaccca gtgcctgcag ccatggctcc 60 cggccagctc gccttattta gtgtctctgc aaaaccggcc ttgtgaattt gcaagaaacc 120 tgaccgctct tggtttgaat ctggtcgctt ccggagggac tgcaaaagct ctcagggatg 180 ctggtctggc agtcagagat gtctctgagt tgacgggatt tcctgaaatg ttggggggac 240 gtgtgaaaac tttgcatcct gcagtccatg ctggaatcct agctcgtaat attccagaag 300 ataatgctga catggccaga cttgatttca atcttataag agttgttgcc tgcaatctct 360 atccctttgt aaagacagtg gcttctccag gtgtaactgt tgaggaggct gtggagcaaa 420 ttgacattgg tggagtaacc ttactgagag ctgcagccaa aaaccacgct cgagtgacag 480 tggtgtgtga accagaggac tatgtgggtg ggtgtccacg gagatgcaga gctccgagag 540 taagga 546 <210> 247 <211> 564 <212> DNA
<213> Homo sapiens <400> 247 gaattcggca ccagagatca cgtgcagtga gatgcagcaa aaagttgaac ttctgagata 60 tgaatctgaa aagcttcaac aggaaaattc tattttgaga aatgaaatta ctactttaaa 120 tgaagaagat agcatttcta acctgaaatt agggacatta aatggatctc aggaagaaat 180 gtggcaaaaa acggaaactg taaaacaaga aaatgctgca gttcagaaga tggttgaaaa 240 tttaaagaaa cagatttcag aattaaaaat caaaaaccaa caattggatt tggaaaatac 300 agaacttagc caaaagaact ctcaaaacca ggaaaaactg caagaactta atcaacgtct 360 aacagaaatg ctatgccaga aggaaaaaga gccaggaaac agtgcattgg aggaacggga 420 acaagagaag tttaatctga aagaagaact ggaacgttgt aaagtgcagt cctccacttt 480 agtgtcttct ctggaggcgg agctctctga agttaaaata cagacccata ttgtgcaaca 540 ggaaaaccac cttctcaaag atga 564 <210> 248 <211> 434 <212> DNA
<213> Homo Sapiens <400> 248 gttcttgttt gtggatcgct gtgatcgtca cttgacaatg cagatcttcg tgaagactct 60 gactggtaag accatcaccc tcgaggttga gcccagtgac accatcgaga atgtcaaggc 120 aaagatccaa gataaggaag gcatccctcc tgaccagcag aggctgatct ttgctggaaa 180 acagctggaa gatgggcgca ccctgtctga ctacaacatc cagaaagagt ccaccctgca 240 cctggtgctc cgtctcagag gtgggatgca aatcttcgtg aagacactca ctggcaagac 300 catcaccctt gaggtggagc ccagtgacac catcgagaac gtcaaagcaa agatccagga 360 caaggaaggc attcctcctg accagcagag gttgatcttt gccggaaagc cagcctggga 420 agatggggcc gcca 434 <210> 249 <211> 416 <212> DNA
<213> Homo Sapiens <400> 249 gcgggcccag gaggcggcgg cggcggcggc ggacgggccc cccgcggcag acggcgagga 60 cggacaggac ccgcacagca agcacctgta cacggccgac atgttcacgc acgggatcca 120 gagcgccgcg cacttcgtCa tgttcttcgc gccctggtgt ggacactgcc agcggctgca 180 gccgacttgg aatgacctgg gagacaaata caacagcatg gaagatgcca aagtctatgt 240 ggctaaagtg gactgcacgg cccactccga cgtgtgctcc gcccaggggg tgcgaggata 300 ccccacctta aagcttttca agccaggcca agaagctgtg aagtaccagg gtcctcggga 360 cttccagaca ctggaaaact ggatgctgca gacactgaac gaggagccag tgacac 416 <210> 250 <211> 504 <212> DNA
<213> Homo Sapiens <400> 250 gaattcggca cgaggcgggt aacgttatag tatttgtcag aagttggggt ctccgtgggc 60 attgtgatcc gtcccaggca gtggattagg aggccagaag gagatccctt ccacggtgct 120 aggctgagat ggatcctctc agggcccaac agctggctgc ggagctggag gtggagatga 180 tggccgatat gtacaacaga atgaccagtg cctgccaccg gaagtgtgtg cctcctcact 240 acaaggaagc agagctctcc aagggcgagt ctgtgtgcct ggaccgatgt gtctctaagt 300 acctggacat ccatgagcgg atgggcaaaa agttgacaga gttgtctatg caggatgaag 360 agctgatgaa gagggtgcag cagagctctg ggcctgcatg aggtccctgt cagtatacac 420 cctggggtgt accccacccc ttcccacttt aataaacgtg ctccctgttg ggtgtcatct 480 gtgaagactg ccaggCCtag ctct 504 <210> 251 ' <211> 607 <212> DNA
<213> Homo Sapiens <400> 251 gatgaaaata cacaatttta ctagcaaatg cctctactgt aatcgctatt tacccacaga 60 tactctgctc aaccatatgt taattcatgg tctgtcttgt ccatattgcc gttcaacttt 120 caatgatgtg gaaaagatgg ccgcacacat gcggatggtt cacattgatg aagagatggg 180 acctaaaaca gattctactt tgagttttga tttgacattg cagcagggta gtcacactaa 240 catccatctc ctggtaacta catacaatct gagggatgcc ccagctgaat ctgttgctta 300 ccatgcccaa aataatcctc cagttcctcc aaagccacag ccaaaggttc aggaaaaggc 360 agatatccct gtaaaaagtt cacctcaagc tgcagtgccc tataaaaaag atgttgggaa 420 aaccctttgt cctctttgct tttcaatcct aaaaggaccc atatctgatg cacttgcaca 480 tcacttacga gagaggcacc aagttattca gacggttcat ccagttgaga aaaagctcac 540 ctacaaatgt atccattgcc ttggtgtgta taccagcaac atgaccgcct caactatcac 600 tctgcat 607 <210> 252 <211> 618 <212> DNA
<213> Homo sapiens <400> 252 gaattcgcac caggggtcct gctggtcttc gcctttcttc tccgcttcta ccccgtcggc 60 cgctgccact ggggtccctg gccccaccga catggcggcg gtgttgagca agtcctggag 120 cgcacggagc tgaacaagct gcccaagtct gtccagaaca aacttgaaaa gttccttgct 180 gatcagcaat ccgagatcga tggcctgaag gggcggcatg agaaatttaa ggtggagagc 240 gaacaacagt attttgaaat agaaaagagg ttgtcccaca gtcaggagag acttgtgaat 300 gaaacccgag agtgtcaaag cttgcggctt gagctagaga aactcaacaa tcaactgaag 360 gcactaactg agaaaaacaa agaacttgaa attgctcagg atcgcaatat tgccattcag 420 agccaattta caagaacaaa ggaagaatta gaagctgaga aaagagactt aattagaacc 480 aatgagagac tatctcaaga acttgaatac ttaacagagg atgttaaacg tctgaatgaa 540 aaacttaaag aaagcaatac aacaaagggt gaacttcagt taaaattgga tgaacttcaa 600 gcttctgatg tttctgtt 628 <210> 253 <211> 1201 <212> DNA
<213> Homo sapiens <400> 253 gaattcggca ccagggtggc gagcgcggct gctgtgctgg ggcgagcagc ggggaccgtg 60 tgtgagtttg gcatgatttg gtcccctggg attctgcctt agcaagaaag aagttggaaa 120 tacttcctgg aagaaaacta aaacaataca aaagccacag cttattgatt gcatgtcagc 180 ccccttacaa atatggacac atttcctagc ctatttccac ctggaggaga tagtaggctg 240 aatcctgagc ctgagttcca aaatatgtta attgatgaaa gggtacgctg tgaacatcat 300 aaacataatt atcaggctct gaaaattgaa cacaaaaggt tgcaggaaga atatgtaaaa 360 tcacaaaatg aacttaaacg tgtattaatt gaaaagcaag caagccagga aaaattccaa 420 ctgctccttg aagacttaag gggagaatta gtagagaaag ctagagacat agaaaaaatg 480 aaactgcagg tactaacacc acaaaaattg gaattggtaa aagcccaact acaacaagaa 540 ttagaagctc caatgcgaga acgttttcgg actcttgatg aagaagtgga aaggtacaga 600 gctgagtata acaagctgcg ctacgagtat acatttctca agtcagagtt tgaacaccag 660 aaagaagagt ttactcgggt ttcagaagaa gagaaaatga aatacaagtc agaggttgca 720 cgactggaga aggacaaaga ggagctacat aaccagctgc ttagtgttga tcccacgaga 780 gacagcaaac gaatggagca acttgttcga gaaaaaaccc atttgcttca gaaattgaaa 840 agtttagagg ctgaagtagc agaattaagg gctgagaaag aaaattctgg tgctcaggta 900 gaaaatgtcc aaagaataca ggtgaggcag ttggctgaga tgcaggctac actcagatcc 960 ttggaggctg aaaagcagtc agctaaacta caagctgagc gtttagaaaa agaactacaa 1020 tcaagcaatg aacagaatac ctgcttaatc agcaaactgc atagagctga ccgagaaatc 1080 agcacactgg ccagtgaagt gaaagagctt aaacatgcaa acaaactaga aataactgac 1140 atcaaactgg aggcagcaag agctaagagt gagctcgaaa gagaaaggaa taagatccaa 1200 a 1201 <210> 254 <211> 560 <212> DNA
<213> Homo Sapiens <400> 254 gaattcggca ccagtttggg gggtgaggtt taattggaaa tggtctctgg ggactgaaaa 60 ctgatgtttt tgcagattac ctcagggaaa cggaggtttg ttgagttaca gacacattaa 120 accaaaggcc gtgggaaaac ccctctccag ctccagggga ttggtcagga ccacccacta 180 accagtgcct tccttcttaa cat'tcacttt~tagcagcttg tgtttatttt acatgggcag 240 ttttgatggg aaattgccat gaccacaggg gtttggagtt ctgctttttt tttttcttct 300 tctttttcgg gggactgggg gactcctccc aagatcacat tttagcatct ttctctccta 360 ctccatttag aaaaataagt aacaggtgaa atgtggtctc agtgttaacg ggataattct 420 gctaccggct cctccctgat gattctgaaa tacactactg aacgagctct ggctggtcct 480 ttctatcctg gatgtggttc ttctgtgtag caattccttg atgtccagtt tggaaagatg 540 tactcttctc aacaagaaaa 560 <210> 255 <211> 612 <212> DNA
<213> Homo Sapiens <400> 255 gaattcggca ccaggcgggg cagcagggcc gcggccatgg ggagcttgaa ggaggagctg 60 ctcaaagcca tctggcacgc cttcaccgac tcgaccagga ccacagggca aggtctccaa 120 gtcccagctc aaggtccttt cccataacct gtgcacggtg ctgaaggttc ctcatgaccc 180 agttgccctt gaagagcact tcagggatga tgatgagggt ccagtgtcca accagggcta 240 catgccttat ttaaacaggt tcattttgga aaaggtccaa gacaactttg acaagattga 300 attcaatagg atgtgttgga ccctctgtgt caaaaaaaaa cctcacaaag aatcccctgc 360 tcattacaga agaagatgca tttaaaatat gggttatttt caacttttta tctgaggaca 420 agtatccatt aattattgtg tcagaagaga ttgaatacct gcttaagaag cttacagaag 480 ctatgggagg aggttggcag caagaacaat ttgaacatta taaaatcaac tttgatgaca 540 gtaaaaatgg cctttctgca tgggaactta ttgagcttat tggaaatgga cagtttagca 600 aaggcatgga cc 612 <210> 256 <211> 1132 <212> DNA
<213> Homo Sapiens <400> 256 gaattcggca cgaggtctgg gagaggcctc tggagcagga ggcccagtgg ctcttctgac 60 ccaaggcccc gccgtccagc ttctaagtgc cagatgatgg aggagcgtgc caacctgatg 120 cacatgatga aactcagcat caaggtgttg ctccagtcgg ctctgagcct gggccgcagc 180 ctggatgcgg accatgcccc cttgcagcag ttctttgtag tgatggagca ctgcctcaaa 240 catgggctga aagttaagaa gagttttatt ggccaaaata aatcattctt tggtcctttg 300 gagctggtgg agaaactttg tccagaagca tcagatatag cgactagtgt cagaaatctt 360 ccagaattaa agacagctgt gggaagaggc cgagcgtggc tttatcttgc actcatgcaa 420 aagaaactgg cagattatct gaaagtgctt atagacaata aacatctctt aagcgagttc 480 tatgagcctg aggctttaat gatggaggaa gaagggatgg tgattgttgg tctgctggtg 540 ggactcaatg ttctcgatgc caatctctgc ttgaaaggag aagacttgga ttctcaggtt 600 ggagtaatag atttttccct ctaccttaag gatgtgcagg atcttgatgg tggcaaggag 660 catgaaagaa ttactgatgt ccttgatcaa aaaaattatg tggaagaact taaccggcac 720 ttgagctgca cagttgggga tcttcaaacc aagatagatg gcttggaaaa gactaactca 780 aagcttcaag aagagctttc agctgcaaca gaccgaattt gctcacttca agaagaacag 840 cagcagttaa gagaacaaaa tgaattaatt cgagaaagaa gtgaaaagag tgtagagata 900 acaaaacagg ataccaaagt tgagctggag acttacaagc aaactcggca aggtctggat 960 gaaatgtaca gtgatgtgtg gaagcagcta aaagaggaga agaaagtccg gttggaactg 1020 gaaaaagaac tggagttaca aattggaatg aaaaccgaaa tggaaattgc aatgaagtta 1080 ctggaaaagg acacccacga gaagcaggac acactagttg ccctccgcca gc 1132 <210> 257 <211> 519 <212> DNA
<213> Homo Sapiens <400> 257 gaattcgtga cacgaggtgc tcgagatgaa ccccagcgcc cccagctacc ccatggcctc 60 tctgtacgtg ggggacctgc accccgacgt gaccgaggcg atgctctacg agaagttcag 120 cccggccggg cccatcctct ccatccgggt ctgcagggac atgatcaccc gccgctcctt 180 gggctacgcg tacgtgaact tccagcagcc ggcggacgcg gaacgtgctt tggacaccat 240 gaattttgat gttataaagg gcaagccagt acgcatcatg tggtctcagc gtgatccatc 300 acttcgcaaa agtggagtag gcaacatatt cattaaaaat ttggacaaat ccatcgacaa 360 taaagcacta tatgatacgt tttctgcgtt tggtaacatc ctttcatgta aggtggtttg 420 tgatgaaaat ggctccaagg gctatggatt tgtacacttt gaaacacagg aagcagctga 480 aagagctatt gaaaaaatga atgggatgct tctaaatga 519 <210> 258 <211> 596 <212> DNA
<213> Homo Sapiens <400> 258 gctttgccaa agacttagaa gctaagcaga aaatgagctt aacatcctgg tttttggtga 60 gcagtggagg cactcgccac aggctgccac gagaaatgat ttttgttgga agagatgact 120 gtgagctcat gttgcagtct cgtagtgtgg ataagcaaca cgctgtcatc aactatgatg 180 cgtctacgga tgagcattta gtgaaggatt tgggcagcct caatgggact tttgtgaatg 240 atgtaaggat tccggaacag acttatatca ccttgaaact tgaagataag ctgagatttg 300 gatatgatac aaatcttttc actgtagtac aaggagaaat gagggtccct gaagaagctc 360 ttaagcatga gaagtttacc attcagcttc agttgtccca aaaatcttca gaatcagaat 420 tatccaaatc tgcaagtgcc aaaagcatag attcaaaggt agcagacgct gctactgaag 480 tgcagcacaa aactactgaa gcactgaaat ccgaggaaaa agccatggat atttctgcta 540 tgccccgtgg tactccatta tatgggcagc cgtcatggtg gggggatgat gaggtg 596 <210> 259 <211> 595 <212> DNA
<213> Homo Sapiens <400> 259 gaattcggca ccagagaaaa agcttcaagg tatattgagt cagagtcaag ataaatcact 60 tcggagaatt tcagaattaa gagaggagct gcaaatggac cagcaagcaa agaaacatct 120 tcaggacgag tttgatgcat gtttggagga gaaagatcag tatatcagtg ttctccagac 180 tcaggtttct cttctaaagc agcgattaca gaatggccca atgaatgttg atgctcccaa 240 acccctccct cccggggagc tccaggcaga agtgcacggt gacacggaga agatggaggg 300 cgtcggggaa ccagtgggag gtgggacttc cgctaaaacc ctggaaatgc tccagcaaag 360 agtgaaacgt caggagaatc tgcttcagcg ctgtaaggag acaattgggt cccacaagga 420 gcagtgcgca ctgctgctga gtgagaagga ggcactgcag gagcagttgg atgaaaggct 480 gcaggagctg gaaaagatga aggggatggt aataaccgag acgaagcggc aaatgcttga 540 gaccctggaa ctgaaagaag atgaaattgc tcagcttcgt agtcatatca aacag 595 <210> 260 <211> 994 <2l2> DNA
<213> Homo sapiens <400> 260 gaattcggca cgaggcgttg cctgccttct tgctgtctat cagcctttct tgcctcttcc 60 ttttcgcctt ccctgttctt ccctttctca aacaaacaag acatggcaaa ccgcagtcta 120 acccagccct ttgaaattat ccatagtttt acagacagct ccaggccatg agccacaatg 180 tccaaaatta ttcttgagca ctgatataaa ttacttagac cttctttgag ggcagaactc 240 agctgttgct ctcatgatgg gcagtgctgg aaagggttct ggtatgtctt caaaatgagt 300 ccacgagttt actgagtgct tacaggtaaa ggaatgaata taagatgtct ttctgatcag 360 aacaggtgtc ccttcacatg agctttacta gactctggga gggaaaagta gccaagtact 420 tctgaaccat tttttaatac ttgttttgtc atggtgaaat tatagcagtt atcccaaaat 480 gttttaatta tcaaaatact gtcttttaaa aaaaaaaaaa agtaacacct tttaaagcat 540 tagatttcac ttgggtttct tttccaaaaa atgctaggta gacaaggcat tgtaaacatg 600 agtttccttt aagaaccatc agaatataaa tttaacatga agaaaactgc tatatctagt 660 agaaataata tctaaagttt aacaactaaa gtaccctcac agaatagcaa. atacccttct 720 gttctggaca tgggttcaaa tttgaatatg gaaataattt ccttggaagt ccctagaggc 780 aggtcagagg aagtatgcat taagagggaa aggagagaat ggaaataaaa gtcactataa 840 tgcagattta tgccttattt tttagcattt tttaaatgtt gggtctttca aggtgttttt 900 tgctttttat tagatctata taaataagtt aactagcaat ttagttttgt atttaagcta 960 cacttaatct ttttctttgg tgatatttat ttct 994 <210> 261 <211> 594 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <222> (538) <223> n=A,T,C or G
<400> 261 gaattcggca ccagtggaga tccagctgaa ccatgccaac cgccaggctg cggaggcaat 60 caggaacctt cggaacaccc agggaatgct gaaggacaca cagctgcacc tggacgatgc 120 tctcagaggc caggacgacc tgaaagagca gctggccatg gttgagcgca gagccaacct 180 gatgcaggct gagatcgagg agctcagggc atccctggaa cagacagaga ggagcaggag 240 agtggccgag caagagctac tggatgccag tgagcgcgtg cagctcctcc acacccagaa 300 caccagcctc atcaacacca agaagaagct ggagacagac atttcccaaa tccagggaga 360 gatggaagac atcgtccagg aagcccgcaa cgcagaagag aaggccaaga aagccatcac 420 tgatgccgcc atgatggcgg aggagctgaa gaaggagcag gacaccagcg cccacctgga 480 gcggatgaag aagaacatgg agcagaccgt gaaggacctg cagcaccgtc tggacgangc 540 tgagcagctt ggcgctgaag ggcgggcaag aagcagatcc agaaactgga ggct 594 <210> 262 <211> 594 <212> DNA
<213> Homo Sapiens <400> 262 gaaaaggtgg ctggagccaa aggcatagtc agggttaatg ctcctttttc tttatcccaa 60 atcagatagt gtttaggctt tttcatcaaa tataaaaacc cagcccagtt catggctcat 120 tcggcagcaa ccctgagacg ctttacagct ctagacccta aaaggtcaaa aggccgtctt 180 atgctcaata tacattttat tacccaatct gccccggaca ttaaataaaa ctccaaaaat 240 taaatccggc cctcaaaccc cacaacagga cttaattgac ctcaccttca aggtgtagaa 300 taataaaaaa aaaaagttgc aattccttgc ctccgctgtg agacaaaccc cagccacatc 360 tccagcacac aagaacttcc aaacgcctga accacagcag ccaggcgttc ctccagaacc 420 tcctccccca ggagcttgct acatgtgccg gaaatctggc cactaggcca aggaatgcct 480 gcagccccgg attcctccta agccgtgtcc catctgtgcg ggaccccact gaaaatcgga 540 ctgttcaact cacctggcag ccactctcag agaccctgga actctggccc aagg 594 <210> 263 <211> 506 <212> DNA
<213> Homo Sapiens <400> 263 gaattcggca cgagcggaaa cttaggggcc acgtgagcca cggccacggc cgcataggca 60 agcaccggaa gcaccccggc ggccgcggta atgctggtgg tctgcatcac caccggatca 120 acttcgacaa ataccaccca ggctactttg ggaaagttgg tatgaagcat taccacttaa 180 agaggaacca gagcttctgc ccaactgtca accttgacaa attgtggact ttggtcagtg 240 aacagacacg ggtgaatgct gctaaaaaca agactggggc tgctcccatc attgatgtgg 300 tgcgatcggg ctactataaa gttctgggaa agggaaagct cccaaagcag cctgtcatcg 360 tgaaggccaa attcttcagc agaagagctg aggagaagat taagagtgtt gggggggcct 420 gtgtcctggt ggcttgaagc cacatggagg gagtttcatt aaatgctaac tactttttaa 480 aaaaaaaaaa aaaaaaaaaa ctcgag 506 <210> 264 <211> 600 <212> DNA
<213> Homo Sapiens <220>
<221> misc feature <222> (32) <223> n=A, T, C or G
<400> 264 ggctcgtgaa cacacactga cagctatagg gnaggcggcg gcaccgtccc cgcttcccct 60 cggcggcggg gtgtcccgtc ggcggccctg aagtgaccca taaacatgtc ttgtgagagg 120 aaaggcctct cggagctgcg atcggagctc tacttcctca tcgcccggtt cctggaagat 180 ggaccctgtc agcaggcggc tcaggtgctg atccgcgagg tggccgagaa ggagctgctg 240 ccccggcgca ccgactggac cgggaaggag catcccagga cctaccagaa tctggtgaag 300 tattacagac acttagcacc tgatcacttg ctgcaaatat gtcatcgact aggacctctt 360 cttgaacaag aaattcctca aagtgttcct ggagtacaaa ctttattagg agctggaaga 420 cagtctttac tacgcacaaa taaaagctgc aagcatgttg tgtggaaagg atctgctctg 480 gctgcgttgc actgtggaag accacctgag tcaccagtta actatggtag cccacccagc 540 attgcggata ctctgttttc aaggaagctg aatgggaaat acagacttga gcgacttgtt 600 <210> 265 <211> 534 <212> DNA
<213> Homo Sapiens <400> 265 gaattcggca cgagtgagga gcccatcatg gcgacgcccc ctaagcggcg ggcggtggag 60 gccacggggg agaaagtgct gcgctacgag accttcatca gtgacgtgct gcagcgggac 120 ttgcgaaagg tgctggacca tcgagacaag gtatatgagc agctggccaa ataccttcaa 180 ctgagaaatg tcattgagcg actccaggaa gctaagcact cggagttata tatgcaggtg 240 gatttgggct gtaacttctt cgttgacaca gtggtcccag atacttcacg catctatgtg 300 gccctgggat atggtttttt cctggagttg acactggcag aagctctcaa gttcattgat 360 cgtaagagct ctctcctcac agagctcagc aacagcctca ccaaggactc catgaatatc 420 aaagcccata tccacatgtt gctagagggg cttagagaac tacaaggcct gcagaatttc 480 ccagagaagc ctcaccattg acttcttccc cccatcctca gacattaaag agcc 534 <210> 266 <211> 552 <212> DNA
<213> Homo sapiens <400> 266 gaattcggca ccagggcacc tccgcctcgc cgccgctagg tcggccggct ccgcccggct 60 gccgcctagg atgaatatca tggacttcaa cgtgaagaag ctggcggccg acgcaggcac 120 cttcctcagt cgcgccgtgc agttcacaga agaaaagctt ggccaggctg agaagacaga 180 attggatgct cacttagaga acctccttag caaagctgaa tgtaccaaaa tatggacaga 240 aaaaataatg aaacaaactg aagtgttatt gcagccaaat ccaaatgcca ggatagaaga 300 atttgtttat gagaaactgg atagaaaagc tccaagtcgt ataaacaacc cagaactttt 360 gggacaatat atgattgatg cagggactga gtttggccca ggaacagctt atggtaatgc 420 ccttattaaa tgtggagaaa cccaaaaaag aattggaaca gcagacagag aactgattca 480 aacgtcagcc ttaaattttc ttactccttt aagaaacttt atagaaggag attacaaaac 540 aattgctaaa ga 552 <210> 267 <211> 551 <212> DNA
<213> Homo Sapiens <400> 267 gaagcctacc agccaggtgc cggccccccc acccccggcc cagccccctc ctgcagcggt 60 ggaagcggct cggcagatcg agcgtgaggc ccagcagcag cagcacctgt accgggtgaa 120 catcaacaac agcatgcccc caggacgcac gggcatgggg accccgggga gccagatggc 180 ccccgtgagc ctgaatgtg.c cccgacccaa ccaggtgagc gggcccgtca tgcccagcat 240 gcctcccggg cagtggcagc aggcgcccct tccccagcag cagcccatgc caggcttgcc 300 caggcctgtg atatccatgc aggcccaggc ggccgtggct gggccccgga tgcccagcgt 360 gcagccaccc aggagcatct cacccagcgc tctgcaagac ctgctgcgga ccctgaagtc 420 gcccagctcc cctcagcagc aacagcaggt gctgaacatt ctcaaatcaa acccgcagct 480 aatggcagct ttcatcaaac agcgcacagc caagtacgtg gccaatcagc ccggcatgca 540 gccccagcct g 551 <210> 268 <211> 573 <212> DNA
<213> Homo Sapiens <400> 268 gaattcggca ccagggttcc ttgtgggcta gaagaatcct gcaaaaatgt ctctctatcc 60 atctctcgaa gacttgaagg tagacaaagt aattcaggct caaactgctt tttctgcaaa 120 ccctgccaat ccagcaattt tgtcagaagc ttctgctcct atccctcacg atggaaatct 180 ctatcccaga ctgtatccag agctctctca atacatgggg ctgagtttaa atgaagaaga 240 aatacgtgca aatgtggccg tggtttctgg tgcaccactt caggggcagt tggtagcaag 300 accttccagt ataaactata tggtggctcc tgtaactggt aatgatgttg gaattcgtag 360 agcagaaatt aagcaaggga ttcgtgaagt cattttgtgt aaggatcaag atggaaaaat 420 tggactcagg cttaaatcaa tagataatgg tatatttgtt cagctagtcc aggctaattc 480 tccagcctca ttggttggtc tgagatttgg ggaccaagta cttcagatca atggtgaaaa 540 ctgtgcagga tggagctctg ataaagcgca caa _ 573 <210> 269 <211> 500 <212> DNA
<213> Homo sapiens <400> 269 gaatcggcac caggaaacct ttattagcag agatagctgg cttggatcag attacgggga 60 atgtggggga gccatgaaga aactaactaa aggggagcct ttggggacca gggggagaca 120 agtcactatt ttgagggaga aagctctgga ttgattctga caggacactt gagtgtgaac 180 tgtccaagct aagcctctgg gtgtgtagag agagccctta cagatagata gcacctttgc 240 tttcagagtg gaaggactag ccactaagga ccagaccaag atgcatgtag gtcactgaca 300 agcacctgat gaagaggagg ggtctcctcc aagtttgtgt ttggaactcc tcctgtgttc 360 aatttcctaa aagccataat ccagcaagct gaactcatga gaaggtctgc ttcatgttga 420 gcatggaaga cagaacacag acggaaactg cagtgatggt gtgaagacac cacggatagg 480 ttaggggcag tgaggaggaa 500 <210> 270 <211> 224 <212> DNA
<213> Homo Sapiens <400> 270 gaattcggca cgagaagact acaatctcca gggaaacctg gggcgtctcg cgcaaacgtc 60 cataactgaa agtagctaag gcaccccagc cggaggaagt gagctctcct ggggcgtggt 120 tgttcgtgat ccttgcatct gttacttagg gtcaaggctt gggtcttgcc ccgcagaccc 180 ttgggacgac ccggccccag cgcagctatg aacctggagc gagt 224 <210> 271 , <211> 447 <212> DNA
<213> Homo Sapiens <400> 271 gaattcggca cgaggctggg ccgggcccga gcggatcgcg ggctcgggct gcggggctcc 60 ggctgcgggc gctgggccgc gaggcgcgga gcttgggagc ggagcccagg ccgtgccgcg 120 cggcgccatg aagggcaagg aggagaagga gggcggcgca cggctgggcg ctggcggcgg 180 aagccccgag aagagcccga gcgcgcagga gctcaaggag cagggcaatc gtctgttcgt 240 gggccgaaag tacccggagg cggcggcctg ctacggccgc gcgatcaccc ggaacccgct 300 ggtggccgtg tattacacca accgggcctt gtgctacctg aagatgcagc agcacgagca 360 ggccctggcc gactgccggc gcgccctgga gctggacggg cagtctgtga aggcgcactt 420 cttcctgggg cagtgccagc tggagat 447 <210> 272 <211> 606 <212> DNA
<213> Homo sapiens <400> 272 gcaactactt atattccttt gatggataat gctgactcaa gtcctgtggt agataagaga 60 gaggttattg atttgcttaa acctgaccaa gtagaaggga tccagaaatc tgggactaaa 120 aaactgaaga ccgaaactga caaagaaaat gctgaagtga agtttaaaga ttttcttctg 180 tccttgaaga ctatgatgtt ttctgaagat gaggctcttt gtgttgtaga cttgctaaag 240 gagaagtctg gtgtaataca agatgcttta aagaagtcaa gtaagggaga attgactacg 300 cttatacatc agcttcaaga aaaggacaag ttactcgctg ctgtgaagga agatgctgct 360 gctacaaagg atcggtgtaa gcagttaacc caggaaatga tgacagagaa agaaagaagc 420 aatgtggtta taacaaggat gaaagatcga attggaacat tagaaaagga acataatgta 480 tttcaaaaca aaatacatgt cagttatcaa gagactcaac agatgcagat gaagtttcag 540 caagttcgtg agcagatgga ggcagagata gctcacttga agcaggaaaa tgggtatact 600 ggagaa 606 <210> 273 <211> 598 <212> DNA
<213> Homo sapiens <400> 273 gaattcggca ccaggcccgg tcccgcggtc gcagctccag ccgcctcctc cgcgcagccg 60 ccgcctcagc tgctcgctct gtgggtcggt cctctccggc acttgggctc cagtcgcgcc 120 ctccaagccc ttcaggccgc cccagtgtcc tcctccttct ccggccagac ccagccccgc 180 gaagatggtg gaccgcgagc aactggtgca gaaagcccgg ctggccgagc aggcggagcg 240 ctacgacgac atggccgcgg ccatgaagaa cgtgacagag ctgaatgagc cactgtcgaa 300 tgaggaaCga aaccttctgt ctgtggccta caagaacgtt gtgggggcac gccgctcttc 360 ctggagggtc atcagtagca ttgagcagaa gacatctgca gacggcaatg agaagaagat 420 tgagatggtc cgtgcgtacc gggagaagat agagaaggag ttggaggctg tgtgccagga 480 tgtgctgagc ctgctggata actacctgat caagaattgc agcgagaccc agtacgagag 540 caaagtgttc tacctgaaga tgaaagggga ctactaccgc tacctggctg aagtggcc 598 <210> 274 <211> 536 <212> DNA
<213> Homo sapiens <400> 274 gcaccaagag actaaacaag aaagtggatc agggaagaag aaagcttcat caaagaaaca 60 aaagacagaa aatgtcttcg tagatgaacc ccttattcat gcaactactt atattccttt 120 gatggataat gctgactcaa gtcctgtggt agataagaga gaggttattg atttgcttaa 180 acctgaccaa gtagaaggga tccagaaatc tgggactaaa aaactgaaga ccgaaactga 240 caaagaaaat gctgaagtga agtttaaaga ttttcttctg tccttgaaga ctatgatgtt 300 ttctgaagat gaggctcttt gtgttgtaga cttgctaaag gagaagtctg gtgtaataca 360 agatgcttta aagaagtcaa gtaagggaga attgactacg cttatacatc agcttcaaga 420 aaaggacaag ttactcgctg ctgtgaagga agatgctgct gctacaaagg atcggtgtaa 480 gcagttaacc caggaaatga tgacagagaa agaaagaagc aatgtggtta taacaa 536 <210> 275 <211> 494 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <222> (379) <223> n=A,T,C or G
<400> 275 gaattcggca ccagggtcgc ggttcttgtt tgtggatcgc tgtgatcgtc acttgacaat 60 gcagatcttc gtgaagactc tgactggtaa gaccatcacc ctcgaggttg agcccagtga 120 caccatcgag aatgtcaagg caaagatcca agataaggaa ggcatccctc ctgaccagca 180 gaggctgatc tttgctggaa aacagctgga agatgggcgc accctgtctg actacaacat 240 ccagaaagag tccaccctgc acctggtgct ccgtctcaga ggtgggatgc aaatcttcgt 300 gaagacactc actggcaaga ccatcaccct tgaggtggag cccagtgaca ccatcgagaa 360 cgtcaaagca aagatccang acaaggaagg cattcctcct gaccagcaga ggttgatctt 420 tgccggaaag cagctggaag atgggcgcac cctgtctgac tacaacatcc agaaagagtc 480 taccctgcac ctgg 494 <210> 276 <211> 484 <212> DNA
<213> Homo Sapiens <400> 276 ggcttttaac cagaagtcaa acctgttcag acagaaggca gtcacagcag aaaaatcttc 60 agacaaaagg cagtcacagg tgtgcaggga gtgtgggcga ggctttagca ggaagtcaca 120 gctcatcata caccagagga cacacacagg agaaaagcct tatgtctgcg gagagtgtgg 180 gcgaggcttt atagttgagt cagtcctccg caaccacctg agtacacact ccggggagaa 240 accttatgtg tgcagccatt gtgggcgagg ctttagctgc aagccatacc tcatcagaca 300 tcagaggaca cacacaaggg agaaatcgtt tatgtgcaca gtgtgtgggc gaggctttcg 360 tgaaaagtca gagctcatta agcaccagag aattcacacg ggggataagc cttatgtgtg 420 cagagattga ggccgaggct ttgtaaagga gatcatgtct caacacacac cagaggatta 480 catt 484 <210> 277 <211> 513 <212> DNA
<213> Homo sapiens <400> 277 gcttgaggct gccaatcaga gcttggcaga gctgagagat cagcggcagg gggagcgcct 60 ggaacatgca gcagctttgc gggccctaca agatcaggta tccatccaga gtgcagatgc 120 acaggaacaa gtggaagggc ttttggctga gaacaatgcc ttgaggacta gcctggctgc 180 cctggagcag atccaaacag caaagaccca agaactgaat atgctccggg aacagaccac 240 tgggctggca gctgagttgc agcagcagca ggctgagtac gaggacctta tgggacagaa 300 agatgacctc aactcccagc tccaggagtc attacgggcc aatagtcgac tgctggaaca 360 acttcaagaa atagggcagg agaaggagca gttgacccag gaattacagg aggctcggaa 420 gagtgcggag aagcggaagg ccatgcttgg atgagctagc aatggaaacg ctgcaagaga 480 agtcccacac aaggaagagc ttgggagcag ttc 513 <210> 278 <211> 471 <212> DNA
<213> Homo Sapiens <400> 278 gaattcggca ccagccaagg ccctgtccct ggctcgggcc cttgaagagg ccttggaagc 60 caaagaggaa ctcgagcgga ccaacaaaat gctcaaagcc gaaatggaag acctggtcag 120 ctccaaggat gacgtgggca agaacgtcca tgagctggag aagtccaagc gggccctgga 180 gacccagatg gaggagatga agacgcagct ggaagagctg gaggacgagc tgcaagccac 240 ggaggacgcc aaactgcggc tggaagtcaa catgcaggcg ctcaagggcc agttcgaaag 300 ggatctccaa gcccgggacg agcagaatga ggagaagagg aggcaactgc agagacagct 360 tcacgagtat gagacggaac tggaagacga gcgaaagcaa cgtgccctgg cagctgcagc 420 aaagaagaag ctggaagggg acctgaaaga cctggagctt caggccgact t 471 <210> 279 <211> 497 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <222> (457) <223> n=A,T,C or G
<221> misc_feature <222> (471) <223> n=A,T,C or G
<400> 279 gaattcggca cgaggccaca gaggcggcgg agagatggcc ttcagcggtt cccaggctcc 60 ctacctgagt ccagctgtcc ccttttctgg gactattcaa ggaggtctcc aggacggact 120 tcagatcact gtcaatggga ccgttctcag ctccagtgga accaggtttg ctgtgaactt 180 tcagactggc ttcagtggaa atgacattgc cttccacttc aaccctcggt ttgaagatgg 240 agggtacgtg gtgtgcaaca cgaggcagaa cggaagctgg gggcccgagg agaggaagac 300 acacatgcct ttccagaagg ggatgccctt tgacctctgc ttcctggtgc agagctcaga 360 tttcaaggtg atggtgaacg ggatcctctt cgtgcagtac ttccaccgcg tgcccttcca 420 ccgtgtggac accatctccg tcaatggctc tgtgcanctg tcctacatca ncttccagac 480 ccagacagtc atccaca 497 <210> 280 <211> 544 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <222> (451) <223> n=A,T,C or G
<400> 280 gaattcggca ccagaatagg aacagctccg gtctacagct cccagcgtga gcgacgcaga 60 agacgggtga tttctgcatt tccatctgag gtaccgggtt catctcacta gggagtgcca 120 gacagtgggc gcaggccagt gtgtgtgcgc accgtgcgcg agccgaagca gggcgaggca 180 ttgcctcacc tgggaagcac aaggggtcag ggagttccct ttccgagtca aagaaagggg 240 tgacggacgc acctggaaaa tcgggtcact cccacccgaa tattgtgctt ttcagaccgg 300 cttaagaaac ggcgcaccac gagactatat cccacacctg gctcagaggg tcctacgccc 360 acggaatctc gctgattgct agcacagcag tcttagatca aactgcaagg ggggcaacga 420 ggctggggga ggggcgcccg ccattgccca ngcttgctta ggtaaacaaa gcagccggga 480 agcttgaact gggtggagcc caccacagct caaggaggcc tgcctgcctc tgtagctcca 540 cctc 544 <210> 281 <2I1> 527 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <222> (456) <223> n=A,T,C or G
<400> 281 gaattcggca cgaggcctcg ctcagctcca acatggcaaa aatctccagc cctacagaga 60 ctgagcggtg catcgagtcc ctgatt,gctg tcttccagaa gtatgctgga aaggatggtt 120 ataactacac tctctccaag acagagttcc taagcttcat gaatacagaa ctagctgcct 180 tcacaaagaa ccagaaggac cctggtgtcc ttgaccgcat gatgaagaaa ctggacacca 240 acagtgatgg tcagctagat ttctcagaat ttctt aatct gattggtggc ctagctatgg 300 cttgccatga ctccttcctc aaggctgtcc cttcccagaa gcggacctga ggaccccttg 360 gccctggcct tcaaacccac occctttcct tccagccttt ctgtcatcat ctccacagcc 420 cacccatccc ctgagcacac taaccacctc atgcanggcc cccctgccaa tagtaataaa 480 gcaatgtcct tttttaaaac atgaaaaaaa aaaaaaaaaa actcgag 527 <210> 282 <211> 514 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <222> (494) <223> n=A,T;C or G
<400> 282 ggaagactgg agcctttgcg gcggcgctgc ccctcccctg gtccccgcga gctcggaggg 60 cccggctggt gctgcggggg ccccgggagg ttgaaaacta agcatgggga agagctgcaa 120 ggtggtcgtg tgtggccagg cgtctgtggg caaaacttca atcctggagc agcttctgta 180 tgggaaccat gtagtgggtt cggagatgat cgagacgcag gaggacatct acgtgggctc 240 cattgagaca gaccgggggg tgcgagagca ggtgcgtttc tatgacaccc gggggctccg 300 agatggggcc gaactgcccc gacactgctt ctcttgcact gatggctacg tcctggtcta 360 tagcacagat agcagagagt~ cttttcagcg tgtggagctg ctcaagaagg agattgacaa 420 atccaaggac aagaaggagg tcaccatcgt ggtccttggc aacaagtgtg acttacagga 480 gcagcggcgt gtanacccaa atgtggctca acac 514 <210> 283 <212> 484 <212> DNA
<213> Homo Sapiens <400> 283 gggcgggcgg tggacagtca tggcggcccg gcgcggggct ctcatagtgc tggagggcgt 60 ggaccgcgcc gggaagagca cgcagagccg caagctggtg gaagcgctgt gcgccgcggg 120 ccaccgcgcc gaactgctcc ggttcccgga aagatcaact gaaatcggca aacttctgag 180 ttcctacttg caaaagaaaa gtgacgtgga ggatcactcg gtgcacctgc ttttttctgc 240 aaatcgctgg gaacaagtgc cgttaattaa ggaaaagttg agccagggcg tgaccctcgt 300 cgtggacaga tacgcatttt ctggtgtggc cttcaccggt gccaaggaga atttttccct 360 agactggtgt aaacagccag acgtgggcct tcccaaaccc gacctggtcc tgttcctcca 420 gttacagctg gcggatgctg ccaagcgggg agcgtttggc catgagcgct atgagaacgg 480 ggct 484 <210> 284 <211> 514 <212> DNA
<213> Homo Sapiens <400> 284 gaattcggca cgaggcggag gccgcggagg ctcctcggtc cttcagcacc cctcggcccg 60 acgcacccac gcccctcacc ccccgagagc cgaaaatgga cccaagtggg gtcaaagtgc 120 tggaaacagc agaggacatc caggagaggc ggcagcaggt cctagaccga taccaccgct 180 tcaaggaact ctcaaccctt aggcgtcaga agctggaaga ttcctatcga ttccagttct 240 ttcaaagaga tgctgaagag ctggagaaat ggatacagga aaaacttcag attgcatctg 300 atgagaatta taaagaccca accaacttgc agggaaagct tcagaagcat caagcatttg 360 aagctgaagt gcaggccaac tcaggagcca ttgttaagct ggatgaaact ggaaacctga 420 tgatctcaga agggcatttt gcatctgaaa ccatacggac ccgtttgatg gagctgcacc 480 gc,cagtggga attacttttg gagaagatgc gaga 514 <210> 285 <211> 383 <212> DNA
<213> Homo Sapiens <400> 285 gaattcggca cgaggccggg ctccaccgcg catcctgctc cactctggcg accgcccccg 60 gggcccccgc cgcgggcgcg gcgcccgcca tgggcgagga ggactactat ctggagctgt 120 gcgagcggcc ggtgcagttc gagaaggcga accctgtcaa ctgcgtcttc ttcgatgagg 180 ccaacaagca ggtttttgct gttcgatctg gtggagctac tggcgtggta gttaaaggcc 240 cagatgatag gaatcccatc tcatttagaa tggatgacaa aggagaagtg aagtgcatta 300 agttttcctt agaaaataag atattggctg ttcagaggac ctcaaagact gtggattttt 360 gtaattttat ccctgataat tcc 383 <210> 286 <211> 943 <212> DNA
<213> Homo Sapiens <400> 286 gaattcggca ccagggccgt ggcggaggag gagcgctgca cggtggagcg tcgggccgac 60 ctcacctacg cggagttcgt gcagcagtac gtgcgcccct gatcgcggag gtcgcgtcct 120 gttcaccggc ccgtctgccc cgaccgccca aggccgcctt cccctgacct cgcgcgcacg 180 cgtggggctg gggcggcgag gctggcggtc cggcctggcc gcgactctgc ccttctttcc 240 agaggttccg ggccctgtgc tcccgcgaca ggttgctggc ttcgtttggg gacagagtgg 300 tccggctgag caccgccaac acctactcct accacaaagt ggacttgccc ttccaggagt 360 atgtggagca gctgctgcac ccccaggacc ccacctccct gggcaatggt gaggcagccc 420 taggcggcgg tagggggtgg ggacgcttgg agtctccagg tgccaggatc cctgtccccg 480 ccgtctctgt tggcagacac cctgtacttc ttcggggaca acaacttcac cgagtgggcc 540 tctctctttc ggcactactc cccaccccca tttggcctgc tgggaaccgc tccagcttac 600 agctttggaa tcgcaggagc tggctcgggg gtgcccttcc actggcatgg acccgggtac 660 tcagaagtga tctacggtcg taagcgctgg ttcctttacc cacctgagaa gacgccagag 720 ttccacccca acaagaccac actggcctgg ctccgggaca catacccagc cctgccaccg 780 tctgcacggc ccctggagtg taccatccgg gctggtgagg tgctgtactt ccccgaccgc 840 tggtggcatg ctacgctcaa ccttgacacc agcgtcttca tctccacctt cctcggctag 900 ccaaaacagc tggcaggact gccggtcaca caccagcacg tcc 943 <210> 287 <211> 1143 <212> DNA
<213> Homo Sapiens <400> 287 gaattcggca cgagggaaga acagctgttg gaacaacaag aatatttaga aaaagaaatg 60 gaggaagcaa agaaaatgat atcaggacta caggccttac tgctcaatgg atccttacct 120 gaagatgaac aggagaggcc cttggccctc tgtgaaccag gtgtcaatcc cgaggaacaa 180 ctgattataa tccaaagtcg tctggatcag agtatggagg agaatcagga cttaaagaag 240 gaactgctga aatgtaaaca agaagccaga aacttacagg ggataaagga tgccttgcag 300 cagagattga ctcagcagga cacatctgtt cttcagctca aacaagagct actgagggca 360 aatatggaca aagatgagct gcacaaccag aatgtggatc tgcagaggaa gctagatgag 420 aggaaccggc tcttgggaga atataaaaaa gagctggggc agaaggatcg ccttcttcag 480 cagcaccagg ccaagttaga agaagcactc cggaaactct ctgatgtcag ttaccaccag 540 gtggatctag agcgagagct agaacacaaa gatgtcctct tggctcactg tatgaaaaga 600 gaggcagatg aggcgaccaa ctacaacagt cacaactctc aaagcaatgg ttttctcctt 660 ccaacggcag gaaaaggagc tacttcagtc agcaacagag ggaccagcga cctgcagctt 720 gttcgagatg ctctccgcag cctgcgcaac agcttcagtg gccacgatcc tcagcaccac 780 actattgaca gcttggagca gggcatttct agcctcatgg agcgcctgca tgttatggag 840 acgcagaaga aacaagaaag aaaggttcgg gtcaagtcac ccagaactca agtaggtagt 900 gaataccggg agtcctggcc ccctaactca aagttgcctc actcacagag ctctccaact 960 gtcagcagca cctgtactaa agtgctctat ttcactgacc ggtcacttac gcccttcatg 1020 gtcaatatac caaagaggtt ggaggaggtg acgttaaagg attttaaagc agctattgat 1080 cgggaaggaa atcaccggta tcacttcaaa gcactggatc'ctgagtttgg cactgtcaaa 1140 gag 1143 <210> 288 <211> 881 <212> DNA
<213> Homo Sapiens <400> 288 gtgagagcgg gccgaggaga ttggcgacgg tgtcgcccgt gttttcgttg gcgggtgcct 60 gggctggtgg gaacagccgc ccgaaggaag caccatgatt tcggccgcgc agttgttgga 120 tgagttaatg ggccgggacc gaaacctagc cccggacgag aagcgcagca acgtgcggtg 180 ggaccacgag agcgtttgta aatattatct ctgtggtttt tgtcctgcgg aattgttcac 240 aaatacacgt tctgatcttg gtccgtgtga aaaaattcat gatgaaaatc tacgaaaaca 300 gtatgagaag agctctcgtt tcatgaaagt tggctatgag agagattttt tgcgatactt 360 acagagctta cttgcagaag tagaacgtag gatcagacga ggccatgctc gtttggcatt 420 atctcaaaac cagca,gtctt ctggggccgc tggcccaaca ggcaaaaatg aagaaaaaat 480 tcaggttcta acagacaaaa ttgatgtact tctgcaacag attgaagaat tagggtctga 540 aggaaaagta gaagaagccc aggggatgat gaaattagtt gagcaattaa aagaagagag 600 agaactgcta aggtccacaa cgtcgacaat tgaaagcttt gctgcacaag aaaaacaaat 660 ggaagtttgt gaagtatgtg gagccttttt aatagtagga gatgcccagt cccgggtaga 720 tgaccatttg atgggaaaac aacacatggg ctatgccaaa attaaagcta ctgtagaaga 780 attaaaagaa aagttaagga aaagaaccga agaacctgat cgtgatgagc gtctaaaaaa 840 ggagaagcaa gaaagagaaa aaaaaaaaaa aaaaactcga g 881 <210> 289 <211> 987 <212> DNA
<213> Homo Sapiens <400> 289 gaattcggca cgagggactg tggtttccag gaatggtggc gtctcacgct tcttgtgctt 60 tttcctttgg ggcctccgag cggctggggt tgggggactg ggcaggaggc tccctgtaaa 120 catttggact tgggctgggg caggggctgg tgttgggcaa agctgggggt ccaggctgga 180 gaagcagggg cccctccaga cgcagccttg ggagactcag catgtgcccc cctcccctca 240 tcacagaaca agacaatggt taaaaaccag aacagatgcc cagaaggggg taccatggcc 300 attaccagca tctcagacaa gggcaggctt caaacaggga ggcctgtggc aacccctccc 360 ctacgtotgg agctgagggg acagggggag ctgagaacaa agagaggaaa gaggagaaaa 420 gcggcggggg aacaggcggg gagcgtgatc ttcttgcccc catcttcctc aggggttggg 480 gggtacaaag tcggcggtgg cccatcccgc caggccccgc tgcccctcag aagaggccgc 540 agtccttcag gttgttcttg atgatgacat cggtgacggc gtcaaacacg aactgcacgt 600 tcttggtgtc ggtggcgcac gtgaagtgcg tgtagatctc cttggtgtct ttgcgcttat 660 tcaggtcctc aaacttactc tggatgtagc tggctgcctc atcatatttg ttggcccctg 720 tatactcagg gaagcagatg gtcaggggac tgtgtgtgat Cttctcctca aacaggtcct 78O
tcttgttgag gaagaggatg atggacgtgt ctgtgaacca cttgttgttg cagatgctat 840 cgaatagctt catgctctca tgcatgcggt tcatctcctc gtcctcagct agcaccaagt 900 cataggcgct caaggctacg cagaagatga tggctgtgac gccctcaaag cagtggatcc 960 acttcttccg ctcagaccgc tgaccac 987 <210> 290 <211> 300 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (2). .(300) <223> n = A,T,C or G
<400> 290 gattcaagat gtaccccatt gactttgaga aggatgatga cagcaacttt catatggatt 60 toatcgtggc tgcatccaac ctccgggcag aaaactatga cattccttct gcagaccggc 120 acaagagcaa gctgattgca gggaagatca tcccagccat tgccacgacc acagcagccg 180 tggttggcct tgtgtgtctg gagctgtaca aggttgtgca ggggcaccga cancttgact 240 cctacangaa tgggtgcctc aacttgagcc ctgcctttct ttggtttctc tgaacccctt 300 <210> 291 <211> 352 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1). .(352) <223> n = A,T,C ox G

<400> 291 aaccaagctgccaccgggggtggatcggatgcggcttgagaggcatctgtctgccgagga 60 cttctcaagggtatttgccatgtcccctgaagagtttggcaagctggctctgtggaagcg 120 gaatgagctcaagaagaaggcctctctcttctgatggcccccacctgctccgggacggcc 180 cccttacccctgctgcttcagggtttttccccggcgggttgggaggggcaggaggtgggg 240 tggaaatngggtgggcncctttcctcaggtagagnggggggccaaaacctctgcngtccc 300 cggagngagctatggactttcttccccctcacaaggntgggggcctcctgct 352 <210> 292 <211> 511 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1)...(511) <223> n = A,T,C or G
<400> 292 cgcggtggctgcgcactcngcctgagaaactcggcaagcgcgcagtgtcgactccccggt 60 ctatgccaggcgcatctcagctaatccaaaagtaaatgagaaacttagaaaaagattgcc 120 aattccaaatcaacatatttagagaaaattggaaaaggagaagcttactacagctttatt 180 tgaggactttttaaagaacgctgggttctatctgtgagctgcaaatcttggagcaaaaac 240 cagagacattgccagagcaaacaagaacagaaatacaaatggagaactggtcaaaagaca 300 taacccacagttatcttgaacaagaaactacggggataaataaaagtacgcanccagatg 360 agcaactgactatgaattctgagaaaagtatgcatcggaaatccactgaattagntaatg 420 aaataacatgngagaacacagaatggccaggggcagagatcaacgaattttcanatcatc 480 agttcttatccagatgatgagtctgtttact 511 <210> 293 <211> 526 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1)...(526) <223> n = A,T,C or G
<400> 293 gataaaaagaactttaatggaaggcactgttgtccaaaatcacataaagggtaagagccc 60 acacggtaccaccctgctctcctacttctcaaacccacatccaccacccagacaggaggg 120 tgcanaccccacaggaaattacctcc,cggagcactgactgatatttttccttaaaacaaa 180 aaaatggctgtctcagactaataacagaacatcttaagagctataccagctattacagcc 240 tggtaatanaagcagctttctaanaattcccaagtttataanaggcccaanaaatgcatt 300 tattctgttgtctattaagcctccatgacaaggagaaagttatgagtaaatccttggttc 360 atcaggagttaagagctgtgngcctcatgaggagttaanagctgtgtgcataagcaggtt 420 caagaaacaaactcctgtttgtttgcctctttgatggttcaaaaacattcagctgctttc 480 acctctangacaaaatgcttaaagaatttactctcatcaccttggg 526 <210> 294 ' <211> 601 <212> DNA
<213> Homo sapien <220>
<221> misc feature <222> (1)...(601) <223> n = A,T,C or G
<400>

actttaaaagccaaatatatttttaaaagatcatgcttataataagtaaattacncatta 60 aggaaacatcaaaataaagtagatgaataaaaaggcacactcgaaaaatttgagcgcaga 120 aaggacagttctttttgttttgtttctaatgtcggaagaaaaagaaagagatatattaaa 180 atcattgttttcaagtgaaggtttctgtcagttgaagtagttagcaatggcttcttttct 240 cccgtgtccaaagcaggctcttcctgcgctgacttctgaggaggngttcagtcctctgcc 300 atgtataggcgatacatcaaggcgacggccactgcagagatggcagggatcacccagttg 360 gtccaccaactggaactagaatcaatagtagtgataagagtttccggaggcttgtttaac 420 tttggtctgtcatctggatggagctccccaatgatgaatgttttggacatttccctggca 480 tctgtagantgcccgacatcctcaaagttctcagtagcngtcacctccacttgttccctt 540 aaaacttcttccccaccaggatgctcttccagaaatttgggncaaatcgnacaccttgtg 600 g 601 <210> 295 <211> 262 <212> DNA
<213> Homo sapien <400> 295 cccttagccc caagggccct gggggcagcc accctcccgc ctgtcggccc gtagatttat 60 caagggtgtt atgggcccag ctttgggggg ccagtcccga tgcactttga ggggtgttgg 120 agaggggact cccccactcg cacttaactc aacggctctc gggccctggg gctgttttta 180 ccatgtttgt ttttgaagct caggtgtctc acgtctgggc tgcaccaggc gaagagagaa 240 attaaagatt tgaggttttt cc 262 <210> 296 <211> 598 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1). .(598) <223> n = A,T,C or G
<400>

gttagaacaactcagcaaaataaaattcctgtttattgttggacaacattgtttcacaca 60 tacatcaaacaggccaaaaaaaataaacagcaacttcatagacaaaaaaggaaaaaaaaa 120 gaaaccttttatctttggcctttttaaccatctcatacaaaccaactacttatagtacag 180 ctaagtacatacacaaaaaagttactggaatgctcggaataagattgtttttctgttgtc 240 atttttgctttttttacaaggntttttttctcctttgagattataatgaacatggncaca 300 ccacaagtaaagtcagaagtaggacaganaacgctccgaaggctggtttggtcatccgan 360 atcattaaaaatggctgaccctaacaatatgtacaaaaatataaaatgtaaataaaaaat 420 acaaacaaatttcctttttaaagtacttttaagaaaaaaagcagggccttggaagttttg 480 gttcttttttcctcccctgttgcaaattctcatggtttgggttgggtggngganancccg 540 tgtcatctgcgggtggcactgccccggngggcgggcgggcctctctctcgaangngac 598 <210> 297 <211> 509 <212> DNA
<2l3> Homo sapien <400> 297 agaacacagg tgtcgtgaaa actaccccta aaagccaaaa tgggaaagga aaagactcat 60 atcaacattg tcgtcattgg acacgtagat tcgggcaagt ccaccactac tggccatctg 120 atctataaatgcggtggcatcgacaaaagaaccattgaaaaatttgagaaggaggctgct 180 gagatgggaaagggctccttcaagtatgcctgggtcttggataaactgaaagctgagcgt 240 gaacgtggtatcaccattgatatctccttgtggaaatttgagaccagcaagtactatgtg 300 actatcattgatgccccaggacacagagactttatcaaaaacatgattacagggacatct 360 caggctgactgtgctgtcctgattgttgctgctggtgttggtgaatttgaagctggtatc 420 tccaagaatgggcaggacccgagagcatgcccttctggcttacacactgggtgtgaaaca 480 actaattgtcggtgttaacaaaatggatt 509 <210> 298 <211> 267 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1)...(267) <223> n = A,T,C or G
<400>

gggacgggggaaaggagacgcttcttcctcttgctgctcttctcgttcccgagatcagcg 60 gcggcggtgaccgcgagtgggtcggcaccgtctccggctccgggngcnaacaatgctgac 120 tgatagcggaggcggnggcacctccttnnaggaggacctggactctgtggctccgcgatc 180 cgccccagctggggcctcggagccgcctccgccgggaggggtcggtctggggatccncac 240 cgngaggctntttggggagggogggcc 267 <210> 299 <211> 121 <212> DNA
<213> Homo sapien <400> 299 ggcacgaggg ccctcggagc tcgtttccag atcgaggtaa gagggacttt cttaaaggcc 60 tagtctatgg gatggggcgg cggagggaat tttttgagaa ataaaatgaa gctgcagtgt 120 a 121 <210> 300 <211> 533 <212> DNA
<213> Homo sapien <400>

aaggtgcacagtatttgatgcaggctgctggtcttggtcgtatgaagccaaacacacttg 60 tccttggatttaagaaagattggttgcaagcagatatgagggatgtggatatgtatataa 120 acttatttcatgatgcttttgacatacaatatggagtagtggttattcgcctaaaagaag 180 gtctggatatatctcatcttcaaggacaagaagaattattgtcatcacaagagaaatctc 240 ctggcaccaaggatgtggtagtaagtgtggaatatagtaaaaagtccgatttagatactt 300 ccaaaccactcagtgaaaaaccaattacacacaaagttgaggaagaggatggcaagactg 360 caactcaaccactgttgaaaaaagaatccaaaggccctattgtgcctttaaatgtagctg 420 accaaaagcttcttgaagctagtacacagtttcagaaaaaacaaggaaagaatactattg 480 atgtctggtggctttttgatgatggaggtttgaccttattgataccttacctt 533 <210> 301 <211> 560 <212> DNA
<213> Homo sapien <220>
<221> misc feature <222> (1)...(560) <223> n = A,T,C or G
<400> 301 ataaatgatcccttttattgtaagtaatgcgcaacactggcctggctttgcactgcaagc 60 cctcggtcaagatatagtcaaataactatggctgcaggttccacagttccacaataacca 120 tggctgcacgatccacaattcagacacagacatagagctggggtgggtggaaggggcagg 180 agggtggcagagtgcggactgtccccagccctggcctctccatgcanagttggcccaggc 240 agacacaccccatggaatgatgagaaagtgacggcacggccccttcccacagcaagcctg 300 gggctgccaggaactgcccttcanaacctttgggcccaggtcnccctgaanccccacaac 360 tttttatctggaataagtattaaaaaacaataaattaagcaaacaacntggnccttgaag 420 gatgttgaccnacatggtccacagtt,tttggcncaaaaaaataagggctggtttgctttt 480 tttggaaggcagggtttgtggnttggctttcaaatnattttcaaaccattccccagggag 540 gganaacccccgggggggaa 560 <210> 302 <211> 599 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1)...(599) <223> n = A,T,C or G
<400> 302 gcaaagttacaaatttattggtctggaaataaatacaaatatctcattaanaaactcctc 60 tggaaagacttgtgcacaatagtttcccatccgtactcagCCtCtCttgCCCCgatCCCC 120 gacttttctactcaaggccagggaaggcctccaaggngatgggcggcaggtaacgagtca 180 ttgcctctcacgccacctggaaggctggactacttcctcctcccaactgcggggtcccan 240 aaatcctcgggtcccagnggctgacttacaatattcaattcactctgaccaaacttccta 300 tganaaaatccacggngagccaaaatgaaaagtacaaggcagtagtacaggaacctggca 360 gccgcactggccgcccanaaacgtcagtggngctgccccattcggcgaaaggttagggag 420 caggaaaagaggaagcaggagagggaaggaaagtcccatggaatatgtattccanaatcc 480 ttacattttctcagccaccgctccccacgtgagttcccacccccaccccgacaagaagca 540 aagagttctgaggatccaagaacgtgaccgggtcanacangttcagctactgagttcac 599 <210> 303 <211> 591 <212> DNA
<213> Homo sapien <400> 303 cggagttgtaacgctccactgactgatagagcgaccggccgaccatggcgcccggagtgg 60 cccgcgggccgacgccgtactggaggttgcgcctcggtggcgccgcgctgctcctgctgc 120 tcatcccggtggccgccgcgcaggagcctcccggagctgcttgttctcagaacacaaaca 180 aaacctgtgaagagtgcctgaagaacgtctcctgtctttggtgcaacactaacaaggctt 240 gtctggactacccagttacaagcgtcttgccaccggcttccctttgtaaattgagctctg 300 cacgctggggagtttgttgggtgaactttgaggcgctgatcatcaccatgtcggtagtcg 360 ggggaaccctcctcctgggcattgccatctgctgctgctgctgctgcaggaggaagagga 420 gccggaagccggacaggagtgaggagaaggccatgcgtgagcgggaggagaggcggatac 480 ggcaggaggaacggagagcagagatgaagacaagacatgatgaaatcagaaaaaaatatg 540 gcctgtttaaagaagaaaacccgtatgctagatttgaaaacaactaaagcg 591 <210> 304 <211> 441 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1) . . . (441) <223> n -- A,T,C or G
<400>

gctggacggagacctgctggaggaggaggagctggaggaagcagaggaggaggaccggtc 60 gtcgctgctgctgctgtcgccgcccgcggccaccgcctctcagacccagcagatcccagg 120 cgggtccctggggtctgtgctgctgccagccgccaggttcgatgcccgggaggcggcggc 180 ggcggcgggggtgctgtacggaggggacgatgcccagggcatgatggcggcgatgctgtc 240 ccacgcctacggccccggcggttgtggggcggcggcggccgccctgaacggggagcaggc 300 ggccctgctccggagaaagagcgtcaacaccaccgagtgcgtcccggtgcccagctccga 360 gcacgtcgccgagatcgtcggccgccagggttgtaaaattaaagcactganagccaagac 420 aaacacgtatatcaagactcc 441 <210> 305 <211> 491 <212> DNA
<213> Homo sapien <400>

tcgccatgcccccttcttagcactgcaccgccaggtccatgctgctgccaccccagacct 60 gggctttgcctgccacctctgtgggcagagcttccgaggctgggtggccctggttctgca 120 tctgcgggcccattcagctgcaaagcggcccatcgcttgtcccaaatgcgagagacgctt 180 ctggcgacgaaagcagcttcgagctcatctgcggcggtgccaccctcccgccccggaggc 240 ccggcccttcatatgcggcaactgtggccggagctttgcccagtgggaccagctagttgc 300 ccacaagcgggtgcacgtagctgaggccctggaggaggccgcagccaaggctctggggcc 360 ccggcccaggggccgccccgcggtgaccgccccccggcccggtggagatgccgtcgaccg 420 ccccttccagtgtgcctgttgtggcaagcgcttccggcacaagcccaacttgatcgctca 480 cccgcgcgtgc 491 <210> 306 <211> 547 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1)...(547) <223> n = A,T,C or G
<400> 306 tctctttcttttaagacaggaatgtaagccacaacatttacaaatacaatgttttaactc 60 tctacatgtaggaagccaacctgctcctttttgatcttcttctttggcacaacctcagtg 120 gatttctctgattcagaacgagttctaattgatcttctctgttgcttcttttctactgag 180 cctgtagaaccagatgttgcttcaggagatgatacactctgcgttggcttttcatttctc 240 tggtttggtgtagaaattataagcctgtcttgcccccfigacacttatttctgttttgtta 300 ccaattccctttgttgaataaacaaattgatcgataaatttcccatcccctgtagcattc 360 tgaagagcaaacacttgttcaattttcacaactggagacatgttacacttctgcaaatcc 420 aggctccctttgtgcatccgtaatggaagctggtaaggatttccttgctgccgcagtttt 480 ccaggctat.tttaacaggcggnggctcttcctctttccgcacttgtgtgccgcctctggc 540 tatgtct 547 <210> 307 <211> 571 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1)...(571) <223> n = A,T,C or G
<400> 307 cgctgcatgtgataatgtcatcatttatttttaaatggttctaaattgcanatttaagtt 60 gatttcaaatcaaccctatttttaaattacttttaataggaanaaatgaagcaaggacat 120 acataatctactatatttgaaggactcaaacaaatacatgtttggctgtgaattctgtac 180 tctcaccaaaacagagataaaaatccacctaaaatacactttccttcatttagtgcttgt 240 ggganaaggtcaagtattgcactttaaaattactttcatctaacatttgccccaactttc 300 cccctgaattcactatatgttttcagcaaacatgattttataaattttaagtataaaagc 360 aactaggttttctaattcaactttggaaggtttactttactctacanagctatttttgta 420 aaacggcatatttacttacaaaattganagataggggcatccagctgaggtacatttcct 480 cccttggcgttgagtttctggacttgggtcgggggcacaggcttgtgtgactgccccgtg 540 gcccgatacatggcctggaccccaggatgcg 571 <210> 308 <211> 591 <212> DNA , <213> Homo sapien <220>
<221> misc_feature <222> (1). .(591) <223> n = A,T,C or G
<400> 308 ctccttatgtgtctgcctacttcattcttcggcatttcctgcttatccaagttcaccatt 60 tcaggtcaccactggatatcagttgcctgtatataattatcaggcatttcctgcttatcc 120 aagttcaccatttcaggtcaccactggatatcagttgcctgtatataattatcaggcatt 180 tcctgcttatccaagttcaccatttcaggtcaccaCtggatatcagttgcctgtatataa 240 ttatcaggcatttcctgcttatccaagttcaccatttcaggtcaccactggatatcagtt 300 gcctgtatataattatcaggcatttcctgcttatccaagttcaccatttcaggtcaccac 360 tggatatcagttgcctgtatataattatcaggcatttcctgcttatccaagttcaccatt 420 tcaggtcaccactggatatcagttgcctgtatataattatcaggcatttcctgcttatcc 480 aaattcagcagttcaggtcaccactggatatcagttccatgtatacaattaccagatgcc 540 accgcagtgccctgttgggggagcaaaggagaaatntgtggaccgaagcat 591 <210> 309 <211> 591 <212> DNA
<213> Homo sapien <400> 309 agggggtgcacgtactcccaactgtggtcgcgctctcaccccttctgctgctctcgtggc 60 cccctcgcgatggcgggcatcctgtttgaggatattttcgatgtgaaggatattgacccg 120 gagggcaagaagtttgaccgaggtaagtaagtgtctcgactgcattgtgagagtgaatct 180 ttcaagatggatctaatcttagatgtaaacattcaaatttaccctgtagacttgggtgac 240 aagtttcggttggtcatagctagtaccttgtatgaagatggtaccctggatgatggtgaa 300 tacaaccccactgatgataggccttccagggctgaccagtttgagtatgtaatgtatgga 360 aaagtgtacaggattgagggagatgaaacttctactgaagcagcaacacgcctgctgaga 420 ttgagagctgctgagtggcagtgctccagaatcacgggatggggccttctgtttcagctc 480 ~

tgcgtacgtgtcctatgggggcctgctcatgaggctgcagggggatgccaacaacctgca 540 tggattcgaggtggactccagagtttatctcctgatgaagaagctagcctt 591 <210> 310 <211> 488 <212> DNA
<213> Homo sapien <400> 310 tggtctcaagcctgaagaggctccgcccacaagctggcccatgaagttagcaatgcctgt 60 ggcttcagtcaattgtcttgagactgtgaagaggctgaaagacaccttcccgggtggaag 120 aaggagttcactgaaaacttatcttaaactgacccttccctttgagtgagtcttcattcc 180 tctcccatgtgggaacccagcctccgatgccccggggactaggggaaacagttggaggtc 240 cgtgccgtccccagcctgccacgggtgcgaggacagccaagtcctgagtgactcaagatg 300 cttcacttacatggaagaaacttctaaaactctaccgagtggtttttgtatatactaaag 360 ttctatttagagcttttctgttttgggcaagttcgctgctccttctatttgggcactttg 420 gtttttgtactgtcttttgtgacggcattgattgaacattttttactagtagtcttatga 480 cttttgta 488 <210> 311 <211> 511 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1)...(511) <223> n = A,T,C or G
<400> 311 cccgtttntgnagcaaaanagggggaagatttataggtagaggcgacaaacctaccgagc 60 ctggtgatagctggttgtccaagatagaatctta,gttcaactttaaatttgcccacagaa 120 ccctctaaatccccttgtaaatttaactgttagtccaaagaggaacagctctttggacac 180 taggaaaaaaccttgtagagagagtaaaaaatttaacacccatagtaggcctaaaagcag 240 ccaccaattaagaaagcgttcaagctcaacacccactacctaaaaaatcccaaacatata 300 actgaactcctcacacccaattggaccaatctatcaccctatagaagaactaatgttagt 3~0 ataagtaacatgaaaacattctcctccgcataagcctgcgtcagattaaaacactgaact 420 gacaattaacagcccaatatctacaatcaaccaacaagtcattattaccctcactgtcaa 480 cccaacacaggcatgctcataaggaaaggtt 511 <210> 312 <211> 591 <212> DNA
<213> Homo sapien <400> 312 gaacttgcgttgaaggaagcagaaactgatgaaataaaaattttgctggaagaaagcaga 60 gcccagcagaaggagaccttgaaatctcttcttgaacaagagacagaaaatttgagaaca 120 gaaattagtaaactcaaccaaaagattcaggataataatgaaaattatcaggtgggctta 180 gcagagctaagaactttaatgacaattgaaaaagatcagtgtatttccgagttaattagt 24.0 agacatgaagaagaatctaatatacttaaagctgaattaaacaaagtaacatctttgcat 300 aaccaagcatttgaaatagaaaaaaacctaaaagaacaaataattgaactgcagagtaaa 360 ttggattcagaattgagtgctcttgaaagacaaaaagatgaaaaaattacccaacaagaa 420 gagaaatacgaagctattatccagaaccttgagaaagacagacaaaaattggtcagcagc 480 caggagcaagacagagaacagttaattcagaagcttaattgtgaaaaagatgaagctatt 540 cagactgccctaaaagaatttaaattggagagagaagttgttgagaaagag 591 <210> 313 <211> 373 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1)...(373) <223> n = A, T, C or G
<400> 313 ttgatttttattctgnattttattactgaaatangttgtcctantnatcccaccccacaa 60 taaaaatntnacccangccccccntttctttncctnatnccctnttccaccacaccatcc 120 cggaacaagtgctccaggattccctgcccactggccattttggagtgtgnccattgggta 180 gcaatgtggaaaccaccaaggcctttgtgganaaaatggagggggttgagggagncccan 240 gaggggctnatttgagggcctttgccacttgctcataggcgagctcnatctcctcntnat 300 ctgnacangtggaagcaaattcttcccgggcgtnggnantgctnaagnaccgatgcactc 360 cccggaaggnctn 373 <210> 314 <221> 591 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1). .(591) <223> n = A,T,C or G
<400> 314 cccgtgccgccgccgcctcctgggaagagaggaagcgggagaggagcccacgtcgcctgt 60 cacccaatatctccagccgcgcagtcccgaagagtgtaagatgttcgcctgcgccaagct 120 cgcctgcaccccctctctgatccgagctggatccagagttgcatacagaccaatttctgc 180 atcagtgttatctcgaccagaggctagtaggactggagagggctctacggtatttaatgg 240 ggcccagaatggtgtgtctcagctaatccaaagggagtttcagaccagtgcaatcagcag 300 agacattgatactgctgccaaatttattggtgcaggtgctgcaacagtaggagtggctgg 360 ttctggtgctggtattggaacagtctttggcagccttatcattggttatgccagaaaccc 420 ttcgctgaagcagcagctgttctcatatgctatcctgggatttgccttgtctgaagctat 480 gggtctcttttgtttgatggttgctttcttgattttgtttgccatgtaacaaattactgc 540 ttgacatgttggcattcatattaattacngatgtaattctgtgtatcttac 591 <210> 315 <211> 591 <212> DNA
<213> Homo sapien <220>
<221> misc_feature <222> (1). .(591) <223> n = A,T,C or G
<400> 315 aagcccttcaccaacaaagatgcctatacttgtgcaaattgcagtgcttttgtccacaaa 60 ggctgccgagaaagtctagcctcctgtgcaaaggtcaaaatgaagcagcccaaagggagc 120 cttcaggcacatgacacatcatcactgcccacggtcattatgagaaacaagccctcacag 180 cccaaggagcgtcctcggtccgcagtcctcctggtggatgaaaccgctaccaccccaata 240 tttgccaatagacgatcccagcagagtgtctcgctctccaaaagtgtctccatacagaac 300 attactggagttggcaatgatgagaacatgtcaaacacctggaaattcctgtctcattca 360 acagactcactaaataaaatcagcaaggtcaatgagtcaacagaatcacttactgatgag 420 ggtacagacatgaatgaaggacaactactgggagactttgagattgagtccaaacagctg 480 gaagcagagtcttggagtcggataatagacagcaagtttctaaaacagccaaaagaaaga 540 tgtgggtcaaacngcgagaagtaatatatgagttggatgcagacagagttt 591 DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

~~ TTENANT LES PAGES 1 A 264 NOTE : Pour les tomes additionels, veuillez contacter 1e Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME
NOTE POUR LE TOME / VOLUME NOTE:

Claims (17)

What is Claimed:

1. An isolated polynucleotide comprising a sequence selected from the group consisting of:
(a) sequences provided in SEQ ID NO: 390; 392, 394, 396; 398-420, 422-424, 428-433 and 440-583;
(b) complements of the sequences provided in SEQ ID NO: 390, 392, 394, 396, 398-420; 422-424, 428-433 and 440-583;
(c) sequences consisting of at least 20 contiguous residues of a sequence provided in SEQ ID NO: 390, 392, 394, 396, 398-420, 422-424, 428-433 and 440-583;
(d) sequences that hybridize to a sequence provided in SEQ ID NO:
390, 392, 394, 396, 398-420, 422-424, 428-433 and 440-583, under moderately stringent conditions;
(e) sequences having at least 75% identity to a sequence of SEQ ID
NO: 390, 392, 394, 396, 398-420, 422-424, 428-433 and 440-583;
(f) sequences having at least 90% identity to a sequence of SEQ ID
NO: 390, 392, 394, 396, 398-420 422-424, 428-433 and 440-583; and (g) degenerate variants of a sequence provided in SEQ ID NO: 390, 392, 394, 396, 398-420, 422-424, 428-433 and 440-583.

2. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of:
(a) SEQ ID NO: 584-587;
(b) sequences encoded-by a polynucleotide of claim 1; and (c) sequences having at least 70% identity to a sequence encoded by a polynucleotide of claim 1; and (d) sequences having at least 90% identity to a sequence encoded by a polynucleotide of claim 1.

3. An expression vector comprising a polynucleotide of claim 1 operably linked to an expression control sequence.

4. A host cell transformed or transfected with an expression vector according to claim 3.

5. Are isolated antibody, or antigen-binding fragment thereof, that specifically-binds to a polypeptide of claim 2.

6. A method for detecting the presence of a cancer in a patient, comprising the steps of:
(a) obtaining a biological sample from the patient;
(b) contacting the biological sample with a binding agent that binds to a polypeptide of claim 2;
(c) detecting in the sample an amount of polypeptide that binds to the binding agent; and (d) comparing the amount of polypeptide to a predetermined cut-off value and therefrom determining the presence of a cancer in the patient.

7. A fusion protein comprising at least one polypeptide according to claim 2.

8. An oligonucleotide that hybridizes to a sequence recited in SEQ
ID NO: 390, 392, 394, 396, 398-420 422-424, 428-433 and 440-583 under moderately stringent conditions.

9. A method for stimulating and/or expanding T cells specific for a tumor protein, comprising contacting T cells with at least one component selected from the group consisting of:
(a) polypeptides according to claim 2;

(b) polynucleotides according to-claim 1; and (c) antigen-presenting cells that express a polypeptide according to claim 1, under conditions and for a time sufficient to permit the stimulation and/or expansion of T cells.

14. An isolated T cell population, comprising T cells prepared according to the method of claim 9.

11. A composition comprising a first component selected from the group consisting of physiologically acceptable carriers and immunostimulants, and a second component selected from the group consisting of:

(a) polypeptides according to claim 2;
(b) polynucleotides according to claim 1;
(c) antibodies according to claim 5;
(d) fusion proteins according to claim 7;
(e) T-cell populations according to claim 10; and (f) antigen presenting cells that express a polypeptide according to claim 2.

12. A method for stimulating an immune response in a patient, comprising administering to the patient a composition of claim 11.

13. A method for the treatment of a cancer in a patient, comprising administering to the patient a composition of claim 11.

14. A method for determining the presence of a cancer in a patient, comprising the steps of:
(a) obtaining a biological sample from the patient;

(b) contacting the biological sample with am oligonucleotide according to claim 8;
(c) detecting in the sample an amount of a polynucleotide that hybridizes to the oligonucleotide; and (d) compare the amount of polynucleotide that hybridizes to the oligonucleotide to a predetermined cut-off value, and therefrom determining the presence of the cancer in the patient.

15. A diagnostic kit comprising at last one oligonucleotide according to claim 8.

16. A diagnostic kit comprising at least one antibody according to claim 5 and a detection reagent, wherein the detection reagent comprises a reporter group.

17. A method for inhibiting the development of a cancer in a patient, comprising the steps of:
(a) incubating CID4+ and/or CD8+ T yells isolated from a patient with at least one component selected from the group consisting of: (c) polypeptides according to claim 2; (ii) polynucleotides according to claim 1; and (iii) antigen presenting cells that express a polypeptide of claim 2, such that T cell proliferate;
(b) administering to the patient an effective amount of the proliferated T cells, and thereby inhibiting the development of a cancer in the patient.