Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITIONS AND METHODS FOR THE THERAPY AND
DIAGNOSIS OF PROSTATE CANCER
s TECHNICAL FIELD
The present invention relates generally to therapy and diagnosis of cancer,
such as
prostate cancer. The invention is more specifically related to polypeptides
comprising at least a
portion of a prostate-specific protein, and to polynucleotides encoding such
polypeptides. Such
polypeptides and polynucleotides may be used in vaccines and pharmaceutical
compositions for
l0 prevention and treatment of prostate cancer, and for the diagnosis and
monitoring of such cancers.
BACKGROUND OF THE INVENTION
Prostate cancer is the most common form of cancer among males, with an
estimated
incidence of 30% in men over the age of 50. Overwhelming clinical evidence
shows that human
prostate cancer has the propensity to metastasize to bone, and the disease
appears to progress
1 s inevitably from androgen dependent to androgen refractory status, leading
to increased patient
mortality. This prevalent disease is currently the second leading cause of
cancer death among men
in the U.S.
In spite of considerable research into therapies for the disease, prostate
cancer
remains difficult to treat. Commonly, treatment is based on surgery and/or
radiation therapy, 'but
20 these methods are ineffective in a significant percentage of cases. Two
previously identified
prostate specific proteins - prostate specific antigen (PSA) and prostatic
acid phosphatase (PAP) -
have limited therapeutic and diagnostic potential. For example, PSA levels do
not always correlate
well with the presence of prostate cancer, being positive in a percentage of
non-prostate cancer
cases, including benign prostatic hyperplasia (BPH). Furthermore, PSA
measurements correlate
2s with prostate volume, and do not indicate the level of metastasis.
In spite of considerable research into therapies for these and other cancers,
prostate
cancer remains difficult to diagnose and treat effectively. Accordingly, there
is a need in the art for
improved methods for detecting and treating such cancers. The present
invention fulfills these
needs and further provides other related advantages.
3o SUMMARY OF THE INVENTION
Briefly stated, the present invention provides compositions and methods for
the
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diagnosis and therapy of cancer, such as prostate cancer. In one aspect, the
present invention
provides polypeptides comprising at least a portion of a prostate-specific
protein, or a variant
thereof. Certain portions and other variants are immunogenic, such that the
ability of the variant to
react with antigen-specific antisera is not substantially diminished. Within
certain embodiments,
the polypeptide comprises at least an immunogenic portion of a prostate-
specific protein, or a
variant thereof, wherein the protein comprises an amino acid sequence that is
encoded by a
polynucleotide sequence selected from the group consisting of: (a) sequences
recited in any one of
SEQ ID NOs:I-111, 115-171, 173-175, 177, 179-305, 307-315, 326, 328, 330, 332-
335, 340-375,
381, 382,384-476, 524, 526, 530, 531, 533, 535 and 536; (b) sequences that
hybridize to any of the
to foregoing sequences under moderately stringent conditions; and (c)
complements of any of the
sequence of (a) or (b). In certain specific embodiments, such a polypeptide
comprises at least a
portion, or variant thereof, of a protein that includes an amino acid sequence
selected from the
group consisting of sequences recited in any one of SEQ ID NO: 112-114, 172,
176, 178, 327, 329,
331, 336, 339, 376-380, 383, 477-483, 496, 504, 505, 519, 520, 522, 525, 527,
532, 534, 537-550.
The present invention further provides polynucleotides that encode a
polypeptide as
described above, or a portion thereof (such as a portion encoding at least 15
amino acid residues of a
prostate-specific protein), expression vectors comprising such polynucleotides
and host cells
transformed or transfected with such expression vectors.
Within other aspects, the present invention provides pharmaceutical
compositions
2o comprising a polypeptide or polynucleotide as described above and a
physiologically acceptable
carrier.
Within a related aspect of the present invention, vaccines for prophylactic or
therapeutic use are provided. Such vaccines comprise a polypeptide or
polynucleotide as described
above and an immunostimulant.
The present invention further provides pharmaceutical compositions that
comprise:
(a) an antibody or antigen-binding fragment thereof that specifically binds to
a prostate-specific
protein; and (b) a physiologically acceptable carrier. In certain embodiments,
the present invention
provides monoclonal antibodies that specifically bind to an amino acid
sequence selected from the
group consisting of SEQ ID NO: 496, 504, 505, 509-517, 522 and 541-550,
together with
3o monoclonal antibodies comprising a complementarity determining region
selected from the group
consisting of SEQ ID NO: 502, 503 and 506-508.
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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. Antigen presenting cells
include dendritic cells,
macrophages, monocytes, fibroblasts and B cells.
s Within related aspects, vaccines 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.
Within related aspects, pharmaceutical compositions comprising a fusion
protein, or
a polynucleotide encoding a fusion protein, in combination with a
physiologically acceptable carrier
are provided.
Vaccines are further provided, within other aspects, that comprise a fusion
protein, or
a polynucleotide encoding a fusion protein, in combination with an
immunostimulant.
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 or vaccine as recited above.
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 prostate-specific protein, 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.
Methods are further provided, within other aspects, for stimulating and/or
expanding
T cells specific for a prostate-specific protein, 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 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.
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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 CD8+
T cells isolated from
a patient with one or more of: (i) a polypeptide comprising at least an
immunogenic portion of a
prostate-specific protein; (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.
to 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 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 cancer may be prostate cancer.
The present invention also provides, within other aspects, methods for
monitoring
the progression of a cancer in a patient. Such methods comprise the steps of:
(a) contacting a
2o biological sample obtained from a patient at a first point in time 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 prostate-specific protein; (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
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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 prostate-
specific protein; (b)
1o 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.
Within further aspects, the present invention provides antibodies, such as
t 5 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 and attached drawings. All
references disclosed
2o herein are hereby incorporated by reference in their entirety as if each
was incorporated
individually.
BRIEF DESCRIPTION OF THE DRAWINGS AND SEQUENCE IDENTIFIERS
Figure 1 illustrates the ability of T cells to kill fibroblasts expressing the
representative prostate-specific polypeptide P502S, as compared to control
fibroblasts. The
25 percentage lysis is shown as a series of effectoraarget ratios, as
indicated.
Figures 2A and 2B illustrate the ability of T cells to recognize cells
expressing the
representative prostate-specific polypeptide P502S. In each case, the number
of y-interferon spots is
shown for different numbers of responders. In Figure 2A, data is presented for
fibroblasts pulsed
with the P2S-12 peptide, as compared to fibroblasts pulsed with a control E75
peptide. In Figure
3o 2B, data is presented for fibroblasts expressing P502S, as compared to
fibroblasts expressing HER-
2/neu.
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Figure 3 represents a peptide competition binding assay showing that the
P1S#10
peptide, derived from P501 S, binds HLA-A2. Peptide P 1 S# 10 inhibits HLA-A2
restricted
presentation of fluM58 peptide to CTL clone D150M58 in TNF release bioassay.
D150M58 CTL is
specific for the HLA-A2 binding influenza matrix peptide fluM58.
Figure 4 illustrates the ability of T cell lines generated from P 1 S# 10
immunized mice
to specifically lyse P 1 S# 10-pulsed Jurkat A2Kb targets and P501 S-
transduced Jurkat A2Kb targets, ,
as compared to EGFP-transduced Jurkat A2Kb. The percent lysis is shown as a
series of effector to
target ratios, as indicated.
Figure 5 illustrates the ability of a T cell clone to recognize and
specifically lyse
Jurkat A2Kb cells expressing the representative prostate-specific polypeptide
P501 S, thereby
demonstrating that the P 1 S# 10 peptide may be a naturally processed epitope
of the P501 S
polypeptide.
Figures 6A and 6B are graphs illustrating the specificity of a CD8+ cell line
(3A-1)
for a representative prostate-specific antigen (PSO1S). Figure 6A shows the
results of a 5'Cr release
assay. The percent specific lysis is shown as a series of effectoraarget
ratios, as indicated. Figure
6B shows the production of interferon-gamma by 3A-1 cells stimulated with
autologous B-LCL
transduced with P501 S, at varying effectoraarget rations as indicated.
Figure 7 is a Western blot showing the expression of P501 S in baculovirus.
Figure 8 illustrates the results of epitope mapping studies on P501 S.
Figure 9 is a schematic representation of the P501 S protein showing the
location of
transmembrane domains and predicted intracellular and extracellular domains.
Figure 10 is a genomic map showing the location of the prostate genes P775P,
P704P, B305D, P712P and P774P within the Cat Eye Syndrome region of chromosome
22q11.2
Figure 11 shows the results of an ELISA assay of antibody specificity to P501
S
peptides.
SEQ ID NO: 1 is the determined cDNA sequence for F1-13
SEQ ID NO: 2 is the determined 3' cDNA sequence for F1-12
SEQ ID NO: 3 is the determined 5' cDNA sequence for F1-12
SEQ ID NO: 4 is the determined 3' cDNA sequence for F1-16
SEQ ID NO: 5 is the determined 3' cDNA sequence for H1-1
SEQ ID NO: 6 is the determined 3' cDNA sequence for Hl-9
SEQ ID NO: 7 is the determined 3' cDNA sequence for H1-4
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SEQ ID NO: 8 is the determined 3' cDNA sequence for J1-17
SEQ ID NO: 9 is the determined 5' cDNA sequence for J1-17
SEQ ID NO: 10 is the determined 3' cDNA sequence for L1-12
SEQ ID NO: 11 is the determined 5' cDNA sequence for L1-12
SEQ ID NO: 12 is the determined 3' cDNA sequence for N1-1862
SEQ ID NO: 13 is the determinedcDNA sequence for
5' N1-1862
SEQ ID NO: 14 is the determinedcDNA sequence for
3' J1-13
SEQ ID NO: 15 is the determinedcDNA sequence for
5' J1-13
SEQ ID NO: 16 is the determinedcDNA sequence for
3' J1-19
1o SEQ ID NO: 17 is the determinedcDNA sequence for
5' J1-19
SEQ ID NO: 18 is the determinedcDNA sequence for
3' J1-25
SEQ ID NO: 19 is the determinedcDNA sequence for
5' J1-25
SEQ ID NO: 20 is the determinedcDNA sequence for
5' J 1-24
SEQ ID NO: 21 is the determinedcDNA sequence for
3' J1-24
SEQ ID NO: 22 is the determinedcDNA sequence for
5' Kl-58
SEQ ID NO: 23 is the determinedcDNA sequence for
3' K1-58
SEQ ID NO: 24 is the determinedcDNA sequence for
5' K1-63
SEQ ID NO: 25 is the determinedcDNA sequence for
3' K1-63
SEQ ID NO: 26 is the determinedcDNA sequence for
5' L1-4
2o SEQ ID NO: 27 is the determinedcDNA sequence for
3' L1-4
SEQ ID NO: 28 is the determinedcDNA sequence for
5' L1-14
SEQ ID NO: 29 is the determinedcDNA sequence for
3' L1-14
SEQ ID NO: 30 is the determinedcDNA sequence for
3' J1-12
SEQ ID NO: 31 is the determinedcDNA sequence for
3' J1-16
SEQ ID NO: 32 is the determinedcDNA sequence for
3' J1-21
SEQ ID NO: 33 is the determinedcDNA sequence for
3' K1-48
SEQ ID NO: 34 is the determinedcDNA sequence for
3' K1-55
SEQ ID NO: 35 is the determinedcDNA sequence for
3' L1-2
SEQ ID NO: 36 is the determinedcDNA sequence for
3' L1-6
3o SEQ ID NO: 37 is the determinedcDNA sequence for
3' N1-1858
SEQ ID NO: 38 is the determinedcDNA sequence for
3' N1-1860
SEQ ID NO: 39 is the determinedcDNA sequence for
3' Nl-1861
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SEQ ID NO: 40 is the determined 3' cDNA sequence for N1-1864
SEQ ID NO: 41 is the determined cDNA sequence for PS
SEQ ID NO: 42 is the determined cDNA sequence for P8
SEQ ID NO: 43 is the determined cDNA sequence for P9
SEQ ID NO: 44 is the determined cDNA sequence for P 18
SEQ ID NO: 45 is the determined cDNA sequence for P20
SEQ ID NO: 46 is the determined cDNA sequence for P29
SEQ ID NO: 47 is the determined cDNA sequence for P30
SEQ ID NO: 48 is the determined cDNA sequence for P34
1o SEQ ID NO: 49 is the determined cDNA sequence for P36
SEQ ID NO: 50 is the determined cDNA sequence for P38
SEQ ID NO: S 1 is the determined cDNA sequence for P39
SEQ ID NO: 52 is the determined cDNA sequence for P42
SEQ ID NO: 53 is the determined cDNA sequence for P47
SEQ ID NO: 54 is the determined cDNA sequence for P49
SEQ ID NO: 55 is the determined cDNA sequence for P50
SEQ ID NO: 56 is the determined cDNA sequence for P53
SEQ ID NO: 57 is the determined cDNA sequence for P55
SEQ ID NO: 58 is the determined cDNA sequence for P60
2o SEQ ID NO: 59 is the determined cDNA sequence for P64
SEQ ID NO: 60 is the determined cDNA sequence for P65
SEQ ID NO: 61 is the determined cDNA sequence for P73
SEQ ID NO: 62 is the determined cDNA sequence for P75
SEQ ID NO: 63 is the determined cDNA sequence for P76
SEQ ID NO: 64 is the determined cDNA sequence for P79
SEQ ID NO: 65 is the determined cDNA sequence for P84
SEQ ID NO: 66 is the determined cDNA sequence for P68
SEQ ID NO: 67 is the determined cDNA sequence for P80
SEQ ID NO: 68 is the determined cDNA sequence for P82
3o SEQ ID NO: 69 is the determined cDNA sequence for U1-3064
SEQ ID NO: 70 is the determined cDNA sequence for U1-3065
SEQ ID NO: 71 is the determined cDNA sequence for V 1-3692
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SEQ ID NO: 72 is the determined cDNA sequence for 1A-3905
SEQ ID NO: 73 is the determined cDNA sequence for V1-3686
SEQ ID NO: 74 is the determined cDNA sequence for R1-2330
SEQ ID NO: 75 is the determined cDNA sequence for 1B-3976
SEQ ID NO: 76 is the determined cDNA sequence for Vl-3679
SEQ ID NO: 77 is the determined cDNA sequence forlG-4736
SEQ ID NO: 78 is the determined cDNA sequence for 1G-4738
SEQ ID NO: 79 is the determined cDNA sequence for 1 G-4741
SEQ ID NO: 80 is the determined cDNA sequence for 1 G-4744
l0 SEQ ID NO: 81 is the determined cDNA sequence for 1 G-4734
SEQ ID NO: 82 is the determined cDNA sequence for 1H-4774
SEQ ID NO: 83 is the determined cDNA sequence for 1H-4781
SEQ ID NO: 84 is the determined cDNA sequence for 1H-4785
SEQ ID NO: 85 is the determined cDNA sequence for 1H-4787
is SEQ ID NO: 86 is the determined cDNA sequence for 1H-4796
SEQ ID NO: 87 is the determined cDNA sequence for 1I-4807
SEQ ID NO: 88 is the determined cDNA sequence for 1I-4810
SEQ ID NO: 89 is the determined cDNA sequence for 1I-4811
SEQ ID NO: 90 is the determined cDNA sequence for 1J-4876
2o SEQ ID NO: 91 is the determined cDNA sequence for 1K-4884
SEQ ID NO: 92 is the determined cDNA sequence for 1K-4896
SEQ ID NO: 93 is the determined cDNA sequence for 1 G-4761
SEQ ID NO: 94 is the determined cDNA sequence for 1 G-4762
SEQ ID NO: 95 is the determined cDNA sequence for 1 H-4766
25 SEQ ID NO: 96 is the determined cDNA sequence for 1H-4770
SEQ ID NO: 97 is the determined cDNA sequence for 1H-4771
SEQ ID NO: 98 is the determined cDNA sequence for 1 H-4772
SEQ ID NO: 99 is the determined cDNA sequence for 1 D-4297
SEQ ID NO: 100 is the determined cDNA sequence for 1D-4309
3o SEQ ID NO: 101 is the determined cDNA sequence for 1D.1-4278
SEQ ID NO: 102 is the determined cDNA sequence for 1 D-4288
SEQ ID NO: 103 is the determined cDNA sequence for 1D-4283
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SEQ ID NO: 104 is the determined cDNA sequence for 1D-4304
SEQ ID NO: 105 is the determined cDNA sequence for 1D-4296
SEQ ID NO: 106 is the determined cDNA sequence for 1D-4280
SEQ ID NO: 107 is the determined full length cDNA sequence for F1-12 (also
referred to as P504S)
SEQ ID NO: 108 is the predicted amino acid sequence for F1-12
SEQ ID NO: 109 is the determined full length cDNA sequence for J1-17
SEQ ID NO: 110 is the determined full length cDNA sequence for L1-12 (also
referred to as P501 S)
SEQ ID NO: 111 is the determined full length cDNA sequence for N1-1862 (also
referred to as
to P503S)
SEQ ID NO: 112 is the predicted amino acid sequence for J1-17
SEQ ID NO: 113 is the predicted amino acid sequence for L1-12 (also referred
to as P501 S)
SEQ ID NO: 114 is the predicted amino acid sequence for N1-1862 (also referred
to as P503S)
SEQ ID NO: 115 is the determined cDNA sequence for P89
1 s SEQ ID NO: 116 is the determined cDNA sequence for P90
SEQ ID NO: 117 is the determined cDNA sequence for P92
SEQ ID NO: 118 is the determined cDNA sequence for P95
SEQ ID NO: 119 is the determined cDNA sequence for P98
SEQ ID NO: 120 is the determined cDNA sequence for P 102
20 SEQ ID NO: 121 is the determined cDNA sequence for P110
SEQ ID NO: 122 is the determined cDNA sequence for P111
SEQ ID NO: 123 is the determined cDNA sequence for P114
SEQ ID NO: 124 is the determined cDNA sequence for P 115
SEQ ID NO: 125 is the determined cDNA sequence for Pl 16
2s SEQ ID NO: 126 is the determined cDNA sequence for P 124
SEQ ID NO: 127 is the determined cDNA sequence for P 126
SEQ ID NO: 128 is the determined cDNA sequence for P130
SEQ ID NO: 129 is the determined cDNA sequence for P133
SEQ ID NO: 130 is the determined cDNA sequence for P138
3o SEQ ID NO: 131 is the determined cDNA sequence for P143
SEQ ID NO: 132 is the determined cDNA sequence for P151
SEQ ID NO: 133 is the determined cDNA sequence for P156
to
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SEQ ID NO: 134 is the determined cDNA sequence for P157
SEQ ID NO: 135 is the determined cDNA sequence for P166
SEQ ID NO: 136 is the determined cDNA sequence for P176
SEQ ID NO: 137 is the determined cDNA sequence for P178
SEQ ID NO: 138 is the determined cDNA sequence for P179
SEQ ID NO: 139 is the determined cDNA sequence for P185
SEQ ID NO: 140 is the determined cDNA sequence for P 192
SEQ ID NO: 141 is the determined cDNA sequence for P201
SEQ ID NO: 142 is the determined cDNA sequence for P204
to SEQ ID NO: 143 is the determined cDNA sequence for P208
SEQ ID NO: 144 is the determined cDNA sequence for P211
SEQ ID NO: 145 is the determined cDNA sequence for P213
SEQ ID NO: 146 is the determined cDNA sequence for P219
SEQ ID NO: 147 is the determined cDNA sequence for P237
SEQ ID NO: 148 is the determined cDNA sequence for P239
SEQ ID NO: 149 is the determined cDNA sequence for P248
SEQ ID NO: 150 is the determined cDNA sequence for P251
SEQ ID NO: 151 is the determined cDNA sequence for P255
SEQ ID NO: 152 is the determined cDNA sequence for P256
2o SEQ ID NO: 153 is the determined cDNA sequence for P259
SEQ ID NO: 154 is the determined cDNA sequence for P260
SEQ ID NO: 155 is the determined cDNA sequence for P263
SEQ ID NO: 156 is the determined cDNA sequence for P264
SEQ ID NO: 157 is the determined cDNA sequence for P266
SEQ ID NO: 158 is the determined cDNA sequence for P270
SEQ ID NO: 159 is the determined cDNA sequence for P272
SEQ ID NO: 160 is the determined cDNA sequence for P278
SEQ ID NO: 161 is the determined cDNA sequence for P105
SEQ ID NO: 162 is the determined cDNA sequence for P 107
3o SEQ ID NO: 163 is the determined cDNA sequence for P137
SEQ ID NO: 164 is the determined cDNA sequence for P 194
SEQ ID NO: 165 is the determined cDNA sequence for P195
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SEQ ID NO: 166 is the determined cDNA sequence for P196
SEQ ID NO: 167 is the determined cDNA sequence for P220
SEQ ID NO: 168 is the determined cDNA sequence for P234
SEQ ID NO: 169 is the determined cDNA sequence for P235
SEQ ID NO: 170 is the determined cDNA sequence for P243
SEQ ID NO: 171 is the determined cDNA sequence for P703P-DE1
SEQ ID NO: 172 is the predicted amino acid sequence for P703P-DE1
SEQ ID NO: 173 is the determined cDNA sequence for P703P-DE2
SEQ ID NO: 174 is the determined cDNA sequence for P703P-DE6
SEQ ID NO: 175 is the determined cDNA sequence for P703P-DE13
SEQ ID NO: 176 is the predicted amino acid sequence for P703P-DE13
SEQ ID NO: 177 is the determined cDNA sequence for P703P-DE14
SEQ ID NO: 178 is the predicted amino acid sequence for P703P-DE14
SEQ ID NO: 179 is the determined extended cDNA sequence for 1G-4736
SEQ ID NO: 180 is the determined extended cDNA sequence for 1G-4738
SEQ ID NO: 181 is the determined extended cDNA sequence for 1 G-4741
SEQ ID NO: 182 is the determined extended cDNA sequence for 1 G-4744
SEQ ID NO: 183 is the determined extended cDNA sequence for 1H-4774
SEQ ID NO: 184 is the determined extended cDNA sequence for 1H-4781
SEQ ID NO: 185 is the determined extended cDNA sequence for 1H-4785
SEQ ID NO: 186 is the determined extended cDNA sequence for 1 H-4787
SEQ ID NO: 187 is the determined extended cDNA sequence for 1H-4796
SEQ ID NO: 188 is the determined extended cDNA sequence for 1I-4807
SEQ ID NO: 189 is the determined 3' cDNA sequence for 1I-4810
SEQ ID NO: 190 is the determined 3' cDNA sequence for l I-4811
SEQ ID NO: 191 is the determined extended cDNA sequence for 1 J-4876
SEQ ID NO: 192 is the determined extended cDNA sequence for 1K-4884
SEQ ID NO: 193 is the determined extended cDNA sequence for 1K-4896
SEQ ID NO: 194 is the determined extended cDNA sequence for 1 G-4761
SEQ ID NO: 195 is the determined extended cDNA sequence for 1 G-4762
SEQ ID NO: 196 is the determined extended cDNA sequence for 1H-4766
SEQ ID NO: 197 is the determined 3' cDNA sequence for 1 H-4770
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SEQ ID NO: 198 is the determined 3' cDNA sequence for 1 H-4771
SEQ ID NO: 199 is the determined extended cDNA sequence for 1 H-4772
SEQ ID NO: 200 is the determined extended cDNA sequence for 1D-4309
SEQ ID NO: 201 is the determined extended cDNA sequence for 1D.1-4278
SEQ ID NO: 202 is the determined extended cDNA sequence for 1D-4288
SEQ ID NO: 203 is the determined extended cDNA sequence for 1D-4283
SEQ ID NO: 204 is the determined extended cDNA sequence for 1D-4304
SEQ ID NO: 205 is the determined extended cDNA sequence for 1 D-4296
SEQ ID NO: 206 is the determined extended cDNA sequence for 1D-4280
t o SEQ ID NO: 207 is the determined cDNA sequence for 10-d8fwd
SEQ ID NO: 208 is the determined cDNA sequence for 10-HlOcon
SEQ ID NO: 209 is the determined cDNA sequence for 11-CBrev
SEQ ID NO: 210 is the determined cDNA sequence for 7.g6fwd
SEQ ID NO: 211 is the determined cDNA sequence for 7.g6rev
t 5 SEQ ID NO: 212 is the determined cDNA sequence for 8-b5fwd
SEQ ID NO: 213 is the determined cDNA sequence for 8-b5rev
SEQ ID NO: 214 is the determined cDNA sequence for 8-b6fwd
SEQ ID NO: 21 S is the determined cDNA sequence for 8-b6 rev
SEQ ID NO: 216 is the determined cDNA sequence for 8-d4fwd
20 SEQ ID NO: 217 is the determined cDNA sequence for 8-d9rev
SEQ ID NO: 218 is the determined cDNA sequence for 8-g3fwd
SEQ ID NO: 219 is the determined cDNA sequence for 8-g3rev
SEQ ID NO: 220 is the determined cDNA sequence for 8-h 11 rev
SEQ ID NO: 221 is the determined cDNA sequence for g-fl2fwd
25 SEQ ID NO: 222 is the determined cDNA sequence for g-f3rev
SEQ ID NO: 223 is the determined cDNA sequence for P509S
SEQ ID NO: 224 is the determined cDNA sequence for PS l OS
SEQ ID NO: 225 is the determined cDNA sequence for P703DE5
SEQ ID NO: 226 is the determined cDNA sequence for 9-A11
3o SEQ ID NO: 227 is the determined cDNA sequence for 8-C6
SEQ ID NO: 228 is the determined cDNA sequence for 8-H7
SEQ ID NO: 229 is the determined cDNA sequence for JPTPN13
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SEQ ID NO: 230 is the determined cDNA sequence for JPTPN14
SEQ ID NO: 231 is the determined cDNA sequence for JPTPN23
SEQ ID NO: 232 is the determined cDNA sequence for JPTPN24
SEQ ID NO: 233 is the determined cDNA sequence for JPTPN25
SEQ ID NO: 234 is the determined cDNA sequence for JPTPN30
SEQ ID NO: 235 is the determined cDNA sequence for JPTPN34
SEQ ID NO: 236 is the determined cDNA sequence for PTPN35
SEQ ID NO: 237 is the determined cDNA sequence for JPTPN36
SEQ ID NO: 238 is the determined cDNA sequence for JPTPN38
to SEQ ID NO: 239 is the determined cDNA sequence for JPTPN39
SEQ ID NO: 240 is the determined cDNA sequence for JPTPN40
SEQ ID NO: 241 is the determined cDNA sequence for JPTPN41
SEQ ID NO: 242 is the determined cDNA sequence for JPTPN42
SEQ ID NO: 243 is the determined cDNA sequence for JPTPN45
SEQ ID NO: 244 is the determined cDNA sequence for JPTPN46
SEQ ID NO: 245 is the determined cDNA sequence for JPTPN51
SEQ ID NO: 246 is the determined cDNA sequence for JPTPN56
SEQ ID NO: 247 is the determined cDNA sequence for PTPN64
SEQ ID NO: 248 is the determined cDNA sequence for JPTPN65
SEQ ID NO: 249 is the determined cDNA sequence for JPTPN67
SEQ ID NO: 250 is the determined cDNA sequence for JPTPN76
SEQ ID NO: 251 is the determined cDNA sequence for JPTPN84
SEQ ID NO: 252 is the determined cDNA sequence for JPTPN85
SEQ ID NO: 253 is the determined cDNA sequence for JPTPN86
SEQ ID NO: 254 is the determined cDNA sequence for JPTPN87
SEQ ID NO: 255 is the determined cDNA sequence for JPTPN88
SEQ ID NO: 256 is the determined cDNA sequence for JP 1 F 1
SEQ ID NO: 257 is the determined cDNA sequence for JP1F2
SEQ ID NO: 258 is the determined cDNA sequence for JP 1 C2
3o SEQ ID NO: 259 is the determined cDNA sequence for JP1B1
SEQ ID NO: 260 is the determined cDNA sequence for JP 1 B2
SEQ ID NO: 261 is the determined cDNA sequence for JP1D3
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SEQ ID NO: 262 is the determined cDNA sequence for JP1A4
SEQ ID NO: 263 is the determined cDNA sequence for JP1F5
SEQ ID NO: 264 is the determined cDNA sequence for JP1E6
SEQ ID NO: 265 is the determined cDNA sequence for JP 1 D6
SEQ ID NO: 266 is the determined cDNA sequence for JP 1 B 5
SEQ ID NO: 267 is the determined cDNA sequence for JP 1 A6
SEQ ID NO: 268 is the determined cDNA sequence for JP 1 E8
SEQ ID NO: 269 is the determined cDNA sequence for JP1D7
SEQ ID NO: 270 is the determined cDNA sequence for JP1D9
1 o SEQ ID NO: 271 is the determined cDNA sequence for JP 1 C 10
SEQ ID NO: 272 is the determined cDNA sequence for JP1A9
SEQ ID NO: 273 is the determined cDNA sequence for JP 1 F 12
SEQ ID NO: 274 is the determined cDNA sequence for JP 1 E 12
SEQ ID NO: 275 is the determined cDNA sequence for JP 1 D 11
SEQ ID NO: 276 is the determined cDNA sequence for JP 1 C 11
SEQ ID NO: 277 is the determined cDNA sequence for JP 1 C 12
SEQ ID NO: 278 is the determined cDNA sequence for JP 1 B 12
SEQ ID NO: 279 is the determined cDNA sequence for JP 1 A 12
SEQ ID NO: 280 is the determined cDNA sequence for JP8G2
SEQ ID NO: 281 is the determined cDNA sequence for JP8H1
SEQ ID NO: 282 is the determined cDNA sequence for JP8H2 -
SEQ ID NO: 283 is the determined cDNA sequence for JP8A3
SEQ ID NO: 284 is the determined cDNA sequence for JP8A4
SEQ ID NO: 285 is the determined cDNA sequence for JP8C3
SEQ ID NO: 286 is the determined cDNA sequence for JP8G4
SEQ ID NO: 287 is the determined cDNA sequence for JP8B6
SEQ ID NO: 288 is the determined cDNA sequence for JP8D6
SEQ ID NO: 289 is the determined cDNA sequence for JP8F5
SEQ ID NO: 290 is the determined cDNA sequence for JP8A8
3o SEQ ID NO: 291 is the determined cDNA sequence for JP8C7
SEQ ID NO: 292 is the determined cDNA sequence for JP8D7
SEQ ID NO: 293 is the determined cDNA sequence for P8D8
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SEQ ID NO: 294 is the determined cDNA sequence for JP8E7
SEQ ID NO: 295 is the determined cDNA sequence for JP8F8
SEQ ID NO: 296 is the determined cDNA sequence for JP8G8
SEQ ID NO: 297 is the determined cDNA sequence for JP8B10
SEQ ID NO: 298 is the determined cDNA sequence for JP8C10
SEQ ID NO: 299 is the determined cDNA sequence for JP8E9
SEQ ID NO: 300 is the determined cDNA sequence for JP8E10
SEQ ID NO: 301 is the determined cDNA sequence for JP8F9
SEQ ID NO: 302 is the determined cDNA sequence for JP8H9
l0 SEQ ID NO: 303 is the determined cDNA sequence for JP8C12
SEQ ID NO: 304 is the determined cDNA sequence for JP8E11
SEQ ID NO: 305 is the determined cDNA sequence for JP8E12
SEQ ID NO: 306 is the amino acid sequence for the peptide PS2#12
SEQ ID NO: 307 is the determined cDNA sequence for P711P
SEQ ID NO: 308 is the determined cDNA sequence for P712P
SEQ ID NO: 309 is the determined cDNA sequence for CLONE23
SEQ ID NO: 310 is the determined cDNA sequence for P774P
SEQ ID NO: 311 is the determined cDNA sequence for P775P
SEQ ID NO: 312 is the determined cDNA sequence for P715P
SEQ ID NO: 313 is the determined cDNA sequence for P714P
SEQ ID NO: 314 is the determined cDNA sequence for P767P
SEQ ID NO: 315 is the determined cDNA sequence for P768P
SEQ ID NO: 316-325 are the determined cDNA sequences of previously isolated
genes
SEQ ID NO: 326 is the determined cDNA sequence for P703PDE5
SEQ ID NO: 327 is the predicted amino acid sequence for P703PDE5
SEQ ID NO: 328 is the determined cDNA sequence for P703P6.26
SEQ ID NO: 329 is the predicted amino acid sequence for P703P6.26
SEQ ID NO: 330 is the determined cDNA sequence for P703PX-23
SEQ ID NO: 331 is the predicted amino acid sequence for P703PX-23
3o SEQ ID NO: 332 is the determined full length cDNA sequence for P509S
SEQ ID NO: 333 is the determined extended cDNA sequence for P707P (also
referred to as 11-C9)
SEQ ID NO: 334 is the determined cDNA sequence for P714P
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SEQ ID NO: 335 is the determined cDNA sequence for P705P (also referred to as
9-F3)
SEQ ID NO: 336 is the predicted amino acid sequence for P705P
SEQ ID NO: 337 is the amino acid sequence of the peptide P1S#10
SEQ ID NO: 338 is the amino acid sequence of the peptide p5
SEQ ID NO: 339 is the predicted amino acid sequence of P509S
SEQ ID NO: 340 is the determined cDNA sequence for P778P
SEQ ID NO: 341 is the determined cDNA sequence for P786P
SEQ ID NO: 342 is the determined cDNA sequence for P789P
SEQ ID NO: 343 is the determined cDNA sequence for a clone showing homology to
Homo
l0 sapiens MM46 mRNA
SEQ ID NO: 344 is the determined cDNA sequence for a clone showing homology to
Homo
Sapiens TNF-alpha stimulated ABC protein (ABC50) mRNA
SEQ ID NO: 345 is the determined cDNA sequence for a clone showing homology to
Homo
Sapiens mRNA for E-cadherin
SEQ ID NO: 346 is the determined cDNA sequence for a clone showing homology to
Human
nuclear-encoded mitochondria) serine hydroxymethyltransferase (SHMT)
SEQ ID NO: 347 is the determined cDNA sequence for a clone showing homology to
Homo
Sapiens natural resistance-associated macrophage protein2 (NRAMP2)
SEQ ID NO: 348 is the determined cDNA sequence for a clone showing homology to
Homo
Sapiens phosphoglucomutase-related protein (PGMRP)
SEQ ID NO: 349 is the determined cDNA sequence for a clone showing homology to
Human
mRNA for proteosome subunit p40
SEQ ID NO: 350 is the determined cDNA sequence for P777P
SEQ ID NO: 351 is the determined cDNA sequence for P779P
SEQ ID NO: 352 is the determined cDNA sequence for P790P
SEQ ID NO: 353 is the determined cDNA sequence for P784P
SEQ ID NO: 354 is the determined cDNA sequence for P776P
SEQ ID NO: 355 is the determined cDNA sequence for P780P
SEQ ID NO: 356 is the determined cDNA sequence for.P544S
SEQ ID NO: 357 is the determined cDNA sequence for P745S
SEQ ID NO: 358 is the determined cDNA sequence for P782P
SEQ ID NO: 359 is the determined cDNA sequence for P783P
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SEQ ID NO: 360 is the determined cDNA sequence for unknown 17984
SEQ ID NO: 361 is the determined cDNA sequence for P787P
SEQ ID NO: 362 is the determined cDNA sequence for P788P
SEQ ID NO: 363 is the determined cDNA sequence for unknown 17994
SEQ ID NO: 364 is the determined cDNA sequence for P781P
SEQ ID NO: 365 is the determined cDNA sequence for P785P
SEQ ID NO: 366-375 are the determined cDNA sequences for splice variants of
B305D.
SEQ ID NO: 376 is the predicted amino acid sequence encoded by the sequence of
SEQ ID NO:
366.
SEQ ID NO: 377 is the predicted amino acid sequence encoded by the sequence of
SEQ ID NO:
372.
SEQ ID NO: 378 is the predicted amino acid sequence encoded by the sequence of
SEQ ID NO:
373.
SEQ ID NO: 379 is the predicted amino acid sequence encoded by the sequence of
SEQ ID NO:
374.
SEQ ID NO: 380 is the predicted amino acid sequence encoded by the sequence of
SEQ ID NO:
375.
SEQ ID NO: 381 is the determined cDNA sequence for B716P.
SEQ ID NO: 382 is the determined full-length cDNA sequence for P711P.
SEQ ID NO: 383 is the predicted amino acid sequence for P711P.
SEQ ID NO: 384 is the cDNA sequence for P1000C.
SEQ ID NO: 385 is the cDNA sequence for CGI-82.
SEQ ID N0:386 is the cDNA sequence for 23320.
SEQ ID N0:387 is the cDNA sequence for CGI-69.
SEQ ID N0:388 is the cDNA sequence for L-iditol-2-dehydrogenase.
SEQ ID N0:389 is the cDNA sequence for 23379.
SEQ ID N0:390 is the cDNA sequence for 23381.
SEQ ID N0:391 is the cDNA sequence for KIAA0122.
SEQ ID N0:392 is the cDNA sequence for 23399.
SEQ ID N0:393 is the cDNA sequence for a previously identified gene.
SEQ ID N0:394 is the cDNA sequence for HCLBP.
SEQ ID N0:395 is the cDNA sequence for transglutaminase.
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SEQ ID N0:396 is the cDNA sequence for a previously identified gene.
SEQ ID N0:397 is the cDNA sequence for PAP.
SEQ ID N0:398 is the cDNA sequence for Ets transcription factor PDEF.
SEQ ID N0:399 is the cDNA sequence for hTGR.
SEQ ID N0:400 is the cDNA sequence for KIAA0295.
SEQ ID N0:401 is the cDNA sequence for 22545.
SEQ ID N0:402 is the cDNA sequence for 22547.
SEQ ID N0:403 is the cDNA sequence for 22548:
SEQ ID N0:404 is the cDNA sequence for 22550.
to SEQ ID N0:405 is the cDNA sequence for 22551.
SEQ ID N0:406 is the cDNA sequence for 22552.
SEQ ID N0:407 is the cDNA sequence for 22553.
SEQ ID N0:408 is the cDNA sequence for 22558.
SEQ ID N0:409 is the cDNA sequence for 22562.
SEQ ID N0:410 is the cDNA sequence for 22565.
SEQ ID N0:411 is the cDNA sequence for 22567.
SEQ ID N0:412 is the cDNA sequence for 22568.
SEQ ID N0:413 is the cDNA sequence for 22570.
SEQ ID N0:414 is the cDNA sequence for 22571.
2o SEQ ID N0:415 is the cDNA sequence for 22572.
SEQ ID N0:416 is the cDNA sequence for 22573.
SEQ ID N0:417 is the cDNA sequence for 22573.
SEQ ID N0:418 is the cDNA sequence for 22575.
SEQ ID N0:419 is the cDNA sequence for 22580.
SEQ ID N0:420 is the cDNA sequence for 22581.
SEQ ID N0:421 is the cDNA sequence for 22582.
SEQ ID N0:422 is the cDNA sequence for 22583.
SEQ ID N0:423 is the cDNA sequence for 22584.
SEQ ID N0:424 is the cDNA sequence for 22585.
3o SEQ ID N0:425 is the cDNA sequence for 22586.
SEQ ID N0:426 is the cDNA sequence for 22587.
SEQ ID N0:427 is the cDNA sequence for 22588.
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SEQ ID N0:428 is the cDNA sequence for 22589.
SEQ ID N0:429 is the cDNA sequence for 22590.
SEQ ID N0:430 is the cDNA sequence for 22591.
SEQ ID N0:431 is the cDNA sequence for 22592.
SEQ ID N0:432 is the cDNA sequence for 22593.
SEQ ID N0:433 is the cDNA sequence for 22594.
SEQ ID N0:434 is the cDNA sequence for 22595.
SEQ ID N0:435 is the cDNA sequence for 22596.
SEQ ID N0:436 is the cDNA sequence for 22847.
1o SEQ ID N0:437 is the cDNA sequence for 22848.
SEQ ID N0:438 is the cDNA sequence for 22849.
SEQ ID N0:439 is the cDNA sequence for 22851.
SEQ ID N0:440 is the cDNA sequence for 22852.
SEQ ID N0:441 is the cDNA sequence for 22853.
SEQ ID N0:442 is the cDNA sequence for 22854.
SEQ ID N0:443 is the cDNA sequence for 22855.
SEQ ID N0:444 is the cDNA sequence for 22856.
SEQ ID N0:445 is the cDNA sequence for 22857.
SEQ ID N0:446 is the cDNA sequence for 23601.
2o SEQ ID N0:447 is the cDNA sequence for 23602.
SEQ ID N0:448 is the cDNA sequence for 23605.
SEQ ID N0:449 is the cDNA sequence for 23606.
SEQ ID N0:450 is the cDNA sequence for 23612.
SEQ ID N0:451 is the cDNA sequence for 23614.
SEQ ID N0:452 is the cDNA sequence for 23618.
SEQ ID N0:453 is the cDNA sequence for 23622.
SEQ ID N0:454 is the cDNA sequence for folate hydrolase.
SEQ ID N0:455 is the cDNA sequence for LIM protein.
SEQ ID N0:456 is the cDNA sequence for a known gene.
SEQ ID N0:457 is the cDNA sequence for a known gene.
SEQ ID N0:458 is the cDNA sequence for a previously identified gene.
SEQ ID N0:459 is the cDNA sequence for 23045.
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SEQ ID N0:460 is the cDNA sequence for 23032.
SEQ ID N0:461 is the cDNA sequence for 23054.
SEQ ID N0:462-467 are cDNA sequences for known genes.
SEQ ID N0:468-471 are cDNA sequences for P710P.
SEQ ID N0:472 is a cDNA sequence for P 1001 C.
SEQ ID NO: 473 is the determined cDNA sequence for a first splice variant of
P775P (referred to as
27505).
SEQ ID NO: 474 is the determined cDNA sequence for a second splice variant of
P775P (referred
to as 19947).
SEQ ID NO: 475 is the determined cDNA sequence for a third splice variant of
P775P (referred to
as 19941 ).
SEQ ID NO: 476 is the determined cDNA sequence for a fourth splice variant of
P775P (referred to
as 19937).
SEQ ID NO: 477 is a first predicted amino acid sequence encoded by the
sequence of SEQ ID NO:
t 5 474.
SEQ ID NO: 478 is a second predicted amino acid sequence encoded by the
sequence of SEQ ID
NO: 474.
SEQ ID NO: 479 is the predicted amino acid sequence encoded by the sequence of
SEQ ID NO:
475.
2o SEQ ID NO: 480 is a first predicted amino acid sequence encoded by the
sequence of SEQ ID NO:
473.
SEQ ID NO: 481 is a second predicted amino acid sequence encoded by the
sequence of SEQ ID
NO: 473.
SEQ ID NO: 482 is a third predicted amino acid sequence encoded by the
sequence of SEQ ID NO:
25 473.
SEQ ID NO: 483 is a fourth predicted amino acid sequence encoded by the
sequence of SEQ ID
NO: 473.
SEQ ID NO: 484 is the first 30 amino acids of the M. tuberculosis antigen
Ral2.
SEQ ID NO: 485 is the PCR primer AW025.
3o SEQ ID NO: 486 is the PCR primer AW003.
SEQ ID NO: 487 is the PCR primer AW027.
SEQ ID NO: 488 is the PCR primer AW026.
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SEQ ID NO: 489-501 are peptides employed in epitope mapping studies.
SEQ ID NO: 502 is the determined cDNA sequence of the complementarity
determining region for
the anti-P503S monoclonal antibody 20D4.
SEQ ID NO: 503 is the determined cDNA sequence of the complementarity
determining region for
the anti-P503S monoclonal antibody JA1.
SEQ ID NO: 504 & 505 are peptides employed in epitope mapping studies.
SEQ ID NO: 506 is the determined cDNA sequence of the complementarity
determining region for
the anti-P703P monoclonal antibody 8H2.
SEQ ID NO: 507 is the determined cDNA sequence of the complementarity
determining region for
to the anti-P703P monoclonal antibody 7H8.
SEQ ID NO: 508 is the determined cDNA sequence of the complementarity
determining region for
the anti-P703P monoclonal antibody 2D4.
SEQ ID NO: 509-522 are peptides employed in epitope mapping studies.
SEQ ID NO: 523 is a mature form of P703P used to raise antibodies against
P703P.SEQ ID NO:
524 is the putative full-length cDNA sequence of P703P.
SEQ ID NO: 525 is the predicted amino acid sequence encoded by SEQ ID NO: 524.
SEQ ID NO: 526 is the full-length cDNA sequence for P790P.
SEQ ID NO: 527 is the predicted amino acid sequence for P790P.
SEQ ID NO: 528 & 529 are PCR primers.
2o SEQ ID NO: 530 is the cDNA sequence of a splice variant of SEQ ID NO: 366.
SEQ ID NO: 531 is the cDNA sequence of the open reading frame of SEQ ID NO:
530.
SEQ ID NO: 532 is the predicted amino acid encoded by the sequence of SEQ ID
NO: 531.
SEQ ID NO: 533 is the DNA sequence of a putative ORF of P775P.
SEQ ID NO: 534 is the predicted amino acid sequence encoded by SEQ ID NO: 533.
SEQ ID NO: 535 is a first full-length cDNA sequence for P510S.
SEQ ID NO: 536 is a second full-length cDNA sequence for P510S.
SEQ ID NO: 537 is the predicted amino acid sequence encoded by SEQ ID NO: 535.
SEQ ID NO: 538 is the predicted amino acid sequence encoded by SEQ ID NO: 536.
SEQ ID NO: 539 is the peptide P501 S-370.
3o SEQ ID NO: 540 is the peptide P501 S-376.
SEQ ID NO: 541-550 are epitopes of P501 S.
SEQ ID NO: 551 corresponds to amino acids 543-553 of P501 S.
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DETAILED DESCRIPTION OF THE INVENTION
As noted above, the present invention is generally directed to compositions
and
methods for the therapy and diagnosis of cancer, such as prostate cancer. The
compositions
described herein may include prostate-specific polypeptides, polynucleotides
encoding such
polypeptides, binding agents such as antibodies, antigen presenting cells
(APCs) and/or immune
system cells (e.g., T cells). Polypeptides of the present invention generally
comprise at least a
portion (such as an immunogenic portion) of a prostate-specific protein or a
variant thereof. A
"prostate-specific protein" is a protein that is expressed in normal prostate
and/or prostate tumor
cells at a level that is at least two fold, and preferably at least five fold,
greater than the level of
expression in a non-prostate normal tissue, as determined using a
representative assay provided
herein. Certain prostate-specific proteins are proteins that react detectably
(within an immunoassay,
such as an ELISA or Western blot) with antisera of a patient afflicted with
prostate cancer.
Polynucleotides of the subject invention generally comprise a DNA or RNA
sequence that encodes
~ 5 all or a portion of such a polypeptide, or that is complementary to such a
sequence. Antibodies are
generally immune system proteins, or antigen-binding fragments thereof, that
are capable of binding
to a polypeptide as described above. Antigen presenting cells include
dendritic cells, macrophages,
monocytes, fibroblasts and B-cells that express a polypeptide as described
above. T cells that may
be employed within such compositions are generally T cells that are specific
for a polypeptide as
20 described above.
The present invention is based on the discovery of human prostate-specific
proteins.
Sequences of polynucleotides encoding certain prostate-specific proteins, or
portions thereof, are
provided in SEQ ID NOs:l-111, 115-171, 173-175, 177, 179-305, 307-315, 326,
328, 330, 332-335,
340-375, 381, 382, 384-476, 524, 526, 530, 531, 533, 535 and 536. Sequences of
polypeptides
25 comprising at least a portion of a prostate-specific protein are provided
in SEQ ID NOs:l 12-114,
172, 176, 178, 327, 329, 331, 336, 339, 376-380, 383, 477-483, 496, 504, 505,
519, 520, 522, 525,
527, 532, 534 and 537-550.
PROSTATE-SPECIFIC PROTEIN POLYNUCLEOTIDES
30 Any polynucleotide that encodes a prostate-specific protein or a portion or
other
variant thereof as described herein is encompassed by the present invention.
Preferred
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polynucleotides comprise at least 15 consecutive nucleotides, preferably at
least 30 consecutive
nucleotides and more preferably at least 45 consecutive nucleotides, that
encode a portion of a
prostate-specific protein. More preferably, a polynucleotide encodes an
immunogenic portion of a
prostate-specific protein. Polynucleotides complementary to any such sequences
are also
encompassed by the present invention. Polynucleotides may be single-stranded
(coding or
antisense) or double-stranded, and may be DNA (genomic, cDNA or synthetic) or
RNA molecules.
RNA molecules 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 present within a
polynucleotide of the
1o present invention, and a polynucleotide may, but need not, be linked to
other molecules and/or
support materials.
Polynucleotides may comprise a native sequence (i. e., an endogenous sequence
that
encodes a prostate-specific protein or a portion thereof) or may comprise a
variant of such a
sequence. Polynucleotide variants may contain one or more substitutions,
additions, deletions
and/or insertions such that the immunogenicity of the encoded polypeptide is
not diminished,
relative to a native protein. The effect on the immunogenicity of the encoded
polypeptide may
generally be assessed as described herein. Variants preferably exhibit at
least about 70% identity,
more preferably at least about 80% identity and most preferably at least about
90% identity to a
polynucleotide sequence that encodes a native prostate-specific protein or a
portion thereof. The
2o term "variants" also encompasses homologous genes of xenogenic origin.
Two polynucleotide or polypeptide sequences are said to be "identical" if the
sequence of nucleotides or amino acids in the two sequences is the same when
aligned for
maximum correspondence as described below. Comparisons between two sequences
are typically
performed by comparing the sequences over a comparison window to identify and
compare local
regions of sequence similarity. 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 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
3o Megalign program in the Lasergene suite of bioinformatics 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
24
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WO 01/34802 PCT/US00/30904
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 Alignment and Phylogenes pp. 626-645 Methods in
Enzymology vol.
183, Academic Press, Inc., San Diego, CA; Higgins, D.G. and 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
11:105; Santou, N. Nes, M. (1987) Mol. Biol. Evol. 4:406-425; Sneath, P.H.A.
and Sokal, R.R.
( 1973) Numerical Taxonomy - the Principles and Practice of Numerical
Taxonomy, Freeman Press,
San Francisco, CA; Wilbur, W.J. and Lipman, D.J. (1983) Proc. Natl. Acad ,
Sci. USA 80:726-730.
Preferably, 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 polynucleotide or polypeptide sequence 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) for
optimal alignment of the two sequences. The percentage is calculated by
determining the number of
t 5 positions at which the identical nucleic acid bases or amino acid residue
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.
Variants may also, or alternatively, be substantially homologous to a native
gene, or
2o a portion or complement thereof. Such polynucleotide variants are capable
of hybridizing under
moderately stringent conditions to a naturally occurring DNA sequence encoding
a native prostate
specific protein (or a complementary sequence). Suitable moderately stringent
conditions include
prewashing in a solution of 5 X SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0);
hybridizing at 50°C
65°C, 5 X SSC, overnight; followed by washing twice at 65°C for
20 minutes with each of 2X,
25 O.SX and 0.2X SSC containing 0.1% SDS.
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 the
nucleotide
sequence of any native gene. Nonetheless, polynucleotides that vary due to
differences in codon
30 usage are specifically contemplated by the present invention. Further,
alleles 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
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
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).
Polynucleotides may be prepared using any of a variety of techniques. For
example,
a polynucleotide may be identified, as described in more detail below, by
screening a microarray of
cDNAs for tumor-associated expression (i. e., expression that is at least five
fold greater in a
prostate-specific than in normal tissue, as determined using a representative
assay provided herein).
Such screens may be performed using a Synteni microarray (Palo Alto, CA)
according to the
manufacturer's instructions (and essentially as described by Schena et al.,
Proc. Natl. Acid. Sci.
to USA 93:10614-10619, 1996 and Heller et al., Proc. Natl. Acid. Sci. USA
94:2150-2155, 1997).
Alternatively, polypeptides may be amplified from cDNA prepared from cells
expressing the
proteins described herein, such as prostate-specific cells. Such
polynucleotides may be amplified
via polymerise chain reaction (PCR). For this approach, sequence-specific
primers may be
designed based on the sequences provided herein, and may be purchased or
synthesized.
An amplified portion may be used to isolate a full length gene from a suitable
library (e.g., a prostate-specific 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.
2o 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 screened by hybridizing filters containing denatured bacterial
colonies (or lawns
containing phage plaques) with the labeled probe (see Sambrook et al.,
Molecular Cloning: A
Laboratory Manual, Cold Spring Harbor Laboratories, Cold Spring Harbor, NY,
1989).
Hybridizing colonies or plaques are selected and expanded, and the DNA is
isolated for further
analysis. cDNA clones may be analyzed to determine the amount of additional
sequence by, for
example, PCR using a primer from the partial sequence and a primer from the
vector. Restriction
maps and partial sequences may be generated to identify one or more
overlapping clones. The
3o complete sequence may then be determined using standard techniques, which
may involve
generating a series of deletion clones. The resulting overlapping sequences
are then assembled into
26
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a single contiguous sequence. A full length cDNA molecule can be generated by
ligating suitable
fragments; using well known techniques.
Alternatively, there are numerous amplification techniques for obtaining a
full length
coding sequence from a partial cDNA sequence. Within such techniques,
amplification is generally
performed via PCR. Any of a variety of commercially available kits may be used
to perform the
amplification step. Primers may be designed using, for example, software well
known in the art.
Primers are preferably 22-30 nucleotides in length, have a GC content of at
least 50% and anneal to
the target sequence at temperatures of about 68°C to 72°C. The
amplified region may be sequenced
as described above, and overlapping sequences assembled into a contiguous
sequence.
t o One such amplification technique is inverse PCR (see Triglia et al., Nucl.
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 retrieved by amplification with a primer
to a linker sequence
and a primer specific to a known region. The amplified sequences are typically
subjected to a
second round of amplification with the same linker primer and a second primer
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
2o 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 cDNA sequence by
analysis
of sequences provided in an expressed sequence tag (EST) database, such as
that available from
GenBank. Searches for overlapping ESTs may generally be performed using well
known programs
(e.g., NCBI BLAST searches), and such ESTs may be used to generate a
contiguous full length
sequence. Full length DNA sequences may also be obtained by analysis of
genomic fragments.
3o Certain nucleic acid sequences of cDNA molecules encoding at least a
portion of a
prostate-specific protein are provided in SEQ ID NO:1-111, 115-171, 173-175,
177, 179-305, 307-
315, 326, 328, 330, 332-335, 340-375, 381, 382, 384-476, 524, 526, 530, 531,
533, 535 and 536.
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Isolation of these polynucleotides is described below. Each of. these prostate-
specific proteins was
overexpressed in prostate tumor tissue.
Polynucleotide variants may generally be prepared by any method known in the
art,
including chemical synthesis by, for example, solid phase phosphoramidite
chemical synthesis.
Modifications in a polynucleotide sequence may also be introduced using
standard mutagenesis
techniques, such as oligonucleotide-directed site-specific mutagenesis (see
Adelman et al., DNA
2:183, 1983). Alternatively, RNA molecules may be generated by in vitro or in
vivo transcription of
DNA sequences encoding a prostate-specific protein, or portion thereof,
provided that the DNA is
incorporated into a vector with a suitable RNA polymerase promoter (such as T7
or SP6). Certain
1 o portions may be used to prepare an encoded polypeptide, as described
herein. In addition, or
alternatively, a portion may be administered to a patient such that the
encoded polypeptide is
generated in vivo (e.g., by transfecting antigen-presenting cells, such as
dendritic cells, with a cDNA
construct encoding a prostate-specific polypeptide, and administering the
transfected cells to the
patient).
A portion of a sequence complementary to a coding sequence (i.e., an antisense
polynucleotide) may also be used as a probe or to modulate gene expression.
cDNA constructs that
can be transcribed into antisense RNA may also be introduced into cells of
tissues to facilitate the
production of antisense RNA. An antisense polynucleotide may be used, as
described herein, to
inhibit expression of a protein. Antisense technology can be used to control
gene expression
through triple-helix formation, which compromises the ability of the double
helix to open
sufficiently for the binding of polymerases, transcription factors or
regulatory molecules (see Gee et
al., In Huber and Carr, Molecular and Immunologic Approaches, Futura
Publishing Co. (Mt. Kisco,
NY; 1994)). Alternatively, an antisense molecule may be designed to hybridize
with a control
region of a gene (e.g., promoter, enhancer or transcription initiation site),
and block transcription of
the gene; or to block translation by inhibiting binding of a transcript to
ribosomes.
A portion of a coding sequence, or of a complementary sequence, may also be
designed as a probe or primer to detect gene expression. Probes may be labeled
with a variety of
reporter groups, such as radionuclides and enzymes, and are preferably at
least 10 nucleotides in
length, more preferably at least 20 nucleotides in length and still more
preferably at least 30
3o nucleotides in length. Primers, as noted above, are preferably 22-30
nucleotides in length.
Any polynucleotide may be further modified to increase stability in vivo.
Possible
modifications include, but are not limited to, the addition of flanking
sequences at the 5' and/or 3'
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WO 01/34802 PCT/US00/30904
ends; the use of phosphorothioate 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-, thio- and other modified forms of adenine, cytidine,
guanine, thymine and
uridine.
Nucleotide sequences as described herein may be joined to a variety of other
nucleotide sequences using established recombinant DNA techniques. For
example, a
polynucleotide may be cloned into any of a variety of cloning vectors,
including plasmids,
phagemids, lambda phage derivatives and cosmids. Vectors of particular
interest include expression
vectors, replication vectors, probe generation vectors and sequencing vectors.
In general, a vector
will contain an origin of replication functional in at least one organism,
convenient restriction
endonuclease sites and one or more selectable markers. Other elements will
depend upon the
desired use, and will be apparent to those of ordinary skill in the art.
Within certain embodiments, polynucleotides may be formulated so as to permit
entry into a cell of a mammal, and expression therein. Such formulations are
particularly useful for
~ 5 therapeutic purposes, as described below. Those of ordinary skill in the
art will appreciate that there
are many ways to achieve expression of a polynucleotide in a target cell, and
any suitable method
may be employed. For example, a polynucleotide may be incorporated into a
viral vector such as,
but not limited to, adenovirus, adeno-associated virus, retrovirus, or
vaccinia or other pox virus
(e.g., avian pox virus). The polynucleotides may also be administered as naked
plasmid vectors.
2o Techniques for incorporating DNA into such vectors are well known to those
of ordinary skill in the
art. A retroviral vector may additionally transfer or incorporate a gene for a
selectable marker (to
aid in the identification or selection of transduced cells) and/or a targeting
moiety, such as a gene
that encodes a ligand for a receptor on a specific target cell, to render the
vector target specific.
Targeting may also be accomplished using an antibody, by methods known to
those of ordinary
25 skill in the art.
Other formulations for therapeutic purposes include colloidal dispersion
systems,
such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-
based systems
including oil-in-water emulsions, micelles, mixed micelles, and liposomes. A
preferred colloidal
system for use as a delivery vehicle in vitro and in vivo is a liposome (i.
e., an artificial membrane
3o vesicle). The preparation and use of such systems is well known in the art.
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PROSTATE-SPECIFIC POLYPEPTIDES
Within the context of the present invention, polypeptides may comprise at
least an
immunogenic portion of a prostate-specific protein or a variant thereof, as
described herein. As
noted above, a "prostate-specific protein" is a protein that is expressed by
normal prostate and/or
prostate tumor cells. Proteins that are prostate-specific proteins also react
detectably within an
immunoassay (such as an ELISA) with antisera from a patient with prostate
cancer. Polypeptides as
described herein may be of any length. Additional sequences derived from the
native protein and/or
heterologous sequences may be present, and such sequences may (but need not)
possess further
immunogenic or antigenic properties.
. An "immunogenic portion," as used herein is a portion of a protein that is
recognized
(i. e., specifically bound) by a B-cell and/or T-cell surface antigen
receptor. Such immunogenic
portions generally comprise at least 5 amino acid residues, more preferably at
least 10, and still
more preferably at least 20 amino acid residues of a prostate-specific protein
or a variant thereof.
Certain preferred immunogenic portions include peptides in which an N-terminal
leader sequence
and/or transmembrane domain have been deleted. Other preferred immunogenic
portions may
contain a small N- and/or C-terminal deletion (e.g., 1-30 amino acids,
preferably 5-15 amino acids),
relative to the mature protein.
Immunogenic portions may generally be identified using well known techniques,
such as those summarized in Paul, Fundamental Immunology, 3rd ed., 243-247
(Raven Press, 1993)
2o and references 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 and
antibodies are "antigen-specific" if they specifically bind to an antigen (i.
e., they react with the
protein in an ELISA or other immunoassay, and do not react detectably with
unrelated proteins).
Such antisera and antibodies may be prepared as described herein, and using
well known
techniques. An immunogenic portion of a native prostate-specific protein is a
portion that reacts
with such antisera and/or T-cells at a level that is not substantially less
than the reactivity of the full
length polypeptide (e.g., in an ELISA and/or T-cell reactivity assay). Such
immunogenic portions
may react within such assays at a level that is similar to or greater than the
reactivity of the full
length polypeptide. Such screens may generally be performed using methods well
known to those
of ordinary skill in the art, such as those described in Harlow and Lane,
Antibodies: A Laboratory
Manual, Cold Spring Harbor Laboratory, 1988. For 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
CA 02391369 2002-05-10
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immobilized polypeptide. Unbound sera may then be removed and bound antibodies
detected
using, for example,'ZSI-labeled Protein A.
As noted above, a composition may comprise a variant of a native prostate-
specific
protein. A polypeptide "variant," as used herein, is a polypeptide that
differs from a native prostate-
s specific protein in one or more substitutions, deletions, additions and/or
insertions, such that the
immunogenicity of the polypeptide is not substantially diminished. In other
words, the ability of a
variant to react with antigen-specific antisera may be enhanced or unchanged,
relative to the native
protein, or may be diminished by less than 50%, and preferably less than 20%,
relative to the native
protein. Such variants may generally be identified by modifying one of the
above polypeptide
sequences and evaluating the reactivity of the modified polypeptide with
antigen-specific antibodies
or antisera as described herein. Preferred variants include those in which one
or more portions, such
as an N-terminal leader sequence or transmembrane domain, have been removed.
Other preferred
variants include variants in which a small portion (e.g., 1-30 amino acids,
preferably 5-15 amino
acids) has been removed from the N- and/or C-terminal of the mature protein.
Polypeptide variants
~ 5 preferably exhibit at least about 70%, more preferably at least about 90%
and most preferably at
least about 95% identity (determined as described above) to the identified
polypeptides.
Preferably, a variant contains conservative substitutions. A "conservative
substitution" is one in which an amino acid is substituted for another amino
acid that has similar
properties, such that one skilled in the art of peptide chemistry would expect
the secondary structure
and hydropathic nature of the polypeptide to be substantially unchanged. Amino
acid substitutions
may generally be made on the basis of similarity in polarity, charge,
solubility, hydrophobicity,
hydrophilicity and/or the amphipathic nature of the residues. For example,
negatively charged
amino acids include aspartic acid and glutamic acid; positively charged amino
acids include lysine
and arginine; and amino acids with uncharged polar head groups having similar
hydrophilicity
values include leucine, isoleucine and valine; glycine and alanine; asparagine
and glutamine; and
serine, threonine, phenylalanine 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 nonconservative changes. In a preferred embodiment,
variant polypeptides
differ from 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
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WO 01/34802 PCT/US00/30904
acids that have minimal influence on the immunogenicity, secondary structure
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.
Polypeptides may be prepared using any of a variety of well known techniques.
1o Recombinant polypeptides encoded by DNA sequences as described above may be
readily prepared
from the DNA sequences using any of a variety of expression vectors known to
those of ordinary
skill in the art. Expression may be achieved in any appropriate host cell that
has been transformed
or transfected with an expression vector containing a DNA molecule that
encodes a recombinant
polypeptide. Suitable host cells include prokaryotes, yeast, higher eukaryotic
and plant cells.
Preferably, the host cells employed are E. coli, yeast or a mammalian cell
line such as COS or CHO.
Supernatants from suitable host/vector systems which secrete recombinant
protein or polypeptide
into culture media may be first concentrated using a commercially available
filter. Following
concentration, the concentrate may be applied to a suitable purification
matrix such as an affinity
matrix or an ion exchange resin. Finally, one or more reverse phase HPLC steps
can be employed
2o to further purify a recombinant polypeptide.
Portions and other variants having fewer than about 100 amino acids, and
generally
fewer than about 50 amino acids, may also be generated by synthetic means,
using techniques well
known to those of ordinary skill in the art. For example, such polypeptides
may be synthesized
using any of the commercially available solid-phase techniques, such as the
Merrifield solid-phase
synthesis method, where amino acids are sequentially added to a growing amino
acid chain. See
Merrifield, J. Am. Chem. Soc. 85:2149-2146, 1963. Equipment for automated
synthesis of
polypeptides is commercially available from suppliers such as Perkin
Elmer/Applied BioSystems
Division (Foster City, CA), and may be operated according to the
manufacturer's instructions.
Within certain specific embodiments, a polypeptide may be a fusion protein
that
3o comprises multiple polypeptides as described herein, or that comprises at
least one polypeptide as
described herein and an unrelated sequence, such as a known prostate-specific
protein. A fusion
partner may, for example, assist in providing T helper epitopes (an
immunological fusion partner),
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preferably T helper epitopes recognized by humans, or may assist in expressing
the protein (an
expression enhancer) at higher yields than the native recombinant protein.
Certain preferred fusion
partners are both immunological and expression enhancing fusion partners.
Other fusion partners
may be selected so as to increase the solubility of the protein or to enable
the protein to be targeted
to desired intracellular compartments. Still further fusion partners include
affinity tags, which
facilitate purification of the protein.
Fusion proteins may generally be prepared using standard techniques, including
chemical conjugation. Preferably, a fusion protein is expressed as a
recombinant protein, allowing
the production of increased levels, relative to a non-fused protein, in an
expression system: Briefly,
1o 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 polypeptide component so that the reading frames of the sequences
are in phase. This
permits translation into a single fusion protein that retains the biological
activity of both component
polypeptides.
A peptide linker sequence may be employed to separate the first and the 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
incorporated into the fusion
protein using standard techniques well known in the art. Suitable peptide
linker sequences may be
2o chosen based on the following factors: (1) their ability to adopt a
flexible extended conformation;
(2) their inability to adopt a secondary structure that could interact with
functional epitopes on the
first and second polypeptides; and (3) the lack of hydrophobic or charged
residues that might react
with the polypeptide functional epitopes. Preferred peptide linker sequences
contain Gly, Asn and
Ser residues. Other near neutral amino acids, such as Thr and Ala may also be
used in the linker
sequence. Amino acid sequences which may be usefully employed as linkers
include those
disclosed in Maratea et al., Gene 40:39-46, 1985; Murphy et al., Proc. Natl.
Acad. Sci. USA
83:8258-8262, 1986; U.S. Patent No.4,935,233 and U.S. Patent No.4,751,180. 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 polypeptides have non-essential N-terminal
amino acid regions
3o that can be used to separate the functional domains and prevent steric
interference.
The ligated DNA sequences are operably linked to suitable transcriptional or
translational regulatory elements. The regulatory elements responsible for
expression of DNA are
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located only 5' to the DNA sequence encoding the first polypeptides.
Similarly, stop codons
required to end translation and transcription termination signals are only
present 3' to the DNA
sequence encoding the second polypeptide.
Fusion proteins are also provided that comprise a polypeptide of the present
invention together with an unrelated immunogenic protein. Preferably the
immunogenic protein is
capable of eliciting a recall response. Examples of such proteins include
tetanus, tuberculosis and
hepatitis proteins (see, for example, Stoute et al. New Engl. J. Med., 336:86-
91, 1997).
Within preferred embodiments, an immunological fusion partner is derived from
protein D, a surface protein of the gram-negative bacterium Haemophilus
influenza B (WO
l0 91/18926). 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 embodiments, 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. coli (thus functioning as an
expression enhancer). The
lipid tail ensures 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
2o LYTA, or a portion thereof (preferably a C-terminal portion). LYTA is
derived from Streptococcus
pneumoniae, which synthesizes an N-acetyl-L-alanine amidase known as amidase
LYTA (encoded
by the LytA gene; Gene 43:265-292, 1986). LYTA is an autolysin 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 some choline analogues such as DEAE.
This property has been
exploited for the development of E. coli C-LYTA expressing plasmids useful for
expression of
fusion proteins. Purification of hybrid proteins containing the C-LYTA
fragment 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
protein. A repeat portion
is found in the C-terminal region starting at residue 178. A particularly
preferred repeat portion
3o incorporates residues 188-305.
In general, polypeptides (including fusion proteins) and polynucleotides as
described
herein are isolated. An "isolated" polypeptide or polynucleotide is one that
is removed from its
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original environment. For example, a naturally-occurring protein is isolated
if it is separated from
some or all of the coexisting materials in the natural system. Preferably,
such polypeptides are at
least about 90% pure, more preferably at least about 95% pure and most
preferably at least about
99% pure. A polynucleotide is considered to be isolated if, for example, it is
cloned into a vector
that is not a part of the natural environment.
BINDING AGENTS
The present invention further provides agents, such as antibodies and antigen
binding fragments thereof, that specifically bind to a prostate-specific
protein. As used herein, an
to antibody, or antigen-binding fragment thereof, is said to "specifically
bind" to a prostate-specific
protein if it reacts at a detectable level (within, for example, an ELISA)
with a prostate-specific
protein, and does not react detectably with unrelated proteins under similar
conditions. As used
herein, "binding" refers to a noncovalent association between two separate
molecules such that a
complex is formed. The ability to bind may be evaluated by, for example,
determining a binding
constant for the formation of the complex. The binding constant is the value
obtained when the
concentration of the complex is divided by the product of the component
concentrations. In
general, two compounds are said to "bind," in the context of the present
invention, when the binding
constant for complex formation exceeds about 10' L/mol. The binding constant
may be determined
using methods well known in the art.
2o Binding agents may be further capable of differentiating between patients
with and
without a cancer, such as prostate cancer, using the representative assays
provided herein. In other
words, antibodies or other binding agents that bind to a prostate-specific
protein will generate a
signal indicating the presence of a cancer in at least about 20% of patients
with the disease, and will
generate a negative signal indicating the absence of the disease in at least
about 90% of individuals
without the cancer. To determine whether a binding agent satisfies this
requirement, biological
samples (e.g., blood, sera, urine and/or tumor biopsies) from patients with
and without a cancer (as
determined using standard clinical tests) may be assayed as described herein
for the presence of
polypeptides that bind to the binding agent. It will be apparent that a
statistically significant number
of samples with and without the disease should be assayed. Each binding agent
should satisfy the
3o above criteria; however, those of ordinary skill in the art will recognize
that binding agents may be
used in combination to improve sensitivity.
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Any agent that satisfies the above requirements may be a binding agent. For
example, a binding agent may be a ribosome, with or without a peptide
component, an RNA
molecule or a polypeptide. In a preferred embodiment, a binding agent is an
antibody or an antigen-
binding fragment thereof. Most preferably, antibodies employed in the
inventive methods have the
ability to induce lysis of tumor cells by activation of complement and
mediation of antibody-
dependent cellular cytotoxicity (ADCC). Antibodies of different classes and
subclasses differ in
these properties. For example, mouse antibodies of the IgG2a and IgG3 classes
are capable of
activating serum complement upon binding to target cells which express the
antigen against which
the antibodies were raised, and can mediate ADCC.
l0 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 recombinant 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 incorporating one or more booster immunizations, and
the animals are bled
periodically. Polyclonal antibodies specific for the polypeptide may then be
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. J.
Immunol. 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 myeloma cell fusion partner, preferably one that is
syngeneic with the
immunized animal. A variety of fusion techniques may be employed. For example,
the spleen cells
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and myeloma 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 not myeloma cells.
A preferred selection technique uses HAT (hypoxanthine, aminopterin,
thymidine) 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 may be isolated from the supernatants of growing
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.
l0 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 polypeptides of this invention
may be used in the
purification process in, for example, an affinity chromatography step.
The preparation of mouse and rabbit monoclonal antibodies that specifically
bind to
polypeptides of the present invention is described in detail below. However,
the antibodies of the
present invention are not limited to those derived from mice. Human antibodies
may also be
employed in the inventive methods and may prove to be preferable. Such
antibodies can be
obtained using human hybridomas as described by Cote et al. (Monoclonal
Antibodies and Cancer
Therapy, Alan R. Lisa, p. 77, 1985). The present invention also encompasses
antibodies made by
recombinant means such as chimeric antibodies, wherein the variable region and
constant region are
derived from different species, and CDR-grafted antibodies, wherein the
complementarity
determining region is derived from a different species, as described in US
Patents 4,816,567 and
5,225,539. Chimeric antibodies may be prepared by splicing genes for a mouse
antibody molecule
having a desired antigen specificity together with genes for a human antibody
molecule having the
desired biological activity, such as activation of human complement and
mediation of ADCC
(Morrison et al. Proc. Natl. Acad. Sci. USA 81:6851, 1984; Neuberger et al.
Nature 312:604, 1984;
Takeda et al. Nature 314:452, 1985).
Within certain embodiments, the use of antigen-binding fragments of antibodies
may
be preferred. Such fragments include Fab fragments, which may be prepared
using standard
techniques. Briefly, immunoglobulins may be purified from rabbit serum by
affinity
chromatography on Protein A bead columns (Harlow and Lane, Antibodies: A
Laboratory Manual,
37
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
Cold Spring Harbor Laboratory, 1988) and digested by papain to yield Fab and
Fc fragments. The
Fab and Fc fragments may be separated by affinity chromatography on protein A
bead columns.
Monoclonal antibodies of the present invention may be coupled to one or more
therapeutic agents. Suitable agents in this regard include radionuclides,
differentiation inducers,
drugs, toxins, and derivatives thereof. Preferred radionuclides include
9°Y, 'z'h 'zsl, '3'I, 's6Re, 'g$Re,
z"At, and z'zBi. Preferred drugs include methotrexate, and pyrimidine and
purine analogs.
Preferred differentiation inducers include phorbol esters and butyric acid.
Preferred toxins include
ricin, abrin, diptheria toxin, cholera toxin, gelonin, Pseudomonas exotoxin,
Shigella toxin, and
pokeweed antiviral protein.
1o 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 nucleophilic group, such as an amino or
sulflrydryl group, on one
may be capable of reacting with a carbonyl-containing group, such as an
anhydride or an acid
halide, or with an alkyl group containing a good leaving group (e.g., a
halide) on the other.
Alternatively, it may be desirable to couple a therapeutic agent and an
antibody via a
linker group. A linker group can function as a spacer to distance an antibody
from an agent in order
to avoid interference with binding capabilities. A linker group can also serve
to increase the
chemical reactivity of a substituent on an agent or an antibody, and thus
increase the coupling
2o efficiency. An increase in 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 homo- and hetero-functional (such as those
described in the catalog of
the Pierce Chemical Co., Rockford, IL), may be employed as the linker group.
Coupling may be
effected, for example, through amino groups, carboxyl groups, sulfhydryl
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 portion
of the
immunoconjugates of the present invention, it may be desirable to use a linker
group which is
3o 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 reduction of a disulfide bond (e.g., U.S. Patent
No. 4,489,710, to
38
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WO 01/34802 PCT/US00/30904
Spider), by irradiation of a photolabile bond (e.g., U.S. Patent No.
4,625,014, to Senter et al.), by
hydrolysis of derivatized amino acid side chains (e.g., U.S. Patent No.
4,638,045, to Kohn et al.), by
serum complement-mediated hydrolysis (e.g., U.S. Patent No. 4,671,958, to
Rodwell et al.), and
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 another
embodiment, more than one type of agent may be coupled to one antibody.
Regardless of the
particular embodiment, immunoconjugates 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 which provide multiple sites for attachment can be used.
Alternatively, a carrier can be
used.
A carrier may bear the agents in a variety of ways, including covalent bonding
either
directly or via a linker group. Suitable carriers include proteins such as
albumins (e.g., U.S. Patent
No. 4,507,234, to Kato et al.), peptides and polysaccharides such as
aminodextran (e.g., U.S. Patent
t 5 No. 4,699,784, to Shih et al.). A carrier may also bear an agent by
noncovalent bonding or by
encapsulation, such as within a liposome vesicle (e.g., U.S. Patent Nos.
4,429,008 and 4,873,088).
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
2o compounds that include those containing nitrogen and sulfur atoms as the
donor atoms for binding
the metal, or metal oxide, radionuclide. For example, U.S. Patent No.
4,673,562, to Davison et al.
discloses representative chelating compounds and their synthesis.
A variety of routes of administration for the antibodies and immunoconjugates
may
be used. Typically, administration will be intravenous, intramuscular,
subcutaneous or in the bed of
25 a resected tumor. It will be evident that the precise dose of the
antibody/immunoconjugate will vary
depending upon the antibody used, the antigen density on the tumor, and the
rate of clearance of the
antibody.
T CELLS
30 Immunotherapeutic compositions may also, or alternatively, comprise T cells
specific for a prostate-specific protein. Such cells may generally be prepared
in vitro or ex vivo,
using standard procedures. For example, T cells may be isolated from bone
marrow, peripheral
39
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WO 01/34802 PCT/US00/30904
blood, or a fraction of bone marrow or peripheral blood of a patient, using a
commercially available
cell separation system, such as the ISOLEXT"~ 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
91/16116 and WO 92/07243). Alternatively, T cells may be derived from related
or unrelated
humans, non-human mammals, cell lines or cultures.
T cells may be stimulated with a prostate-specific polypeptide, polynucleotide
encoding a prostate-specific 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.
Preferably, a prostate-specific
to polypeptide or polynucleotide is present within a delivery vehicle, such as
a microsphere, to
facilitate the generation of specific T cells.
T cells are considered to be specific for a prostate-specific polypeptide if
the T cells
specifically proliferate, secrete cytokines or kill target cells coated with
the polypeptide or
expressing a gene encoding the polypeptide. T cell specificity may be
evaluated using any of a
variety of standard techniques. For example, within 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 may be performed,
for example, as
described in Chen et al., Cancer Re.s. 54:1065-1070, 1994. Alternatively,
detection of the
proliferation of T cells may be accomplished by a variety of known techniques.
For example, T cell
2o 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 prostate-specific polypeptide (100
ng/ml - 100 ~g/ml,
preferably 200 ng/ml - 25 ~g/ml) for 3 - 7 days should 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 cells
that have been
activated in response to a prostate-specific polypeptide, polynucleotide or
polypeptide-expressing
APC may be CD4+ and/or CD8+. Prostate-specific protein-specific T cells may be
expanded using
3o standard techniques. Within preferred embodiments, the T cells are derived
from either a patient or
a related, or unrelated, donor and are administered to the patient following
stimulation and
expansion.
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WO 01/34802 PCT/US00/30904
For therapeutic purposes, CD4+ or CD8+ T cells that proliferate in response to
a
prostate-specific polypeptide, polynucleotide or APC can be expanded in number
either in vitro or
in 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 prostate-specific polypeptide, or
a short peptide
corresponding to an immunogenic portion of such a polypeptide, with or without
the addition of
T cell growth factors, such as interleukin-2, and/or stimulator cells that
synthesize a prostate-
specific polypeptide. Alternatively, one or more T cells that proliferate in
the presence of a
prostate-specific protein can be expanded in number by cloning. Methods for
cloning cells are well
known in the art, and include limiting dilution.
PHARMACEUTICAL COMPOSITIONS AND VACCINES
Within certain aspects, polypeptides, polynucleotides, T cells and/or binding
agents
disclosed herein may be incorporated into pharmaceutical compositions or
immunogenic
compositions (i. e., vaccines). Pharmaceutical compositions comprise one or
more such compounds
and a physiologically acceptable carrier. Vaccines may comprise one or more
such compounds and
an immunostimulant. An immunostimulant may be any substance that enhances an
immune
response to an exogenous antigen. Examples of immunostimulants include
adjuvants,
biodegradable microspheres (e.g., polylactic galactide) and liposomes (into
which the compound is
incorporated; see e.g., Fullerton, U.S. Patent No. 4,235,877). Vaccine
preparation is generally
2o described in, for example, M.F. Powell and M.J. Newman, eds., "Vaccine
Design (the subunit and
adjuvant approach)," Plenum Press (NY, 1995). Pharmaceutical compositions and
vaccines within
the scope of the present invention may also contain other compounds, which may
be biologically
active or inactive. For example, one or more immunogenic portions of other
tumor antigens may be
present, either incorporated into a fusion polypeptide or as a separate
compound, within the
composition or vaccine.
A pharmaceutical composition or vaccine may contain DNA encoding one or more
of the polypeptides as described above, such that the polypeptide is generated
in situ. As noted
above, the DNA may be present within any of a variety of delivery systems
known to those of
ordinary skill in the art, including nucleic acid expression systems, bacteria
and viral expression
3o systems. Numerous gene delivery techniques are well known in the art, such
as those described by
Rolland, Crit. Rev. Therap. Drug Carrier Systems 15:143-198, 1998, and
references cited therein.
Appropriate nucleic acid expression systems contain the necessary DNA
sequences for expression
41
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WO 01/34802 PCT/US00/30904
in the patient (such as a suitable promoter and terminating signal). Bacterial
delivery systems
involve the administration of a bacterium (such as Bacillus-Calmette-Guerrin)
that expresses an
immunogenic portion of the polypeptide on its cell surface or secretes such an
epitope. In a
preferred embodiment, the DNA may be introduced using a viral expression
system (e.g., vaccinia
or other pox virus, retrovirus, or adenovirus), which may involve the use of a
non-pathogenic
(defective), replication competent virus. Suitable systems are disclosed, for
example, in Fisher-
Hoch et al., Proc. Natl. Acad. Sci. USA 86:317-321, 1989; Flexner et al., Ann.
N. Y. Acad. Sci.
569:86-103, 1989; Flexner et al., Vaccine 8:17-21, 1990; U.S. Patent Nos.
4,603,112, 4,769,330,
and 5,017,487; WO 89/01973; U.S. Patent No. 4,777,127; GB 2,200,651; EP
0,345,242;
1o WO 91/02805; Berkner, Biotechniques 6:616-627, 1988; Rosenfeld et al.,
Science 252:431-434,
1991; Kolls et al., Proc. Natl. Acad. Sci. USA 91:215-219, 1994; Kass-Eisler
et al., Proc. Natl.
Acad. Sci. USA 90:11498-11502, 1993; Guzman et al., Circulation 88:2838-2848,
1993; and
Guzman et al., Cir. Res. 73:1202-1207, 1993. Techniques for incorporating DNA
into such
expression systems are well known to those of ordinary skill in the art. The
DNA may also be
1s "naked," as described, for example, 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.
While 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 vary
20 depending on the mode of administration. Compositions of the present
invention may be
formulated for any appropriate manner of administration, including for
example, topical, oral, nasal,
intravenous, intracranial, intraperitoneal, subcutaneous or intramuscular
administration. For
parenteral administration, such as subcutaneous injection, the carrier
preferably comprises water,
saline, alcohol, a fat, a wax or a buffer. For oral administration, any of the
above carriers or a solid
25 carrier, such as mannitol, lactose, starch, magnesium stearate, sodium
saccharine, talcum, cellulose,
glucose, sucrose, and magnesium carbonate, may be employed. Biodegradable
microspheres (e.g.,
polylactate polyglycolate) may also be employed as carriers for the
pharmaceutical compositions of
this invention. Suitable biodegradable microspheres are disclosed, for
example, in U.S. Patent
Nos. 4,897,268 and 5,075,109.
3o Such compositions may also comprise buffers (e.g., neutral buffered saline
or
phosphate buffered saline), carbohydrates (e.g., glucose, mannose, sucrose or
dextrans), mannitol,
proteins, polypeptides or amino acids such as glycine, antioxidants, chelating
agents such as EDTA
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WO 01/34802 PCT/US00/30904
or glutathione, adjuvants (e.g., aluminum hydroxide) and/or preservatives.
Alternatively,
compositions of the present invention may be formulated as a lyophilizate.
Compounds may also
be encapsulated within liposomes using well known technology.
Any of a variety of immunostimulants may be employed in the vaccines of this
s invention. For example, an adjuvant may be included. Most adjuvants contain
a substance
designed to protect the antigen from rapid catabolism, such as aluminum
hydroxide or mineral oil,
and a stimulator of immune responses, such as lipid A, Bortadella pertussis or
Mycobacterium
tuberculosis derived proteins. Suitable adjuvants are commercially available
as, for example,
Freund's Incomplete Adjuvant and Complete Adjuvant (Difco Laboratories,
Detroit, MI); Merck
Adjuvant 65 (Merck and Company, Inc., Rahway, NJ); aluminum salts such as
aluminum hydroxide
gel (alum) or aluminum phosphate; salts of calcium, iron or zinc; an insoluble
suspension of
acylated tyrosine; acylated sugars; cationically or anionically derivatized
polysaccharides;
polyphosphazenes; biodegradable microspheres; monophosphoryl lipid A and quit
A. Cytokines,
such as GM-CSF or interleukin-2, -7, or -12, may also be used as adjuvants.
Within the vaccines provided herein, the adjuvant composition is preferably
designed
to induce an immune response predominantly of the Thl type. High levels of Thl-
type cytokines
(e.g., IFN-y, TNFa, IL-2 and IL-12) tend to favor the induction of cell
mediated immune 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 humoral immune responses. Following
application of a
2o vaccine as provided herein, a patient will support an immune response that
includes Thl- and Th2-
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 extent than the
level of Th2-type cytokines.
The levels of these cytokines may be readily assessed using standard assays.
For a review of the
families of cytokines, see Mosmann and Coffman, Ann. Rev. Immunol. 7:145-173,
1989.
Preferred adjuvants for use in eliciting a predominantly Thl-type response
include,
for example, a combination of monophosphoryl lipid A, preferably 3-de-O-
acylated
monophosphoryl lipid A (3D-MPL), together with an aluminum salt. MPL adjuvants
are available
from Ribi ImmunoChem Research Inc. (Hamilton, MT; see US Patent Nos.
4,436,727; 4,877,611;
4,866,034 and 4,912,094). CpG-containing oligonucleotides (in which the CpG
dinucleotide is
unmethylated) also induce a predominantly Thl response. Such oligonucleotides
are well known
and are described, for example, in WO 96/02555. Another preferred adjuvant is
a saponin,
preferably QS21, which may be used alone or in combination with other
adjuvants. For example,
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WO 01/34802 PCT/US00/30904
an enhanced system involves the combination of a monophosphoryl lipid A and
saponin derivative,
such as the combination of QS21 and 3D-MPL as described in WO 94/00153, or a
less reactogenic
composition where the QS21 is quenched with cholesterol, as described in WO
96/33739. Other
preferred formulations comprises an oil-in-water emulsion and tocopherol. A
particularly potent
adjuvant formulation involving QS21, 3D-MPL and tocopherol in an oil-in-water
emulsion is
described in WO 95/17210. Any vaccine provided herein may be prepared using
well known
methods that result in a combination of antigen, immune response enhancer and
a suitable carrier or
excipient.
The compositions described herein may be administered as part of a sustained
release
1 o formulation (i. e., a formulation such as a capsule, sponge or gel
(composed of polysaccharides for
example) that effects a slow release of compound following administration).
Such formulations
may generally be prepared using well known technology and administered by, for
example, oral,
rectal or subcutaneous implantation, or by implantation at the desired target
site. Sustained-release
formulations may contain a polypeptide, polynucleotide or antibody dispersed
in a carrier matrix
and/or contained within a reservoir surrounded by a rate controlling membrane.
Carriers for use
within such formulations are biocompatible, and may also be biodegradable;
preferably the
formulation provides a relatively constant level of active component release.
The amount of active
compound contained within a sustained release formulation depends upon the
site of implantation,
the rate and expected duration of release and the nature of the condition to
be treated or prevented.
2o Any of a variety of delivery vehicles may be employed within pharmaceutical
compositions and vaccines to facilitate production of an antigen-specific
immune response that
targets tumor cells. Delivery vehicles include antigen presenting cells
(APCs), such as dendritic
cells, macrophages, B cells, monocytes and other cells that may be engineered
to be efficient APCs.
Such cells may, but need not, 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 immunologically compatible with the receiver (i. e.,
matched HLA haplotype).
APCs may generally be isolated from any of a variety of biological fluids and
organs, including
tumor and peritumoral tissues, and may be autologous, allogeneic, syngeneic or
xenogeneic cells.
Certain preferred embodiments of the present invention use dendritic cells or
3o progenitors thereof as antigen-presenting cells. Dendritic cells are highly
potent APCs (Banchereau
and Steinman, Nature 392:245-251, 1998) and have been shown to be effective as
a physiological
adjuvant for eliciting prophylactic or therapeutic antitumor immunity (see
Timmerman and Levy,
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WO 01/34802 PCT/US00/30904
Ann. Rev. Med. 50:507-529, 1999). In general, dendritic cells may be
identified based on their
typical shape (stellate in situ, with marked cytoplasmic processes (dendrites)
visible in vitro), their
ability to take-up, process and 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 exosomes) may
be used within a
vaccine (see Zitvogel et al., Nature Med. 4:594-600, 1998).
Dendritic cells and 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,
dendritic cells may be
differentiated ex vivo by adding a combination of cytokines such as GM-CSF, IL-
4, IL-13 and/or
TNFa 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 GM-CSF, IL-3,
TNFa, CD40
ligand, LPS, flt3 ligand and/or other compounds) that induce differentiation,
maturation and
proliferation of dendritic 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
2o 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 and
processing, which correlates with the high expression of Fcy receptor and
mannose receptor. The
mature phenotype is typically characterized by a lower expression of these
markers, but a high
expression of cell surface molecules responsible for T cell activation such as
class I and class II
MHC, adhesion molecules (e.g., CD54 and CD11) and costimulatory molecules
(e.g., CD40, CD80,
CD86 and 4-1BB).
APCs may generally be transfected with a polynucleotide encoding a prostate-
specific protein (or portion or other variant thereof) such that the prostate-
specific polypeptide, or an
immunogenic portion thereof, is expressed on the cell surface. Such
transfection may take place ex
3o vivo, and a composition or vaccine comprising such transfected cells may
then be used for
therapeutic purposes, as described herein. Alternatively, a gene delivery
vehicle that targets a
dendritic or other antigen presenting cell may be administered to a patient,
resulting in transfection
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WO 01/34802 PCT/US00/30904
that occurs in vivo. In vivo and ex vivo transfection of dendritic cells, for
example, may generally be
performed using any methods known in the art, such as those described in WO
97/24447, or the
gene gun approach described by Mahvi et al., Immunology and cell Biology
75:456-460, 1997.
Antigen loading of dendritic cells may be achieved by incubating dendritic
cells or progenitor cells
with the prostate-specific 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 may be covalently
conjugated to an
irrimunological partner that provides T cell help (e.g., a carrier molecule).
Alternatively, a dendritic
cell may be pulsed with a non-conjugated immunological partner, separately or
in the presence of
to the polypeptide.
CANCER THERAPY
In further aspects of the present invention, the compositions described herein
may be
used for immunotherapy of cancer, such as prostate cancer. Within such
methods, pharmaceutical
compositions and vaccines are typically administered to a patient. As used
herein, a "patient" refers
to any warm-blooded animal, preferably a human. A patient may or may not be
afflicted with
cancer. Accordingly, the above pharmaceutical compositions and vaccines may be
used to prevent
the development of a cancer or to treat a patient afflicted with a cancer. A
cancer may be diagnosed
using criteria generally accepted in the art, including the presence of a
malignant tumor.
2o 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.
Within certain embodiments, immunotherapy may be active immunotherapy, in
which treatment relies on the in vivo stimulation of the endogenous host
immune system to react
against tumors with the administration of immune response-modifying agents
(such as polypeptides
and polynucleotides disclosed herein).
Within other embodiments, immunotherapy may be passive immunotherapy, in
which treatment involves the delivery of agents with established tumor-immune
reactivity (such as
effector cells or antibodies) that can directly or indirectly mediate
antitumor effects and does not
3o necessarily depend on an intact host immune system. Examples of effector
cells include T cells as
discussed above, T lymphocytes (such as CD8+ cytotoxic T lymphocytes and CD4+
T-helper tumor-
infiltrating lymphocytes), killer cells (such as Natural Killer cells and
lymphokine-activated killer
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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
for 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
antibodies 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
immunotherapy by growth in vitro, as described herein. Culture conditions for
expanding single
antigen-specific effector cells to several billion in number with retention of
antigen recognition in
t o vivo are well known in the art. Such in 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, immunoreactive 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
immunotherapy. In particular, antigen-presenting cells, such as dendritic,
macrophage, monocyte,
fibroblast or B cells, may be pulsed with immunoreactive polypeptides or
transfected with one or
more polynucleotides using standard techniques well known in the art. For
example, antigen-
presenting cells can be transfected with a polynucleotide having a promoter
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 widely, and to survive long
term in vivo. Studies
2o have shown that cultured effector cells can be induced to grow in vivo and
to survive long term in
substantial numbers by repeated stimulation with antigen supplemented with IL-
2 (see, for example,
Cheever et al., Immunological Reviews 157:177, 1997).
Alternatively, a vector expressing a polypeptide recited herein may be
introduced
into antigen presenting cells taken from a patient and clonally propagated ex
vivo for transplant back
into the same patient. Transfected cells may be reintroduced into the patient
using any means
known in the art, preferably in sterile form by intravenous, intracavitary,
intraperitoneal or
intratumor administration.
Routes and frequency of administration of the therapeutic compositions
disclosed
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
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WO 01/34802 PCT/US00/30904
over a 52 week period. Preferably, 6 doses are administered, at intervals of 1
month, and booster
vaccinations may be given periodically thereafter. Alternate protocols may be
appropriate for
individual patients. A suitable dose is an amount 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 in 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 pharmaceutical compositions and vaccines
comprising one or
more polypeptides, the amount of each polypeptide present in a dose ranges
from about 25 ~g to
5 mg per kg of host. Suitable dose sizes will vary with the size of the
patient, but will typically
range from about 0.1 mL to about 5 mL.
In general, an appropriate dosage and treatment regimen provides the active
I5 compounds) in an amount sufficient to provide therapeutic and/or
prophylactic benefit. Such a
response can be monitored by establishing an improved clinical outcome (e.g.,
more frequent
remissions, complete or partial, or longer disease-free survival) in treated
patients as compared to
non-treated patients. Increases in preexisting immune responses to a prostate-
specific protein
generally correlate with an improved clinical outcome. Such immune responses
may generally be
2o evaluated using standard proliferation, cytotoxicity or cytokine assays,
which may be performed
using samples obtained from a patient before and after treatment.
METHODS FOR DETECTING CANCER
In general, a cancer may be detected in a patient based on the presence of one
or
25 more prostate-specific proteins and/or polynucleotides encoding such
proteins in a biological
sample (for example, blood, sera, 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
prostate 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
3o agent in the biological sample. Polynucleotide primers and 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.
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In general, a prostate tumor sequence should be present at a level that is at
least three fold higher in
tumor tissue than in normal tissue
There are 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 Manual, Cold Spring Harbor Laboratory, 1988. 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 sample a level of
polypeptide that binds to
the binding agent; and (c) comparing the level of polypeptide with a
predetermined cut-off value.
In a preferred embodiment, the assay involves the use of binding agent
immobilized
l0 on a solid support to bind to and remove 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/polypeptide complex. Such detection
reagents may
comprise, for example, a binding agent that specifically binds to the
polypeptide or an antibody or
other agent that specifically binds to the binding agent, such as an anti-
immunoglobulin, protein G,
protein A or a lectin. Alternatively, a competitive assay may be utilized, in
which a polypeptide 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 of the labeled polypeptide to the binding agent is indicative of the
reactivity of the sample
with the immobilized binding agent. Suitable polypeptides for use within such
assays include full
length prostate-specific proteins and 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 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 polyvinylchloride.
The support may also be a magnetic particle or a fiber optic sensor, such 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 variety of techniques known to those of skill in the art, which axe
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 functional 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
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membrane is preferred. In such cases, adsorption may be achieved by 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 1 hour and about 1 day. In
general, contacting a
well of a plastic microtiter plate (such as polystyrene or polyvinylchloride)
with an amount of
binding agent ranging from about 10 ng to about 10 fig, and preferably about
100 ng to about 1 fig,
is sufficient to immobilize an adequate amount of binding agent.
Covalent attachment of binding agent to a solid support may generally be
achieved
by first reacting the support with a bifunctional reagent that will react with
both the support and a
functional group, such as a hydroxyl or amino group, on the binding agent. For
example, the
1o binding agent may be covalently attached to supports having an appropriate
polymer coating using
benzoquinone or by condensation of an aldehyde group on the support with an
amine and an active
hydrogen on the binding partner (see, e.g., Pierce Immunotechnology Catalog
and Handbook, 1991,
at A12-A13).
In certain embodiments, the assay is a two-antibody sandwich assay. This assay
may
~ s be performed by first contacting an antibody that has been immobilized 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 and a detection reagent (preferably
a second antibody
capable of binding to a different site on the polypeptide) containing a
reporter group is added. The
2o amount of 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
blocked. Any suitable
blocking agent known to those of ordinary skill in the art, such as bovine
serum albumin or Tween
2s 20TM (Sigma Chemical Co., St. Louis, MO). The immobilized antibody is then
incubated with the
sample, and polypeptide is allowed to bind to the antibody. The sample may be
diluted with 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 a sample obtained from an individual with
prostate cancer.
3o Preferably, the contact time is sufficient to achieve a level of binding
that is at least about 95% of
that achieved at equilibrium between bound and unbound polypeptide. Those of
ordinary skill in
the art will recognize that the time necessary to achieve equilibrium may be
readily determined by
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assaying the level of binding that occurs over a period of time. At room
temperature, an incubation
time of about 30 minutes is generally sufficient.
Unbound sample may then be removed by washing the solid support with an
appropriate buffer, such as PBS containing 0.1% Tween 20TM. 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 amount
of time may generally be determined by assaying the level of binding that
occurs over a period of
to 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. Biotin may be detected using avidin, coupled to a
different reporter group
(commonly a radioactive or fluorescent group or an enzyme). Enzyme reporter
groups may
generally be detected by the addition of substrate (generally for a specific
period of time), followed
by spectroscopic or other analysis of the reaction products.
To determine the presence or absence of a cancer, such as prostate cancer, the
signal
detected from the reporter group that remains bound to the solid support is
generally compared to a
2o signal that corresponds to a predetermined cut-off value. In one preferred
embodiment, the cut-off
value for the detection of a cancer is the average mean signal obtained when
the immobilized
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 cancer. In an alternate preferred embodiment, the
cut-off value is
determined using a Receiver Operator Curve, according to the method of Sackett
et al., Clinical
Epidemiology: A Basic Science for Clinical Medicine, Little Brown and Co.,
1985, p. 106-7.
Briefly, in this embodiment, the cut-off value may be determined from a plot
of pairs of true
positive rates (i.e., sensitivity) and false positive rates (100%-specificity)
that correspond to each
possible cut-off value for the diagnostic test result. The cut-off value on
the plot that is the closest
3o 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 may be considered positive. Alternatively, the cut-off value may be
shifted to the left along
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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 for a cancer.
In a related embodiment, the assay is performed in a flow-through or strip
test
format, wherein the binding agent is immobilized on a membrane, 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
flows through the
membrane. The detection of bound second binding agent may then be performed as
described
1o above. In the strip test format, one end of the membrane to which binding
agent is bound is
immersed 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 at the area of immobilized antibody
indicates the presence of
a cancer. Typically, the concentration of second binding agent at that site
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 immobilized 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 format
discussed above. Preferred binding agents for use in such assays are
antibodies and antigen-binding
2o fragments thereof. Preferably, the amount of antibody immobilized on the
membrane ranges from
about 25 ng to about 1 fig, and more preferably from about 50 ng to about 500
ng. Such tests can
typically be performed with a very small amount of biological sample.
Of course, numerous other assay protocols exist that are suitable for use with
the
proteins or binding agents of the present invention. The above descriptions
are intended to be
exemplary only. For example, it will be apparent to those of ordinary skill in
the art that the above
protocols may be readily modified to use prostate-specific polypeptides to
detect antibodies that
bind to such polypeptides in a biological sample. The detection of such
prostate-specific 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
3o specifically react with a prostate-specific 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
prostate-specific polypeptide, a polynucleotide encoding such a polypeptide
and/or an APC that
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expresses at least an immunogenic 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
prostate-specific polypeptide (e.g.,
5 - 25 ~.g/ml). It may be desirable to incubate another aliquot of a T cell
sample in the absence of
prostate-specific polypeptide to serve as a control. For CD4+ T cells,
activation is preferably
detected by evaluating proliferation of the T cells. For CD8+ T cells,
activation is preferably
detected by evaluating cytolytic activity. A level of proliferation that is at
least two fold greater
to 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
mRNA encoding a prostate-specific protein in a biological sample. For example,
at least two
oligonucleotide primers may be employed in a polymerase chain reaction (PCR)
based assay to
amplify a portion of a prostate-specific cDNA derived from a biological
sample, wherein at least
one of the oligonucleotide primers is specific for (i. e., hybridizes to) a
polynucleotide encoding the
prostate-specific protein. The amplified cDNA is then separated and detected
using techniques well
known in the art, such as gel electrophoresis. Similarly, oligonucleotide
probes that specifically
hybridize to a polynucleotide encoding a prostate-specific protein may be used
in a hybridization
2o assay to detect the presence of polynucleotide encoding the protein in a
biological sample.
To permit hybridization under assay conditions, oligonucleotide primers and
probes
should comprise 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
prostate-specific protein that is at least 10 nucleotides, and preferably at
least 20 nucleotides, in
length. Preferably, oligonucleotide primers and/or probes will hybridize to a
polynucleotide
encoding a polypeptide disclosed herein under moderately stringent conditions,
as defined above.
Oligonucleotide primers and/or probes which may be usefully employed in the
diagnostic methods
described herein preferably are at least 10-40 nucleotides in length. In a
preferred embodiment, the
oligonucleotide primers comprise at least 10 contiguous nucleotides, more
preferably at least 15
3o contiguous nucleotides, of a DNA molecule having a sequence recited in SEQ
ID NO: 1-111, 115-
171, 173-175, 177, 179-305, 307-315, 326, 328, 330, 332-335, 340-375, 381,
382, 384-476, 524,
526, 530, 531, 533, 535 and 536. Techniques for both PCR based assays and
hybridization assays
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are well known in the art (see, for example, Mullis et al., Cold Spring Harbor
Symp. Quant. Biol.,
51:263, 1987; Erlich ed., PCR Technology, Stockton Press, NY, 1989).
One preferred assay 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,
and is reverse transcribed to produce cDNA molecules. PCR amplification using
at least one
specific primer generates a cDNA molecule, which may be separated and
visualized using, for
example, gel electrophoresis. Amplification may be performed on biological
samples taken from a
test patient and from an individual who is not afflicted with a cancer. The
amplification reaction
may be performed on several dilutions of cDNA spanning two orders of
magnitude. A two-fold or
1 o greater increase in expression in several dilutions of the test patient
sample as compared to the same
dilutions of the non-cancerous sample is typically considered positive.
In another embodiment, the disclosed compositions may be used as markers 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 evaluated. For example, the assays may be performed every 24-72
hours for a
period 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 when the level of
reactive polypeptide or
polynucleotide either remains constant or decreases with time.
2o 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 then be
detected directly or indirectly via a reporter group. Such binding agents may
also be used in
histological applications. Alternatively, polynucleotide probes may be used
within such
applications.
As noted above, to improve sensitivity, multiple prostate-specific 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 protein markers may be based
on routine
experiments to determine combinations that results in optimal sensitivity. In
addition, or
3o alternatively, assays for proteins provided herein may be combined with
assays for other known
tumor antigens.
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DIAGNOSTIC KITS
The present invention further 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 may be compounds, reagents, containers and/or
equipment. For
example, one container within a kit may contain a monoclonal antibody or
fragment thereof that
specifically binds to a prostate-specific protein. Such antibodies or
fragments may be provided
attached to a support material, as described above. One or more additional
containers may enclose
elements, such as reagents or buffers, to be used in the assay. Such kits may
also, or alternatively,
contain a detection reagent as described above that contains a reporter group
suitable for direct or
I o indirect detection of antibody binding.
Alternatively, a kit may be designed to detect the level of mRNA encoding a
prostate-specific protein in a biological sample. Such kits generally comprise
at least one
oligonucleotide probe or primer, as described above, that hybridizes to a
polynucleotide encoding a
prostate-specific protein. Such an oligonucleotide may be used, for example,
within a PCR or
~ 5 hybridization assay. Additional components that may be present within such
kits include a second
oligonucleotide and/or a diagnostic reagent or container to facilitate the
detection of a
polynucleotide encoding a prostate-specific protein.
The following Examples are offered by way of illustration and not by way of
limitation.
CA 02391369 2002-05-10
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EXAMPLES
EXAMPLE 1
0
ISOLATION AND CHARACTERIZATION OF PROSTATE-SPECIFIC POLYPEPTIDES
This Example describes the isolation of certain prostate-specific polypeptides
from a
prostate tumor cDNA library.
A human prostate tumor cDNA expression library was constructed from prostate
tumor poly A+ RNA using a Superscript Plasmid System for cDNA Synthesis and
Plasmid Cloning
kit (BRL Life Technologies, Gaithersburg, MD 20897) following the
manufacturer's protocol.
Specifically, prostate tumor tissues were homogenized with polytron
(Kinematica, Switzerland) and
total RNA was extracted using Trizol reagent (BRL Life Technologies) as
directed by the
manufacturer. The poly A+ RNA was then purified using a Qiagen oligotex spin
column mRNA
purification kit (Qiagen, Santa Clarita, CA 91355) according to the
manufacturer's protocol. First-
strand cDNA was synthesized using the NotI/Oligo-dTl8 primer. Double-stranded
cDNA was
synthesized, ligated with EcoRI/BAXI adaptors (Invitrogen, San Diego, CA) and
digested with
NotI. Following size fractionation with Chroma Spin-1000 columns (Clontech,
Palo Alto, CA), the
cDNA was ligated into the EcoRI/NotI site of pCDNA3.1 (Invitrogen) and
transformed into
2o ElectroMax E. coli DH10B cells (BRL Life Technologies) by electroporation.
Using the same procedure, a normal human pancreas cDNA expression library was
prepared from a pool of six tissue specimens (Clontech). The cDNA libraries
were characterized by
determining the number of independent colonies, the percentage of clones that
carried insert, the
average insert size and by sequence analysis. The prostate tumor library
contained 1.64 x 10'
independent colonies, with 70% of clones having an insert and the average
insert size being 1745
base pairs. The normal pancreas cDNA library contained 3.3 x 106 independent
colonies, with 69%
of clones having inserts and the average insert size being 1120 base pairs.
For both libraries,
sequence analysis showed that the majority of clones had a full length cDNA
sequence and were
synthesized from mRNA, with minimal rRNA and mitochondrial DNA.contamination.
3o cDNA library subtraction was performed using the above prostate tumor and
normal
pancreas cDNA libraries, as described by Hara et al. (Blood, 84:189-199, 1994)
with some
modifications. Specifically, a prostate tumor-specific subtracted cDNA library
was generated as
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follows. Normal pancreas cDNA library (70 fig) was digested with EcoRI, NotI,
and SfuI, followed
by a filling-in reaction with DNA polymerise Klenow fragment. After phenol-
chloroform
extraction and ethanol precipitation, the DNA was dissolved in 100 p1 of HZO,
heat-denatured and
mixed with 100 p1 (100 fig) of Photoprobe biotin (Vector Laboratories,
Burlingame, CA). As
recommended by the manufacturer, the resulting mixture was irradiated with a
270 W sunlamp on
ice for 20 minutes. Additional Photoprobe biotin (50 ~1) was added and the
biotinylation reaction
was repeated. After extraction with butanol five times, the DNA was ethanol-
precipitated and
dissolved in 23 ~1 HZO to form the driver DNA.
To form the tracer DNA, 10 ~g prostate tumor cDNA library was digested with
BamHI and XhoI, phenol chloroform extracted and passed through Chroma spin-400
columns
(Clontech). Following ethanol precipitation, the tracer DNA was dissolved in 5
p1 HzO. Tracer
DNA was mixed with 15 ~1 driver DNA and 20 ~1 of 2 x hybridization buffer (1.5
M NaCI/10 mM
EDTA/SO mM HEPES pH 7.5/0.2% sodium dodecyl sulfate), overlaid with mineral
oil, and heat-
denatured completely. The sample was immediately transferred into a 68
°C water bath and
incubated for 20 hours (long hybridization [LH]). The reaction mixture was
then subjected to a
streptavidin treatment followed by phenol/chloroform extraction. This process
was repeated three
more times. Subtracted DNA was precipitated, dissolved in 12 ~1 H20, mixed
with 8 p.1 driver
DNA and 20 p1 of 2 x hybridization buffer, and subjected to a hybridization at
68 °C for 2 hours
(short hybridization [SH]). After removal of biotinylated double-stranded DNA,
subtracted cDNA
was ligated into BamHI/XhoI site of chloramphenicol resistant pBCSK+
(Stratagene, La Jolla, CA
92037) and transformed into ElectroMax E coli DH10B cells by electroporation
to generate a
prostate tumor specific subtracted cDNA library (referred to as "prostate
subtraction 1 ").
To analyze the subtracted cDNA library, plasmid DNA was prepared from 100
independent clones, randomly picked from the subtracted prostate tumor
specific library and
grouped based on insert size. Representative cDNA clones were further
characterized by DNA
sequencing with a Perkin Elmer/Applied Biosystems Division Automated Sequencer
Model 373A
(Foster City, CA). Six cDNA clones, hereinafter referred to as Fl-13, F1-12,
F1-16, H1-1, H1-9
and H1-4, were shown to be abundant in the subtracted prostate-specific cDNA
library. The
determined 3' and 5' cDNA sequences for F1-12 are provided in SEQ ID NO: 2 and
3, respectively,
with determined 3' cDNA sequences for F1-13, F1-16, H1-1, H1-9 and H1-4 being
provided in SEQ
ID NO: 1 and 4-7, respectively.
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The cDNA sequences for the isolated clones were compared to known sequences in
the gene bank using the EMBL and GenBank databases (release 96). Four of the
prostate tumor
cDNA clones, F1-13, F1-16, Hl-1, and H1-4, were determined to encode the
following previously
identified proteins: prostate specific antigen (PSA), human glandular
kallikrein, human tumor
expression enhanced gene, and mitochondria cytochrome C oxidase subunit II. H1-
9 was found to
be identical to a previously identified human autonomously replicating
sequence. No significant
homologies to the cDNA sequence for F1-12 were found.
Subsequent studies led to the isolation of a full-length cDNA sequence for Fl-
12.
This sequence is provided in SEQ ID NO: 107, with the corresponding predicted
amino acid
l0 sequence being provided in SEQ ID NO: 108.
To clone less abundant prostate tumor specific genes, cDNA library subtraction
was
performed by subtracting the prostate tumor cDNA library described above with
the normal
pancreas cDNA library and with the three most abundant genes in the previously
subtracted prostate
tumor specific cDNA library: human glandular kallikrein, prostate specific
antigen (PSA), and
mitochondria cytochrome C oxidase subunit II. Specifically, 1 p.g each of
human glandular
kallikrein, PSA and mitochondria cytochrome C oxidase subunit II cDNAs in
pCDNA3.1 were
added to the driver DNA and subtraction was performed as described above to
provide a second
subtracted cDNA library hereinafter referred to as the "subtracted prostate
tumor specific cDNA
library with spike".
2o Twenty-two cDNA clones were isolated from the subtracted prostate tumor
specific
cDNA library with spike. The determined 3' and 5' cDNA sequences for the
clones referred to as
Jl-17, L1-12, N1-1862, J1-13, J1-19, J1-25, J1-24, K1-58, K1-63, L1-4 and Ll-
14 are provided in
SEQ ID NOS: 8-9, 10-11, 12-13, 14-15, 16-17, 18-19, 20-21, 22-23, 24-25, 26-27
and 28-29,
respectively. The determined 3' cDNA sequences for the clones referred to as
J1-12, J1-16, J1-21,
K1-48, Kl-55, Ll-2, L1-6, N1-1858, N1-1860, N1-1861, N1-1864 are provided in
SEQ ID NOS:
30-40, respectively. Comparison of these sequences with those in the gene bank
as described
above, revealed no significant homologies to three of the five most abundant
DNA species, (J1-17,
L1-12 and N1-1862; SEQ ID NOS: 8-9, 10-11 and 12-13, respectively). Of the
remaining two most
abundant species, one (J1-12; SEQ ID N0:30) was found to be identical to the
previously identified
3o human pulmonary surfactant-associated protein, and the other (K1-48; SEQ ID
N0:33) was
determined to have some homology to R. norvegicus mRNA for 2-arylpropionyl-CoA
epimerase.
Of the 17 less abundant cDNA clones isolated from the subtracted prostate
tumor specific cDNA
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library with spike, four (J1-16, K1-55, L1-6 and N1-1864; SEQ ID NOS:31, 34,
36 and 40,
respectively) were found to be identical to previously identified sequences,
two (J1-21 and N1-
1860; SEQ ID NOS: 32 and 38, respectively) were found to show some homology to
non-human
sequences, and two (L1-2 and N1-1861; SEQ ID NOS: 35 and 39, respectively)
were found to show
some homology to known human sequences. No significant homologies were found
to the
polypeptides J1-13, J1-19, J1-24, J1-25, K1-58, K1-63, L1-4, L1-14 (SEQ ID
NOS: 14-15, 16-17,
20-21, 18-19, 22-23, 24-25, 26-27, 28-29, respectively).
Subsequent studies led to the isolation of full length cDNA sequences for J1-
17, L1-
12 and N1-1862 (SEQ ID NOS: 109-111, respectively). The corresponding
predicted amino acid
1o sequences are provided in SEQ ID NOS: 112-114. L1-12 is also referred to as
PSO1S.
In a further experiment, four additional clones were identified by subtracting
a
prostate tumor cDNA library with normal prostate cDNA prepared from a pool of
three normal
prostate poly A+ RNA (referred to as "prostate subtraction 2"). The determined
cDNA sequences
for these clones, hereinafter referred to as U1-3064, U1-3065, V1-3692 and 1A-
3905, are provided
in SEQ ID NO: 69-72, respectively. Comparison of the determined sequences with
those in the
gene bank revealed no significant homologies to U1-3065.
A second subtraction with spike (referred to as "prostate subtraction spike
2") was
performed by subtracting a prostate tumor specific cDNA library with spike
with normal pancreas
cDNA library and further spiked with PSA, J1-17, pulmonary surfactant-
associated protein,
2o mitochondrial DNA, cytochrome c oxidase subunit II, N1-1862, autonomously
replicating
sequence, L1-12 and tumor expression enhanced gene. Four additional clones,
hereinafter referred
to as V1-3686, R1-2330, 1B-3976 and V1-3679, were isolated. The determined
cDNA sequences
for these clones are provided in SEQ ID N0:73-76, respectively. Comparison of
these sequences
with those in the gene bank revealed no significant homologies to V 1-3686 and
R1-2330.
Further analysis of the three prostate subtractions described above (prostate
subtraction 2, subtracted prostate tumor specific cDNA library with spike, and
prostate subtraction
spike 2) resulted in the identification of sixteen additional clones, referred
to as 1G-4736, 1G-4738,
1G-4741, 1G-4744, 1G-4734, 1H-4774, 1H-4781, 1H-4785, 1H-4787, 1H-4796, 1I-
4810, 1I-4811,
1J-4876, 1K-4884 and 1K-4896. The determined cDNA sequences for these clones
are provided in
3o SEQ ID NOS: 77-92, respectively. Comparison of these sequences with those
in the gene bank as
described above, revealed no significant homologies to 1G-4741, 1G-4734, 1I-
4807, 1J-4876 and
1K-4896 (SEQ ID NOS: 79, 81, 87, 90 and 92, respectively). Further analysis of
the isolated
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clones led to the determination of extended cDNA sequences for 1 G-4736, 1 G-
4738, 1 G-4741, 1 6
4744, 1H-4774, 1H-4781, 1H-4785, 1H-4787, 1H-4796, 1I-4807, 1J-4876, 1K-4884
and 1K-4896,
provided in SEQ ID NOS: 179-188 and 191-193, respectively, and to the
determination of
additional partial cDNA sequences for 1I-4810 and 1I-4811, provided in SEQ ID
NOS: 189 and
190, respectively.
Additional studies with prostate subtraction spike 2 resulted in the isolation
of three
more clones. Their sequences were determined as described above and compared
to the most recent
GenBank. All three clones were found to have homology to known genes, which
are Cysteine-rich
protein, KIAA0242, and KIAA0280 (SEQ ID NO: 317, 319, and 320, respectively).
Further
1 o analysis of these clones by Synteni microarray (Synteni, Palo Alto, CA)
demonstrated that all three
clones were over-expressed in most prostate tumors and prostate BPH, as well
as in the majority of
normal prostate tissues tested, but low expression in all other normal
tissues.
An additional subtraction was performed by subtracting a normal prostate cDNA
library with normal pancreas cDNA (referred to as "prostate subtraction 3").
This led to the
~ 5 identification of six additional clones referred to as 1 G-4761, 1 G-4762,
1 H-4766, 1 H-4770, 1 H-
4771 and 1H-4772 (SEQ ID NOS: 93-98). Comparison of these sequences with those
in the gene
bank revealed no significant homologies to 1G-4761 and 1H-4771 (SEQ ID NOS: 93
and 97,
respectively). Further analysis of the isolated clones led to the
determination of extended cDNA
sequences for 1G-4761, 1G-4762, 1H-4766 and 1H-4772 provided in SEQ ID NOS:
194-196 and
20 199, respectively, and to the determination of additional partial cDNA
sequences for 1 H-4770 and
1H-4771, provided in SEQ ID NOS: 197 and 198, respectively.
Subtraction of a prostate tumor cDNA library, prepared from a pool of polyA+
RNA
from three prostate cancer patients, with a normal pancreas cDNA library
(prostate subtraction 4)
led to the identification of eight clones, referred to as 1D-4297, 1D-4309,
1D.1-4278, 1D-4288, 1D-
25 4283, 1D-4304, 1D-4296 and 1D-4280 (SEQ ID NOS: 99-107). These sequences
were compared to
those in the gene bank as described above. No significant homologies were
found to 1D-4283 and
1D-4304 (SEQ ID NOS: 103 and 104, respectively). Further analysis of the
isolated clones led to
the determination of extended cDNA sequences for 1D-4309, 1D.1-4278, 1D-4288,
1D-4283, 1D-
4304, 1D-4296 and 1D-4280, provided in SEQ ID NOS: 200-206, respectively.
3o cDNA clones isolated in prostate subtraction 1 and prostate subtraction 2,
described
above, were colony PCR amplified and their mRNA expression levels in prostate
tumor, normal
prostate and in various other normal tissues were determined using microarray
technology (Synteni,
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Palo Alto, CA). Briefly, the PCR amplification products were dotted onto
slides in an array format,
with each product occupying a unique location in the array. mRNA was extracted
from the tissue
sample to be tested, reverse transcribed, and fluorescent-labeled cDNA probes
were generated. The
microarrays were probed with the labeled cDNA probes, the slides scanned and
fluorescence
intensity was measured. This intensity correlates with the hybridization
intensity. Two clones
(referred to as P509S and PS l OS) were found to be over-expressed in prostate
tumor and normal
prostate and expressed at low levels in all other normal tissues tested
(liver, pancreas, skin, bone
marrow, brain, breast, adrenal gland, bladder, testes, salivary gland, large
intestine, kidney, ovary,
lung, spinal cord, skeletal muscle and colon). The determined cDNA sequences
for P509S and
to PS l OS are provided in SEQ ID NO: 223 and 224, respectively. Comparison of
these sequences with
those in the gene bank as described above, revealed some homology to
previously identified ESTs.
Additional, studies led to the isolation of the full-length cDNA sequence for
P509S.
This sequence is provided in SEQ ID NO: 332, with the corresponding predicted
amino acid
sequence being provided in SEQ ID NO: 339. Two variant full-length cDNA
sequences for PS l OS
are provided in SEQ ID NO: 535 and 536, with the corresponding predicted amino
acid sequences
being provided in SEQ ID NO: 537 and 538, respectively.
EXAMPLE 2
DETERMINATION OF TISSUE SPECIFICITY OF PROSTATE-SPECIFIC POLYPEPTIDES
Using gene specific primers, mRNA expression levels for the representative
prostate-
specific polypeptides F1-16, H1-1, J1-17 (also referred to as P502S), L1-12
(also referred to as
PSO1S), F1-12 (also referred to as P504S) and N1-1862 (also referred to as
P503S) were examined
in a variety of normal and tumor tissues using RT-PCR.
Briefly, total RNA was extracted from a variety of normal and tumor tissues
using
Trizol reagent as described above. First strand synthesis was carried out
using 1-2 ~g of total RNA
with Superscript II reverse transcriptase (BRL Life Technologies) at 42
°C for one hour. The
cDNA was then amplified by PCR with gene-specific primers. To ensure the semi-
quantitative
nature of the RT-PCR, ~3-actin was used as an internal control for each of the
tissues examined.
First, serial dilutions of the first strand cDNAs were prepared and RT-PCR
assays were performed
3o using (3-actin specific primers. A dilution was then chosen that enabled
the linear range
amplification of the ~3-actin template and which was sensitive enough to
reflect the differences in
the initial copy numbers. Using these conditions, the (3-actin levels were
determined for each
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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 four different types of tumor tissue
(prostate tumor from 2 patients, breast tumor from 3 patients, colon tumor,
lung tumor), and sixteen
different normal tissues, including prostate, colon, kidney, liver, lung,
ovary, pancreas, skeletal
muscle, skin, stomach, testes, bone marrow and brain. Fl-16 was found to be
expressed at high
levels in prostate tumor tissue, colon tumor and normal prostate, and at lower
levels in normal liver,
skin and testes, with expression being undetectable in the other tissues
examined. H1-1 was found
1o to be expressed at high levels in prostate tumor, lung tumor, breast tumor,
normal prostate, normal
colon and normal brain, at much lower levels in normal lung, pancreas,
skeletal muscle, skin, small
intestine, bone marrow, and was not detected in the other tissues tested. J1-
17 (P502S) and L1-12
(P501 S) appear to be specifically over-expressed in prostate, with both genes
being expressed at
high levels in prostate tumor and normal prostate but at low to undetectable
levels in all the other
tissues examined. N1-1862 (P503S) was found to be over-expressed in 60% of
prostate tumors and
detectable in normal colon and kidney. The RT-PCR results thus indicate that
F1-16, H1-1, J1-17
(P502S), N1-1862 (P503S) and L1-12 (PSO1S) are either prostate specific or are
expressed at
significantly elevated levels in prostate.
Further RT-PCR studies showed that F1-12 (P504S) is over-expressed in 60% of
2o prostate tumors, detectable in normal kidney but not detectable in all
other tissues tested. Similarly,
R1-2330 was shown to be over-expressed in 40% of prostate tumors, detectable
in normal kidney
and liver, but not detectable in all other tissues tested. U1-3064 was found
to be over-expressed in
60% of prostate tumors, and also expressed in breast and colon tumors, but was
not detectable in
normal tissues.
RT-PCR characterization of R1-2330, U1-3064 and 1D-4279 showed that these
three
antigens are over-expressed in prostate and/or prostate tumors.
Northern analysis with four prostate tumors, two normal prostate samples, two
BPH
prostates, and normal colon, kidney, liver, lung, pancrease, skeletal muscle,
brain, stomach, testes,
small intestine and bone marrow, showed that L1-12 (PSO1S) is over-expressed
in prostate tumors
3o and normal prostate, while being undetectable in other normal tissues
tested. J1-17 (P502S) was
detected in two prostate tumors and not in the other tissues tested. N1-1862
(P503S) was found to
be over-expressed in three prostate tumors and to be expressed in normal
prostate, colon and kidney,
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but not in other tissues tested. F1-12 (P504S) was found to be highly
expressed in two prostate
tumors and to be undetectable in all other tissues tested.
The microarray technology described above was used to determine the expression
levels of representative antigens described herein in prostate tumor, breast
tumor and the following
normal tissues: prostate, liver, pancreas, skin, bone marrow, brain, breast,
adrenal gland, bladder,
testes, salivary gland, large intestine, kidney, ovary, lung, spinal cord,
skeletal muscle and colon.
L1-12 (P501S) was found to be over-expressed in normal prostate and prostate
tumor, with some
expression being detected in normal skeletal muscle. Both J1-12 and F1-12
(P504S) were found to
be over-expressed in prostate tumor, with expression being lower or
undetectable in all other tissues
tested. N1-1862 (P503S) was found to be expressed at high levels in prostate
tumor and normal
prostate, and at low levels in normal large intestine and normal colon, with
expression being
undetectable in all other tissues tested. R1-2330 was found to be over-
expressed in prostate tumor
and normal prostate, and to be expressed at lower levels in all other tissues
tested. 1 D-4279 was
found to be over-expressed in prostate tumor and normal prostate, expressed at
lower levels in
normal spinal cord, and to be undetectable in all other tissues tested.
Further microarray analysis to specifically address the extent to which P501 S
(SEQ
ID NO: 110) was expressed in breast tumor revealed moderate over-expression
not only in breast
tumor, but also in metastatic breast tumor (2/31 ), with negligible to low
expression in normal
tissues. This data suggests that P501 S may be over-expressed in various
breast tumors as well as in
2o prostate tumors.
The expression levels of 32 ESTs (expressed sequence tags) described by
Vasmatzis
et al. (Proc. Natl. Acad. Sci. USA 95:300-304, 1998) in a variety of tumor and
normal tissues were
examined by microarray technology as described above. Two of these clones
(referred to as
P 1 OOOC and P 1001 C) were found to be over-expressed in prostate tumor and
normal prostate, and
expressed at low to undetectable levels in all other tissues tested (normal
aorta, thymus, resting and
activated PBMC, epithelial cells, spinal cord, adrenal gland, fetal tissues,
skin, salivary gland, large
intestine, bone marrow, liver, lung, dendritic cells, stomach, lymph nodes,
brain, heart, small
intestine, skeletal muscle, colon and kidney. The determined cDNA sequences
for P 1 OOOC and
P 1001 C are provided in SEQ ID NO: 3 84 and 472, respectively. The sequence
of P 1001 C was
3o found to show some homology to the previously isolated Human mRNA for JM27
protein. No
significant homologies were found to the sequence of P 1000C.
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The expression of the polypeptide encoded by the full length cDNA sequence for
F1-
12 (also referred to as P504S; SEQ ID NO: 108) was investigated by
immunohistochemical
analysis. Rabbit-anti-P504S polyclonal antibodies were generated against the
full length P504S
protein by standard techniques. Subsequent isolation and characterization of
the polyclonal
antibodies were also performed by techniques well known in the art.
Immunohistochemical
analysis showed that the P504S polypeptide was expressed in 100% of prostate
carcinoma samples
tested (n=5).
The rabbit-anti-P504S polyclonal antibody did not appear to label benign
prostate
cells with the same cytoplasmic granular staining, but rather with light
nuclear staining. Analysis
to of normal tissues revealed that the encoded polypeptide was found to be
expressed in some, but
not all normal human tissues. Positive cytoplasmic staining with rabbit-anti-
P504S polyclonal
antibody was found in normal human kidney, liver, brain, colon and lung-
associated macrophages,
whereas heart and bone marrow were negative.
This data indicates that the P504S polypeptide is present in prostate cancer
tissues,
and that there are qualitative and quantitative differences in the staining
between benign prostatic
hyperplasia tissues and prostate cancer tissues, suggesting that this
polypeptide may be detected
selectively in prostate tumors and therefore be useful in the diagnosis of
prostate cancer.
2o EXAMPLE 3
ISOLATION AND CHARACTERIZATION OF PROSTATE-SPECIFIC POLYPEPTIDES BY
PCR-BASED SUBTRACTION
A cDNA subtraction library, containing cDNA from normal prostate subtracted
with
ten other normal tissue cDNAs (brain, heart, kidney, liver, lung, ovary,
placenta, skeletal muscle,
spleen and thymus) and then submitted to a first round of PCR amplification,
was purchased from
Clontech. This library was subjected to a second round of PCR amplification,
following the
manufacturer's protocol. The resulting cDNA fragments were subcloned into the
vector pT7 Blue
T-vector (Novagen, Madison, WI) and transformed into XL-1 Blue MRF' E. coli
(Stratagene).
3o DNA was isolated from independent clones and sequenced using a Perkin
Elmer/Applied
Biosystems Division Automated Sequencer Model 373A.
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Fifty-nine positive clones were sequenced. Comparison of the DNA sequences of
these clones with those in the gene bank, as described above, revealed no
significant homologies to
25 of these clones, hereinafter referred to as P5, P8, P9, P18, P20, P30, P34,
P36, P38, P39, P42,
P49, P50, P53, P55, P60, P64, P65, P73, P75, P76, P79 and P84. The determined
cDNA sequences
s for these clones are provided in SEQ ID NO: 41-45, 47-52 and 54-65,
respectively. P29, P47, P68,
P80 and P82 (SEQ ID NO: 46, 53 and 66-68, respectively) were found to show
some degree of
homology to previously identified DNA sequences. To the best of the inventors'
knowledge, none
of these sequences have been previously shown to be present in prostate.
Further studies using the PCR-based methodology described above resulted in
the
to isolation of more than 180 additional clones, of which 23 clones were found
to show no significant
homologies to known sequences. The determined cDNA sequences for these clones
are provided in
SEQ ID NO: 115-123, 127, 131, 137, 145, 147-151, 153, 156-158 and 160. Twenty-
three clones
(SEQ ID NO: 124-126, 128-130, 132-136, 138-144, 146, 152, 154, 155 and 159)
were found to
show some homology to previously identified ESTs. , An additional ten clones
(SEQ ID NO: 161-
15 170) were found to have some degree of homology to known genes. Larger cDNA
clones
containing the P20 sequence represent splice variants of a gene referred to as
P703P. The
determined DNA sequence for the variants referred to as DE 1, DE 13 and DE 14
are provided in
SEQ ID NOS: 171, 175 and 177, respectively, with the corresponding predicted
amino acid
sequences being provided in SEQ ID NO: 172, 176 and 178, respectively. The
determined cDNA
2o sequence for an extended spliced form of P703 is provided in SEQ ID NO:
225. The DNA
sequences for the splice variants referred to as DE2 and DE6 are provided in
SEQ ID NOS: 173 and
174, respectively.
mRNA Expression levels for representative clones in tumor tissues (prostate
(n=5),
breast (n=2), colon and lung) normal tissues (prostate (n=5), colon, kidney,
liver, lung (n=2), ovary
2s (n=2), skeletal muscle, skin, stomach, small intestine and brain), and
activated and non-activated
PBMC was determined by RT-PCR as described above. Expression was examined in
one sample of
each tissue type unless otherwise indicated.
P9 was found to be highly expressed in normal prostate and prostate tumor
compared
to all normal tissues tested except for normal colon which showed comparable
expression. P20, a
3o portion of the P703P gene, was found to be highly expressed in normal
prostate and prostate tumor,
compared to all twelve normal tissues tested. A modest increase in expression
of P20 in breast
tumor (n=2), colon tumor and lung tumor was seen compared to all normal
tissues except lung (1 of
6s
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2). Increased expression of P 18 was found in normal prostate, prostate tumor
and breast tumor
compared to other normal tissues except lung and stomach. A modest increase in
expression of PS
was observed in normal prostate compared to most other normal tissues.
However, some elevated
expression was seen in normal lung and PBMC. Elevated expression of P5 was
also observed in
prostate tumors (2 of 5), breast tumor and one lung tumor sample. For P30,
similar expression
levels were seen in normal prostate and prostate tumor, compared to six of
twelve other normal
tissues tested. Increased expression was seen in breast tumors, one lung tumor
sample and one
colon tumor sample, and also in normal PBMC. P29 was found to be over-
expressed in prostate
tumor (5 of 5) and normal prostate (5 of 5) compared to the majority of normal
tissues. However,
1o substantial expression of P29 was observed in normal colon and normal lung
(2 of 2). P80 was
found to be over-expressed in prostate tumor (5 of 5) and normal prostate (5
of 5) compared to all
other normal tissues tested, with increased expression also being seen in
colon tumor.
Further studies resulted in the isolation of twelve additional clones,
hereinafter
referred to as 10-d8, 10-h10, 11-c8, 7-g6, 8-b5, 8-b6, 8-d4, 8-d9, 8-g3, 8-hl
l, 9-f12 and 9-f3. The
determined DNA sequences for 10-d8, 10-h10, 11-c8, 8-d4, 8-d9, 8-hll, 9-f12
and 9-f3 are
provided in SEQ ID NO: 207, 208, 209, 216, 217, 220, 221 and 222,
respectively. The determined
forward and reverse DNA sequences for 7-g6, 8-b5, 8-b6 and 8-g3 are provided
in SEQ ID NO: 210
and 211; 212 and 213; 214 and 215; and 218 and 219, respectively. Comparison
of these sequences
with those in the gene bank revealed no significant homologies to the sequence
of 9-f3. The clones
10-d8, 11-c8 and 8-hl l were found to show some homology to previously
isolated ESTs, while 10-
h10, 8-b5, 8-b6, 8-d4, 8-d9, 8-g3 and 9-f12 were found to show some homology
to previously
identified genes. Further characterization of 7-G6 and 8-G3 showed identity to
the known genes
PAP and PSA, respectively.
mRNA expression levels for these clones were determined using the micro-array
technology described above. The clones 7-G6, 8-G3, 8-B5, 8-B6, 8-D4, 8-D9, 9-
F3, 9-F12, 9-H3,
10-A2, 10-A4, 11-C9 and 11-F2 were found to be over-expressed in prostate
tumor and normal
prostate, with expression in other tissues tested being low or undetectable.
Increased expression of
8-F 11 was seen in prostate tumor and normal prostate, bladder, skeletal
muscle and colon.
Increased expression of 10-H10 was seen in prostate tumor and normal prostate,
bladder, lung,
3o colon, brain and large intestine. Increased expression of 9-B 1 was seen in
prostate tumor, breast
tumor, and normal prostate, salivary gland, large intestine and skin, with
increased expression of 11-
C8 being seen in prostate tumor, and normal prostate and large intestine.
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An additional cDNA fragment derived from the PCR-based normal prostate
subtraction, described above, was found to be prostate specific by both micro-
array technology and
RT-PCR. The determined cDNA sequence of this clone (referred to as 9-A11) is
provided in SEQ
ID NO: 226. Comparison of this sequence with those in the public databases
revealed 99% identity
s to the known gene HOXB 13.
Further studies led to the isolation of the clones 8-C6 and 8-H7. The
determined
cDNA sequences for these clones are provided in SEQ ID NO: 227 and 228,
respectively. These
sequences were found to show some homology to previously isolated ESTs.
PCR and hybridization-based methodologies were employed to obtain longer cDNA
1o sequences for clone P20 (also referred to as P703P), yielding three
additional cDNA fragments that
progressively extend the 5' end of the gene. These fragments, referred to as
P703PDE5, P703P6.26,
and P703PX-23 (SEQ ID NO: 326, 328 and 330, with the predicted corresponding
amino acid
sequences being provided in SEQ ID NO: 327, 329 and 331, respectively) contain
additional 5'
sequence. P703PDE5 was recovered by screening of a cDNA library (#141-26) with
a portion of
15 P703P as a probe. P703P6.26 was recovered from a mixture of three prostate
tumor cDNAs and
P703PX 23 was recovered from cDNA library (#438-48). Together, the additional
sequences
include all of the putative mature serine protease along with part of the
putative signal sequence.
The putative full-length cDNA sequence for P703P is provided in SEQ ID NO:
524, with the
corresponding predicted amino acid sequence being provided in SEQ ID NO: 525.
2o Further studies using a PCR-based subtraction library of a prostate tumor
pool
subtracted against a pool of normal tissues (referred to as JP: PCR
subtraction) resulted in the
isolation of thirteen additional clones, seven of which did not share any
significant homology to
known GenBank sequences. The determined cDNA sequences for these seven clones
(P711 P,
P712P, novel 23, P774P, P775P, P710P and P768P) are provided in SEQ ID NO: 307-
31 l, 313 and
25 315, respectively. The remaining six clones (SEQ ID NO: 316 and 321-325)
were shown to share
some homology to known genes. By microarray analysis, all thirteen clones
showed three or more
fold over-expression in prostate tissues, including prostate tumors, BPH and
normal prostate as
compared to normal non-prostate tissues. Clones P711P, P712P, novel 23 and
P768P showed over-
expression in most prostate tumors and BPH tissues tested (n=29), and in the
majority of normal
3o prostate tissues (n=4), but background to low expression levels in all
normal tissues. Clones P774P,
P775P and P710P showed comparatively lower expression and expression in fewer
prostate tumors
and BPH samples, with negative to low expression in normal prostate.
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The full-length cDNA for P711 P was obtained by employing the partial sequence
of
SEQ ID NO: 307 to screen a prostate cDNA library. Specifically, a
directionally cloned prostate
cDNA library was prepared using standard techniques. One million colonies of
this library were
plated onto LB/Amp plates. Nylon membrane filters were used to lift these
colonies, and the
cDNAs which were picked up by these filters were denatured and cross-linked to
the filters by UV
light. The P711P cDNA fragment of SEQ ID NO: 307 was radio-labeled and used to
hybridize with
these filters. Positive clones were selected, and cDNAs were prepared and
sequenced using an
automatic Perkin Elmer/Applied Biosystems sequencer. The determined full-
length sequence of
P711P is provided in SEQ ID NO: 382, with the corresponding predicted amino
acid sequence
to being provided in SEQ ID NO: 383.
Using PCR and hybridization-based methodologies, additional cDNA sequence
information was derived for two clones described above, 11-C9 and 9-F3, herein
after referred to as
P707P and P714P, respectively (SEQ ID NO: 333 and 334). After comparison with
the most recent
GenBank, P707P was found to be a splice variant of the known gene HoxB 13. In
contrast, no
significant homologies to P714P were found.
Clones 8-B3, P89, P98, P130 and P201 (as disclosed in U.S. Patent Application
No.
09/020,956, filed February 9, 1998) were found to be contained within one
contiguous sequence,
referred to as P705P (SEQ ID NO: 335, with the predicted amino acid sequence
provided in SEQ ID
NO: 336), which was determined to be a splice variant of the known gene NKX
3.1.
Further studies on P775P resulted in the isolation of four additional
sequences (SEQ
ID NO: 473-476) which are all splice variants of the P775P gene. The sequence
of SEQ ID NO:
474 was found to contain two open reading frames (ORFs). The predicted amino
acid sequences
encoded by these ORFs are provided in SEQ ID NO: 477 and 478. The cDNA
sequence of SEQ ID
NO: 475 was found to contain an ORF which encodes the amino acid sequence of
SEQ ID NO: 479.
The cDNA sequence of SEQ ID NO: 473 was found to contain four ORFs. The
predicted amino
acid sequences encoded by these ORFs are provided in SEQ ID NO: 480-483.
Subsequent studies led to the identification of a genomic region on chromosome
22q11.2, known as the Cat Eye Syndrome region, that contains the five prostate
genes P704P,
P712P, P774P, P775P and B305D. The relative location of each of these five
genes within the
3o genomic region is shown in Fig. 10. This region may therefore be associated
with malignant
tumors, and other potential tumor genes may be contained within this region.
These studies also led
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to the identification of a potential open reading frame (ORF) for P775P
(provided in SEQ ID NO:
533), which encodes the amino acid sequence of SEQ ID NO: 534.
EXAMPLE 4
SYNTHESIS OF POLYPEPTIDES
Polypeptides may be synthesized on a Perkin Elmer/Applied Biosystems 430A
peptide synthesizer using FMOC chemistry with HPTU (O-Benzotriazole-N,N,N',N'-
tetramethyluronium hexafluorophosphate) activation. A Gly-Cys-Gly sequence may
be attached to
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
acid:ethanedithiolahioanisole:water:phenol (40:1:2:2:3). After cleaving for 2
hours, the peptides
may be precipitated in cold methyl-t-butyl-ether. The peptide pellets may then
be dissolved in
water containing 0.1 % trifluoroacetic acid (TFA) and lyophilized prior to
purification by C 18
reverse 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. Following
lyophilization of the pure
fractions, the peptides may be characterized using electrospray or other types
of mass spectrometry
and by amino acid analysis.
EXAMPLE 5
FURTHER ISOLATION AND CHARACTERIZATION OF PROSTATE-SPECIFIC
POLYPEPTIDES BY PCR-BASED SUBTRACTION
A cDNA library generated from prostate primary tumor mRNA as described above
was subtracted with cDNA from normal prostate. The subtraction was performed
using a PCR-
based protocol (Clontech), which was modified to generate larger fragments.
Within this protocol,
tester and driver double stranded cDNA were separately digested with five
restriction enzymes that
3o recognize six-nucleotide restriction sites (MIuI, MscI, PvuII, SaII and
StuI). This digestion resulted
in an average cDNA size of 600 bp, rather than the average size of 300 by that
results from
digestion with RsaI according to the Clontech protocol. This modification did
not affect the
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subtraction efficiency. Two tester populations were then created with
different adapters, and the
driver library remained without adapters.
The tester and driver libraries were then hybridized using excess driver cDNA.
In
the first hybridization step, driver was separately hybridized with each of
the two tester cDNA
populations. This resulted in populations of (a) unhybridized tester cDNAs,
(b) tester cDNAs
hybridized to other tester cDNAs, (c) tester cDNAs hybridized to driver cDNAs
and (d)
unhybridized driver cDNAs. The two separate hybridization reactions were then
combined, and
rehybridized in the presence of additional denatured driver cDNA. Following
this second
hybridization, in addition to populations (a) through (d), a fifth population
(e) was generated in
t o which tester cDNA with one adapter hybridized to tester cDNA with the
second adapter.
Accordingly, the second hybridization step resulted in enrichment of
differentially expressed
sequences which could be used as templates for PCR amplification with adaptor-
specific primers.
The ends were then filled in, and PCR amplification was performed using
adaptor-
specific primers. Only population (e), which contained tester cDNA that did
not hybridize to driver
~ 5 cDNA, was amplified exponentially. A second PCR amplification step was
then performed, to
reduce background and further enrich differentially expressed sequences.
This PCR-based subtraction technique normalizes differentially expressed cDNAs
so
that rare transcripts that are overexpressed in prostate tumor tissue may be
recoverable. Such
transcripts would be difficult to recover by traditional subtraction methods.
2o In addition to genes known to be overexpressed in prostate tumor, seventy-
seven
further clones were identified. Sequences of these partial cDNAs are provided
in SEQ ID NO: 29 to
305. Most of these clones had no significant homology to database sequences.
Exceptions were
JPTPN23 (SEQ ID NO: 231; similarity to pig valosin-containing protein),
JPTPN30 (SEQ ID NO:
234; similarity to rat mRNA for proteasome subunit), JPTPN45 (SEQ ID NO: 243;
similarity to rat
25 norvegicus cytosolic NADP-dependent isocitrate dehydrogenase), JPTPN46 (SEQ
ID NO: 244;
similarity to human subclone H8 4 d4 DNA sequence), JP 1 D6 (SEQ ID NO: 265;
similarity to G.
gallus dynein light chain-A), JP8D6 (SEQ ID NO: 288; similarity to human BAC
clone RG016J04),
JP8F5 (SEQ ID NO: 289; similarity to human subclone H8 3 b5 DNA sequence), and
JP8E9 (SEQ
ID NO: 299; similarity to human Alu sequence).
3o Additional studies using the PCR-based subtraction library consisting of a
prostate
tumor pool subtracted against a normal prostate pool (referred to as PT-PN PCR
subtraction)
yielded three additional clones. Comparison of the cDNA sequences of these
clones with the most
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recent release of GenBank revealed no significant homologies to the two clones
referred to as
P715P and P767P (SEQ ID NO: 312 and 314). The remaining clone was found to
show some
homology to the known gene KIAA0056 (SEQ ID NO: 318). Using microarray
analysis to measure
mRNA expression levels in various tissues, all three clones were found to be
over-expressed in
prostate tumors and BPH tissues. Specifically, clone P715P was over-expressed
in most prostate
tumors and BPH tissues by a factor of three or greater, with elevated
expression seen in the majority
of normal prostate samples and in fetal tissue, but negative to low expression
in all other normal
tissues. Clone P767P was over-expressed in several prostate tumors and BPH
tissues, with
moderate expression levels in half of the normal prostate samples, and
background to low
to expression in all other normal tissues tested.
Further analysis, by microarray as described above, of the PT-PN PCR
subtraction
library and of a DNA subtraction library containing cDNA from prostate tumor
subtracted with a
pool of normal tissue cDNAs, led to the isolation of 27 additional clones (SEQ
ID NO: 340-365 and
381) which were determined to be over-expressed in prostate tumor. The clones
of SEQ ID NO:
341, 342, 345, 347, 348, 349, 351, 355-359, 361, 362 and 364 were also found
to be expressed in
normal prostate. Expression of all 26 clones in a variety of normal tissues
was found to be low or
undetectable, with the exception of P544S (SEQ ID NO: 356) which was found to
be expressed in
small intestine. Of the 26 clones, 10 (SEQ ID NO: 340-349) were found to show
some homology to
previously identified sequences. No significant homologies were found to the
clones of SEQ ID
2o NO: 350, 351 and 353-365.
Further studies on the clone of SEQ ID NO: 352 (referred to as P790P) led to
the
isolation of the full-length cDNA sequence of SEQ ID NO: 526. The
corresponding predicted
amino acid is provided in SEQ ID NO: 527. Data from two quantitative PCR
experiments indicated
that P790P is over-expressed in 11/15 tested prostate tumor samples and is
expressed at low levels
in spinal cord, with no expression being seen in all other normal samples
tested. Data from further
PCR experiments and microarray experiments showed over-expression in normal
prostate and
prostate tumor with little or no expression in other tissues tested. P790P was
subsequently found to
show significant homology to a previously identified G-protein coupled
prostate tissue receptor.
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EXAMPLE 6
PEPTIDE PRIMING OF MICE AND PROPAGATION OF CTL LINES
6.1. This Example illustrates the preparation of a CTL cell line specific for
cells
expressing the P502S gene.
Mice expressing the transgene for human HLA A2Kb (provided by Dr L. Sherman,
The Scripps Research Institute, La Jolla, CA) were immunized with P2S#12
peptide (VLGWVAEL;
SEQ ID NO: 306), which is derived from the P502S gene (also referred to herein
as J1-17, SEQ ID
1o NO: 8), as described by Theobald et al., Proc. Natl. Acad. Sci. USA
92:11993-11997, 1995 with the
following modifications. Mice were immunized with 100pg of P2S#12 and 120p,g
of an I-Ab
binding peptide derived from hepatitis B Virus protein emulsified in
incomplete Freund's adjuvant.
Three weeks later these mice were sacrificed and using a nylon mesh single
cell suspensions
prepared. Cells were then resuspended at 6 x 10G cells/ml in complete media
(RPMI-1640; Gibco
BRL, Gaithersburg, MD) containing 10% FCS, 2mM Glutamine (Gibco BRL), sodium
pyruvate
(Gibco BRL), non-essential amino acids (Gibco BRL), 2 x 10-5 M 2-
mercaptoethanol, SOU/ml
penicillin and streptomycin, and cultured in the presence of irradiated (3000
rads) P2S#12-pulsed
(Smg/ml P2S#12 and lOmg/ml (32-microglobulin) LPS blasts (A2 transgenic
spleens cells cultured
in the presence of 7pg/ml dextran sulfate and 25~g/ml LPS for 3 days). Six
days later, cells (S x
105/m1) were restimulated with 2.5 x 106/m1 peptide pulsed irradiated (20,000
rads) EL4A2Kb cells
(Sherman et al, Science 258:815-818, 1992) and 3 x 106/m1 A2 transgenic spleen
feeder cells. Cells
were cultured in the presence of 20U/ml IL-2. Cells continued to be
restimulated on a weekly basis
as described, in preparation for cloning the line.
P2S#12 line was cloned by limiting dilution analysis with peptide pulsed EL4
A2Kb
tumor cells (1 x 104 cells/ well) as stimulators and A2 transgenic spleen
cells as feeders ( 5 x 105
cells/ well) grown in the presence of 30U/ml IL-2. On day 14, cells were
restimulated as before. On
day 21, clones that were growing were isolated and maintained in culture.
Several of these clones
demonstrated significantly higher reactivity (lysis) against human fibroblasts
(HLA A2Kb
expressing) transduced with P502S than against control fibroblasts. An example
is presented in
3o Figure 1.
This data indicates that P2S #12 represents a naturally processed epitope of
the
P502S protein that is expressed in the context of the human HLA A2Kb molecule.
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6.2. This Example illustrates the preparation of murine CTL lines and CTL
clones
specific for cells expressing the P501 S gene.
This series of experiments were performed similarly to that described above.
Mice
s were immunized with the P1S#10 peptide (SEQ ID NO: 337), which is derived
from the P501S
gene (also referred to herein as L1-12, SEQ ID NO: 110). The P1S#10 peptide
was derived by
analysis of the predicted polypeptide sequence for P501 S for potential HLA-A2
binding sequences
as defined by published HLA-A2 binding motifs (Parker, KC, et al, J. Immunol.,
152:163, 1994).
P1S#10 peptide was synthesized as described in Example 4, and empirically
tested for HLA-A2
binding using a T cell based competition assay. Predicted A2 binding peptides
were tested for their
ability to compete HLA-A2 specific peptide presentation to an HLA-A2
restricted CTL clone
(D150M58), which is specific for the HLA-A2 binding influenza matrix peptide
fluM58. D150M58
CTL secretes TNF in response to self presentation of peptide fluM58. In the
competition assay, test
peptides at 100-200 ~g/ml were added to cultures of D150M58 CTL in order to
bind HLA-A2 on
the CTL. After thirty minutes, CTL cultured with test peptides, or control
peptides, were tested for
their antigen dose response to the fluM58 peptide in a standard TNF bioassay.
As shown in Figure
3, peptide P1S#10 competes HLA-A2 restricted presentation of fluM58,
demonstrating that peptide
P 1 S# 10 binds HLA-A2.
Mice expressing the transgene for human HLA A2Kb were immunized as described
2o by Theobald et al. (Proc. Natl. Acad. Sci. USA 92:11993-11997, 1995) with
the following
modifications. Mice were immunized with 62.S~g of P1S #10 and 120pg of an I-Ab
binding
peptide derived from Hepatitis B Virus protein emulsified in incomplete
Freund's adjuvant. Three
weeks later these mice were sacrificed and single cell suspensions prepared
using a nylon mesh.
Cells were then resuspended at 6 x 106 cells/ml in complete media (as
described above) and cultured
2s in the presence of irradiated (3000 rads) P1S#10-pulsed (2~g/ml P1S#10 and
lOmg/ml (32-
microglobulin) LPS blasts (A2 transgenic spleens cells cultured in the
presence of 7~g/ml dextran
sulfate and 25p.g/ml LPS for 3 days). Six days later cells (5 x 105/m1) were
restimulated with 2.5 x
106/m1 peptide-pulsed irradiated (20,000 rads) EL4A2Kb cells, as described
above, and 3 x 106/m1
A2 transgenic spleen feeder cells. Cells were cultured in the presence of 20
U/ml IL-2. Cells were
3o restimulated on a weekly basis in preparation for cloning. After three
rounds of in vitro
stimulations, one line was generated that recognized P 1 S# 10-pulsed Jurkat
A2Kb targets and
P501 S-transduced Jurkat targets as shown in Figure 4.
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A P 1 S# 10-specific CTL line was cloned by limiting dilution analysis with
peptide
pulsed EL4 A2Kb tumor cells (1 x 104 cells/ well) as stimulators and A2
transgenic spleen cells as
feeders ( 5 x 105 cells/ well) grown in the presence of 30U/ml IL-2. On day
14, cells were
restimulated as before. On day 21, viable clones were isolated and maintained
in culture. As shown
in Figure 5, five of these clones demonstrated specific cytolytic reactivity
against P501 S-transduced
Jurkat A2Kb targets. This data indicates that P1S#10 represents a naturally
processed epitope of the
P501 S protein that is expressed in the context of the human HLA-A2.1
molecule.
EXAMPLE 7
PRIMING OF CTL IN VIVO USING NAKED DNA IMMUNIZATION
WITH A PROSTATE ANTIGEN
The prostate-specific antigen Ll-12, as described above, is also referred to
as PSO1S.
HLA A2Kb Tg mice (provided by Dr L. Sherman, The Scripps Research Institute,
La Jolla, CA)
were immunized with 100 ~g P501 S in the vector VR1012 either intramuscularly
or intradermally.
The mice were immunized three times, with a two week interval between
immunizations. Two
weeks after the last immunization, immune spleen cells were cultured with
Jurkat A2Kb-P501 S
transduced stimulator cells. CTL lines were stimulated weekly. After two weeks
of in vitro
stimulation, CTL activity was assessed against P501 S transduced targets. Two
out of 8 mice
developed strong anti-P501 S CTL responses. These results demonstrate that
P501 S contains at
least one naturally processed HLA-A2-restricted CTL epitope.
EXAMPLE 8
ABILITY OF HUMAN T CELLS TO RECOGNIZE PROSTATE-SPECIFIC POLYPEPTIDES
This Example illustrates the ability of T cells specific for a prostate tumor
polypeptide to recognize human tumor.
Human CD8+ T cells were primed in vitro to the P2S-12 peptide (SEQ ID NO: 306)
derived from P502S (also referred to as J1-17) using dendritic cells according
to the protocol of Van
Tsai et al. (Critical Reviews in Immunology 18:65-75, 1998). The resulting
CD8+ T cell
microcultures were tested for their ability to recognize the P2S-12 peptide
presented by autologous
fibroblasts or fibroblasts which were transduced to express the P502S gene in
a r-interferon
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ELISPOT assay (see Lalvani et al., J. Exp. Med. 186:859-865, 1997). Briefly,
titrating numbers of
T cells were assayed in duplicate on 104 fibroblasts in the presence of 3
~g/ml human p2-
microglobulin and 1 ~g/ml P2S-12 peptide or control E75 peptide. In addition,
T cells were
simultaneously assayed on autologous fibroblasts transduced with the P502S
gene or as a control,
fibroblasts transduced with HER-2/neu. Prior to the assay, the fibroblasts
were treated with 10
ng/ml y-interferon for 48 hours to upregulate class I MHC expression. One of
the microcultures
(#5) demonstrated strong recognition of both peptide pulsed fibroblasts as
well as transduced
fibroblasts in a y-interferon ELISPOT assay. Figure 2A demonstrates that there
was a strong
increase in the number of y-interferon spots with increasing numbers of T
cells on fibroblasts pulsed
to with the P2S-12 peptide (solid bars) but not with the control E75 peptide
(open bars). This shows
the ability of these T cells to specifically recognize the P2S-12 peptide. As
shown in Figure 2B,
this microculture also demonstrated an increase in the number of r-interferon
spots with increasing
numbers of T cells on fibroblasts transduced to express the P502S gene but not
the HER-2/neu
gene. These results provide additional confirmatory evidence that the P2S-12
peptide is a naturally
processed epitope of the P502S protein. Furthermore, this also demonstrates
that there exists in the
human T cell repertoire, high affinity T cells which are capable of
recognizing this epitope. These T
cells should also be capable of recognizing human tumors which express the
P502S gene.
2o EXAMPLE 9
ELICITATION OF PROSTATE ANTIGEN-SPECIFIC CTL RESPONSES
IN HUMAN BLOOD
This Example illustrates the ability of a prostate-specific antigen to elicit
a CTL
response in blood of normal humans.
Autologous dendritic cells (DC) were differentiated from monocyte cultures
derived
from PBMC of normal donors by growth for five days in RPMI medium containing
10% human
serum, 50 ng/ml GMCSF and 30 ng/ml IL-4. Following culture, DC were infected
overnight with
recombinant P501 S-expressing vaccinia virus at an M.O.I. of 5 and matured for
8 hours by the
3o addition of 2 micrograms/ml CD40 ligand. Virus was inactivated by UV
irradiation, CD8+ cells
were isolated by positive selection using magnetic beads, and priming cultures
were initiated in 24-
well plates. Following five stimulation cycles using autologous fibroblasts
retrovirally transduced
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to express P501 S and CD80, CD8+ lines were identified that specifically
produced interferon-
gamma when stimulated with autologous P501 S-transduced fibroblasts. The P501
S-specific
activity of cell line 3A-1 could be maintained following additional
stimulation cycles on autologous
B-LCL transduced with P501 S. Line 3A-1 was shown to specifically recognize
autologous B-LCL
transduced to express P501 S, but not EGFP-transduced autologous B-LCL, as
measured by
cytotoxicity assays (5'Cr release) and interferon-gamma production (Interferon-
gamma Elispot; see
above and Lalvani et al., J. Exp. Med. 186:859-865, 1997). The results of
these assays are presented
in Figures 6A and 6B.
1o EXAMPLE 10
IDENTIFICATION OF A NATURALLY PROCESSED CTL EPITOPE CONTAINED WITHIN A
PROSTATE-SPECIFIC ANTIGEN
The 9-mer peptide p5 (SEQ ID NO: 338) was derived from the P703P antigen (also
referred to as P20). The p5 peptide is immunogenic in human HLA-A2 donors and
is a naturally
processed epitope. Antigen specific human CD8+ T cells can be primed following
repeated in vitro
stimulations with monocytes pulsed with p5 peptide. These CTL specifically
recognize p5-pulsed
and P703P-transduced target cells in both ELISPOT (as described above) and
chromium release
assays. Additionally, immunization of HLA-A2Kb transgenic mice with p5 leads
to the generation
of CTL lines which recognize a variety of HLA-A2Kb or HLA-A2 transduced target
cells
expressing P703P.
Initial studies demonstrating that p5 is a naturally processed epitope were
done using
HLA-A2Kb transgenic mice. HLA-A2Kb transgenic mice were immunized
subcutaneously in the
footpad with 100 pg of p5 peptide together with 140 ~g of hepatitis B virus
core peptide (a Th
2s peptide) in Freund's incomplete adjuvant. Three weeks post immunization,
spleen cells from
immunized mice were stimulated in vitro with peptide-pulsed LPS blasts. CTL
activity was
assessed by chromium release assay five days after primary in vitro
stimulation. Retrovirally
transduced cells expressing the control antigen P703P and HLA-A2Kb were used
as targets. CTL
lines that specifically recognized both p5-pulsed targets as well as P703P-
expressing targets were
3o identified.
Human in vitro priming experiments demonstrated that the p5 peptide is
immunogenic in humans. Dendritic cells (DC) were differentiated from monocyte
cultures derived
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from PBMC of normal human donors by culturing for five days in RPMI medium
containing 10%
human serum, 50 ng/ml human GM-CSF and 30 ng/ml human IL-4. Following culture,
the DC
were pulsed with 1 ug/ml p5 peptide and cultured with CD8+ T cell enriched
PBMC. CTL lines
were restimulated on a weekly basis with p5-pulsed monocytes. Five to six
weeks after initiation of
the CTL cultures, CTL recognition of p5-pulsed target cells was demonstrated.
CTL were
additionally shown to recognize human cells transduced to express P703P,
demonstrating that p5 is
a naturally processed epitope.
EXAMPLE 11
to EXPRESSION OF A BREAST TUMOR-DERIVED ANTIGEN
IN PROSTATE
Isolation of the antigen B305D from breast tumor by differential display is
described
in US Patent Application No. 08/700,014, filed August 20, 1996. Several
different splice forms of
this antigen were isolated. The determined cDNA sequences for these splice
forms are provided in
t 5 SEQ ID NO: 366-375, with the predicted amino acid sequences corresponding
to the sequences of
SEQ ID NO: 292, 298 and 301-303 being provided in SEQ ID NO: 299-306,
respectively. In
further studies, a splice variant of the cDNA sequence of SEQ ID NO: 366 was
isolated which was
found to contain an additional guanine residue at position 884 (SEQ ID NO:
530), leading to a
frameshift in the open reading frame. The determined DNA sequence of this ORF
is provided in
2o SEQ ID NO: 531. This frameshift generates a protein sequence (provided in
SEQ ID NO: 532) of
293 amino acids that contains the C-terminal domain common to the other
isoforms of B305D but
that differs in the N-terminal region.
The expression levels of B305D in a variety of tumor and normal tissues were
examined by real time PCR and by Northern analysis. The results indicated that
B305D is highly
25 expressed in breast tumor, prostate tumor, normal prostate and normal
testes, with expression being
low or undetectable in all other tissues examined (colon tumor, lung tumor,
ovary tumor, and
normal bone marrow, colon, kidney, liver, lung, ovary, skin, small intestine,
stomach).
EXAMPLE 12
3o GENERATION OF HUMAN CTL IN VITRO USING WHOLE GENE PRIMING AND
STIMULATION TECHNIQUES WITH PROSTATE-SPECIFIC ANTIGEN
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Using in vitro whole-gene priming with P501 S-vaccinia infected DC (see, for
example, Yee et al, The Journal of Immunology, 157(9):4079-86, 1996), human
CTL lines were
derived that specifically recognize autologous fibroblasts transduced with
P501 S (also known as
L1-12), as determined by interferon-y ELISPOT analysis as described above.
Using a panel of
HLA-mismatched B-LCL lines transduced with P501 S, these CTL lines were shown
to be likely
restricted to HLAB class I allele. Specifically, dendritic cells (DC) were
differentiated from
monocyte cultures derived from PBMC of normal human donors by growing for five
days in RPMI
medium containing 10% human serum, 50 ng/ml human GM-CSF and 30 ng/ml human IL-
4.
Following culture, DC were infected overnight with recombinant P501 S vaccinia
virus at a
multiplicity of infection (M.O.I) of five, and matured overnight by the
addition of 3 pg/ml CD40
ligand. Virus was inactivated by UV irradiation. CD8+ T cells were isolated
using a magnetic bead
system, and priming cultures were initiated using standard culture techniques.
Cultures were
restimulated every 7-10 days using autologous primary fibroblasts retrovirally
transduced with
P501 S and CD80. Following four stimulation cycles, CD8+ T cell lines were
identified that
specifically produced interferon-y when stimulated with P501 S and CD80-
transduced autologous
fibroblasts. A panel of HLA-mismatched B-LCL lines transduced with P501 S were
generated to
define the restriction allele of the response. By measuring interferon-y in an
ELISPOT assay, the
PSO1 S specific response was shown to be likely restricted by HLA B alleles.
These results
demonstrate that a CD8+ CTL response to P501 S can be elicited.
To identify the epitope(s) recognized, cDNA encoding P501 S was fragmented by
various restriction digests, and sub-cloned into the retroviral expression
vector pBIB-KS. Retroviral
supernatants were generated by transfection of the helper packaging line
Phoenix-Ampho.
Supernatants were then used to transduce Jurkat/A2Kb cells for CTL screening.
CTL were screened
in IFN-gamma ELISPOT assays against these A2Kb targets transduced with the
"library" of P501 S
fragments. Initial positive fragments P501 S/H3 and P501 S/F2 were sequenced
and found to encode
amino acids 106-553 and amino acids 136-547, respectively, of SEQ ID NO: 113.
A truncation of
H3 was made to encode amino acid residues 106-351 of SEQ ID NO: 113, which was
unable to
stimulate the CTL, thus localizing the epitope to amino acid residues 351-547.
Additional
fragments encoding amino acids 1-472 (Fragment A) and amino acids 1-351
(Fragment B) were
3o also constructed. Fragment A but not Fragment B stimulated the CTL thus
localizing the epitope to
amino acid residues 351-472. Overlapping 20-mer and 18-mer peptides
representing this region
were tested by pulsing Jurkat/A2Kb cells versus CTL in an IFN-gamma assay.
Only peptides
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P501 S-369(20) and P501 S-369(18) stimulated the CTL. Nine-mer and 10-mer
peptides
representing this region were synthesized and similarly tested. Peptide P501 S-
370 (SEQ ID NO:
539) was the minimal 9-mer giving a strong response. Peptide P501 S-376 (SEQ
ID NO: 540) also
gave a weak response, suggesting that it might represent a cross-reactive
epitope.
In subsequent studies, the ability of primary human B cells transduced with
P501 S to
prime MHC class I-restricted, P501 S-specific, autologous CD8 T cells was
examined. Primary B
cells were derived from PBMC of a homozygous HLA-A2 donor by culture in CD40
ligand and IL-
4, transduced at high frequency with recombinant PSO1S in the vector pBIB, and
selected with
blastocidin-S. For in vitro priming, purified CD8+ T cells were cultured with
autologous CD40
t o ligand + IL-4 derived, P501 S-transduced B cells in a 96-well microculture
format. These CTL
microcultures were re-stimulated with P501 S-transduced B cells and then
assayed for specificity.
Following this initial screen, microcultures with significant signal above
background were cloned
on autologous EBV-transformed B cells (BLCL), also transduced with PSO1S.
Using IFN-gamma
ELISPOT for detection, several of these CD8 T cell clones were found to be
specific for P501 S, as
demonstrated by reactivity to BLCL/P501 S but not BLCL transduced with control
antigen. It was
further demonstrated that the anti-P501 S CD8 T cell specificity is HLA-A2-
restricted. First,
antibody blocking experiments with anti-HLA-A,B,C monoclonal antibody (W6.32),
anti-HLA-B,C
monoclonal antibody (B 1.23.2) and a control monoclonal antibody showed that
only the anti-HLA-
A,B,C antibody blocked recognition of P501 S-expressing autologous BLCL.
Secondly, the anti-
2o P501 S CTL also recognized an HLA-A2 matched, heterologous BLCL transduced
with P501 S, but
not the corresponding EGFP transduced control BLCL.
EXAMPLE 13
IDENTIFICATION OF PROSTATE-SPECIFIC ANTIGENS
BY MICROARRAY ANALYSIS
This Example describes the isolation of certain prostate-specific polypeptides
from a
prostate tumor cDNA library.
A human prostate tumor cDNA expression library as described above was screened
using microarray analysis to identify clones that display at least a three
fold over-expression in
prostate tumor and/or normal prostate tissue, as compared to non-prostate
normal tissues (not
including testis). 372 clones were identified, and 319 were successfully
sequenced. Table I
presents a summary of these clones, which are shown in SEQ ID NOs:385-400. Of
these sequences
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SEQ ID NOs:386, 389, 390 and 392 correspond to novel genes, and SEQ ID NOs:
393 and 396
correspond to previously identified sequences. The others (SEQ ID NOs:385,
387, 388, 391, 394,
395 and 397-400) correspond to known sequences, as shown in Table I.
Table I
Summary of Prostate Tumor Antigens
Known Genes Previously IdentifiedNovel Genes
Genes
T-cell gamma chain P504S 23379 (SEQ ID
N0:389)
Kallikrein P1000C 23399 (SEQ ID
N0:392)
Vector P501 S 23320 (SEQ ID
N0:386)
CGI-82 protein mRNA (23319; P503S 23381 (SEQ ID
SEQ ID N0:385) N0:390)
PSA P510S
Ald. 6 Dehyd. P784P
L-iditol-2 dehydrogenase (23376;P502S
SEQ ID N0:388)
Ets transcription factor PDEF P706P
(22672; SEQ ID
N0:398)
hTGR (22678; SEQ ID N0:399) 19142.2, bangur.seq
(22621;
SEQ ID N0:396)
KIAA0295(22685; SEQ ID N0:400) 5566.1 Wang (23404;
SEQ ID
N0:393)
Prostatic Acid Phosphatase(22655;P712P
SEQ ID
N0:397)
transglutaminase (22611; SEQ P778P
ID N0:395)
HDLBP (23508; SEQ ID N0:394)
CGI-69 Protein(23367; SEQ ID
N0:387)
KIAA0122(23383; SEQ ID N0:391)
TEEG
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CGI-82 showed 4.06 fold over-expression in prostate tissues as compared to
other
normal tissues tested. It was over-expressed in 43% of prostate tumors, 25%
normal prostate, not
detected in other normal tissues tested. L-iditol-2 dehydrogenase showed 4.94
fold over-expression
in prostate tissues as compared to other normal tissues tested. It was over-
expressed in 90% of
prostate tumors, 100% of normal prostate, and not detected in other normal
tissues tested. Ets
transcription factor PDEF showed 5.55 fold over-expression in prostate tissues
as compared to other
normal tissues tested. It was over-expressed in 47% prostate tumors, 25%
normal prostate and not
detected in other normal tissues tested. hTGRI showed 9.11 fold over-
expression in prostate tissues
as compared to other normal tissues tested. It was over-expressed in 63% of
prostate tumors and is
1o not detected in normal tissues tested including normal prostate. KIAA0295
showed 5.59 fold over-
expression in prostate tissues as compared to other normal tissues tested. It
was over-expressed in
47% of prostate tumors, low to undetectable in normal tissues tested including
normal prostate
tissues. Prostatic acid phosphatase showed 9.14 fold over-expression in
prostate tissues as
compared to other normal tissues tested. It was over-expressed in 67% of
prostate tumors, 50% of
normal prostate, and not detected in other normal tissues tested.
Transglutaminase showed 14.84
fold over-expression in prostate tissues as compared to other normal tissues
tested. It was over-
expressed in 30% of prostate tumors, 50% of normal prostate, and is not
detected in other normal
tissues tested. High density lipoprotein binding protein (HDLBP) showed 28.06
fold over-
expression in prostate tissues as compared to other normal tissues tested. It
was over-expressed in
97% of prostate tumors, 75% of normal prostate, and is undetectable in all
other normal tissues
tested. CGI-69 showed 3.56 fold over-expression in prostate tissues as
compared to other normal
tissues tested. It is a low abundant gene, detected in more than 90% of
prostate tumors, and in 75%
normal prostate tissues. The expression of this gene in normal tissues was
very low. KIAA0122
showed 4.24 fold over-expression in prostate tissues as compared to other
normal tissues tested. It
was over-expressed in 57% of prostate tumors, it was undetectable in all
normal tissues tested
including normal prostate tissues. 19142.2 bangur showed 23.25 fold over-
expression in prostate
tissues as compared to other normal tissues tested. It was over-expressed in
97% of prostate tumors
and 100% of normal prostate. It was undetectable in other normal tissues
tested. 5566.1 Wang
showed 3.31 fold over-expression in prostate tissues as compared to other
normal tissues tested. It
3o was over-expressed in 97% of prostate tumors, 75% normal prostate and was
also over-expressed in
normal bone marrow, pancreas, and activated PBMC. Novel clone 23379 showed
4.86 fold over-
expression in prostate tissues as compared to other normal tissues tested. It
was detectable in 97%
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of prostate tumors and 75% normal prostate and is undetectable in all other
normal tissues tested.
Novel clone 23399 showed 4.09 fold over-expression in prostate tissues as
compared to other
normal tissues tested. It was over-expressed in 27% of prostate tumors and was
undetectable in all
normal tissues tested including normal prostate tissues. Novel clone 23320
showed 3.15 fold over-
expression in prostate tissues as compared to other normal tissues tested. It
was detectable in all
prostate tumors and SO% of normal prostate tissues. It was also expressed in
normal colon and
trachea. Other normal tissues do not express this gene at high level.
1 o EXAMPLE 14
IDENTIFICATION OF PROSTATE-SPECIFIC ANTIGENS
BY ELECTRONIC SUBTRACTION
This Example describes the use of an electronic subtraction technique to
identify
prostate-specific antigens.
Potential prostate-specific genes present in the GenBank human EST database
were
identified by electronic subtraction (similar to that described by Vasmatizis
et al., Proc. Natl. Acad.
Sci. USA 95:300-304, 1998). The sequences of EST clones (43,482) derived from
various prostate
libraries were obtained from the GenBank public human EST database. Each
prostate EST
2o sequence was used as a query sequence in a BLASTN (National Center for
Biotechnology
Information) search against the human EST database. All matches considered
identical (length of
matching sequence > 100 base pairs, density of identical matches over this
region > 70%) were
grouped (aligned) together in a cluster. Clusters containing more than 200
ESTs were discarded
since they probably represented repetitive elements or highly expressed genes
such as those for
ribosomal proteins. If two or more clusters shared common ESTs, those clusters
were grouped
together into a "supercluster," resulting in 4,345 prostate superclusters.
Records for the 479 human cDNA libraries represented in the GenBank release
were
downloaded to create a database of these cDNA library records. These 479 cDNA
libraries were
grouped into three groups: Plus (normal prostate and prostate tumor libraries,
and breast cell line
libraries, in which expression was desired), Minus (libraries from other
normal adult tissues, in
which expression was not desirable), and Other (libraries from fetal tissue,
infant tissue, tissues
found only in women, non-prostate tumors and cell lines other than prostate
cell lines, in which
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expression was considered to be irrelevant). A summary of these library groups
is presented in
Table II.
Table II
Prostate cDNA Libraries and ESTs
Library # of Libraries# of ESTs
Plus 25 43,482
Normal 11 18,875
Tumor 11 21,769
Cell lines 3 2,838
Minus 166
Other 287
Each supercluster was analyzed in terms of the ESTs within the supercluster.
The
tissue source of each EST clone was noted and used to classify the
superclusters into four groups:
1o Type 1- EST clones found in the Plus group libraries only; no expression
detected in Minus or
Other group libraries; Type 2- EST clones derived from the Plus and Other
group libraries only; no
expression detected in the Minus group; Type 3- EST clones derived from the
Plus, Minus and
Other group libraries, but the number of ESTs derived from the Plus group is
higher than in either
the Minus or Other groups; and Type 4- EST clones derived from Plus, Minus and
Other group
libraries, but the number derived from the Plus group is higher than the
number derived from the
Minus group. This analysis identified 4,345 breast clusters (see Table III).
From these clusters,
3,172 EST clones were ordered from Research Genetics, Inc., and were received
as frozen glycerol
stocks in 96-well plates.
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Table III
Prostate Cluster Summary
# of # of ESTs
Type SuperclustersOrdered
1 688 677
2 2899 2484
3 85 11
4 673 0
Total 4345 3172
The EST clone inserts were PCR-amplified using amino-linked PCR primers for
Synteni microarray analysis. When more than one PCR product was obtained for a
particular clone,
that PCR product was not used for expression analysis. In total, 2,528 clones
from the electronic
subtraction method were analyzed by microarray analysis to identify electronic
subtraction breast
clones that had high levels of tumor vs. normal tissue mRNA. Such screens were
performed using a
Synteni (Palo Alto, CA) microarray, according to the manufacturer's
instructions (and essentially as
~ o described by Schena et al., Proc. Natl. Acad. Sci. USA 93:10614-10619,
1996 and Heller et al.,
Proc. Natl. Acad. Sci. USA 94:2150-2155, 1997). Within these analyses, the
clones were arrayed on
the chip, which was then probed with fluorescent probes generated from normal
and tumor prostate
cDNA, as well as various other normal tissues. The slides were scanned and the
fluorescence
intensity was measured.
Clones with an expression ratio greater than 3 (i.e., the level in prostate
tumor and
normal prostate mRNA was at least three times the level in other normal tissue
mRNA) were
identified as prostate tumor-specific sequences (Table IV). The sequences of
these clones are
provided in SEQ ID NO: 401-453, with certain novel sequences shown in SEQ ID
NO: 407, 413,
416-419, 422, 426, 427 and 450.
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Table IV
Prostate-tumor ~ecific Clones
SEQ ID NO. Sequence Comments
Designation
401 22545 previously identified P1000C
402 22547 previously identified P704P
403 22548 known
404 22550 known
405 22551 PSA
406 22552 prostate secretory protein
94
407 22553 novel
408 22558 previously identified P509S
409 22562 glandular kallikrein
410 22565 previously identified P1000C
411 22567 PAP
412 22568 B1006C (breast tumor antigen)
413 22570 novel
414 22571 PSA
415 22572 previously identified P706P
416 22573 novel
417 22574 novel
418 22575 novel
419 22580 novel
420 22581 PAP
421 22582 prostatic secretory protein
94
422 22583 novel
423 22584 prostatic secretory protein
94
424 22585 prostatic secretory protein
94
425 22586 known
426 22587 novel
427 22588 novel
428 22589 PAP
429 22590 known
430 22591 PSA
431 22592 known
432 22593 Previously identified P777P
433 22594 T cell receptor gamma chain
434 22595 Previously identified P705P
435 22596 Previously identified P707P
436 22847 PAP
437 22848 known
438 22849 prostatic secretory protein
57
439 22851 PAP
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440 22852 PAP
441 22853 PAP
442 22854 previously identified P509S
443 22855 previously identified P705P
444 22856 previously identified P774P
445 22857 PSA
446 23601 previously identified P777P
447 23602 PSA
448 23605 PSA
449 23606 PSA
450 23612 novel
451 23614 PSA
452 23618 previously identified P1000C
453 23622 previously identified P705P
EXAMPLE 15
FURTHER IDENTIFICATION OF PROSTATE-SPECIFIC ANTIGENS BY MICROARRAY
ANALYSIS
This Example describes the isolation of additional prostate-specific
polypeptides
from a prostate tumor cDNA library.
A human prostate tumor cDNA expression library as described above was screened
1 o using microarray analysis to identify clones that display at least a three
fold over-expression in
prostate tumor and/or normal prostate tissue, as compared to non-prostate
normal tissues (not
including testis). 142 clones were identified and sequenced. Certain of these
clones are shown in
SEQ ID NO: 454-467. Of these sequences, SEQ ID NO: 459-461 represent novel
genes. The
others (SEQ ID NO: 454-458 and 461-467) correspond to known sequences.
EXAMPLE 16
FURTHER CHARACTERIZATION OF PROSTATE-SPECIFIC ANTIGEN P710P
2o This Example describes the full length cloning of P710P.
The prostate cDNA library described above was screened with the P710P fragment
described above. One million colonies were plated on LB/Ampicillin plates.
Nylon membrane
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filters were used to lift these colonies, and the cDNAs picked up by these
filters were then
denatured and cross-linked to the filters by UV light. The P710P fragment was
radiolabeled and
used to hybridize with the filters. Positive cDNA clones were selected and
their cDNAs recovered
and sequenced by an automatic Perkin Elmer/Applied Biosystems Division
Sequencer. Four
sequences were obtained, and are presented in SEQ ID NO: 468-471 These
sequences appear to
represent different splice variants of the P710P gene.
EXAMPLE 17
PROTEIN EXPRESSION OF THE PROSTATE-SPECIFIC ANTIGEN P501 S
to
This example describes the expression and purification of the prostate-
specific
antigen P501 S in E. coli, baculovirus and mammalian cells.
al Expression in E. coli
Expression of the full-length form of P501 S was attempted by first cloning
P501 S
without the leader sequence (amino acids 36-553 of SEQ ID NO: 113) downstream
of the first 30
amino acids of the M. tuberculosis antigen Ral2 (SEQ ID NO: 484) in pETl7b.
Specifically,
P501 S DNA was used to perform PCR using the primers AW025 (SEQ ID NO: 485)
and AW003
(SEQ ID NO: 486). AW025 is a sense cloning primer that contains a HindIII
site. AW003 is an
2o antisense cloning primer that contains an EcoRI site. DNA amplification was
performed using 5 ~l
lOX Pfu buffer, 1 ~1 20 mM dNTPs, 1 ~.1 each of the PCR primers at 10 ~M
concentration, 40 ~1
water, 1 ~1 Pfu DNA polymerase (Stratagene, La Jolla, CA) and 1 ~,l DNA at 100
ng/~1.
Denaturation at 95°C was performed for 30 sec, followed by 10 cycles of
95°C for 30 sec, 60°C for
1 min and by 72°C for 3 min. 20 cycles of 95°C for 30 sec,
65°C for 1 min and by 72°C for 3 min,
and lastly by 1 cycle of 72°C for 10 min. The PCR product was cloned to
Ral2m/pETl7b using
HindIII and EcoRI. The sequence of the resulting fusion construct (referred to
as Ral2-P501 S-F)
was confirmed by DNA sequencing.
The fusion construct was transformed into BL21(DE3)pLysE, pLysS and CodonPlus
E. coli (Stratagene) and grown overnight in LB broth with kanamycin. The
resulting culture was
3o induced with IPTG. Protein was transferred to PVDF membrane and blocked
with 5% non-fat milk
(in PBS-Tween buffer), washed three times and incubated with mouse anti-His
tag antibody
(Clontech) for 1 hour. The membrane was washed 3 times and probed with HRP-
Protein A
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(Zymed) for 30 min. Finally, the membrane was washed 3 times and developed
with ECL
(Amersham). No expression was detected by Western blot. Similarly, no
expression was detected
by Western blot when the Ral2-P501S-F fusion was used for expression in
BL2lCodonPlus by
CE6 phage (Invitrogen).
An N-terminal fragment of P501 S (amino acids 36-325 of SEQ ID NO: 113) was
cloned down-stream of the first 30 amino acids of the M. tuberculosis antigen
Ral2 in pETl7b as
follows. PSOIS DNA was used to perform PCR using the primers AW025 (SEQ ID NO:
485) and
AW027 (SEQ ID NO: 487). AW027 is an antisense cloning primer that contains an
EcoRI site and a
stop codon. DNA amplification was performed essentially as described above.
The resulting PCR
1o product was cloned to Ral2 in pETl7b at the HindIII and EcoRI sites. The
fusion construct
(referred to as Ral2-P501S-N) was confirmed by DNA sequencing.
The Ral2-P501 S-N fusion construct was used for expression in BL21 (DE3)pLysE,
pLysS and CodonPlus, essentially as described above. Using Western blot
analysis, protein bands
were observed at the expected molecular weight of 36 kDa. Some high molecular
weight bands
were also observed, probably due to aggregation of the recombinant protein. No
expression was
detected by Western blot when the Ral2-P501 S-F fusion was used for expression
in
BL21 CodonPlus by CE6 phage.
A fusion construct comprising a C-terminal portion of P501 S (amino acids 257-
553
of SEQ ID NO: 113) located down-stream of the first 30 amino acids of the M.
tuberculosis antigen
2o Ral2 (SEQ ID NO: 484) was prepared as follows. P501 S DNA was used to
perform PCR using the
primers AW026 (SEQ ID NO: 488) and AW003 (SEQ ID NO: 486). AW026 is a sense
cloning
primer that contains a HindIII site. DNA amplification was performed
essentially as described
above. The resulting PCR product was cloned to Ral2 in pETl7b at the HindIII
and EcoRI sites.
The sequence for the fusion construct (referred to as Ral2-P501 S-C) was
confirmed.
The Ral2-PSO1S-C fusion construct was used for expression in BL21(DE3)pLysE,
pLysS and CodonPlus, as described above. A small amount of protein was
detected by Western
blot, with some molecular weight aggregates also being observed. Expression
was also detected by
Western blot when the Ral2-P501 S-C fusion was used for expression in BL21
CodonPlus induced
by CE6 phage.
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b~pression of P501 S in Baculovirus
The Bac-to-Bac baculovirus expression system (BRL Life Technologies, Inc.) was
used to express P501 S protein in insect cells. Full-length P501 S (SEQ ID NO:
113) was amplified
s by PCR and cloned into the XbaI site of the donor plasmid pFastBacI. The
recombinant bacmid
and baculovirus were prepared according to the manufacturer's isntructions.
The recombinant
baculovirus was amplified in S~ cells and the high titer viral stocks were
utilized to infect High
Five cells (Invitrogen) to make the recombinant protein. The identity of the
full-length protein was
confirmed by N-terminal sequencing of the recombinant protein and by Western
blot analysis
to (Figure 7). Specifically, 0.6 million High Five cells in 6-well plates were
infected with either the
unrelated control virus BV/ECD PD (lane 2), with recombinant baculovirus for
P501 S at different
amounts or MOIs (lanes 4-8), or were uninfected (lane 3). Cell lysates were
run on SDS-PAGE
under reducing conditions and analyzed by Western blot with the anti-P501 S
monoclonal antibody
P501 S-10E3-G4D3 (prepared as described below). Lane 1 is the biotinylated
protein molecular
15 weight marker (BioLabs).
The localization of recombinant P501 S in the insect cells was investigated as
follows. The insect cells overexpressing P501 S were fractionated into
fractions of nucleus,
mitochondria, membrane and cytosol. Equal amounts of protein from each
fraction were analyzed
by Western blot with a monoclonal antibody against P501 S. Due to the scheme
of fractionation,
20 both nucleus and mitochondria fractions contain some plasma membrane
components. However,
the membrane fraction is basically free from mitochondria and nucleus. P501 S
was found to be
present in all fractions that contain the membrane component, suggesting that
PSO1S may be
associated with plasma membrane of the insect cells expressing the recombinant
protein.
25 c) Expression of P501 S in mammalian cells
Full-length PSO1S (553AA) was cloned into various mammalian expression
vectors,
including pCEP4 (Invitrogen), pVR1012 (Vital, San Diego, CA) and a modified
form of the
retroviral vector pBMN, referred to as pBIB. Transfection of P501 S/pCEP4 and
P501 S/pVR1012
into HEK293 fibroblasts was carried out using the Fugene transfection reagent
(Boehringer
3o Mannheim). Briefly, 2 u1 of Fugene reagent was diluted into 100 u1 of serum-
free media and
incubated at room temperature for 5-10 min. This mixture was added to 1 ug of
P501 S plasmid
DNA, mixed briefly and incubated for 30 minutes at room temperature. The
Fugene/DNA mixture
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was added to cells and incubated for 24-48 hours. Expression of recombinant
P501 S in transfected
HEK293 fibroblasts was detected by means of Western blot employing a
monoclonal antibody to
P501 S.
Transfection of p501 S/pCEP4 into CHO-K cells (American Type Culture
Collection,
Rockville, MD) was carried out using GenePorter transfection reagent (Gene
Therapy Systems,
San Diego, CA). Briefly, 15 p1 of GenePorter was diluted in 500 p1 of serum-
free media and
incubated at room temperature for 10 min. The GenePorter/media mixture was
added to 2 ~g of
plasmid DNA that was diluted in S00 p1 of serum-free media, mixed briefly and
incubated for 30
min at room temperature. CHO-K cells were rinsed in PBS to remove serum
proteins, and the
l0 GenePorter/DNA mix was added and incubated for 5 hours. The transfected
cells were then fed an
equal volume of 2x media and incubated for 24-48 hours.
FACS analysis of P501 S transiently infected CHO-K cells, demonstrated surface
expression of P501 S. Expression was detected using rabbit polyclonal antisera
raised against a
P501 S peptide, as described below. Flow cytometric analysis was performed
using a FaCScan
I S (Becton Dickinson), and the data were analyzed using the Cell Quest
program.
EXAMPLE 18
PREPARATION AND CHARACTERIZATION OF ANTIBODIES AGAINST PROSTATE-
SPECIFIC POLYPEPTIDES
2o a) Preparation and Characterization of Antibodies against PSO1S
A murine monoclonal antibody directed against the carboxy-terminus of the
prostate-
specific antigen PSO1S was prepared as follows.
A truncated fragment of PSO1S (amino acids 355-526 of SEQ ID NO: 113) was
generated and cloned into the pET28b vector (Novagen) and expressed in E. coli
as a thioredoxin
25 fusion protein with a histidine tag. The trx-P501 S fusion protein was
purified by nickel
chromatography, digested with thrombin to remove the trx fragment and further
purified by an acid
precipitation procedure followed by reverse phase HPLC.
Mice were immunized with truncated P501 S protein. Serum bleeds from mice that
potentially contained anti-P501 S polyclonal sera were tested for P501 S-
specific reactivity using
30 ELISA assays with purified P501 S and trx-P501 S proteins. Serum bleeds
that appeared to react
specifically with P501 S were then screened for P501 S reactivity by Western
analysis. Mice that
contained a P501 S-specific antibody component were sacrificed and spleen
cells were used to
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generate anti-P501 S antibody producing hybridomas using standard techniques.
Hybridoma
supernatants were tested for P501 S-specific reactivity initially by ELISA,
and subsequently by
FAGS analysis of reactivity with P501 S transduced cells. Based on these
results, a monoclonal
hybridoma referred to as 10E3 was chosen for further subcloning. A number of
subclones were
generated, tested for specific reactivity to P501 S using ELISA and typed for
IgG isotype. The
results of this analysis are shown below in Table V. Of the 16 subclones
tested, the monoclonal
antibody 10E3-G4-D3 was selected for further study.
Table V
Isotype analysis of murine anti-P501 S monoclonal antibodies
Hybridoma clone Isotype Estimated [Ig] in supernatant
(~g/ml)
4D 11 IgG l 14.6
1G1 IgGI 0.6
4F6 IgGl 72
4H5 IgGI 13.8
4H5-E12 IgGI 10.7
4H5-EH2 IgGl 9.2
4H5-H2-A10 IgGl 10
4H5-H2-A3 IgGl 12.8
4H5-H2-Al 0-G6 IgGl 13.6
4H5-H2-B 11 IgG 1 12.3
10E3 IgG2a 3.4
10E3-D4 IgG2a 3.8
1 OE3-D4-G3 IgG2a 9.5
10E3-D4-G6 IgG2a 10.4
10E3-E7 IgG2a 6.5
8H12 IgG2a 0.6
The specificity of 10E3-G4-D3 for P501 S was examined by FACS analysis.
~ s Specifically, cells were fixed (2% formaldehyde, 10 minutes),
permeabilized (0.1 % saponin, 10
minutes) and stained with 10E3-G4-D3 at 0.5 - 1 ~g/ml, followed by incubation
with a secondary,
FITC-conjugated goat anti-mouse Ig antibody (Pharmingen, San Diego, CA). Cells
were then
analyzed for FITC fluorescence using an Excalibur fluorescence activated cell
sorter. For FACS
analysis of transduced cells, B-LCL were retrovirally transduced with P501 S.
For analysis of
20 infected cells, B-LCL were infected with a vaccinia vector that expresses
P501 S. To demonstrate
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specificity in these assays, B-LCL transduced with a different antigen (P703P)
and uninfected B-
LCL vectors were utilized. 10E3-G4-D3 was shown to bind with P501 S-transduced
B-LCL and also
with P501 S-infected B-LCL, but not with either uninfected cells or P703P-
transduced cells.
To determine whether the epitope recognized by 10E3-G4-D3 was found on the
surface or in an intracellular compartment of cells, B-LCL were transduced
with PSO1S or HLA-B8
as a control antigen and either fixed and permeabilized as described above or
directly stained with
10E3-G4-D3 and analyzed as above. Specific recognition of P501 S by 10E3-G4-D3
was found to
require permeabilization, suggesting that the epitope recognized by this
antibody is intracellular.
The reactivity of 10E3-G4-D3 with the three prostate tumor cell lines Lncap,
PC-3
to and DU-145, which are known to express high, medium and very low levels of
P501 S, respectively,
was examined by permeabilizing the cells and treating them as described above.
Higher reactivity
of 10E3-G4-D3 was seen with Lncap than with PC-3, which in turn showed higher
reactivity that
DU-145. These results are in agreement with the real time PCR and demonstrate
that the antibody
specifically recognizes P501 S in these tumor cell lines and that the epitope
recognized in prostate
tumor cell lines is also intracellular.
Specificity of 10E3-G4-D3 for P501 S was also demonstrated by Western blot
analysis. Lysates from the prostate tumor cell lines Lncap, DU-145 and PC-3,
from P501 S-
transiently transfected HEK293 cells, and from non-transfected HEK293 cells
were generated.
Western blot analysis of these lysates with 10E3-G4-D3 revealed a 46 kDa
immunoreactive band in
2o Lncap, PC-3 and P501 S-transfected HEK cells, but not in DU-145 cells or
non-transfected HEK293
cells. P501 S mRNA expression is consistent with these results since semi-
quantitative PCR
analysis revealed that P501 S mRNA is expressed in Lncap, to a lesser but
detectable level in PC-3
and not at all in DU-145 cells. Bacterially expressed and purified recombinant
P501 S (referred to as
P501 SStr2) was recognized by 10E3-G4-D3 (24 kDa), as was full-length P501 S
that was transiently
expressed in HEK293 cells using either the expression vector VR1012 or pCEP4.
Although the
predicted molecular weight of P501 S is 60.5 kDa, both transfected and
"native" P501 S run at a
slightly lower mobility due to its hydrophobic nature.
Immunohistochemical analysis was performed on prostate tumor and a panel of
normal tissue sections (prostate, adrenal, breast, cervix, colon, duodenum,
gall bladder, ileum,
kidney, ovary, pancreas, parotid gland, skeletal muscle, spleen and testis).
Tissue samples were
fixed in formalin solution for 24 hours and embedded in paraffin before being
sliced into 10 micron
sections. Tissue sections were permeabilized and incubated with 10E3-G4-D3
antibody for 1 hr.
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HRP-labeled anti-mouse followed by incubation with DAB chromogen was used to
visualize P501 S
immunoreactivity. P501 S was found to be highly expressed in both normal
prostate and prostate
tumor tissue but was not detected in any of the other tissues tested.
To identify the epitope recognized by 10E3-G4-D3, an epitope mapping approach
was pursued. A series of 13 overlapping 20-21 mers (5 amino acid overlap; SEQ
ID NO: 489-501 )
was synthesized that spanned the fragment of P501 S used to generate 1 OE3-G4-
D3. Flat bottom 96
well microtiter plates were coated with either the peptides or the P501 S
fragment used to immunize
mice, at 1 microgram/ml for 2 hours at 37 °C. Wells were then aspirated
and blocked with
phosphate buffered saline containing 1% (w/v) BSA for 2 hours at room
temperature, and
1o subsequently washed in PBS containing 0.1% Tween 20 (PBST). Purified
antibody 10E3-G4-D3
was added at 2 fold dilutions (1000 ng - 16 ng) in PBST and incubated for 30
minutes at room
temperature. This was followed by washing 6 times with PBST and subsequently
incubating with
HRP-conjugated donkey anti-mouse IgG (H+L)Affinipure F(ab') fragment (Jackson
Immunoresearch, West Grove, PA) at 1:20000 for 30 minutes. Plates were then
washed and
~5 incubated for 15 minutes in tetramethyl benzidine. Reactions were stopped
by the addition of 1N
sulfuric acid and plates were read at 450 nm using an ELISA plate reader. As
shown in Fig. 8,
reactivity was seen with the peptide of SEQ ID NO: 496 (corresponding to amino
acids 439-459 of
P501 S) and with the P501 S fragment but not with the remaining peptides,
demonstrating that the
epitope recognized by 10E3-G4-D3 is localized to amino acids 439-459 of SEQ ID
NO: 113.
2o In order to further evaluate the tissue specificity of P501 S, multi-array
immunohistochemical analysis was performed on approximately 4700 different
human tissues
encompassing all the major normal organs as well as neoplasias derived from
these tissues. Sixty-
five of these human tissue samples were of prostate origin. Tissue sections
0.6 mm in diameter
were formalin-fixed and paraffin embedded. Samples were pretreated with HIER
using 10 mM
25 citrate buffer pH 6.0 and boiling for 10 min. Sections were stained with
10E3-G4-D3 and P501 S
immunoreactivity was visualized with HRP. All the 65 prostate tissues samples
(5 normal, 55
untreated prostate tumors, 5 hormone refractory prostate tumors) were
positive, showing distinct
perinuclear staining. All other tissues examined were negative for P501 S
expression.
3o b) Preparation and Characterization of Antibodies against P503S
A fragment of P503S (amino acids 113-241 of SEQ ID NO: 114) was expressed and
purified from bacteria essentially as described above for P501 S and used to
immunize both rabbits
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and mice. Mouse monoclonal antibodies were isolated using standard hybridoma
technology as
described above. Rabbit monoclonal antibodies were isolated using Selected
Lymphocyte Antibody
Method (SLAM) technology at Immgenics Pharmaceuticals (Vancouver, BC, Canada).
Table VI,
below, lists the monoclonal antibodies that were developed against P503S.
Table VI
Antibody Species
20D4 Rabbit
JA 1 Rabbit
1 A4 Mouse
1 C3 Mouse
1 C9 Mouse
1 D 12 Mouse
2A 11 Mouse
2H9 Mouse
4H7 Mouse
8A8 Mouse
8D 10 Mouse
9C 12 Mouse
6D 12 Mouse
The DNA sequences encoding the complementarity determining regions (CDRs) for
to the rabbit monoclonal antibodies 20D4 and JA1 were determined and are
provided in SEQ ID NO:
502 and 503, respectively.
In order to better define the epitope binding region of each of the
antibodies, a series
of overlapping peptides were generated that span amino acids 109-213 of SEQ ID
NO: 114. These
peptides were used to epitope map the anti-P503S monoclonal antibodies by
ELISA as follows.
The recombinant fragment of P503S that was employed as the immunogen was used
as a positive
control. Ninety-six well microtiter plates were coated with either peptide or
recombinant antigen at
ng/well overnight at 4 °C. Plates were aspirated and blocked with
phosphate buffered saline
containing 1% (w/v) BSA for 2 hours at room temperature then washed in PBS
containing 0.1%
Tween 20 (PBST). Purified rabbit monoclonal antibodies diluted in PBST were
added to the wells
2o and incubated for 30 min at room temperature. This was followed by washing
6 times with PBST
and incubation with Protein-A HRP conjugate at a 1:2000 dilution for a further
30 min. Plates were
washed six times in PBST and incubated with tetramethylbenzidine (TMB)
substrate for a further
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15 min. The reaction was stopped by the addition of 1N sulfuric acid and
plates were read at 450
nm using at ELISA plate reader. ELISA with the mouse monoclonal antibodies was
performed with
supernatants from tissue culture run neat in the assay.
All of the antibodies bound to the recombinant P503S fragment, with the
exception
of the negative control SP2 supernatant. 20D4, JA 1 and 1 D 12 bound strictly
to peptide #21 O l
(SEQ ID NO: 504), which corresponds to amino acids 151-169 of SEQ ID NO: 114.
1C3 bound to
peptide #2102 (SEQ ID NO: 505), which corresponds to amino acids 165-184 of
SEQ ID NO: 114.
9C12 bound to peptide #2099 (SEQ ID NO: 522), which corresponds to amino acids
120-139 of
SEQ ID NO: 114. The other antibodies bind to regions that were not examined in
these studies.
l0 Subsequent to epitope mapping, the antibodies were tested by FACS analysis
on a
cell line that stably expressed P503S to confirm that the antibodies bind to
cell surface epitopes.
Cells stably transfected with a control plasmid were employed as a negative
control. Cells were
stained live with no fixative. 0.5 ug of anti-P503S monoclonal antibody was
added and cells were
incubated on ice for 30 min before being washed twice and incubated with a
FITC-labelled goat
anti-rabbit or mouse secondary antibody for 20 min. After being washed twice,
cells were analyzed
with an Excalibur fluorescent activated cell sorter. The monoclonal antibodies
1C3, 1D12, 9C12,
20D4 and JA1, but not 8D3, were found to bind to a cell surface epitope of
P503S.
In order to determine which tissues express P503S, immunohistochemical
analysis
was performed, essentially as described above, on a panel of normal tissues
(prostate, adrenal,
2o breast, cervix, colon, duodenum, gall bladder, ileum, kidney, ovary,
pancreas, parotid gland, skeletal
muscle, spleen and testis). HRP-labeled anti-mouse or anti-rabbit antibody
followed by incubation
with TMB was used to visualize P503S immunoreactivity. P503S was found to be
highly expressed
in prostate tissue, with lower levels of expression being observed in cervix,
colon, ileum and
kidney, and no expression being observed in adrenal, breast, duodenum, gall
bladder, ovary,
pancreas, parotid gland, skeletal muscle, spleen and testis.
Western blot analysis was used to characterize anti-P503S monoclonal antibody
specificity. SDS-PAGE was performed on recombinant (rec) P503S expressed in
and purified from
bacteria and on lysates from HEK293 cells transfected with full length P503S.
Protein was
transferred to nitrocellulose and then Western blotted with each of the anti-
P503 S monoclonal
3o antibodies (20D4, JA 1, 1 D 12, 6D 12 and 9C 12) at an antibody
concentration of 1~ ug/ml. Protein
was detected using horse radish peroxidase (HRP) conjugated to either a goat
anti-mouse
monoclonal antibody or to protein A-sepharose. The monoclonal antibody 20D4
detected the
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appropriate molecular weight 14 kDa recombinant P503S (amino acids 113-241)
and the 23.5 kDa
species in the HEK293 cell lysates transfected with full length P503S. Other
anti-P503S
monoclonal antibodies displayed similar specificity by Western blot.
c) Preparation and Characterization of Antibodies against P703P
Rabbits were immunized with either a truncated (P703Ptrl; SEQ ID NO: 172) or
full-length mature form (P703Pfl; SEQ ID NO: 523) of recombinant P703P protein
was expressed
in and purified from bacteria as described above. Affinity purified polyclonal
antibody was
generated using immunogen P703Pfl or P703Ptrl attached to a solid support.
Rabbit monoclonal
antibodies were isolated using SLAM technology at Immgenics Pharmaceuticals.
Table VII below
lists both the polyclonal and monoclonal antibodies that were generated
against P703P.
Table VII
Antibody Immunogen Species/type
Aff. Purif. P703P (truncated);P703Ptr1 Rabbit polyclonal
#2594
Af Purif. P703P (full length);P703Pfl Rabbit polyclonal
#9245
2D4 P703Ptr1 Rabbit monoclonal
8H2 P703Ptr1 Rabbit monoclonal
7H8 P703Ptr1 Rabbit monoclonal
The DNA sequences encoding the complementarity determining regions (CDRs) for
the rabbit monoclonal antibodies 8H2, 7H8 and 2D4 were determined and are
provided in SEQ ID
NO: 506-508, respectively.
Epitope mapping studies were performed as described above. Monoclonal
antibodies 2D4 and 7H8 were found to specifically bind to the peptides of SEQ
ID NO: 509
(corresponding to amino acids 145-159 of SEQ ID NO: 172) and SEQ ID NO: 510
(corresponding
to amino acids 11-25 of SEQ ID NO: 172), respectively. The polyclonal antibody
2594 was found
to bind to the peptides of SEQ ID NO: 511-514, with the polyclonal antibody
9427 binding to the
peptides of SEQ ID NO: 515-517.
The specificity of the anti-P703P antibodies was determined by Western blot
analysis as follows. SDS-PAGE was performed on (1) bacterially expressed
recombinant antigen;
(2) lysates of HEK293 cells and Ltk-/- cells either untransfected or
transfected with a plasmid
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expressing full length P703P; and (3) supernatant isolated from these cell
cultures. Protein was
transferred to nitrocellulose and then Western blotted using the anti-P703P
polyclonal antibody
#2594 at an antibody concentration of 1 ug/ml. Protein was detected using
horse radish peroxidase
(HRP) conjugated to an anti-rabbit antibody. A 35 kDa immunoreactive band
could be observed
with recombinant P703P. Recombinant P703P runs at a slightly higher molecular
weight since it is
epitope tagged. In lysates and supernatants from cells transfected with full
length P703P, a 30 kDa
band corresponding to P703P was observed. To assure specificity, lysates from
HEK293 cells
stably transfected with a control plasmid were also tested and were negative
for P703P expression.
Other anti-P703P antibodies showed similar results.
Immunohistochemical studies were performed as described above, using anti-
P703P
monoclonal antibody. P703P was found to be expressed at high levels in normal
prostate and
prostate tumor tissue but was not detectable in all other tissues tested
(breast tumor, lung tumor and
normal kidney).
EXAMPLE 19
CHARACTERIZATION OF CELL SURFACE EXPRESSION AND CHROMOSOME
LOCALIZATION OF THE PROSTATE-SPECIFIC ANTIGEN P501 S
This example describes studies demonstrating that the prostate-specific
antigen
2o P501 S is expressed on the surface of cells, together with studies to
determine the probable
chromosomal location of P501 S.
The protein P501 S (SEQ ID NO: 113) is predicted to have 11 transmembrane
domains. Based on the discovery that the epitope recognized by the anti-P501 S
monoclonal
antibody 10E3-G4-D3 (described above in Example 17) is intracellular, it was
predicted that
following transmembrane determinants would allow the prediction of
extracellular domains of
P501 S. Fig. 9 is a schematic representation of the P501 S protein showing the
predicted location of
the transmembrane domains and the intracellular epitope described in Example
17. Underlined
sequence represents the predicted transmembrane domains, bold sequence
represents the predicted
extracellular domains, and italized sequence represents the predicted
intracellular domains.
Sequence that is both bold and underlined represents sequence employed to
generate polyclonal
rabbit serum. The location of the transmembrane domains was predicted using
HHMTOP as
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described by Tusnady and Simon (Principles Governing Amino Acid Composition of
Integral
Membrane Proteins: Applications to Topology Prediction, J. Mol. Biol. 283:489-
506, 1998).
Based on Fig. 9, the P501 S domain flanked by the transmembrane domains
corresponding to amino acids 274-295 and 323-342 is predicted to be
extracellular. The peptide of
SEQ ID NO: 518 corresponds to amino acids 306-320 of P501 S and lies in the
predicted
extracellular domain. The peptide of SEQ ID NO: 519, which is identical to the
peptide of SEQ ID
NO: 518 with the exception of the substitution of the histidine with an
asparginine, was synthesized
as described above. A Cys-Gly was added to the C-terminus of the peptide to
facilitate conjugation
to the carrier protein. Cleavage of the peptide from the solid support was
carried out using the
~ o following cleavage mixture: trifluoroacetic
acid:ethanediolahioanisol:water:phenol (40:1:2:2:3).
After cleaving for two hours, the peptide was precipitated in cold ether. The
peptide pellet was then
dissolved in 10% v/v acetic acid and lyophilized prior to purification by C 18
reverse phase hplc. A
gradient of 5-60% acetonitrile (containing 0.05% TFA) in water (containing
0:05% TFA) was used
to elute the peptide. The purity of the peptide was verified by hplc and mass
spectrometry, and was
determined to be >95%. The purified peptide was used to generate rabbit
polyclonal antisera as
described above.
Surface expression of P501 S was examined by FACS analysis. Cells were stained
with the polyclonal anti-P501 S peptide serum at 10 ~g/ml, washed, incubated
with a secondary
FITC-conjugated goat anti-rabbit Ig antibody (ICN), washed and analyzed for
FITC fluorescence
2o using an Excalibur fluorescence activated cell sorter. For FACS analysis of
transduced cells, B-
~LCL were retrovirally transduced with P501 S. To demonstrate specificity in
these assays, B-LCL
transduced with an irrelevant antigen (P703P) or nontransduced were stained in
parallel. For FACS
analysis of prostate tumor cell lines, Lncap, PC-3 and DU-145 were utilized.
Prostate tumor cell
lines were dissociated from tissue culture plates using cell dissociation
medium and stained as
above. All samples were treated with propidium iodide (PI) prior to FACS
analysis, and data was
obtained from PI-excluding (i.e. intact and non-permeabilized) cells. The
rabbit polyclonal serum
generated against the peptide of SEQ ID NO: S 19 was shown to specifically
recognize the surface
of cells transduced to express P501 S, demonstrating that the epitope
recognized by the polyclonal
serum is extracellular.
To determine biochemically if P501 S is expressed on the cell surface,
peripheral
membranes from Lncap cells were isolated and subjected to Western blot
analysis. Specifically,
Lncap cells were lysed using a dounce homogenizer in 5 ml of homogenization
buffer (250 mM
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sucrose, 10 mM HEPES, 1mM EDTA, pH 8.0, 1 complete protease inhibitor tablet
(Boehringer
Mannheim)). Lysate samples were spun at 1000 g for 5 min at 4 °C. The
supernatant was then spun
at 8000g for 10 min at 4 °C. Supernatant from the 8000g spin was
recovered and subjected to a
100,000g spin for 30 min at 4 °C to recover peripheral membrane.
Samples were then separated by
SDS-PAGE and Western blotted with the mouse monoclonal antibody 10E3-G4-D3
(described
above in Example 17) using conditions described above. Recombinant purified
P501 S, as well as
HEK293 cells transfected with and over-expressing P501 S were included as
positive controls for
P501 S detection. LCL cell lysate was included as a negative control. P501 S
could be detected in
Lncap total cell lysate, the 8000g (internal membrane) fraction and also in
the 100,000g (plasma
to membrane) fraction. These results indicate that PSO1S is expressed at, and
localizes to, the
peripheral membrane.
To demonstrate that the rabbit polyclonal antiserum generated to the peptide
of SEQ
ID NO: 519 specifically recognizes this peptide as well as the corresponding
native peptide of SEQ
ID NO: 518, ELISA analyses were performed. For these analyses, flat-bottomed
96 well microtiter
~ s plates were coated with either the peptide of SEQ ID NO: 519, the longer
peptide of SEQ ID NO:
520 that spans the entire predicted extracellular domain, the peptide of SEQ
ID NO: 521 which
represents the epitope recognized by the P501 S-specific antibody 10E3-G4-D3,
or a P501 S
fragment (corresponding to amino acids 355-526 of SEQ ID NO: 113) that does
not include the
immunizing peptide sequence, at 1 ~g/ml for 2 hours at 37 °C. Wells
were aspirated, blocked with
2o phosphate buffered saline containing 1% (w/v) BSA for 2 hours at room
temperature and
subsequently washed in PBS containing 0.1% Tween 20 (PBST). Purified anti-
PSO1S polyclonal
rabbit serum was added at 2 fold dilutions (1000 ng - 125 ng) in PBST and
incubated for 30 min at
room temperature. This was followed by washing 6 times with PBST and
incubating with HRP-
conjugated goat anti-rabbit IgG (H+L) Affinipure F(ab') fragment at 1:20000
for 30 min. Plates
2s were then washed and incubated for 1 S min in tetramethyl benzidine.
Reactions were stopped by
the addition of 1N sulfuric acid and plates were read at 450 nm using an ELISA
plate reader. As
shown in Fig. 11, the anti-PSO1S polyclonal rabbit serum specifically
recognized the peptide of
SEQ ID NO: 519 used in the immunization as well as the longer peptide of SEQ
ID NO: 520, but
did not recognize the irrelevant P501 S-derived peptides and fragments.
3o In further studies, rabbits were immunized with peptides derived from the
PSO1S
sequence and predicted to be either extracellular or intracellular, as shown
in Fig. 9. Polyclonal
rabbit sera were isolated and polyclonal antibodies in the serum were
purified, as described above.
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To determine specific reactivity with P501 S, FACS analysis was employed,
utilizing either B-LCL
transduced with P501 S or the irrelevant antigen P703P, of B-LCL infected with
vaccinia virus-
expressing P501 S. For surface expression, dead and non-intact cells were
excluded from the
analysis as described above. For intracellular staining, cells were fixed and
permeabilized as
described above. Rabbit polyclonal serum generated against the peptide of SEQ
ID NO: 548, which
corresponds to amino acids 181-198 of PSO1S, was found to recognize a surface
epitope of PSO1S.
Rabbit polyclonal serum generated against the peptide SEQ ID NO: 551, which
corresponds to
amino acids 543-553 of P501 S, was found to recognize an epitope that was
either potentially
extracellular or intracellular since in different experiments intact or
permeabilized cells were
to recognized by the polyclonal sera. Based on similar deductive reasoning,
the sequences of SEQ ID
NO: 541-547, 549 and 550, which correspond to amino acids 109-122, 539-553,
509-520, 37-54,
342-359, 295-323, 217-274, 143-160 and 75-88, respectively, of P501 S, can be
considered to be
potential surface epitopes of P501 S recognized by antibodies.
The chromosomal location of P501 S was determined using the GeneBridge 4
Radiation Hybrid panel (Research Genetics). The PCR primers of SEQ ID NO: 528
and 529 were
employed in PCR with DNA pools from the hybrid panel according to the
manufacturer's
directions. After 38 cycles of amplification, the reaction products were
separated on a 1.2% agarose
gel, and the results were analyzed through the Whitehead Institute/MIT Center
for Genome
Research web server (http://www-genome.wi.mit.edu/cgi-bin/contig/rhmapper.pl)
to determine the
2o probable chromosomal location. Using this approach, P501 S was mapped to
the long arm of
chromosome 1 at WI-9641 between q32 and q42. This region of chromosome 1 has
been linked to
prostate cancer susceptibility in hereditary prostate cancer (Smith et al.
Science 274:1371-1374,
1996 and Berthon et al. Am. J. Hum. Genet. 62:1416-1424, 1998). These results
suggest that PSO1S
may play a role in prostate cancer malignancy.
From the foregoing, it will be appreciated that, although specific embodiments
of the
invention have been described herein for the purposes of illustration, various
modifications may be
made without deviating from the spirit and scope of the invention.
Accordingly, the present
invention is not limited except as by the appended claims.
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1
SEQUENCE LISTING
<110> Corixa Corporation
Xu, Jiangchun
Dillon, Davin C.
Mitcham, Jennifer L.
Harlocker, Susan Louise
Jiang Yuqui
Reed, Steven G.
Kalos, Michael
Fanger, Gary
Retter, Mark
Solk, John
Day, Craig
Skeiky, Yasir A.W.
Wang, Aijun
<120> COMPOSITIONS AND METHODS FOR THE THERAPY AND
DIAGNOSIS OF PROSTATE CANCER
<130> 210121.42720PC
<140> PCT
<141> 2000-11-09
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CA 02391369 2002-05-10
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CA 02391369 2002-05-10
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<400> 6
ttttttttttttttttttttaagaccctcatcaatagatggagacatacagaaatagtca 60
aaccacatctacaaaatgccagtatcaggcggcggcttcgaagccaaagtgatgtttgga 120
tgtaaagtgaaatattagttggcggatgaagcagatagtgaggaaagttgagccaataat 180
gacgtgaagtccgtggaagcctgtggctacaaaaaatgttgagccgtagatgccgtcgga 240
aatggtgaagggagactcgaagtactctgaggcttgtaggagggtaaaatagagacccag 300
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
4
taaaattgtaataagcagtgcttgaattatttggtttcggttgttttctattagactatg 360
gtgagctcaggtgattgatactcctgatgcgagtaatacggatgtgtttaggagtgggac 420
ttctaggggatttagcggggtgatgcctgttgggggccagtgccctcctagttggggggt 480
aggggctaggctggagtggtaaaaggctcagaaaaatcctgcgaagaaaaaaacttctga 540
ggtaataaataggattatcccgtatcgaaggcctttttggacaggtggtgtgtggtggcc 600
ttggtatgtgctttctcgtgttacatcgcgccatcattggtatatggttagtgtgttggg 660
ttantanggcctantatgaagaacttttggantggaattaaatcaatngcttggccggaa 720
gtcattanganggctnaaaaggccctgttangggtctgggctnggttttacccnacccat 780
ggaatncnccccccggacnantgnatccctattcttaa 818
<210> 7
<211> 817
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (817)
<223> n = A,T,C or G
<400>
7
tttttttttttttttttttttggctctagagggggtagagggggtgctatagggtaaata 60
cgggccctatttcaaagatttttaggggaattaattctaggacgatgggtatgaaactgt 120
ggtttgctccacagatttcagagcattgaccgtagtatacccccggtcgtgtagcggtga 180
aagtggtttggtttagacgtccgggaattgcatctgtttttaagcctaatgtggggacag 240
ctcatgagtgcaagacgtcttgtgatgtaattattatacnaatgggggcttcaatcggga 300
gtact.actcgattgtcaacgtcaaggagtcgcaggtcgcctggttctaggaataatgggg 360
gaagtatgtaggaattgaagattaatccgccgtagtcggtgttctcctaggttcaatacc 420
attggtggccaattgatttgatggtaaggggagggatcgttgaactcgtctgttatgtaa 480
aggatnccttngggatgggaaggcnatnaaggactanggatnaatggcgggcangatatt 540
tcaaacngtctctanttcctgaaacgtctgaaatgttaataanaattaantttngttatt 600
gaatnttnnggaaaagggcttacaggactagaaaccaaatangaaaantaatnntaangg 660
cnttatcntnaaaggtnataaccnctcctatnatcccacceaatngnattccccacncnn 720
acnattggat.nccccanttccanaaanggccnccccccggtgnannccnccttttgttcc .780
cttnantgar.ggttattcncccctngcnttatcancc 817
<210> 8
<211> 799
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (799)
<223> n = A,T,C or G
<400>
8
catttccgggtttactttctaaggaaagccgagcggaagctgctaacgtgggaatcggtg 60
cataaggagaactttctgctggcacgcgctagggacaagcgggagagcgactccgagcgt 120
ctgaagcgcacgtcccagaaggtggacttggcactgaaacagctgggacacatccgcgag 180
tacgaacagcgcctgaaagtgctggagcgggaggtccagcagtgtagccgcgtcctgggg 240
tgggtggccgangcctganccgctctgccttgctgcccccangtgggccgccaccccctg 300
acctgcctgggtccaaacactgagccctgctggcggacttcaagganaacccccacangg 360
ggattttgctcctanantaaggctcatctgggcctcggcccccccacctggttggccttg 420
tctttgangtgagccccatgtccatctgggccactgtcnggaccacctttngggagtgtt 480
ctccttacaaccacannatgcccggctcctcccggaaaccantcccancctgngaaggat 540
caagncctgnatccactnntnctanaaccggccnccnccgcngtggaacccnccttntgt 600
tccttttcnttnagggttaatnncgccttggccttnccanngtcctncncnttttccnnt 660
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
gttnaaattg ttangcnccc nccnntcccn cnncnncnan cccgacccnn annttnnann 720
ncctgggggt nccnncngat tgacccnncc nccctntant tgcnttnggg nncnntgccc 780
ctttccctct nggganncg 799
<210> 9
<211> 801
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(801)
<223> n = A,T,C or G
<400> 9
acgccttgatcctcccaggctgggactggttctgggaggagccgggcatgctgtggtttg 60
taangatgacactcccaaaggtggtcctgacagtggcccagatggacatggggctcacct 120
caaggacaaggccaccaggtgcgggggccgaagcccacatgatccttactctatgagcaa 180
aatcccctgtgggggcttctccttgaagtccgccancagggctcagtctttggacccang 240
caggtcatggggttgtngnccaactgggggccncaacgcaaaanggcncagggcctcngn 300
cacccatcccangacgcggctacactnctggacctcccnctccaccactttcatgcgctg 360
ttcntacccgcgnatntgtcccanctgtttcngtgccnactccancttctnggacgtgcg 420
ctacatacgcccggantcncnctcccgctttgtccctatccacgtnccancaacaaattt 480
cnccntantgcaccnattcccacntttnncagntttccncnncgngcttccttntaaaag 540
ggttganccccggaaaatnccccaaagggggggggccnggtacccaactnccccctnata 600
gctgaantccccatnaccnngnctcnatgganccntccnttttaannacnttctnaactt 660
gggaananccctcgnccntncccccnttaatcccnccttgcnangnncntcccccnntcc 720
ncccnnntnggcntntnanncnaaaaaggcccnnnancaatctcctnncncctcanttcg 780
ccanccctcgaaatcggccnc 801
<210> 10
<211> 789
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(789)
<223> n = A,T,C or G
<400>
cagtctatntggccagtgtggcagctttccctgtggctgccggtgccacatgcctgtccc 60
acagtgtggccgtggtgacagcttcagccgccctcaccgggttcaccttctcagccctgc 120
agatcctgccctacacactggcctccctctaccaccgggagaagcaggtgttcctgccca 180
aataccgaggggacactggaggtgctagcagtgaggacagcctgatgaccagcttcctgc 240
caggccctaagcctggagctcccttccctaatggacacgtgggtgctggaggcagtggcc 300
tgctcccacctccacccgcgctctgcggggcctctgcctgtgatgtctccgtacgtgtgg 360
tggtgggtgagcccaccgangccagggtggttccgggccggggcatctgcctggacctcg 420
ccatcctggatagtgcttcctgctgtcccangtggccccatccctgtttatgggctccat 480
tgtccagctcagccagtctgtcactgcctatatggtgtctgccgcaggcctgggtctggt 540
cccatttactttgctacacaggtantatttgacaagaacganttggccaaatactcagcg 600
ttaaaaaattccagcaacattgggggtggaaggcctgcctcactgggtccaactccccgc 660
tcctgttaaccccatggggctgccggcttggccgccaatttctgttgctgccaaantnat 720
gtggctctctgctgccacctgttgctggctgaagtgcntacngcncanctnggggggtng 780
ggngttccc 789
<210> 11
<211> 772
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
6
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(772)
<223> n = A,T,C or G
<400>
11
cccaccctacccaaatattagacaccaacacagaaaagctagcaatggattcccttctac 60
tttgttaaataaataagttaaatatttaaatgcctgtgtctctgtgatggcaacagaagg 120
accaacaggccacatcctgataaaaggtaagaggggggtggatcagcaaaaagacagtgc 180
tgtgggctgaggggacctggttcttgtgtgttgcccctcaggactcttcccctacaaata 240
actttcatatgttcaaatcccatggaggagtgtttcatcctagaaactcccatgcaagag 300
ctacattaaacgaagctgcaggttaaggggcttanagatgggaaaccaggtgactgagtt 360
tattcagctcccaaaaacccttctctaggtgtgtctcaactaggaggctagctgttaacc 420
ctgagcctgggtaatccacctgcagagtccccgcattccagtgcatggaacccttctggc 480
ctccctgtataagtccagactgaaacccccttggaaggnctccagtcaggcagccctana 540
aactggggaaaaaagaaaaggacgccccancccccagctgtgcanctacgcacctcaaca 600
gcacagggtggcagcaaaaaaaccactttactttggcacaaacaaaaactngggggggca 660
accccggcaccccnangggggttaacaggaancngggnaacntggaacccaattnaggca 720
ggcccnccaccccnaatnttgctgggaaatttttcctcccctaaattntttc 772
<210> 12
<211> 751
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(751)
<223> n = A,T,C or G
<400> 12
gccccaattccagctgccacaccacccacggtgactgcattagttcggatgtcatacaaa 60
agctgattgaagcaaccctctactttttggtcgtgagccttttgcttggtgcaggtttca 120
ttggctgtgttggtgacgttgtcattgcaacagaatgggggaaaggcactgttctctttg 180
aagtanggtgagtcctcaaaatccgtatagttggtgaagccacagcacttgagccctttc 240
atggtggtgttccacacttgagtgaagtcttcctgggaaccataatctttcttgatggca 300
ggcactaccagcaacgtcagggaagtgctcagccattgtggtgtacaccaaggcgaccac 360
agcagctgcnacctcagcaatgaagatgangaggangatgaagaagaacgtcncgagggc 420
acacttgctctcagtcttancaccatancagcccntgaaaaccaanancaaagaccacna 480
cnccggctgcgatgaagaaatnaccccncgttgacaaacttgcatggcactggganccac 540
agtggcccnaaaaatcttcaaaaaggatgccccatcnattgaccccccaaatgcccactg 600
ccaacaggggctgccccacncncnnaacgatganccnattgnacaagatctncntggtct 660
tnatnaacntgaaccctgcntngtggctcctgttcaggnccnnggcctgacttctnaann 720
aangaactcngaagnccccacnggananncg 751
<210> 13
<211> 729
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (729)
<223> n = A,T,C or G
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
7
<400> 13
gagccaggcgtccctctgcctgcccactcagtggcaacacccgggagctgttttgtcctt 60
tgtggancctcagcagtnccctctttcagaactcantgccaaganccctgaacaggagcc 120
accatgcagtgcttcagcttcattaagaccatgatgatcctcttcaatttgctcatcttt 180
ctgtgtggtgcagccctgttggcagtgggcatctgggtgtcaatcgatggggcatccttt 240
ctgaagatcttcgggccactgtcgtccagtgccatgcagtttgtcaacgtgggctacttc 300
ctcatcgcagccggcgttgtggtcttagctctaggtttcctgggctgctatggtgctaag 360
actgagagcaagtgtgccctcgtgacgttcttcttcatcctcctcctcatcttcattgct 420
gaggttgcaatgctgtggtcgccttggtgtacaccacaatggctgagcacttcctgacgt 480
tgctggtaatgcctgccatcaanaaaagattatgggttcccaggaanacttcactcaagt 540
gttggaacaccaccatgaaagggctcaagtgctgtggcttcnnccaactatacggatttt 600
gaagantcacctacttcaaagaaaanagtgcctttcccccatttctgttgcaattgacaa 660
acgtccccaacacagccaattgaaaacctgcacccaacccaaangggtccccaaccanaa 720
attnaaggg 729
<210> 14
<211> 816
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) : . (816)
<223> n = A,T,C or G
<400>
14
tgctcttcctcaaagttgttcttgttgccataacaaccaccataggtaaagcgggcgcag 60
tgttcgctgaaggggttgtagtaccagcgcgggatgctctccttgcagagtcctgtgtct 120
ggcaggtccacgcagtgccctttgtcactggggaaatggatgcgctggagctcgtcaaag 180
ccactcgtgtatttttcacaggcagcctcgtccgacgcgtcggggcagttgggggtgtct 240
tcacactccaggaaactgtcnatgcagcagccattgctgcagcggaactgggtgggctga 300
cangtgccagagcacactggatggcgcctttccatgnnangggccctgngggaaagtccc 360
tganccccananctgcctctcaaangccccaccttgcacaccccgacaggctagaatgga 420
atcttcttcccgaaaggtagttnttcttgttgcccaanccanccccntaaacaaactctt 480
gcanatctgctccgngggggtcntantaccancgtgggaaaagaaccccaggcngcgaac 540
caancttgtttggatncgaagcnataatctnctnttctgcttggtggacagcaccantna 600
ctgtnnanctttagnccntggtcctcntgggttgnncttgaacctaatcnccnntcaact 660
gggacaaggtaantngccntcctttnaattcccnancntnccccctggtttggggttttn 720
cncnctcctaccccagaaannccgtgttcccccccaactaggggccnaaaccnnttnttc 780
cacaaccctnccccacccacgggttcngntggttng 816
<210> 15
<211> 783
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (783)
<223> n = A,T,C or G
<400> 15
ccaaggcctgggcaggcatanacttgaaggtacaaccccaggaacccctggtgctgaagg 60
atgtggaaaacacagattggcgcctactgcggggtgacacggatgtcagggtagagagga 120
aagacccaaaccaggtggaactgtggggactcaaggaangcacctacctgttccagctga 180
cagtgactagctcagaccacccagaggacacggccaacgtcacagtcactgtgctgtcca 240
ccaagcagacagaagactactgcctcgcatccaacaangtgggtcgctgccggggctctt 300
tcccacgctggtactatgaccccacggagcagatctgcaagagtttcgtttatggaggct 360
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
8
gcttgggcaacaagaacaactaccttcgggaagaagagtgcattctancctgtcngggtg 420
tgcaaggtgggcctttganangcanctctggggctcangcgactttcccccagggcccct 480
ccatggaaaggcgccatccantgttctctggcacctgtcagcccacccagttccgctgca 540
ncaatggctgctgcatcnacantttcctngaattgtgacaacaccccccantgcccccaa 600
ccctcccaacaaagcttccctgttnaaaaatacnccanttggcttttnacaaacncccgg 660
cncctccnttttccccnntnaacaaagggcnctngcntttgaactgcccnaacccnggaa 720
tctnccnnggaaaaantnccccccctggttcctnnaancccctccncnaaanctnccccc 780
ccc 783
<210> 16
<211> SO1
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(801)
<223> n = A,T,C or G
<400> 16
gccccaattccagctgccacaccacccacggtgactgcattagttcggatgtcatacaaa 60
agctgattgaagcaaccctctactttttggtcgtgagccttttgcttggtgcaggtttca 120
ttggctgtgttggtgacgttgtcattgcaacagaatgggggaaaggcactgttctctttg 180
aagtagggtgagtcctcaaaatccgtatagttggtgaagccacagcacttgagccctttc 240
atggtggtgttccacacttgagtgaagtcttcctgggaaccataatctttcttgatggca 300
ggcactaccagcaacgtcaggaagtgctcagccattgtggtgtacaccaaggcgaccaca 360
gcagctgcaacctcagcaatgaagatgaggaggaggatgaagaagaacgtcncgagggca 420
cacttgctctccgtcttagcaccatagcagcccangaaaccaagagcaaagaccacaacg 480
~
ccngctgcgaatgaaagaaantacccacgttgacaaactgcatggccactggacgacagt 540
tggcccgaanatcttcagaaaagggatgccccatcgattgaacacccanatgcccactgc 600
cnacagggctgcnccncncngaaagaatgagccattgaagaaggatcntcntggtcttaa 660
tgaactgaaaccntgcatggtggcccctgttcagggctcttggcagtgaattctganaaa 720
aaggaacngcntnagcccccccaaanganaaaacacccccgggtgttgccctgaattggc 780
ggccaagganccctgccccng 801
<210> 17
<211> 740
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (740)
<223> n = A,T,C or G
<400> 17
gtgagagccaggcgtccctctgcctgcccactcagtggcaacacccgggagctgttttgt 60
cctttgtggagcctcagcagttccctctttcagaactcactgccaagagccctgaacagg 120
agccaccatgcagtgcttcagcttcattaagaccatgatgatcctcttcaatttgctcat 180
ctttctgtgtggtgcagccctgttggcagtgggcatctgggtgtcaatcgatggggcatc 240
ctttctgaagatcttcgggccactgtcgtccagtgccatgcagtttgtcaacgtgggcta 300
cttcctcatcgcagccggcgttgtggtctttgctcttggtttcctgggctgctatggtgc 360
taagacggagagcaagtgtgccctcgtgacgttcttcttcatcctcctcctcatcttcat 420
tgctgaagttgcagctgctgtggtcgccttggtgtacaccacaatggctgaaccattcct 480
gacgttgctggtantgcctgccatcaanaaagattatgggttcccaggaaaaattcactc 540
aantntggaacaccnccatgaaaagggctccaatttctgntggcttccccaactataccg 600
gaattttgaaagantcnccctacttccaaaaaaaaananttgcctttncccccnttctgt 660
tgcaatgaaaacntcccaanacngccaatnaaaacctgcccnnncaaaaaggntcncaaa 720
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
9
caaaaaaant nnaagggttn 740
<210> 18
<211> 802
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(802)
<223> n = A,T,C or G
<400>
18
ccgctggttgcgctggtccagngnagccacgaagcacgtcagcatacacagcctcaatca 60
caaggtcttccagctgccgcacattacgcagggcaagagcctccagcaacactgcatatg 120
ggatacactttactttagcagccagggtgacaactgagaggtgtcgaagcttattcttct 180
gagcctctgttagtggaggaagattccgggcttcagctaagtagtcagcgtatgtcccat 240
aagcaaacactgtgagcagccggaaggtagaggcaaagtcactctcagccagctctctaa 300
cattgggcatgtccagcagttctccaaacacgtagacaccagnggcctccagcacctgat 360
ggatgagtgtggccagcgctgcccccttggccgacttggctaggagcagaaattgctcct 420
ggttctgccctgtcaccttcacttccgcactcatcactgcactgagtgtgggggacttgg 480
gctcaggatgtccagagacgtggttccgccccctcncttaatgacaccgnccanncaacc 540
gtcggctcccgccgantgngttcgtcgtncctgggtcagggtctgctggccnctacttgc 600
aancttcgtcnggcccatggaattcaccncaccggaactngtangatccactnnttctat 660
aaccggncgccaccgcnnntggaactccactcttnttncctttacttgagggttaaggtc 720
acccttnncgttaccttggtccaaaccntnccntgtgtcganatngtnaatcnggnccna 780
tnccanccncatangaagccng 802
<210> 19
<211> 731.
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(731)
<223> n = A,T,C or G
<400> 19
cnaagcttccaggtnacgggccgcnaancctgacccnaggtancanaangcagncngcgg 60
gagcccaccgtcacgnggnggngtctttatnggagggggcggagccacatcnctggacnt 120
cntgaccccaactccccnccncncantgcagtgatgagtgcagaactgaaggtnacgtgg 180
caggaaccaagancaaannctgctccnntccaagtcggcnnagggggcggggctggccac 240
gcncatccntcnagtgctgnaaagccccnncctgtctacttgtttggagaacngcnnnga 300
catgcccagngttanataacnggcngagagtnantttgcctctcccttccggctgcgcan 360
cgngtntgcttagnggacataacctgactacttaactgaacccnngaatctnccncccct 420
ccactaagctcagaacaaaaaacttcgacaccactcanttgtcacctgnctgctcaagta 480
aagtgtaccccatncccaatgtntgctngangctctgncctgcnttangttcggtcctgg 540
gaagacctatcaattnaagctatgtttctgactgcctcttgctccctgnaacaancnacc 600
cnncnntccaagggggggncggcccccaatccccccaaccntnaattnantttanccccn 660
cccccnggcccggccttttacnancntcnnnnacngggnaaaaccnnngctttncccaac 720
nnaatccncct 731
<210> 20
<211> 754
<212> DNA
<213> Homo sapien
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
<220>
<221> misc_feature
<222> (1). .(754)
<223> n = A,T,C or G
<400>
,tttttttttttttttttttttaaaaaccccctccattnaatgnaaacttccgaaattgtc 60
caaccccctcntccaaatnnccntttccgggngggggttccaaacccaanttanntttgg 120
annttaaattaaatnttnnttggnggnnnaanccnaatgtnangaaagttnaacccanta 180
tnancttnaatncctggaaaccngtngnttccaaaaatntttaacccttaantccctccg 240
aaatngttnanggaaaacccaanttctcntaaggttgtttgaaggntnaatnaaaanccc 300
nnccaattgtttttngccacgcctgaattaattggnttccgntgttttccnttaaaanaa 360
ggnnanccccggttantnaatccccccnnccccaattataccgantttttttngaattgg 420
gancccncgggaattaacggggnnnntccctnttggggggcnggnnccccccccntcggg 480
ggttngggncaggncnnaattgtttaagggtccgaaaaatccctccnagaaaaaaanctc 540
ccaggntgagnntngggtttnccccccccccanggcccctctcgnanagttggggtttgg 600
ggggcctgggattttntttcccctnttncctcccccccccccnggganagaggttngngt 660
tttgntcnncggccccnccnaaganctttnccganttnanttaaatccntgcctnggcga 720
agtccnttgnagggntaaanggccccctnncggg 754
<210> 21
<211> 755
<212> DNA
<2-13> Homo sapien
<220>
<221> misc_feature
<222> (1). .(755)
<223> n = A,T,C or G
<400> 21
atcancccatgaccccnaacnngggaccnctcanccggncnnncnaccnccggccnatca60
nngtnagnncactncnnttnnatcacnccccnccnactacgcccncnanccnacgcncta120
nncanatnccactganngcgcgangtnganngagaaanctnataccanagncaccanacn180
ccagctgtccnanaangcctnnnatacnggnnnatccaatntgnancctccnaagtattn240
nncnncanatgattttcctnanccgattacccntnccccctancccctcccccccaacna300
cgaaggcnctggnccnaaggnngcgncnccccgctagntccccnncaagtcncncnccta360
aactcanccnnattacncgcttcntgagtatcactccccgaatctcaccctactcaactc420
aaaaanatcngatacaaaataatncaagcctgnttatnacactntgactgggtctctatt480
ttagnggtccntnaancntcctaatacttccagtctnccttcnccaatttccnaanggct540
ctttcngacagcatnttttggttcccnnttgggttcttanngaattgcccttcntngaac600
gggctcntcttttccttcggttancctggnttcnnccggccagttattatttcccntttt660
aaattcntnccntttanttttggcnttcnaaacccccggccttgaaaacggccccctggt720
aaaaggttgttttganaaaatttttgttttgttcc 755
<210> 22
<211> 849
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (849)
<223> n = A, T, C or G
<400> 22
tttttttttt tttttangtg tngtcgtgca ggtagaggct tactacaant gtgaanacgt 60
acgctnggan taangcgacc cganttctag ganncnccct aaaatcanac tgtgaagatn 120
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
11
atcctgnnnacggaanggtcaccggnngatnntgctagggtgnccnctcccannncnttn 180
cataactcngnggccctgcccaccaccttcggcggcccngngnccgggcccgggtcattn 240
gnnttaaccncactnngcnancggtttccnnccccnncngacccnggcgatccggggtnc 300
tctgtcttcccctgnagncnanaaantgggccncggncccctttacccctnnacaagcca 360
cngccntctanccncngccccccctccantnngggggactgccnanngctccgttnctng 420
nnaccccnnngggtncctcggttgtcgantcnaccgnangccanggattccnaaggaagg 480
tgcgttnttggcccctacccttcgctncggnncacccttcccgacnanganccgctcccg 540
cncnncgnngcctcncctcgcaacacccgcnctcntcngtncggnnncccccccacccgc 600
nccctcncncngncgnancnctccnccnccgtctcanncaccaccccgccccgccaggcc 660
ntcanccacnggnngacnngnagcncnntcgcnccgcgcngcgncnccctcgccncngaa 720
ctncntcnggccantnncgctcaanccnnacnaaacgccgctgcgcggcccgnagcgncc 780
ncctccncgagtcctcccgncttccnacccangnnttccncgaggacacnnnaccccgcc 840
nncangcgg 849
<210> 23
<211> 872
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(872)
<223> n = A,T,C or G
<400>
23
gcgcaaactatacttcgctcgnactcgtgcgcctcgctnctcttttcctccgcaaccatg 60
tctgacnancccgattnggcngatatcnanaagntcgancagtccaaactgantaacaca 120
cacacncnanaganaaatccnctgccttccanagtanacnattgaacnngagaaccangc 180
nggcgaatcgtaatnaggcgtgcgccgccaatntgtcnccgtttattntnccagcntcnc 240
ctnccnaccctacntcttcnnagctgtcnnacccctngtncgnaccccccnaggtcggga 300
tcgggtttnnnntgaccgngcnncccctccccccntccatnacganccncccgcaccacc 360
nanngcncgcnccccgnnctcttcgccnccctgtcctntncccctgtngcctggcncngn 420
accgcattgaccctcgccnnctncnngaaancgnanacgtccgggttgnnannancgctg 480
tgggnnngcgtctgcnccgcgttccttccnncnncttccaccatcttcnttacngggtct 540
ccncgccntctcnnncacnccctgggacgctntcctntgccccccttnactccccccctt 600
cgncgtgncccgnccccaccntcatttncanacgntcttcacaannncctggntnnctcc 660
cnancngncngtcanccnagggaagggnggggnnccnntgnttgacgttgnggngangtc 720
cgaanantcctcnccntcancnctacccctcgggcgnnctctcngttnccaacttancaa 780
ntctcccccgngngcncntctcagcctcncccnccccnctctctgcantgtnctctgctc 840
tnaccnntacgantnttcgncnccctctttcc 872
<210> 24
<211> 815
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (815)
<223 > n = A, T, C or G
<400>
24
gcatgcaagcttgagtattctatagngtcacctaaatancttggcntaatcatggtcnta 60
nctgncttcctgtgtcaaatgtatacnaantanatatgaatctnatntgacaaganngta 120
tcntncattagtaacaantgtnntgtccatcctgtcngancanattcccatnnattncgn 180
cgcattcncngcncantatntaatngggaantcnnntnnnncaccnncatctatcntncc 240
gcnccctgactggnagagatggatnanttctnntntgaccnacatgttcatcttggattn 300
aananccccccgcngnccaccggttngnngcnagccnntcccaagacctcctgtggaggt 360
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
12
aacctgcgtcaganncatcaaacntgggaaacccgcnnccangtnnaagtngnnncanan 420
gatcccgtccaggnttnaccatcccttcncagcgccccctttngtgccttanagngnagc 480
gtgtccnanccnctcaacatganacgcgccagnccanccgcaattnggcacaatgtcgnc 540
gaaccccctagggggantnatncaaanccccaggattgtccncncangaaatcccncanc 600
cccnccctacccnnctttgggacngtgaccaantcccggagtnccagtccggccngnctc 660
ccccaccggtnnccntgggggggtgaanctcngnntcanccngncgaggnntcgnaagga 720
accggncctnggncgaanngancnntcngaagngccncntcgtataaccccccctcncca 780
nccnacngntagntcccccccngggtncggaangg 815
<210> 25
<211> 775
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(775)
<223> n = A,T,C or G
<400>
25
ccgagatgtctcgctccgtggccttagctgtgctcgcgctactctctctttctggcctgg 60
aggctatccagcgtactccaaagattcaggtttactcacgtcatccagcagagaatggaa 120
agtcaaatttcctgaattgctatgtgtctgggtttcatccatccgacattgaanttgact 180
tactgaagaatgganagagaattgaaaaagtggagcattcagacttgtctttcagcaagg 240
actggtctttctatctcntgtactacactgaattcacccccactgaaaaagatgagtatg 300
cctgccgtgtgaaccatgtgactttgtcacagcccaagatagttaagtgggatcgagaca 360
tgtaagcagncnncatggaagtttgaagatgccgcatttggattggatgaattccaaatt 420
ctgcttgcttgcnttttaatantgatatgcntatacaccctaccctttatgnccccaaat 480
tgtaggggttacatnantgttcncntnggacatgatcttcctttataantccnccnttcg 540
aattgcccgtcncccngttnngaatgtttccnnaaccacggttggctcccccaggtcncc 600
tcttacggaagggcctgggccnctttncaaggttgggggaaccnaaaatttcncttntgc 660
ccncccnccacnntcttgngnncncantttggaacccttccnattccccttggcctcnna 720
nccttnnctaanaaaacttnaaancgtngcnaaanntttnacttccccccttacc 775
<210> 26
<211> 820
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(820)
<223> n = A,T,C or G
<400> 26
anattantacagtgtaatcttttcccagaggtgtgtanagggaacggggcctagaggcat 60
cccanagatancttatancaacagtgctttgaccaagagctgctgggcacatttcctgca 120
gaaaaggtggcggtccccatcactcctcctctcccatagccatcccagaggggtgagtag 180
ccatcangccttcggtgggagggagtcanggaaacaacanaccacagagcanacagacca 240
ntgatgaccatgggcgggagcgagcctcttccctgnaccggggtggcananganagccta 300
nctgaggggtcacactataaacgttaacgaccnagatnancacctgcttcaagtgcaccc 360
ttcctacctgacnaccagngaccnnnaactgcngcctggggacagcnctgggancagcta 420
acnnagcactcacctgcccccccatggccgtncgcntccctggtcctgncaagggaagct 480
ccctgttggaattncgggganaccaaggganccccctcctccanctgtgaaggaaaaann 540
gatggaattttncccttccggccnntcccctcttcctttacacgccccctnntactcntc 600
tccctctnttntcctgncncacttttnaccccnnnatttcccttnattgatcggannctn 660
ganattccactnncgcctnccntcnatcngnaanacnaaanactntctnacccnggggat 720
gggnncctcgntcatcctctctttttcnctaccnccnnttctttgcctctccttngatca 780
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
13
tccaaccntc gntggccntn cccccccnnn tcctttnccc 820
<210> 27
<211> 818
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(818)
<223> n = A,T,C or G
<400> 27
tctgggtgatggcctcttcctcctcagggacctctgactgctctgggccaaagaatctct 60
tgtttcttctccgagccccaggcagcggtgattcagccctgcccaacctgattctgatga 120
ctgcggatgctgtgacggacccaaggggcaaatagggtcccagggtccagggaggggcgc 180
ctgctgagcacttccgcccctcaccctgcccagcccctgccatgagctctgggctgggtc 240
tccgcctccagggttctgctcttccangcangccancaagtggcgctgggccacactggc 300
ttcttcctgccccntccctggctctgantctctgtcttcctgtcctgtgcangcnccttg 360
gatctcagtttccctcnctcanngaactctgtttctganntcttcanttaactntgantt 420
tatnaccnantggnctgtnctgtcnnactttaatgggccngaccggctaatccctccctc 480
nctcccttccanttcnnnnaaccngcttnccntcntctccccntancccgccngggaanc 540
ctcctttgccctnaccangggccnnnaccgcccntnnctnggggggcnnggtnnctncnc 600
ctgntnnccccnctcncnnttncctcgtcccnncnncgcnnngcannttcncngtcccnn 660
tnnctcttcnngtntcgnaangntcncntntnnnnngncnngntnntncntccctctcnc 720
cnnntgnangtnnttnnnncncngnnccccnnnncnnnnnnggnnntnnntctncncngc 780
cccnncccccngnattaaggcctccnntctccggccnc 818
<210> 28
<211> 731
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (731)
<223> n = A,T,C or G
<400>
28
aggaagggcggagggatattgtangggattgagggataggagnataangggggaggtgtg 60
tcccaacatganggtgnngttctcttttgaangagggttgngtttttannccnggtgggt 120
gattnaaccccattgtatggagnnaaaggntttnagggatttttcggctcttatcagtat 180
ntanattcctgtnaatcggaaaatnatntttcnncnggaaaatnttgctcccatccgnaa 240
attnctcccgggtagtgcatnttngggggncngccangtttcccaggctgctanaatcgt 300
actaaagnttnaagtgggantncaaatgaaaacctnncacagagnatccntacccgactg 360
tnnnttnccttcgccctntgactctgcnngagcccaatacccnngngnatgtcncccngn 420
nnngcgncnctgaaannnnctcgnggctnngancatcanggggtttcgcatcaaaagcnn 480
cgtttcncatnaaggcactttngcctcatccaaccnctngccctcnnccatttngccgtc 540
nggttcncctacgctnntngcncctnnntnganattttncccgcctngggnaancctcct 600
gnaatgggtagggncttntcttttnaccnngnggtntactaatcnnctncacgcntnctt 660
tctcnaccccccccctttttcaatcccancggcnaatggggtctccccnncgangggggg 720
nnncccanncc 731
<210> 29
<211> 822
<212> DNA
<213> Homo sapien
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
14
<220>
<221> misc_feature
<222> (1). .(822)
<223> n = A,T,C or G
<400> 29
actagtccagtgtggtggaattccattgtgttggggncncttctatgantantnttagat 60
cgctcanacctcacancctcccnacnangcctataangaanannaataganctgtncnnt 120
atntntacnctcatanncctcnnnacccactccctcttaacccntactgtgcctatngcn 180
tnnctantctntgccgcctncnanccaccngtgggccnaccncnngnattctcnatctcc 240
tcnccatntngcctanantangtncataccctatacctacnccaatgctannnctaancn 300
tccatnanttannntaactaccactgacntngactttcncatnanctcctaatttgaatc 360
tactctgactcccacngcctannnattagcancntcccccnacnatntctcaaccaaatc 420
ntcaacaacctatctanctgttcnccaaccnttncctccgatccccnnacaacccccctc 480
ccaaatacccnccacctgacncctaacccncaccatcccggcaagccnanggncatttan 540
ccactggaatcacnatngganaaaaaaaacccnaactctctancncnnatctccctaana 600
aatnctcctnnaatttactnncantnccatcaancccacntgaaacnnaacccctgtttt 660
tanatcccttctttcgaaaaccnaccctttannncccaacctttngggcccccccnctnc 720
ccnaatgaaggncncccaatcnangaaacgnccntgaaaaancnaggcnaanannntccg 780
canatcctatcccttanttnggggncccttncccngggcccc 822
<210> 30
<211> 787
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(787)
<223> n = A,T,C or G
<400>
30
cggccgcctgctctggcacatgcctcctgaatggcatcaaaagtgatggactgcccattg 60
ctagagaagaccttctctcctactgtcattatggagccctgcagactgagggctcccctt 120
gtctgcaggatttgatgtctgaagtcgtggagtgtggcttggagctcctcatctacatna 180
gctggaagccctggagggcctctctcgccagcctcccccttctctccacgctctccangg 240
acaccaggggctccaggcagcccattattcccagnangacatggtgtttctccacgcgga 300
cccatggggcctgnaaggccagggtctcctttgacaccatctctcccgtcctgcctggca 360
ggccgtgggatccactanttctanaacggncgccaccncggtgggagctccagcttttgt 420
tcccnttaatgaaggttaattgcncgcttggcgtaatcatnggtcanaactntttcctgt 480
gtgaaattgtttntcccctcncnattccncncnacatacnaacccggaancataaagtgt 540
taaagcctgggggtngcctnnngaatnaactnaactcaattaattgcgttggctcatggc 600
ccgctttccnttcnggaaaactgtcntcccctgcnttnntgaatcggccaccccccnggg 660
aaaagcggtttgcnttttngggggntccttccncttcccccctcnctaanccctncgcct 720
cggtcgttncnggtngcggggaangggnatnnnctcccncnaagggggngagnnngntat 780
ccccaaa 787
<210> 31
<211> 799
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(799)
<223> n = A,T,C or G
<400> 31
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
tttttttttttttttttggcgatgctactgtttaattgcaggaggtgggggtgtgtgtac 60
catgtaccagggctattagaagcaagaaggaaggagggagggcagagcgccctgctgagc 120
aacaaaggactcctgcagccttctctgtctgtctcttggcgcaggcacatggggaggcct 180
cccgcagggtgggggccaccagtccaggggtgggagcactacanggggtgggagtgggtg 240
gtggctggtncnaatggcctgncacanatccctacgattcttgacacctggatttcacca 300
ggggaccttctgttctcccanggnaacttcntnnatctcnaaagaacacaactgtttctt 360
cngcanttctggctgttcatggaaagcacaggtgtccnatttnggctgggacttggtaca 420
tatggttccggcccacctctcccntcnaanaagtaattcacccccccccnccntctnttg 480
cctgggcccttaantacccacaccggaactcanttanttattcatcttnggntgggcttg 540
ntnatcnccncctgaangcgccaagttgaaaggccacgccgtncccnctccccatagnan 600
nttttnncntcanctaatgcccccccnggcaacnatccaatccccccccntgggggcccc 660
agcccanggcccccgnctcgggnnnccngncncgnantccccaggntctcccantcngnc 720
ccnnngcncccccgcacgcagaacanaaggntngagccnccgcannnnnnnggtnncnac 780
ctcgccccccccnncgnng 799
<210> 32
<211> 789
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (789)
<223> n = A,T,C or G
<400>
32
tttttttttttttttttttttttttttttttttttttttttttttttttttttttttttt 60
ttttnccnagggcaggtttattgacaacctcncgggacacaancaggctggggacaggac 120
ggcaacaggctccggcggcggcggcggcggccctacctgcggtaccaaatntgcagcctc 180
cgctcccgcttgatnttcctctgcagctgcaggatgccntaaaacagggcctcggccntn 240
ggtgggcaccctgggatttnaatttccacgggcacaatgcggtcgcancccctcaccacc 300
nattaggaatagtggtnttacccnccnccgttggcncactccccntggaaaccacttntc 360
gcggctccggcatctggtcttaaaccttgcaaacnctggggccctctttttggttantnt 420
nccngccacaatcatnactcagactggcncgggctggccccaaaaaancnccccaaaacc 480
ggnccatgtcttnncggggttgctgcnatntncatcacctcccgggcncancaggncaac 540
ccaaaagttcttgnggcccncaaaaaanctccggggggncccagtttcaacaaagtcatc 600
ccccttggcccccaaatcctccccccgnttnctgggtttgggaacccacgcctctnnctt 660
tggnnggcaagntggntcccccttcgggcccccggtgggcccnnctctaangaaaacncc 720
ntcctnnncaccatccccccnngnnacgnctancaangnatccctttttttanaaacggg 780
ccccccncg 789
<210> 33
<211> 793
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(793)
<223> n = A,T,C or G
<400> 33
gacagaacatgttggatggtggagcacctttctatacgacttacaggacagcagatgggg 60
aattcatggctgttggagcaatanaaccccagttctacgagctgctgatcaaaggacttg 120
gactaaagtctgatgaacttcccaatcagatgagcatggatgattggccagaaatgaana 180
agaagtttgcagatgtatttgcaaagaagacgaaggcagagtggtgtcaaatctttgacg 240
gcacagatgcctgtgtgactccggttctgacttttgaggaggttgttcatcatgatcaca 300
acaangaacggggctcgtttatcaccantgaggagcaggacgtgagcccccgccctgcac 360
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
16
ctctgctgttaaacaccccagccatcccttctttcaaaagggatccactacttctagagc 420
ggncgccaccgcggtggagctccagcttttgttccctttagtgagggttaattgcgcgct 480
tggcgtaatcatggtcatanctgtttcctgtgtgaaattgttatccgctcacaattccac 540
acaacatacganccggaagcatnaaattttaaagcctggnggtngcctaatgantgaact 600
nactcacattaattggctttgcgctcactgcccgctttccagtccggaaaacctgtcctt 660
gccagctgccnttaatgaatcnggccaccccccggggaaaaggcngtttgcttnttgggg 720
cgcncttcccgctttctcgcttcctgaantccttccccccggtctttcggcttgcggcna 780
acggtatcnacct 793
<210> 34
<211> 756
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (756)
<223> n = A,T,C or G
<400>
34
gccgcgaccggcatgtacgagcaactcaagggcgagtggaaccgtaaaagccccaatctt 60
ancaagtgcggggaanagctgggtcgactcaagctagttcttctggagctcaacttcttg 120
ccaaccacagggaccaagctgaccaaacagcagctaattctggcccgtgacatactggag 180
atcggggcccaatggagcatcctacgcaangacatcccctccttcgagcgctacatggcc 240
cagctcaaatgctactactttgattacaangagcagctccccgagtcagcctatatgcac 300
cagctcttgggcctcaacctcctcttcctgctgtcccagaaccgggtggctgantnccac 360
acgganttggancggctgcctgcccaangacatacanaccaatgtctacatcnaccacca 420
gtgtcctggagcaatactgatgganggcagctaccncaaagtnttcctggccnagggtaa 480
catcccccgccgagagctacaccttcttcattgacatcctgctcgacactatcagggatg 540
aaaatcgcngggttgctccagaaaggctncaanaanatccttttcnctgaaggcccccgg 600
atncnctagtnctagaatcggcccgccatcgcggtggancctccaacctttcgttnccct 660
ttactgagggttnattgccgcccttggcgttatcatggtcacnccngttncctgtgttga 720
aattnttaaccccccacaattccacgccnacattng 756
<210> 35
<211> 834
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(834)
<223> n = A,T,C or G
<400> 35
ggggatctctanatcnacctgnatgcatggttgtcggtgtggtcgctgtcgatgaanatg 60
aacaggatcttgcccttgaagctctcggctgctgtntttaagttgctcagtctgccgtca 120
tagtcagacacnctcttgggcaaaaaacancaggatntgagtcttgatttcacctccaat 180
aatcttcngggctgtctgctcggtgaactcgatgacnangggcagctggttgtgtntgat 240
aaantccancangttctccttggtgacctccccttcaaagttgttccggccttcatcaaa 300
cttctnnaanangannancccanctttgtcgagctggnatttgganaacacgtcactgtt 360
ggaaactgatcccaaatggtatgtcatccatcgcctctgctgcctgcaaaaaacttgctt 420
ggcncaaatccgactccccntccttgaaagaagccnatcacacccccctccctggactcc 480
nncaangactctnccgctnccccntccnngcagggttggtggcannccgggcccntgcgc 540
ttcttcagccagttcacnatnttcatcagcccctctgccagctgttntattccttggggg 600
ggaanccgtctctcccttcctgaannaactttgaccgtnggaatagccgcgcntcnccnt 660
acntnctgggccgggttcaaantccctccnttgncnntcncctcgggccattctggattt 720
nccnaactttttccttcccccnccccncggngtttggntttttcatngggccccaactct 780
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
17
gctnttggcc antcccctgg gggcntntan cnccccctnt ggtcccntng ggcc 834
<210> 36
<211> 814
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(814)
<223> n = A,T,C or G
<400> 36
cggncgctttccngccgcgccccgtttccatgacnaaggctcccttcangttaaatacnn 60
cctagnaaacattaatgggttgctctactaatacatcatacnaaccagtaagcctgccca 120
naacgccaactcaggccattcctaccaaaggaagaaaggctggtctctccaccccctgta 180
ggaaaggcctgccttgtaagacaccacaatncggctgaatctnaagtcttgtgttttact 240
aatggaaaaaaaaaataaacaanaggttttgttctcatggctgcccaccgcagcctggca 300
ctaaaacancccagcgctcacttctgcttgganaaatattctttgctcttttggacatca 360
ggcttgatggtatcactgccacntttccacccagctgggcncccttcccccatntttgtc 420
antganctggaaggcctgaancttagtctccaaaagtctcngcccacaagaccggccacc 480
aggggangtcntttncagtggatctgccaaanantacccntatcatcnntgaataaaaag 540
gcccctgaacganatgcttccancancctttaagacccataatcctngaaccatggtgcc 600
cttccggtctgatccnaaaggaatgttcctgggtcccantccctcctttgttncttacgt 660
tgtnttggacccntgctngnatnacccaantganatccccngaagcaccctncccctggc 720
atttgantttcntaaattctctgccctacnnctgaaagcacnattccctnggcnccnaan 780
ggngaactcaagaaggtctnngaaaaaccacncn 814
<210> 37
<211> 760
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(760)
<223> n = A,T,C or G
<400>
37
gcatgctgctcttcctcaaagttgttcttgttgccataacaaccaccataggtaaagcgg 60
gcgcagtgttcgctgaaggggttgtagtaccagcgcgggatgctctccttgcagagtcct 120
gtgtctggcaggtccacgcaatgccctttgtcactggggaaatggatgcgctggagctcg 180
tcnaanccactcgtgtatttttcacangcagcctcctccgaagcntccgggcagttgggg 240
gtgtcgtcacactccactaaactgtcgatncancagcccattgctgcagcggaactgggt 300
gggctgacaggtgccagaacacactggatnggcctttccatggaagggcctgggggaaat 360
cncctnancccaaactgcctctcaaaggccaccttgcacaccccgacaggctagaaatgc 420
actcttcttcccaaaggtagttgttcttgttgcccaagcancctccancaaaccaaaanc 480
ttgcaaaatctgctccgtgggggtcatnnntaccanggttggggaaanaaacccggcngn 540
ganccnccttgtttgaatgcnaaggnaataatcctcctgtcttgcttgggtggaanagca 600
caattgaactgttaacnttgggccgngttccnctngggtggtctgaaactaatcaccgtc 660
actggaaaaaggtangtgccttccttgaattcccaaanttcccctngntttgggtnnttt 720
ctcctctnccctaaaaatcgtnttccccccccntanggcg 760
<210> 38
<211> 724
<212> DNA
<213> Homo sapien
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
18
<220>
<221> misc_feature
<222> (1). .(724)
<223> n = A,T,C or G
<400> 38
tttttttttttttttttttttttttttttttttttaaaaaccccctccattgaatgaaaa 60
cttccnaaattgtccaaccccctcnnccaaatnnccatttccgggggggggttccaaacc 120
caaattaattttggantttaaattaaatnttnattnggggaanaanccaaatgtnaagaa 180
aatttaacccattatnaacttaaatncctngaaacccntggnttccaaaaatttttaacc 240
cttaaatccctccgaaattgntaanggaaaaccaaattcncctaaggctntttgaaggtt 300
ngatttaaacccccttnanttnttttnacccnngnctnaantatttngnttccggtgttt 360
tcctnttaancntnggtaactcccgntaatgaannnccctaanccaattaaaccgaattt 420
tttttgaattggaaattccnngggaattnaccggggtttttcccntttgggggccatncc 480
cccnctttcggggtttgggnntaggttgaatttttnnangncccaaaaaancccccaana 540
aaaaaactcccaagnnttaattngaatntcccccttcccaggccttttgggaaaggnggg 600
'
tttntgggggccnggganttcnttcccccnttnccnccccccccccnggtaaanggttat 660
ngnntttggtttttgggccccttnanggaccttccggatngaaattaaatccccgggncg 720
gccg 724
<210> 39
<211> 751
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(751)
<223> n = A,T,C or G
<400> 39
ttttttttttttt.ttctttgctcacatttaatttttattttgattttttttaatgctgca 60
caacacaatatttatttcatttgtttcttttatttcattttatttgtttgctgctgctgt 120
tttatttatttttactgaaagtgagagggaacttttgtggccttttttcctttttctgta 180
ggccgccttaagctttctaaatttggaacatctaagcaagctgaanggaaaagggggttt 240
cgcaaaatcactcgggggaanggaaaggttgctttgttaatcatgccctatggtgggtga 300
ttaactgcttgtacaattacntttcacttttaattaattgtgctnaangctttaattana 360
cttgggggttccctccccanaccaaccccnctgacaaaaagtgccngccctcaaatnatg 420
tcccggcnntcnttgaaacacacngcngaangttctcattntccccncnccaggtnaaaa 480
tgaagggttaccatntttaacnccacctccacntggcnnngcctgaatcctcnaaaancn 540
ccctcaancnaattnctnngccccggtcncgcntnngtcccncccgggctccgggaantn 600
cacccccngaanncnntnncnaacnaaattccgaaaatattcccnntcnctcaattcccc 660
cnnagactntcctcnncnancncaattttcttttnntcacgaacncgnnccnnaaaatgn 720
nnnncncctccnctngtccnnaatcnccanc 751
<210> 40
<211> 753
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(753)
<223> n = A,T,C or G
<400> 40
gtggtatttt ctgtaagatc aggtgttcct ccctcgtagg tttagaggaa acaccctcat 60
agatgaaaac ccccccgaga cagcagcact gcaactgcca agcagccggg gtaggagggg 120
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
19
cgccctatgcacagctgggcccttgagacagcagggcttcgatgtcaggctcgatgtcaa 180
tggtctggaagcggcggctgtacctgcgtaggggcacaccgtcagggcccaccaggaact 240
tctcaaagttccaggcaacntcgttgcgacacaccggagaccaggtgatnagcttggggt 300
cggtcataancgcggtggcgtcgtcgctgggagctggcagggcctcccgcaggaaggcna 360
ataaaaggtgcgcccccgcaccgttcanctcgcacttctcnaanaccatgangttgggct 420
cnaacccaccaccannccggacttccttganggaattcccaaatctcttcgntcttgggc 480
ttctnctgatgccctanctggttgcccngnatgccaancanccccaanccccggggtcct 540
aaancacccncctcctcntttcatctgggttnttntccccggaccntggttcctctcaag 600
ggancccatatctcnaccantactcaccntncccccccntgnnacccanccttctanngn 660
ttcccncccgncctctggcccntcaaanangcttncacnacctgggtctgccttcccccc 720
tnccctatctgnaccccncntttgtctcantnt 753
<210> 41
<211> 341
<212> DNA
<213> Homo sapien
<400> 41
actatatccatcacaacagacatgcttcatcccatagacttcttgacatagcttcaaatg 60
agtgaacccatccttgatttatatacatatatgttctcagtattttgggagcctttccac 120
ttctttaaaccttgttcattatgaacactgaaaataggaatttgtgaagagttaaaaagt 180
tatagcttgtttacgtagtaagtttttgaagtctacattcaatccagacacttagttgag 240
tgttaaactgtgatttttaaaaaatatcatttgagaatattctttcagaggtattttcat 300
ttttactttttgattaattgtgttttatatattagggtagt 341
<210> 42
<211> 101
<212> DNA
<213> Homo sapien
<400> 42
acttactgaa tttagttctg tgctcttcct tatttagtgt tgtatcataa atactttgat 60
gtttcaaaca ttctaaataa ataattttca gtggcttcat a 101
<210> 43
<211> 305
<212> DNA
<213> Homo sapien
<400> 43
acatctttgttacagtctaagatgtgttcttaaatcaccattccttcctggtcctcaccc 60
tccagggtggtctcacactgtaattagagctattgaggagtctttacagcaaattaagat 120
tcagatgccttgctaagtctagagttctagagttatgtttcagaaagtctaagaaaccca 180
cctcttgagaggtcagtaaagaggacttaatatttcatatctacaaaatgaccacaggat 240
tggatacagaacgagagttatcctggataactcagagctgagtacctgcccgggggccgc 300
tcgaa 305
<210> 44
<211> 852
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (852)
<223> n = A,T,C or G
<400> 44
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
acataaatatcagagaaaagtagtctttgaaatatttacgtccaggagttctttgtttct 60
gattatttggtgtgtgttttggtttgtgtccaaagtattggcagcttcagttttcatttt 120
ctctccatcctcgggcattcttcccaaatttatataccagtcttcgtccatccacacgct 180
ccagaatttctcttttgtagtaatatctcatagctcggctgagcttttcataggtcatgc 240
tgctgttgttcttctttttaccccatagctgagccactgcctctgatttcaagaacctga 300
agacgccctcagatcggtcttcccattttattaatcctgggttcttgtctgggttcaaga 360
ggatgtcgcggatgaattcccataagtgagtccctctcgggttgtgctttttggtgtggc 420
acttggcaggggggtcttgctcctttttcatatcaggtgactctgcaacaggaaggtgac 480
tggtggttgtcatggagatctgagcccggcagaaagttttgctgtccaacaaatctactg 540
tgctaccatagttggtgtcatataaatagttctngtctttccaggtgttcatgatggaag 600
gctcagtttgttcagtcttgacaatgacattgtgtgtggactggaacaggtcactactgc 660
actggccgttccacttcagatgctgcaagttgctgtagaggagntgccccgccgtccctg 720
ccgcccgggtgaactcctgcaaactcatgctgcaaaggtgctcgccgttgatgtcgaact 780
cntggaaagggatacaattggcatccagctggttggtgtccaggaggtgatggagccact 840
cccacacctggt 852
<210> 45
<211> 234
<212> DNA
<213> Homo sapien
<400> 45
acaacagacc cttgctcgct aacgacctca tgctcatcaa gttggacgaa tccgtgtccg 60
agtctgacac catccggagc atcagcattg cttcgcagtg ccctaccgcg gggaactctt 120
gcctcgtttc tggctggggt ctgctggcga acggcagaat gcctaccgtg ctgcagtgcg 180
tgaacgtgtc ggtggtgtct gaggaggtct gcagtaagct ctatgacccg ctgt 234
<210> 46
<211> 590
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1)...(590)
<223> n = A,T,C or G
<400>
46
actttttatttaaatgtttataaggcagatctatgagaatgatagaaaacatggtgtgta 60
atttgatagcaatattttggagattacagagttttagtaattaccaattacacagttaaa 120
aagaagataatatattccaagcanatacaaaatatctaatgaaagatcaaggcaggaaaa ,
180
tgantataactaattgacaatggaaaatcaattttaatgtgaattgcacattatccttta 240
aaagctttcaaaanaaanaattattgcagtctanttaattcaaacagtgttaaatggtat 300
caggataaanaactgaagggcanaaagaattaattttcacttcatgtaacncacccanat 360
ttacaatggcttaaatgcanggaaaaagcagtggaagtagggaagtantcaaggtctttc 420
tggtctctaatctgccttactctttgggtgtggctttgatcctctggagacagctgccag 480
ggctcctgttatatccacaatcccagcagcaagatgaagggatgaaaaaggacacatgct 540
gccttcctttgaggagacttcatctcactggccaacactcagtcacatgt 590
<210> 47
<211> 774
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(774)
<223> n = A,T,C or G
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
21
<400>
47
acaagggggcataatgaaggagtgggganagattttaaagaaggaaaaaaaacgaggccc 60
tgaacagaattttcctgnacaacggggcttcaaaataattttcttggggaggttcaagac 120
gcttcactgcttgaaacttaaatggatgtgggacanaattttctgtaatgaccctgaggg 180
cattacagacgggactctgggaggaaggataaacagaaaggggacaaaggctaatcccaa 240
aacatcaaagaaaggaaggtggcgtcatacctcccagcctacacagttctccagggctct 300
cctcatccctggaggacgacagtggaggaacaactgaccatgtccccaggctcctgtgtg 360
ctggctcctggtcttcagcccccagctctggaagcccaccctctgctgatcctgcgtggc 420
ccacactccttgaacacacatccccaggttatattcctggacatggctgaacctcctatt 480
cctacttccgagatgccttgctccctgcagcctgtcaaaatcccactcaccctccaaacc 540
acggcatgggaagcctttctgacttgcctgattactccagcatcttggaacaatccctga 600
ttccccactccttagaggcaagatagggtggttaagagtagggctggaccacttggagcc 660
aggctgctggcttcaaattntggctcatttacgagctatgggaccttgggcaagtnatct 720
tcacttctatgggcntcattttgttctacctgcaaaatgggggataataatagt 774
<210> 48
<211> 124
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(124)
<223> n = A,T,C or G
<400> 48
canaaattga aattttataa aaaggcattt ttctcttata tccataaaat gatataattt 60
ttgcaantat anaaatgtgt cataaattat aatgttcctt aattacagct caacgcaact 120
tggt 124
<210> 49
<211> 147
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(147)
<223> n = A,T,C or G
<400> 49
gccgatgcta ctattttatt gcaggaggtg ggggtgtttt tattattctc tcaacagctt 60
tgtggctaca ggtggtgtct gactgcatna aaaanttttt tacgggtgat tgcaaaaatt 120
ttagggcacc catatcccaa gcantgt 147
<210> 50
<211> 107
<212> DNA
<213> Homo sapien
<400> 50
acattaaatt aataaaagga ctgttggggt tctgctaaaa cacatggctt gatatattgc 60
,atggtttgag gttaggagga gttaggcata tgttttggga gaggggt 107
<210> 51
<211> 204
<212> DNA
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
22
<213> Homo sapien
<400> 51
gtcctaggaa gtctagggga cacacgactc tggggtcacg gggccgacac acttgcacgg 60
cgggaaggaa aggcagagaa gtgacaccgt cagggggaaa tgacagaaag gaaaatcaag 120
gccttgcaag gtcagaaagg ggactcaggg cttccaccac agccctgccc cacttggcca 180
cctccctttt gggaccagca atgt 204
<210> 52
<211> 491
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (491)
<223> n = A,T,C or G
<400> 52
acaaagataacatttatcttataacaaaaatttgatagttttaaaggttagtattgtgta 60
gggtattttccaaaagactaaagagataactcaggtaaaaagttagaaatgtataaaaca 120
ccatcagacaggtttttaaaaaacaacatattacaaaattagacaatcatccttaaaaaa 180
aaaacttcttgtatcaatttcttttgttcaaaatgactgacttaantatttttaaatatt 240
tcanaaacacttcctcaaaaattttcaanatggtagctttcanatgtnccctcagtccca 300
atgttgctcagataaataaatctcgtgagaacttaccacccaccacaagctttctggggc 360
atgcaacagtgtcttttctttnctttttctttttttttttttacaggcacagaaactcat 420
caattttatttggataacaaagggtctccaaattatattgaaaaataaatccaagttaat 480
atcactcttgt 491
<210> 53
<211> 484
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (484)
<223> n = A,T,C or G
<400> 53
acataatttagcagggctaattaccataagatgctatttattaanaggtntatgatctga 60
gtattaacagttgctgaagtttggtatttttatgcagcattttctttttgctttgataac 120
actacagaacccttaaggacactgaaaattagtaagtaaagttcagaaacattagctgct 180
caatcaaatctctacataacactatagtaattaaaacgttaaaaaaaagtgttgaaatct 240
gcactagtatanaccgctcctgtcaggataanactgctttggaacagaaagggaaaaanc 300
agctttgantttctttgtgctgatangaggaaaggctgaattaccttgttgcctctccct 360
aatgattggcaggtcnggtaaatnccaaaacatattccaactcaacacttcttttccncg 420
tancttgantctgtgtattccaggancaggcggatggaatgggccagcccncggatgttc 480
cant 484
<210> 54
<211> 151
<212> DNA
<213> Homo sapien
<400> 54
actaaacctc gtgcttgtga actccataca gaaaacggtg ccatccctga acacggctgg 60
ccactgggta tactgctgac aaccgcaaca acaaaaacac aaatccttgg cactggctag 120
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
23
tctatgtcct ctcaagtgcc tttttgtttg t 151
<210> 55
<211> 91
<212> DNA
<213> Homo sapien
<400> 55
acctggcttg tctccgggtg gttcccggcg ccccccacgg tccccagaac ggacactttc 60
gccctccagt ggatactcga gccaaagtgg t 91
<210> 56
<211> 133
<212> DNA
<213> Homo sapien
<400> 56
ggcggatgtg cgttggttat atacaaatat gtcattttat gtaagggact tgagtatact 60
tggatttttg gtatctgtgg gttgggggga cggtccagga accaataccc catggatacc 120
aagggacaac tgt 133
<210> 57
<211> 147
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(147)
<223> n = A, T, C or G
<400> 57
actctggaga acctgagccg ctgctccgcc tctgggatga ggtgatgcan gcngtggcgc 60
gactgggagc tgagcccttc cctttgcgcc tgcctcagag gattgttgcc gacntgcana 120 w
tctcantggg ctggatncat gcagggt 147
<210> 58
<211> 198
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(198)
<223> n = A,T,C or G
<400> 58
acagggatat aggtttnaag ttattgtnat tgtaaaatac attgaatttt ctgtatactc 60
tgattacata catttatcct ttaaaaaaga tgtaaatctt aatttttatg ccatctatta 120
atttaccaat gagttacctt gtaaatgaga agtcatgata gcactgaatt ttaactagtt 180
ttgacttcta agtttggt 198
<210> 59
<211> 330
<212> DNA
<213> Homo sapien
<400> 59
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
24
acaacaaatgggttgtgaggaagtcttatcagcaaaactggtgatggctactgaaaagat 60
ccattgaaaattatcattaatgattttaaatgacaagttatcaaaaactcactcaatttt 120
cacctgtgctagcttgctaaaatgggagttaactctagagcaaatatagtatcttctgaa 180
tacagtcaataaatgacaaagccagggcctacaggtggtttccagactttccagacccag 240
cagaaggaatctattttatcacatggatctccgtctgtgctcaaaatacctaatgatatt 300
tttcgtctttattggacttctttgaagagt 330
<210> 60
<211> 175
<212> DNA
<213> Homo sapien
<400> 60
accgtgggtg ccttctacat tcctgacggc tccttcacca acatctggtt ctacttcggc 60
gtcgtgggct ccttcctctt catcctcatc cagctggtgc tgctcatcga ctttgcgcac 120
tcctggaacc agcggtggct gggcaaggcc gaggagtgcg attcccgtgc ctggt 175
<210> 61
<211> 154
<212> DNA
<213> Homo sapien
<400> 61
accccacttt tcctcctgtg agcagtctgg acttctcact gctacatgat gagggtgagt 60
ggttgttgct cttcaacagt atcctcccct ttccggatct gctgagccgg acagcagtgc 120
tggactgcac agccccgggg ctccacattg ctgt 154
<210> 62
<211> 30
<212> DNA
<213> Homo sapien
<400> 62
cgctcgagcc ctatagtgag tcgtattaga 30
<210> 63
<211> 89
<212> DNA
<213> Homo sapien
<400> 63
acaagtcatt tcagcaccct ttgctcttca aaactgacca tcttttatat ttaatgcttc 60
ctgtatgaat aaaaatggtt atgtcaagt 89
<210> 64
<211> 97
<212> DNA
<213> Homo sapien
<400> 64
accggagtaa ctgagtcggg acgctgaatc tgaatccacc aataaataaa ggttctgcag 60
aatcagtgca tccaggattg gtccttggat ctggggt 97
<210> 65
<211> 377
<212> DNA
<213> Homo sapien
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
<220>
<221> misc_feature
<222> (1). .(377)
<223> n = A,T,C or G
<400>
65
acaacaanaantcccttctttaggccactgatggaaacctggaacccccttttgatggca 60
'
gcatggcgtcctaggccttgacacagcggctggggtttgggctntcccaaaccgcacacc 120
ccaaccctggtctacccacanttctggctatgggctgtctctgccactgaacatcagggt 180
tcggtcataanatgaaatcccaanggggacagaggtcagtagaggaagctcaatgagaaa 240
ggtgctgtttgctcagccagaaaacagctgcctggcattcgccgctgaactatgaacccg 300
tgggggtgaactacccccangaggaatcatgcctgggcgatgcaanggtgccaacaggag 360
gggcgggaggagcatgt 377
<210> 66
<211> 305
<212> DNA
<213> Homo sapien
<400> 66
acgcctttccctcagaattcagggaagagactgtcgcctgccttcctccgttgttgcgtg 60
agaacccgtgtgccccttcccaccatatccaccctcgctccatctttgaactcaaacacg 120
aggaactaactgcaccctggtcctctccccagtccccagttcaccctccatccctcacct 180
tcctccactctaagggatatcaacactgcccagcacaggggccctgaatttatgtggttt 240
ttatatattttttaataagatgcactttatgtcattttttaataaagtctgaagaattac 300
tgttt 305
<210> 67
<211> 385
<212> DNA
<213> Homo sapien
<400> 67
actacacacactccacttgcccttgtgagacactttgtcccagcactttaggaatgctga 60
ggtcggaccagccacatctcatgtgcaagattgcccagcagacatcaggtctgagagttc 120
cccttttaaaaaaggggacttgcttaaaaaagaagtctagccacgattgtgtagagcagc 180
tgtgctgtgctggagattcacttttgagagagttctcctctgagacctgatctttagagg 240
ctgggcagtcttgcacatgagatggggctggtctgatctcagcactccttagtctgcttg 300
cctctcccagggccccagcctggccacacctgcttacagggcactctcagatgcccatac 360
catagtttctgtgctagtggaccgt 385
<210> 68
<211> 73
<212> DNA
<213> Homo sapien
<400> 68
acttaaccag atatattttt accccagatg gggatattct ttgtaaaaaa tgaaaataaa 60
gtttttttaa tgg 73
<210> 69
<211> 536
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(536)
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
26
<223> n = A,T,C or G
<400>
69
actagtccagtgtggtggaattccattgtgttgggggctctcaccctcctctcctgcagc 60
tccagctttgtgctctgcctctgaggagaccatggcccagcatctgagtaccctgctgct 120
cctgctggccaccctagctgtggccctggcctggagccccaaggaggaggataggataat 180
cccgggtggcatctataacgcagacctcaatgatgagtgggtacagcgtgcccttcactt 240
cgccatcagcgagtataacaaggccaccaaagatgactactacagacgtccgctgcgggt 300
actaagagccaggcaacagaccgttgggggggtgaattacttcttcgacgtagaggtggg 360
ccgaaccatatgtaccaagtcccagcccaacttggacacctgtgccttccatgaacagcc 420
agaactgcagaagaaacagttgtgctctttcgagatctacgaagttccctggggagaaca 480
gaangtccctgggtgaaatccaggtgtcaagaaatcctanggatctgttgccaggc 536
<210> 70
<211> 477
<212> DNA
<213> Homo sapien
<400> 70
atgacccctaacaggggccctctcagccctcctaatgacctccggcctagccatgtgatt 60
tcacttccactccataacgctcctcatactaggcctactaaccaacacactaaccatata 120
ccaatgatggcgcgatgtaacacgagaaagcacataccaaggccaccacacaccacctgt 180
ccaaaaaggccttcgatacgggataatcctatttattacctcagaagtttttttcttcgc 240
agggatttttctgagccttttaccactccagcctagcccctaccccccaactaggagggc 300
actggcccccaacaggcatcaccccgctaaatcccctagaagtcccactcctaaacacat 360
ccgtattactcgcatcaggagtatcaatcacctgagctcaccatagtctaatagaaaaca 420
accgaaaccaaattattcaaagcactgcttattacaattttactgggtctctatttt 477.
<210> 71
<211> 533
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(533)
<223> n = A,T,C or G
<400>
71
agagctataggtacagtgtgatctcagctttgcaaacacattttctacatagatagtact 60
aggtattaatagatatgtaaagaaagaaatcacaccattaataatggtaagattggttta 120
tgtgattttagtggtatttttggcacccttatatatgttttccaaactttcagcagtgat 180
attatttccataacttaaaaagtgagtttgaaaaagaaaatctccagcaagcatctcatt 240
taaataaaggtttgtcatctttaaaaatacagcaatatgtgactttttaaaaaagctgtc 300
aaataggtgtgaccctactaataattattagaaatacatttaaaaacatcgagtacctca 360
agtcagtttgccttgaaaaatatcaaatataactcttagagaaatgtacataaaagaatg 420
cttcgtaattttggagtangaggttccctcctcaattttgtatttttaaaaagtacatgg 480
taaaaaaaaaaattcacaacagtatataaggctgtaaaatgaagaattctgcc 533
<210> 72
<211> 511
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(511)
<223> n = A,T,C or G
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
27
<400>
72
tattacggaaaaacacaccacataattcaactancaaagaanactgcttcagggcgtgta 60
aaatgaaaggcttccaggcagttatctgattaaagaacactaaaagagggacaaggctaa 120
aagccgcaggatgtctacactatancaggcgctatttgggttggctggaggagctgtgga 180
aaacatgganagattggtgctgganatcgccgtggctattcctcattgttattacanagt 240
gaggttctctgtgtgcccactggtttgaaaaccgttctncaataatgatagaatagtaca 300
cacatgagaactgaaatggcccaaacccagaaagaaagcccaactagatcctcagaanac 360
gcttctagggacaataaccgatgaagaaaagatggcctccttgtgcccccgtctgttatg 420
atttctctccattgcagcnanaaacccgttcttctaagcaaacncaggtgatgatggcna 480
aaatacaccccctcttgaagnaccnggagga 511
<210> 73
<211> 499
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(499)
<223> n = A,T,C or G
<400> 73
cagtgccagcactggtgccagtaccagtaccaataacagtgccagtgccagtgccagcac 60
cagtggtggcttcagtgctggtgccagcctgaccgccactctcacatttgggctcttcgc 120
tggccttggtggagctggtgccagcaccagtggcagctctggtgcctgtggtttctccta 180
caagtgagattttagatattgttaatcctgccagtctttctcttcaagccagggtgcatc 240
ctcagaaacctactcaacacagcactctaggcagccactatcaatcaattgaagttgaca 300
ctctgcattaaatctatttgccatttctgaaaaaaaaaaaaaaaaaagggcggccgctcg 360
antctagagggcccgtttaaacccgctgatcagcctcgactgtgccttctanttgccagc 420
catctgttgtttgcccctcccccgntgccttccttgaccctggaaagtgccactcccact 480
gtcctttcctaantaaaat 499
<210> 74
<211> 537
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(537)
<223> n = A,T,C or G
<400>
74
tttcataggagaacacactgaggagatacttgaagaatttggattcagccgcgaagagat 60
ttatcagcttaactcagataaaatcattgaaagtaataaggtaaaagctagtctctaact 120
tccaggcccacggctcaagtgaatttgaatactgcatttacagtgtagagtaacacataa 180
cattgtatgcatggaaacatggaggaacagtattacagtgtcctaccactctaatcaaga 240
aaagaattacagactctgattctacagtgatgattgaattctaaaaatggtaatcattag 300
ggcttttgatttataanactttgggtacttatactaaattatggtagttatactgccttc 360
cagtttgcttgatatatttgttgatattaagattcttgacttatattttgaatgggttct 420
actgaaaaangaatgatatattcttgaagacatcgatatacatttatttacactcttgat 480
tctacaatgtagaaaatgaaggaaatgccccaaattgtatggtgataaaagtcccgt 537
<210> 75
<211> 467
<212> DNA
<213> Homo sapien
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
28
<220>
<221> misc_feature
<222> (1). .(467)
<223> n = A,T,C or G
<400> 75
caaanacaattgttcaaaagatgcaaatgatacactactgctgcagctcacaaacacctc 60
tgcatattacacgtacctcctcctgctcctcaagtagtgtggtctattttgccatcatca 120
cctgctgtctgcttagaagaacggctttctgctgcaanggagagaaatcataacagacgg 180
tggcacaaggaggccatcttttcctcatcggttattgtccctagaagcgtcttctgagga 240
tctagttgggctttctttctgggtttgggccatttcanttctcatgtgtgtactattcta 300
tcattattgtataacggttttcaaaccngtgggcacncagagaacctcactctgtaataa 360
caatgaggaatagccacggtgatctccagcaccaaatctctccatgttnttccagagctc 420
ctccagccaacccaaatagccgctgctatngtgtagaacatccctgn 467
<210> 76
<211> 400
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(400)
<223> n = A,T,C or G
<400>
76
aagctgacagcattcgggccgagatgtctcgctccgtggccttagctgtgctcgcgctac 60
tctctctttctggcctggaggctatccagcgtactccaaagattcaggtttactcacgtc 120
atccagcagagaatggaaagtcaaatttcctgaattgctatgtgtctgggtttcatccat 180
ccgacattgaagttgacttactgaagaatggagagagaattgaaaaagtggagcattcag 240
acttgtctttcagcaaggactggtctttctatctcttgtactacactgaattcaccccca 300
ctgaaaaagatgagtatgcctgccgtgtgaaccatgtgactttgtcacagcccaagatng 360
ttnagtgggatcganacatgtaagcagcancatgggaggt 400
<210> 77
<211> 248
<212> DNA
<213> Homo sapien
<400> 77
ctggagtgccttggtgtttcaagcccctgcaggaagcagaatgcaccttctgaggcacct 60
ccagctgccccggcgggggatgcgaggctcggagcacccttgcccggctgtgattgctgc 120
caggcactgttcatctcagcttttctgtccctttgctcccggcaagcgcttctgctgaaa 180
gttcatatctggagcctgatgtcttaacgaataaaggtcccatgctccacccgaaaaaaa 240
aaaaaaaa 248
<210> 78
<211> 201
<212> DNA
<213> Homo sapien
<400> 78
actagtccag tgtggtggaa ttccattgtg ttgggcccaa cacaatggct acctttaaca 60
tcacccagac cccgccctgc ccgtgcccca cgctgctgct aacgacagta tgatgcttac 120
tctgctactc ggaaactatt tttatgtaat taatgtatgc tttcttgttt ataaatgcct 180
gatttaaaaa aaaaaaaaaa a 201
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
29
<210> 79
<211> 552
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(552)
<223> n = A, T, C or G
<400>
79
tccttttgttaggtttttgagacaaccctagacctaaactgtgtcacagacttctgaatg 60
tttaggcagtgctagtaatttcctcgtaatgattctgttattactttcctattctttatt 120
cctctttcttctgaagattaatgaagttgaaaattgaggtggataaatacaaaaaggtag 180
tgtgatagtataagtatctaagtgcagatgaaagtgtgttatatatatccattcaaaatt 240
atgcaagttagtaattactcagggttaactaaattactttaatatgctgttgaacctact 300
ctgttccttggctagaaaaaattataaacaggactttgttagtttgggaagccaaattga 360
taatattctatgttctaaaagttgggctatacataaantatnaagaaatatggaatttta 420
ttcccaggaatatggggttcatttatgaatantacccggganagaagttttgantnaaac 480
cngttttggttaatacgttaatatgtcctnaatnaacaaggcntgacttatttccaaaaa 540
aaaaaaaaaaas 552
<210> 80
<211> 476
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (476)
<223> n = A,T,C or G
<400> 80
acagggatttgagatgctaaggccccagagatcgtttgatccaaccctcttattttcaga 60
ggggaaaatggggcctagaagttacagagcatctagctggtgcgctggcacccctggcct 120
cacacagactcccgagtagctgggactacaggcacacagtcactgaagcaggccctgttt 180
gcaattcacgttgccacctccaacttaaacattcttcatatgtgatgtccttagtcacta 240
aggttaaactttcccacccagaaaaggcaacttagataaaatcttagagtactttcatac 300
tcttctaagtcctcttccagcctcactttgagtcctccttgggggttgataggaantntc 360
tcttggctttctcaataaaatctctatccatctcatgtttaatttggtacgcntaaaaat 420
gctgaaaaaattaaaatgttctggtttcnctttaaaaaaaaaaaaaaaaaaaaaaa 476
<210> 81
<211> 232
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(232)
<223> n = A,T,C or G
<400> 81
tttttttttg tatgccntcn ctgtggngtt attgttgctg ccaccctgga ggagcccagt 60
ttcttctgta tctttctttt ctgggggatc ttcctggctc tgcccctcca ttcccagcct 120
ctcatcccca tcttgcactt ttgctagggt tggaggcgct ttcctggtag cccctcagag 180
actcagtcag cgggaataag tcctaggggt ggggggtgtg gcaagccggc ct 232
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
<210> 8z
<211> 383
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (383)
<223> n = A,T,C or G
<400>
82
aggcgggagcagaagctaaagccaaagcccaagaagagtggcagtgccagcactggtgcc 60
agtaccagtaccaataacatgccagtgccagtgccagcaccagtggtggcttcagtgctg 120
gtgccagcctgaccgccactctcacatttgggctcttcgctggccttggtggagctggtg 180
ccagcaccagtggcagctctggtgcctgtggtttctcctacaagtgagattttagatatt 240
gttaatcctgccagtctttctcttcaagccagggtgcatcctcagaaacctactcaacac 300
agcactctnggcagccactatcaatcaattgaagttgacactctgcattaaatctatttg 360
ccatttcaaaaaaaaaaaaaaaa 383
<210> 83
<211> 494
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (494)
<223> n = A,T,C or G
<400> 83
accgaattgggaccgctggcttataagcgatcatgtcctccagtattacctcaacgagca 60
gggagatcgagtctatacgctgaagaaatttgacccgatgggacaacagacctgctcagc 120
ccatcctgctcggttctccccagatgacaaatactctcgacaccgaatcaccatcaagaa 180
acgcttcaaggtgctcatgacccagcaaccgcgccctgtcctctgagggtccttaaactg 240
atgtcttttctgccacctgttacccctcggagactccgtaaccaaactcttcggactgtg 300
agccctgatgcctttttgccagccatactctttggcntccagtctctcgtggcgattgat 360
tatgcttgtgtgaggcaatcatggtggcatcacccatnaagggaacacatttganttttt 420
tttcncatattttaaattacnaccagaatanttcagaataaatgaattgaaaaactctta 480
aaaaaaaaaaaaaa 494
<210> 84
<211> 380
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(380)
<223> n = A,T,C or G
<400>
84
gctggtagcctatggcgtggccacggangggctcctgaggcacgggacagtgacttccca 60
agtatcctgcgccgcgtcttctaccgtccctacctgcagatcttcgggcagattccccag 120
gaggacatggacgtggccctcatggagcacagcaactgctcgtcggagcccggcttctgg 180
gcacaccctcctggggcccaggcgggcacctgcgtctcccagtatgccaactggctggtg 240
gtgctgctcctcgtcatcttcctgctcgtggccaacatcctgctggtcacttgctcattg 300
ccatgttcagttacacattcggcaaagtacagggcaacagcnatctctactgggaaggcc 360
agcgttnccgcctcatccgg 380
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
31
<210> 85
<211> 481
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (481)
<223> n = A,T,C or G
<400> 85
gagttagctcctccacaaccttgatgaggtcgtctgcagtggcctctcgcttcataccgc 60
tnccatcgtcatactgtaggtttgccaccacctcctgcatcttggggcggctaatatcca 120
ggaaactctcaatcaagtcaccgtcnatnaaacctgtggctggttctgtcttccgctcgg 180
tgtgaaaggatctccagaaggagtgctcgatcttccccacacttttgatgactttattga 240
gtcgattctgcatgtccagcaggaggttgtaccagctctctgacagtgaggtcaccagcc 300
ctatcatgccnttgaacgtgccgaagaacaccgagccttgtgtggggggtgnagtctcac 360
ccagattctgcattaccaganagccgtggcaaaaganattgacaactcgcccaggnngaa 420
aaagaacacctcctggaagtgctngccgctcctcgtccnttggtggnngcgcntnccttt 480.
t 481
<210> 86
<211> 472
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (472)
<223> n = A,T,C or G
<400>
86
aacatcttcctgtataatgctgtgtaatatcgatccgatnttgtctgctgagaattcatt 60
acttggaaaagcaacttnaagcctggacactggtattaaaattcacaatatgcaacactt 120
taaacagtgtgtcaatctgctcccttactttgtcatcaccagtctgggaataagggtatg 180
ccctattcacacctgttaaaagggcgctaagcatttttgattcaacatctttttttttga 240
cacaagtccgaaaaaagcaaaagtaaacagttnttaatttgttagccaattcactttctt 300
catgggacagagccatttgatttaaaaagcaaattgcataatattgagctttgggagctg 360
atatntgagcggaagantagcctttctacttcaccagacacaactcctttcatattggga 420
tgttnacnaaagttatgtctcttacagatgggatgcttttgtggcaattctg 472
<210> 87
<211> 413
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(413)
<223> n = A,T,C or G
<400> 87
agaaaccagt atctctnaaa acaacctctc ataccttgtg gacctaattt tgtgtgcgtg 60
tgtgtgtgcg cgcatattat atagacaggc acatcttttt tacttttgta aaagcttatg 120
cctctttggt atctatatct gtgaaagttt taatgatctg ccataatgtc ttggggacct 180
ttgtcttctg tgtaaatggt actagagaaa acacctatnt tatgagtcaa tctagttngt 240
tttattcgac atgaaggaaa tttccagatn acaacactna caaactctcc cttgactagg 300
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
32
ggggacaaag aaaagcanaa ctgaacatna gaaacaattn cctggtgaga aattncataa 360
acagaaattg ggtngtatat tgaaananng catcattnaa acgttttttt ttt 413
<210> 88
<211> 448
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(448)
<223> n = A,T,C or G
<400>
88
cgcagcgggtcctctctatctagctccagcctctcgcctgccccactccccgcgtcccgc 60
gtcctagccnaccatggccgggcccctgcgcgccccgctgctcctgctggccatcctggc 120
cgtggccctggccgtgagccccgcggccggctccagtcccggcaagccgccgcgcctggt 180
gggaggcccatggaccccgcgtggaagaagaaggtgtgcggcgtgcactggactttgccg 240
tcggcnantacaacaaacccgcaacnacttttaccnagcncgcgctgcaggttgtgccgc 300
cccaancaaattgttactnggggtaantaattcttggaagttgaacctgggccaaacnng 360
tttaccagaaccnagccaattngaacaattncccctccataacagccccttttaaaaagg 420
gaancantcctgntcttttccaaatttt 448
<210> 89
<211> 463
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(463)
<223> n = A,T,C or G
<400> 89
gaattttgtgcactggccactgtgatggaaccattgggccaggatgctttgagtttatca 60
gtagtgattctgccaaagttggtgttgtaacatgagtatgtaaaatgtcaaaaaattagc 120
agaggtctaggtctgcatatcagcagacagtttgtccgtgtattttgtagccttgaagtt 180
ctcagtgacaagttnnttctgatgcgaagttctnattccagtgttttagtcctttgcatc 240
tttnatgttnagacttgcctctntnaaattgcttttgtnttctgcaggtactatctgtgg 300
tttaacaaaatagaannacttctctgcttngaanatttgaatatcttacatctnaaaatn 360
aattctctccccatannaaaacccangcccttggganaatttgaaaaanggntccttcnn 420
aattcnnanaanttcagntntcatacaacanaacnggancccc 463
<210> 90
<211> 400
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(400)
<223> n = A,T,C or G
<400> 90
agggattgaa ggtctnttnt actgtcggac tgttcancca ccaactctac aagttgctgt 60
cttccactca ctgtctgtaa gcntnttaac ccagactgta tcttcataaa tagaacaaat 120
tcttcaccag tcacatcttc taggaccttt ttggattcag ttagtataag ctcttccact 180
tcctttgtta agacttcatc tggtaaagtc ttaagttttg tagaaaggaa tttaattgct 240
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
33
cgttctctaa caatgtcctc tccttgaagt atttggctga acaacccacc tnaagtccct 300
ttgtgcatcc attttaaata tacttaatag ggcattggtn cactaggtta aattctgcaa 360
gagtcatctg tctgcaaaag ttgcgttagt atatctgcca 400
<210> 91
<211> 480
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (480)
<223> n = A,T,C or G
<400> 91
gagctcggatccaataatctttgtctgagggcagcacacatatncagtgccatggnaact 60
ggtctaccccacatgggagcagcatgccgtagntatataaggtcattccctgagtcagac 120
atgcctctttgactaccgtgtgccagtgctggtgattctcacacacctccnnccgctctt 180
tgtggaaaaactggcacttgnctggaactagcaagacatcacttacaaattcacccacga 240
gacacttgaaaggtgtaacaaagcgactcttgcattgctttttgtccctccggcaccagt 300
tgtcaatactaacccgctggtttgcctccatcacatttgtgatctgtagctctggataca 360
tctcctgacagtactgaagaacttcttcttttgtttcaaaagcaactcttggtgcctgtt 420
ngatcaggttcccatttcccagtccgaatgttcacatggcatatnttacttcccacaaaa 480
<210> 92
<211> 477
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (477)
<223> n = A,T,C or G
<400>
92
atacagcccanatcccaccacgaagatgcgcttgttgactgagaacctgatgcggtcact 60
ggtcccgctgtagccccagcgactctccacctgctggaagcggttgatgctgcactcctt 120
cccacgcaggcagcagcggggccggtcaatgaactccactcgtggcttggggttgacggt 180
taantgcaggaagaggctgaccacctcgcggtccaccaggatgcccgactgtgcgggacc 240
tgcagcgaaactcctcgatggtcatgagcgggaagcgaatgangcccagggccttgccca 300
gaaccttccgcctgttctctggcgtcacctgcagctgctgccgctnacactcggcctcgg 360
accagcggacaaacggcgttgaacagccgcacctcacggatgcccantgtgtcgcgctcc 420
aggaacggcnccagcgtgtccaggtcaatgtcggtgaancctccgcgggtaatggcg 477
<210> 93
<211> 377
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (377)
<223> n = A,T,C or G
<400> 93
gaacggctgg accttgcctc gcattgtgct gctggcagga ataccttggc aagcagctcc 60
agtccgagca gccccagacc gctgccgccc gaagctaagc ctgcctctgg ccttcccctc 120
cgcctcaatg cagaaccant agtgggagca ctgtgtttag agttaagagt gaacactgtn 180
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
34
tgattttact tgggaatttc ctctgttata tagcttttcc caatgctaat ttccaaacaa 240
caacaacaaa ataacatgtt tgcctgttna gttgtataaa agtangtgat tctgtatnta 300
aagaaaatat tactgttaca tatactgctt gcaanttctg tatttattgg tnctctggaa 360
ataaatatat tattaaa 377
<210> 94
<211> 495
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(495)
<223> n = A,T,C or G
<400> 94
ccctttgaggggttagggtccagttcccagtggaagaaacaggccaggagaantgcgtgc 60
cgagctgangcagatttcccacagtgaccccagagccctgggctatagtctctgacccct 120
ccaaggaaagaccaccttctggggacatgggctggagggcaggacctagaggcaccaagg 180
gaaggccccattccggggctgttccccgaggaggaagggaaggggctctgtgtgcccccc 240
acgaggaanaggccctgantcctgggatcanacaccccttcacgtgtatccccacacaaa 300
tgcaagctcaccaaggtcccctctcagtcccttccctacaccctgaacggncactggccc 360
acacccacccagancanccacccgccatggggaatgtnctcaaggaatcgcngggcaacg 420
tggactctngtcccnnaagggggcagaatctccaatagangganngaacccttgctnana 480
aaaaaaaanaaaaaa - 495
<210> 95
<211> 4'72
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (472)
<223> n = A,T,C or G
<400>
95
ggttacttggtttcattgccaccacttagtggatgtcatttagaaccattttgtctgctc 60
cctctggaagccttgcgcagagcggactttgtaattgttggagaataactgctgaatttt 120
tagctgttttgagttgattcgcaccactgcaccacaactcaatatgaaaactatttnact 180
tatttattatcttgtgaaaagtatacaatgaaaattttgttcatactgtatttatcaagt 240
atgatgaaaagcaatagatatatattcttttattatgttnaattatgattgccattatta 300
atcggcaaaatgtggagtgtatgttcttttcacagtaatatatgccttttgtaacttcac 360
ttggttattttattgtaaatgaattacaaaattcttaatttaagaaaatggtangttata 420
tttanttcantaatttctttccttgtttacgttaattttgaaaagaatgcat 472
<210> 96
<211> 476
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(476)
<223> n = A,T,C or G
<400> 96
ctgaagcatt tcttcaaact tntctacttt tgtcattgat acctgtagta agttgacaat 60
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
gtggtgaaatttcaaaattatatgtaacttctactagttttactttctcccccaagtctt 120
ttttaactcatgatttttacacacacaatccagaacttattatatagcctctaagtcttt 180
attcttcacagtagatgatgaaagagtcctccagtgtcttgngcanaatgttctagntat 240
agctggatacatacngtgggagttctataaactcatacctcagtgggactnaaccaaaat 300
tgtgttagtctcaattcctaccacactgagggagcctcccaaatcactatattcttatct 360
gcaggtactcctccagaaaaacngacagggcaggcttgcatgaaaaagtnacatctgcgt 420
tacaaagtctatcttcctcanangtctgtnaaggaacaatttaatcttctagcttt 476
<210> 97
<211> 479
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (479)
<223> n = A,T,C or G
<400>
97
actctttctaatgctgatatgatcttgagtataagaatgcatatgtcactagaatggata 60
aaataatgctgcaaacttaatgttcttatgcaaaatggaacgctaatgaaacacagctta 120
caatcgcaaatcaaaactcacaagtgctcatctgttgtagatttagtgtaataagactta 180
gattgtgctccttcggatatgattgtttctcanatcttgggcaatnttccttagtcaaat 240
caggctactagaattctgttattggatatntgagagcatgaaatttttaanaatacactt 300
gtgattatnaaattaatcacaaatttcacttatacctgctatcagcagctagaaaaacat 360
ntnntttttanatcaaagtattttgtgtttggaantgtnnaaatgaaatctgaatgtggg 420
ttcnatcttattttttcccngacnactanttncttttttagggnctattctganccatc 479
<210> 98
<211> 461
<212> DNA
<213> Homo sapien
<400> 98
agtgacttgtcctccaacaaaaccccttgatcaagtttgtggcactgacaatcagaccta 60
tgctagttcctgtcatctattcgctactaaatgcagactggaggggaccaaaaaggggca 120
tcaactccagctggattattttggagcctgcaaatctattcctacttgtacggactttga 180
agtgattcagtttcctctacggatgagagactggctcaagaatatcctcatgcagcttta 240
tgaagccactctgaacacgctggttatctagatgagaacagagaaataaagtcagaaaat 300
ttacctggagaaaagaggctttggctggggaccatcccattgaaccttctcttaaggact 360
ttaagaaaaactaccacatgttgtgtatcctggtgccggccgtttatgaactgaccaccc 420
tttggaataatcttgacgctcctgaacttgctcctctgcga 461
<210> 99
<211> 171
<212> DNA
<213> Homo sapien
<400> 99
gtggccgcgc gcaggtgttt cctcgtaccg cagggccccc tcccttcccc aggcgtccct 60
cggcgcctct gcgggcccga ggaggagcgg ctggcgggtg gggggagtgt gacccaccct 120
cggtgagaaa agccttctct agcgatctga gaggcgtgcc ttgggggtac c 171
<210> 100
<211> 269
<212> DNA
<213> Homo sapien
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
36
<400> loo
cggccgcaag tgcaactcca gctggggccg tgcggacgaa gattctgcca gcagttggtc 60
cgactgcgac gacggcggcg gcgacagtcg caggtgcagc gcgggcgcct ggggtcttgc 120
aaggctgagc tgacgccgca gaggtcgtgt cacgtcccac gaccttgacg ccgtcgggga 180
cagccggaac agagcccggt gaagcgggag gcctcgggga gcccctcggg aagggcggcc 240
cgagagatac gcaggtgcag gtggccgcc 269
<210> 101
<211> 405
<212> DNA
<213> Homo sapien
<400>
101
ttttttttttttttggaatctactgcgagcacagcaggtcagcaacaagtttattttgca 60
gctagcaaggtaacagggtagggcatggttacatgttcaggtcaacttcctttgtcgtgg 120
ttgattggtttgtctttatgggggcggggtggggtaggggaaacgaagcaaataacatgg 180
agtgggtgcaccctccctgtagaacctggttacaaagcttggggcagttcacctggtctg 240
tgaccgtcattttcttgacatcaatgttattagaagtcaggatatcttttagagagtcca 300
ctgttctggagggagattagggtttcttgccaaatccaacaaaatccactgaaaaagttg 360
gatgatcagtacgaataccgaggcatattctcatatcggtggcca 405
<210> 102
<211> 470
<212> DNA
<213> Homo sapien
<400> 102
tttttttttttttttttttttttttttttttttttttttttttttttttttttttttttt 60
ggcacttaatccatttttatttcaaaatgtctacaaatttaatcccattatacggtattt 120
tcaaaatctaaattattcaaattagccaaatccttaccaaataatacccaaaaatcaaaa 180
atatacttctttcagcaaacttgttacataaattaaaaaaatatatacggctggtgtttt 240
caaagtacaattatcttaacactgcaaacattttaaggaactaaaataaaaaaaaacact 300
ccgcaaaggttaaagggaacaacaaattcttttacaacaccattataaaaatcatatctc 360
aaatcttaggggaatatatacttcacacgggatcttaacttttactcactttgtttattt 420
ttttaaaccattgtttgggcccaacacaatggaatcccccctggactagt 470
<210> 103
<211> 581
<212> DNA
<213> Homo sapien
<400> 103
ttttttttttttttttttgacccccctcttataaaaaacaagttaccattttattttact 60
tacacatatttattttataattggtattagatattcaaaaggcagcttttaaaatcaaac 120
taaatggaaactgccttagatacataattcttaggaattagcttaaaatctgcctaaagt 180
gaaaatcttctctagctcttttgactgtaaatttttgactcttgtaaaacatccaaattc 240
atttttcttgtctttaaaattatctaatctttccattttttccctattccaagtcaattt 300
gcttctctagcctcatttcctagctcttatctactattagtaagtggcttttttcctaaa 360
agggaaaacaggaagagaaatggcacacaaaacaaacattttatattcatatttctacct 420
acgttaataaaatagcattttgtgaagccagctcaaaagaaggcttagatccttttatgt 480
ccattttagtcactaaacgatatcaaagtgccagaatgcaaaaggtttgtgaacatttat 540
tcaaaagctaatataagatatttcacatactcatctttctg 581
<210> 104
<211> 578
<212> DNA
<213> Homo sapien
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
37
<400> 104
tttttttttttttttttttttttttctcttctttttttttgaaatgaggatcgagttttt 60
cactctctagatagggcatgaagaaaactcatctttccagctttaaaataacaatcaaat 120
ctcttatgctatatcatattttaagttaaactaatgagtcactggcttatcttctcctga 180
aggaaatctgttcattcttctcattcatatagttatatcaagtactaccttgcatattga 240
gaggtttttcttctctatttacacatatatttccatgtgaatttgtatcaaacctttatt 300
ttcatgcaaactagaaaataatgtttcttttgcataagagaagagaacaatatagcatta 360
caaaactgctcaaattgtttgttaagttatccattataattagttggcaggagctaatac 420
aaatcacatttacgacagcaataataaaactgaagtaccagttaaatatccaaaataatt 480
aaaggaacatttttagcctgggtataattagctaattcactttacaagcatttattagaa 540
tgaattcacatgttattattcctagcccaacacaatgg 578
<210> 105
<211> 538
<212> DNA
<213> Homo sapien
<400>
105
tttttttttttttttcagtaataatcagaacaatatttatttttatatttaaaattcata 60
gaaaagtgccttacatttaataaaagtttgtttctcaaagtgatcagaggaattagatat 120
gtcttgaacaccaatattaatttgaggaaaatacaccaaaatacattaagtaaattattt 180
aagatcatagagcttgtaagtgaaaagataaaatttgacctcagaaactctgagcattaa 240
aaat.ccactattagcaaataaattactatggacttcttgctttaattttgtgatgaatat 300
ggggtgtcactggtaaaccaacacattctgaaggatacattacttagtgatagattctta~360
tgtactttgctaatacgtggatatgagttgacaagtttctctttcttcaatcttttaagg 420
ggcgagaaatgaggaagaaaagaaaaggattacgcatactgttctttctatggaaggatt 480
agatatgtttcctttgccaatattaaaaaaataataatgtttactactagtgaaaccc 538
.
<210> 106
<211> 473
<212> DNA
<213> Homo sapien
<400> 106
ttttttttttttttttagtcaagtttctatttttattataattaaagtcttggtcatttc 60
atttattagctctgcaacttacatatttaaattaaagaaacgttttagacaactgtacaa 120
tttataaatgtaaggtgccattattgagtaatatattcctccaagagtggatgtgtccct 180
tctcccaccaactaatgaacagcaacattagtttaattttattagtagatatacactgct 240
gcaaacgctaattctcttctccatccccatgtgatattgtgtatatgtgtgagttggtag 300
aatgcatcacaatctacaatcaacagcaagatgaagctaggctgggctttcggtgaaaat 360
agactgtgtctgtctgaatcaaatgatctgacctatcctcggtggcaagaactcttcgaa 420
ccgcttcctcaaaggcgctgccacatttgtggctctttgcacttgtttcaaaa 473
<210> 107
<211> 1621
<212> DNA
<213> Homo sapien
<400>
107
cgccatggcactgcagggcatctcggtcatggagctgtccggcctggccccgggcccgtt 60
ctgtgctatggtcctggctgacttcggggcgcgtgtggtacgcgtggaccggcccggctc 120
ccgctacgacgtgagccgcttgggccggggcaagcgctcgctagtgctggacctgaagca 180
gccgcggggagccgccgtgctgcggcgtctgtgcaagcggtcggatgtgctgctggagcc 240
cttccgccgcggtgtcatggagaaactccagctgggcccagagattctgcagcgggaaaa 300
tccaaggcttatttatgccaggctgagtggatttggccagtcaggaagcttctgccggtt 360
agctggccacgatatcaactatttggctttg~tcaggtgttctctcaaaaattggcagaag 420
tggtgagaatccgtatgccccgctgaatctcctggctgactttgctggtggtggccttat 480
gtgtgcactgggcattataatggctctttttgaccgcacacgcactgacaagggtcaggt 540
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
38
cattgatgcaaatatggtggaaggaacagcatatttaagttcttttctgtggaaaactca600
gaaatcgagtctgtgggaagcacctcgaggacagaacatgttggatggtggagcaccttt660
ctatacgacttacaggacagcagatggggaattcatggctgttggagcaatagaacccca720
gttctacgagctgctgatcaaaggacttggactaaagtctgatgaacttcccaatcagat780
gagcatggatgattggccagaaatgaagaagaagtttgcagatgtatttgcaaagaagac840
gaaggcagagtggtgtcaaatctttgacggcacagatgcctgtgtgactccggttctgac900
ttttgaggaggttgttcatcatgatcacaacaaggaacggggctcgtttatcaccagtga960
ggagcaggacgtgagcccccgccctgcacctctgctgttaaacaccccagccatcccttc1020
tttcaaaagggatcctttcataggagaacacactgaggagatacttgaagaatttggatt1080
cagccgcgaagagatttatcagcttaactcagataaaatcattgaaagtaataaggtaaa1140
agctagtctctaacttccaggcccacggctcaagtgaatttgaatactgcatttacagtg1200
tagagtaacacataacattgtatgcatggaaacatggaggaacagtattacagtgtccta1260
ccactctaatcaagaaaagaattacagactctgattctacagtgatgattgaattctaaa1320
aatggttatcattagggcttttgatttataaaactttgggtacttatactaaattatggt1380
agttattctgccttccagtttgcttgatatatttgttgatattaagattcttgacttata1440
ttttgaatgggttctagtgaaaaaggaatgatatattcttgaagacatcgatatacattt1500
atttacactcttgattctacaatgtagaaaatgaggaaatgccacaaattgtatggtgat1560
aaaagtcacgtgaaacaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa1620
a 1621
<210> 108
<211> 382
<212> PRT
<213> Homo-sapien
<400> 108
Met Ala Leu Gln Gly Ile Ser Val Met Glu Leu Ser Gly Leu Ala Pro
1 5 10 15
Gly Pro Phe Cys Ala Met Val Leu Ala Asp Phe Gly Ala Arg Val Val
20 25 30
Arg Val Asp Arg Pro Gly Ser Arg Tyr Asp Val Ser Arg Leu Gly Arg
35 40 45
Gly hys Arg Ser Leu Val Leu Asp Leu Lys Gln Pro Arg Gly Ala Ala
50 55 60
Val Leu Arg Arg Leu Cys Lys Arg Ser Asp Val Leu Leu Glu Pro Phe
65 70 75 80
Arg Arg Gly Val Met Glu Lys Leu Gln Leu Gly Pro Glu Ile Leu Gln
85 90 95
Arg Glu Asn Pro Arg Leu Ile Tyr Ala Arg Leu Ser Gly Phe Gly Gln
100 105 110
Ser Gly Ser Phe Cys Arg Leu Ala Gly His Asp Ile Asn Tyr Leu Ala
115 120 125
Leu Ser Gly Val Leu Ser Lys Ile Gly Arg Ser Gly Glu Asn Pro Tyr
130 135 140
Ala Pro Leu Asn Leu Leu Ala Asp Phe Ala Gly Gly Gly Leu Met Cys
145 150 155 160
Ala Leu Gly Ile Ile Met Ala Leu Phe Asp Arg Thr Arg Thr Asp Lys
165 170 175
Gly Gln Val Ile Asp Ala Asn Met Val Glu Gly Thr Ala Tyr Leu Ser
180 185 190
Ser Phe Leu Trp Lys Thr Gln Lys Ser Ser Leu Trp Glu Ala Pro Arg
195 200 205
Gly Gln Asn Met Leu Asp Gly Gly Aha Pro Phe Tyr Thr Thr Tyr Arg
210 215 220
Thr Ala Asp Gly Glu Phe Met Ala Val Gly Ala Ile Glu Pro Gln Phe
225 230 235 240
Tyr Glu Leu Leu Ile Lys Gly Leu Gly Leu Lys Ser Asp Glu Leu Pro
245 250 255
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
39
Asn Gln Met Ser Met Asp Asp Trp Pro Glu Met Lys Lys Lys Phe Ala
260 265 270
Asp Val Phe Ala Lys Lys Thr Lys Ala Glu Trp Cys Gln Ile Phe Asp
275 280 285
Gly Thr Asp Ala Cys Val Thr Pro Val Leu Thr Phe Glu Glu Val Val
290 295 300
His His Asp His Asn Lys Glu Arg Gly Ser Phe Ile Thr Ser Glu Glu
305 310 315 320
Gln Asp Val Ser Pro Arg Pro Ala Pro Leu Leu Leu Asn Thr Pro Ala
325 330 335
Ile Pro Ser Phe Lys Arg Asp Pro Phe Ile Gly Glu His Thr Glu Glu
340 345 350
Ile Leu Glu Glu Phe Gly Phe Ser Arg Glu Glu Ile Tyr Gln Leu Asn
355 360 365
Ser Asp Lys Ile Ile Glu Ser Asn Lys Val Lys Ala Ser Leu
370 375 380
<210> 109
<211> 1524
<212> DNA
<213> Homo sapien
<400>
109
ggcacgaggctgcgccagggcctgagcggaggcgggggcagcctcgccagcgggggcccc60
gggcctggccatgcctcactgagccagcgcctgcgcctctacctcgccgacagctggaac120
cagtgcgacctagtggctctcacctgcttcctcctgggcgtgggctgccggctgaccccg180
ggtttgtaccacctgggccgcactgtcctctgcatcgacttcatggttttcacggtgcgg240
ctgcttcacatcttcacggtcaacaaacagctggggcccaagatcgtcatcgtgagcaag300
atgatgaaggacgtgttcttcttcctcttcttcctcggcgtgtggctggtagcctatggc360
gtggccacggaggggctcctgaggccacgggacagtgacttcccaagtatcctgcgccgc420
gtcttctacc.gtccctacctgcagatcttcgggcagattccccaggaggacatggacgtg480
gccctcatggagcacagcaactgctcgtcggagcccggcttctgggcacaccctcctggg540
gcccaggcgggcacctgcgtctcccagtatgccaactggctggtggtgctgctcctcgtc600
atcttcctgctcgtggccaacatcctgctggtcaacttgctcattgccatgttcagttac660
acattcggcaaagtacagggcaacagcgatctctactggaaggcgcagcgttaccgcctc720
atccgggaattccactctcggcccgcgctggccccgccctttatcgtcatctcccacttg780
cgcctcctgctcaggcaattgtgcaggcgaccccggagcccccagccgtcctccccggcc840
ctcgagcatttccgggtttacctttctaaggaagccgagcggaagctgctaacgtgggaa900
tcggtgcataaggagaactttctgctggcacgcgctagggacaagcgggagagcgactcc960
gagcgtctgaagcgcacgtcccagaaggtggacttggcactgaaacagctgggacacatc1020
cgcgagtacgaacagcgcctgaaagtgctggagcgggaggtccagcagtgtagccgcgtc1080
ctggggtgggtggccgaggccctgagccgctctgccttgctgcccccaggtgggccgcca1140
ccccctgacctgcctgggtccaaagactgagccctgctggcggacttcaaggagaagccc1200
ccacaggggattttgctcctagagtaaggctcatctgggcctcggcccccgcacctggtg1260
gccttgtccttgaggtgagccccatgtccatctgggccactgtcaggaccacctttggga1320
gtgtcatccttacaaaccacagcatgcccggctcctcccagaaccagtcccagcctggga1380
ggatcaaggcctggatcccgggccgttatccatctggaggctgcagggtccttggggtaa1440
cagggaccacagacccctcaccactcacagattcctcacactggggaaataaagccattt1500
cagaggaaaaaaaaaaaaaaaaaa 1524
<210> 110
<211> 3410
<212> DNA
<213> Homo sapien
<400> 110
gggaaccagc ctgcacgcgc tggctccggg tgacagccgc gcgcctcggc caggatctga 60
gtgatgagac gtgtccccac tgaggtgccc cacagcagca ggtgttgagc atgggctgag 120
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
aagctggaccggcaccaaagggctggcagaaatgggcgcctggctgattcctaggcagtt180
ggcggcagcaaggaggagaggccgcagcttctggagcagagccgagacgaagcagttctg240
gagtgcctgaacggccccctgagccctacccgcctggcccactatggtccagaggctgtg300
ggtgagccgcctgctgcggcaccggaaagcccagctcttgctggtcaacctgctaacctt360
tggcctggaggtgtgtttggccgcaggcatcacctatgtgccgcctctgctgctggaagt420
gggggtagaggagaagttcatgaccatggtgctgggcattggtccagtgctgggcctggt480
ctgtgtcccgctcctaggctcagccagtgaccactggcgtggacgctatggccgccgccg540
gcccttcatctgggcactgtccttgggcatcctgctgagcctctttctcatcccaagggc600
cggctggctagcagggctgctgtgcccggatcccaggcccctggagctggcactgctcat660
cctgggcgtggggctgctggacttctgtggccaggtgtgcttcactccactggaggccct720
gctctctgacctcttccgggacccggaccactgtcgccaggcctactctgtctatgcctt780
catgatcagtcttgggggctgcctgggctacctcctgcctgccattgactgggacaccag840
tgccctggccccctacctgggcacccaggaggagtgcctctttggcctgctcaccctcat900
cttcctcacctgcgtagcagccacactgctggtggctgaggaggcagcgctgggccccac960
cgagccagcagaagggctgtcggccccctccttgtcgccccactgctgtccatgccgggc1020
ccgcttggctttccggaacctgggcgccctgcttccccggctgcaccagctgtgctgccg1080
catgccccgcaccctgcgccggctcttcgtggctgagctgtgcagctggatggcactcat1140
gaccttcacgctgttttacacggatttcgtgggcgaggggctgtaccagggcgtgcccag1200
agctgagccgggcaccgaggcccggagacactatgatgaaggcgttcggatgggcagcct1260
ggggctgttcctgcagtgcgccatctccctggtcttctctctggtcatggaccggctggt1320
gcagcgattcggcactcgagcagtctatttggccagtgtggcagctttccctgtggctgc1380
cggtgccacatgcctgtcccacagtgtggccgtggtgacagcttcagccgccctcaccgg1440
gttcaccttctcagccctgcagatcctgccctacacactggcctccctctaccaccggga1500
gaagcaggtgttcctgcccaaataccgaggggacactggaggtgctagcagtgaggacag1560
cctgatgaccagcttcctgccaggccctaagcctggagctcccttccctaatggacacgt1620
.
gggtgctggaggcagtggcctgctcccacctccacccgcgctctgcggggcctctgcctg1680
tgatgtctccgtacgtgtggtggtgggtgagcccaccgaggccagggtggttccgggccg1740
gggcatctgcctggacctcgccatcctggatagtgccttcctgctgtcccaggtggcccc1800
.
atccctgtttatgggctccattgtccagctcagccagtctgtcactgcctatatggtgtc1860:
tgccgcaggcctgggtctggtcgccatttactttgctacacaggtagtatttgacaagag1920
cgacttggccaaatactcagcgtagaaaacttccagcacattggggtggagggcctgcct1980.
cactgggtcccagctccccgctcctgttagccccatggggctgccgggctggccgccagt2040
ttctgttgctgccaaagtaatgtggctctctgctgccaccctgtgctgctgaggtgcgta2100_
gctgcacagctgggggctggggcgtccctctcctctctccccagtctctagggctgcctg2160
actggaggccttccaagggggtttcagtctggacttatacagggaggccagaagggctcc2220
atgcactggaatgcggggactctgcaggtggattacccaggctcagggttaacagctagc2280
ctcctagttgagacacacctagagaagggtttttgggagctgaataaactcagtcacctg2340
gtttcccatctctaagccccttaacctgcagcttcgtttaatgtagctcttgcatgggag2400
tttctaggatgaaacactcctccatgggatttgaacatatgacttatttgtaggggaaga2460
gtcctgaggggcaacacacaagaaccaggtcccctcagcccacagcactgtctttttgct2520
gatccacccccctcttaccttttatcaggatgtggcctgttggtccttctgttgccatca2580
cagagacacaggcatttaaatatttaacttatttatttaacaaagtagaagggaatccat2640
tgctagcttttctgtgttggtgtctaatatttgggtagggtgggggatccccaacaatca2700
ggtcccctgagatagctggtcattgggctgatcattgccagaatcttcttctcctggggt2760
ctggccccccaaaatgcctaacccaggaccttggaaattctactcatcccaaatgataat2820
tccaaatgctgttacccaaggttagggtgttgaaggaaggtagagggtggggcttcaggt2880
ctcaacggcttccctaaccacccctcttctcttggcccagcctggttccccccacttcca2940
ctcccctctactctctctaggactgggctgatgaaggcactgcccaaaatttcccctacc3000
cccaactttcccctacccccaactttccccaccagctccacaaccctgtttggagctact3060
gcaggaccagaagcacaaagtgcggtttcccaagcctttgtccatctcagcccccagagt3120
atatctgtgcttggggaatctcacacagaaactcaggagcaccccctgcctgagctaagg3180
gaggtcttatctctcagggggggtttaagtgccgtttgcaataatgtcgtcttatttatt3240
tagcggggtgaatattttatactgtaagtgagcaatcagagtataatgtttatggtgaca3300
aaattaaaggctttcttatatgtttaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa3360
aaaaaaaaraaaaaaaaaaaaaaaaaaaaaaaaaaaataaaaaaaaaaaa 3410
<210> 111
<211> 1289
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
41
<212> DNA
<213> Homo sapien
<400>
111
agccaggcgtccctctgcctgcccactcagtggcaacacccgggagctgttttgtccttt60
gtggagcctcagcagttccctctttcagaactcactgccaagagccctgaacaggagcca120
ccatgcagtgcttcagcttcattaagaccatgatgatcctcttcaatttgctcatctttc180
tgtgtggtgcagccctgttggcagtgggcatctgggtgtcaatcgatggggcatcctttc240
tgaagatcttcgggccactgtcgtccagtgccatgcagtttgtcaacgtgggctacttcc300
tcatcgcagccggcgttgtggtctttgctcttggtttcctgggctgctatggtgctaaga360
ctgagagcaagtgtgccctcgtgacgttcttcttcatcctcctcctcatcttcattgctg420
aggttgcagctgctgtggtcgccttggtgtacaccacaatggctgagcacttcctgacgt480
tgctggtagtgcctgccatcaagaaagattatggttcccaggaagacttcactcaagtgt540
ggaacaccaccatgaaagggctcaagtgctgtggcttcaccaactatacggattttgagg600
actcaccctacttcaaagagaacagtgcctttcccccattctgttgcaatgacaacgtca660
ccaacacagccaatgaaacctgcaccaagcaaaaggctcacgaccaaaaagtagagggtt720
gcttcaatcagcttttgtatgacatccgaactaatgcagtcaccgtgggtggtgtggcag780
ctggaattgggggcctcgagctggctgccatgattgtgtccatgtatctgtactgcaatc840
tacaataagtccacttctgcctctgccactactgctgccacatgggaactgtgaagaggc900
accctggcaagcagcagtgattgggggaggggacaggatctaacaatgtcacttgggcca960
gaatggacctgccctttctgctccagacttggggctagatagggaccactccttttagcg1020
atgcctgactttccttccattggtgggtggatgggtggggggcattccagagcctctaag1080
gtagccagttctgttgcccattcccccagtctattaaacccttgatatgccccctaggcc1140
tagtggtgatcccagtgctctactgggggatgagagaaaggcattttatagcctgggcat1200
aagtgaaatcagcagagcctctgggtggatgtgtagaaggcacttcaaaatgcataaacc1260
tgttacaatgttaaaaaaaaaaaaaaaaa 1289
<210> 112
<211> 315
<212> PRT
<213> Homo sapien
<400> 112
Met Val Phe Thr Val Arg Leu Leu His Ile Phe Thr Val Asn Lys Gln
1 5 10 15
Leu Gly Pro Lys Ile Val Ile Val Ser Lys Met Met Lys Asp Val Phe
20 25 30
Phe Phe Leu Phe Phe Leu Gly Val Trp Leu Val Ala Tyr Gly Val Ala
35 40 45
Thr Glu Gly Leu Leu Arg Pro Arg Asp Ser Asp Phe Pro Ser Ile Leu
50 55 60
Arg Arg Val Phe Tyr Arg Pro Tyr Leu Gln Ile Phe Gly Gln Ile Pro
65 70 75 80
Gln Glu Asp Met Asp Val Ala Leu Met Glu His Ser Asn Cys Ser Ser
85 90 95
Glu Pro Gly Phe Trp Ala His Pro Pro Gly Ala Gln Ala Gly Thr Cys
100 105 110
Val Ser Gln Tyr Ala Asn Trp Leu Val Val Leu Leu Leu Val Ile Phe
115 120 125
Leu Leu Val Ala Asn Ile Leu Leu Val Asn Leu Leu Ile Ala Met Phe
130 135 140
Ser Tyr Thr Phe Gly Lys Val Gln Gly Asn Ser Asp Leu Tyr Trp Lys
145 150 155 160
Ala Gln Arg Tyr Arg Leu Ile Arg Glu Phe His Ser Arg Pro Ala Leu
165 170 175
Ala Pro Pro Phe Ile Val Ile Ser His Leu Arg Leu Leu Leu Arg Gln
180 185 190
Leu Cys Arg Arg Pro Arg Ser Pro Gln Pro Ser Ser Pro Ala Leu Glu
CA 02391369 2002-05-10
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42
195 200 205
His Phe Arg Val Tyr Leu Ser Lys Glu Ala Glu Arg Lys Leu Leu Thr
210 215 220
Trp Glu Ser Val His Lys Glu Asn Phe Leu Leu Ala Arg Ala Arg Asp
225 230 235 240
Lys Arg Glu Ser Asp Ser Glu Arg Leu Lys Arg Thr Ser Gln Lys Val
245 250 255
Asp Leu Ala Leu Lys Gln Leu Gly His Ile Arg Glu Tyr Glu Gln Arg
260 265 270
Leu Lys Val Leu Glu Arg Glu Val Gln Gln Cys Ser Arg Val Leu Gly
275 280 285
Trp Val Ala Glu Ala Leu Ser Arg Ser Ala Leu Leu Pro Pro Gly Gly
290 295 300
Pro Pro Pro Pro Asp Leu Pro Gly Ser Lys Asp
305 310 315
<210> 113
<211> 553
<212> PRT
<213> Homo sapien
<400> 113
Met Val Gln Arg Leu Trp Val Ser Arg Leu Leu Arg His Arg Lys Ala
1 5 10 15
Gln Leu Leu Leu Val Asn Leu Leu Thr Phe Gly Leu Glu Val Cys Leu
20 25 30
Ala Ala Gly Ile Thr Tyr Val Pro Pro Leu Leu Leu Glu Val Gly Val
35 40 45
Glu Glu Lys Phe Met Thr Met Val Leu Gly Ile Gly Pro Val Leu Gly
50 55 60
Leu Val Cys Val Pro Leu Leu Gly Ser Ala Ser Asp His Trp Arg Gly
65 70 75 80
Arg Tyr Gly Arg Arg Arg Pro Phe Ile Trp Ala Leu Ser Leu Gly Ile
85 90 95
Leu Leu Ser Leu Phe Leu Ile Pro Arg Ala Gly Trp Leu Ala Gly Leu
100 105 110
Leu Cys Pro Asp Pro Arg Pro Leu Glu Leu Ala Leu Leu Ile Leu Gly
115 120 125
Val Gly Leu Leu Asp Phe Cys Gly Gln Val Cys Phe Thr Pro Leu Glu
130 135 140
Ala Leu Leu Ser Asp Leu Phe Arg Asp Pro Asp His Cys Arg Gln Ala
145 150 155 160
Tyr Ser Val Tyr Ala Phe Met Ile Ser Leu Gly Gly Cys Leu Gly Tyr
165 170 175
Leu Leu Pro Ala Ile Asp Trp Asp Thr Ser Ala Leu Ala Pro Tyr Leu
180 185 190
Gly Thr Gln Glu Glu Cys Leu Phe Gly Leu Leu Thr Leu Ile Phe Leu
195 200 205
Thr Cys Val Ala Ala Thr Leu Leu Val Ala Glu Glu Ala Ala Leu Gly
210 215 220
Pro Thr Glu Pro Ala Glu Gly Leu Ser Ala Pro Ser Leu Ser Pro His
225 230 235 240
Cys Cys Pro Cys Arg Ala Arg Leu Ala Phe Arg Asn Leu Gly Ala Leu
245 250 255
Leu Pro Arg Leu His Gln Leu Cys Cys Arg Met Pro Arg Thr Leu Arg
260 265 270
Arg Leu Phe Val Ala Glu Leu Cys Ser Trp Met Ala Leu Met Thr Phe
275 280 285
CA 02391369 2002-05-10
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43
Thr Leu Phe Tyr Thr Asp Phe Val Gly Glu Gly Leu Tyr Gln Gly Val
290 295 300
Pro Arg Ala Glu Pro Gly Thr Glu Ala Arg Arg His Tyr Asp Glu Gly
305 310 315 320
Val Arg Met Gly Ser Leu Gly Leu Phe Leu Gln Cys Ala Ile Ser Leu
325 330 335
Val Phe Ser Leu Val Met Asp Arg Leu Val Gln Arg Phe Gly Thr Arg
340 345 350
Ala Val Tyr Leu Ala Ser Val Ala Ala Phe Pro Val Ala Ala Gly Ala
355 360 365
Thr Cys Leu Ser His Ser Val Ala Val Val Thr Ala Ser Ala Ala Leu
370 375 380
Thr Gly Phe Thr Phe Ser Ala Leu Gln Ile Leu Pro Tyr Thr Leu Ala
385 390 395 400
Ser Leu Tyr His Arg Glu Lys Gln Val Phe Leu Pro Lys Tyr Arg Gly
405 410 415
Asp Thr Gly Gly Ala Ser Ser Glu Asp Ser Leu Met Thr Ser Phe Leu
420 425 430
Pro Gly Pro Lys Pro Gly Ala Pro Phe Pro Asn Gly His Val Gly Ala
435 440 445
Gly Gly Ser Gly Leu Leu Pro Pro Pro Pro Ala Leu Cys Gly Ala Ser
450 455 460
Ala Cys Asp Val Ser Val Arg Val Val Val Gly Glu Pro Thr Glu Ala
465 470 475 480
Arg Val Val Pro Gly Arg Gly Ile Cys Leu Asp Leu Ala Ile Leu Asp
485 490 495
Ser Ala Phe Leu Leu Ser Gln Val Ala Pro Ser Leu Phe Met Gly Ser
500 505 510
Ile Val Gln Leu Ser Gln Ser Val Thr Ala Tyr Met Val Ser Ala Ala
515 520 525
Gly Leu Gly Leu Val Ala Ile Tyr Phe Ala Thr Gln Val Val Phe Asp
530 535 540
Lys Ser Asp Leu Ala Lys Tyr Ser Ala
545 550
<210> 114
<211> 241
<212> PRT
<213> Homo sapien
<400> 114
Met Gln Cys Phe Ser Phe Ile Lys Thr Met Met Ile Leu Phe Asn Leu
1 5 10 15
Leu Ile Phe Leu Cys Gly Ala Ala Leu Leu Ala Val Gly Ile Trp Val
20 25 30
Ser Ile Asp Gly Ala Ser Phe Leu Lys Ile Phe Gly Pro Leu Ser Ser
35 40 45
Ser Ala Met Gln Phe Val Asn Val Gly Tyr Phe Leu Ile Ala Ala Gly
50 55 60
Val Val Val Phe Ala Leu Gly Phe Leu Gly Cys Tyr Gly Ala Lys Thr
65 70 75 80
Glu Ser Lys Cys Ala Leu Val Thr Phe Phe Phe Ile Leu Leu Leu Ile
85 90 95
Phe Ile Ala Glu Val Ala Ala Ala Val Val Ala Leu Val Tyr Thr Thr
100 105 110
Met Ala Glu His Phe Leu Thr Leu Leu Val Val Pro Ala Ile Lys Lys
115 120 125
Asp Tyr Gly Ser Gln Glu Asp Phe Thr Gln Val Trp Asn Thr Thr Met
CA 02391369 2002-05-10
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44
130 135 140
Lys Gly Leu Lys Cys Cys Gly Phe Thr Asn Tyr Thr Asp Phe Glu Asp
145 150 155 160
Ser Pro Tyr Phe Lys Glu Asn Ser Ala Phe Pro Pro Phe Cys Cys Asn
165 170 175
Asp Asn Val Thr Asn Thr Ala Asn Glu Thr Cys Thr Lys Gln Lys Ala
180 185 190
His Asp Gln Lys Val Glu Gly Cys Phe Asn Gln Leu Leu Tyr Asp Ile
195 200 205
Arg Thr Asn Ala Val Thr Val Gly Gly Val Ala Ala Gly Ile Gly Gly
210 215 220
Leu Glu Leu Ala Ala Met Ile Val Ser Met Tyr Leu Tyr Cys Asn Leu
225 230 235 240
Gln
<210> 115
<211> 366
<212> DNA
<213> Homo sapien
<400>
115
gctctttctctcccctcctctgaatttaattctttcaacttgcaatttgcaaggattaca 60
catttcactgtgatgtatattgtgttgcaaaaaaaaaaaagtgtctttgtttaaaattac 120
ttggtttgtgaatccatcttgctttttccccattggaactagtcattaacccatctctga 180
~
actggtagaaaaacatctgaagagctagtctatcagcatctgacaggtgaattggatggt 240
tctcagaaccatttcacccagacagcctgtttctatcctgtttaataaattagtttgggt 300
tctctacatgcataacaaaccctgctccaatctgtcacataaaagtctgtgacttgaagt 360
ttagtc 366
<210> 116
<211> 282
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (282)
<223> n = A,T,C or G
<400> 116
acaaagatgaaccatttcctatattatagcaaaattaaaatctacccgtattctaatatt 60
gagaaatgagatnaaacacaatnttataaagtctacttagagaagatcaagtgacctcaa 120
agactttactattttcatattttaagacacatgatttatcctattttagtaacctggttc 180
atacgttaaacaaaggataatgtgaacagcagagaggatttgttggcagaaaatctatgt 240
tcaatctngaactatctanatcacagacatttctattccttt 282
<210> 117
<211> 305
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(305)
<223> n = A,T,C or G
<400> 117
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
acacatgtcgcttcactgccttcttagatgcttctggtcaacatanaggaacagggacca 60
tatttatcctccctcctgaaacaattgcaaaataanacaaaatatatgaaacaattgcaa 120
aataaggcaaaatatatgaaacaacaggtctcgagatattggaaatcagtcaatgaagga 180
tactgatccctgatcactgtcctaatgcaggatgtgggaaacagatgaggtcacctctgt 240
gactgccccagcttactgcctgtagagagtttctangctgcagttcagacagggagaaat 300
tgggt 305
<210> 118
<211> 71
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(71)
<223> n = A,T,C or G
<400> 118
accaaggtgt ntgaatctct gacgtgggga tctctgattc ccgcacaatc tgagtggaaa 60
aantcctggg t 71
<210> 119
<211> 212
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (212)
<223> n = A,T,C or G
<400> 119
actccggttg gtgtcagcag cacgtggcat tgaacatngc aatgtggagc ccaaaccaca 60
gaaaatgggg tgaaattggc caactttcta tnaacttatg ttggcaantt tgccaccaac 120
agtaagctgg cccttctaat aaaagaaaat tgaaaggttt ctcactaanc ggaattaant 180
aatggantca aganactccc aggcctcagc gt 212
<210> 120
<211> 90
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(90)
<223> n = A,T,C or G
<400> 120
actcgttgca natcaggggc cccccagagt caccgttgca ggagtccttc tggtcttgcc 60
ctccgccggc gcagaacatg ctggggtggt 90
<210> 121
<211> 218
<212> DNA
<213> Homo sapien
<220>
<221> misc feature
CA 02391369 2002-05-10
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46
<222> (1)...(218)
<223> n = A,T,C or G
<400> 121
tgtancgtga anacgacaga nagggttgtc aaaaatggag aanccttgaa gtcattttga 60
gaataagatt tgctaaaaga tttggggcta aaacatggtt attgggagac atttctgaag 120
atatncangt aaattangga atgaattcat ggttcttttg ggaattcctt tacgatngcc 180
agcatanact tcatgtgggg atancagcta cccttgta 218
<210> 122
<211> 171
<212> DNA
<213> Homo sapien
<400> 122
taggggtgta tgcaactgta aggacaaaaa ttgagactca actggcttaa ccaataaagg 60
catttgttag ctcatggaac aggaagtcgg atggtggggc atcttcagtg ctgcatgagt 120
caccaccccg gcggggtcat ctgtgccaca ggtccctgtt gacagtgcgg t 171
<210> 123
<211> 76
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (76)
<223> n = A,T,C or G
<400> 123
tgtagcgtga agacnacaga atggtgtgtg ctgtgctatc caggaacaca tttattatca 60
ttatcaanta ttgtgt 76
<210> 124
<211> 131
<212> DNA
<213> Homo sapien
<400> 124
acctttcccc aaggccaatg tcctgtgtgc taactggccg gctgcaggac agctgcaatt 60
caatgtgctg ggtcatatgg aggggaggag actctaaaat agccaatttt attctcttgg 120
ttaagatttg t 131
<210> 125
<211> 432
<212> DNA
<213> Homo sapien
<400> 125
actttatctactggctatgaaatagatggtggaaaattgcgttaccaactataccactgg 60
cttgaaaaagaggtgatagctcttcagaggacttgtgacttttgctcagatgctgaagaa 120
ctacagtctgcatttggcagaaatgaagatgaatttggattaaatgaggatgctgaagat 180
ttgcctcaccaaacaaaagtgaaacaactgagagaaaattttcaggaaaaaagacagtgg 240
ctcttgaagtatcagtcacttttgagaatgtttcttagttactgcatacttcatggatcc 300
catggtgggggtcttgcatctgtaagaatggaattgattttgcttttgcaagaatctcag 360
~
caggaaacatcagaaccactattttctagccctctgtcagagcaaacctcagtgcctctc 420
ctctttgcttgt , 432
CA 02391369 2002-05-10
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47
<210> 126
<211> 112
<212> DNA
<213> Homo sapien
<400> 126
acacaacttg aatagtaaaa tagaaactga gctgaaattt ctaattcact ttctaaccat 60
agtaagaatg atatttcccc ccagggatca ccaaatattt ataaaaattt gt 112
<210> 127
<211> 54
<212> DNA
<213> Homo sapien
<400> 127
accacgaaac cacaaacaag atggaagcat caatccactt gccaagcaca gcag 54
<210> 128
<2.11> 323
<212> DNA
<213> Homo sapien
<400>
128
acctcattagtaattgttttgttgtttcatttttttctaatgtctcccctctaccagctc 60
acctgagataacagaatgaaaatggaaggacagccagatttctcctttgctctctgctca 120
ttctctctgaagtctaggttacccattttggggacccattataggcaataaacacagttc 180
ccaaagcatttggacagtttcttgttgtgttttagaatggttttcctttttcttagcctt 240
ttcctgcaaaaggctcactcagtcccttgcttgctcagtggactgggctccccagggcct 300
aggctgccttcttttccatgtcc . 323
<210> 129
<211> 192
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(192)
<223> n = A,T,C or G
<400> 129
acatacatgt gtgtatattt ttaaatatca cttttgtatc actctgactt tttagcatac 60
tgaaaacaca ctaacataat ttntgtgaac catgatcaga tacaacccaa atcattcatc 120
tagcacattc atctgtgata naaagatagg tgagtttcat ttccttcacg ttggccaatg 180
gataaacaaa gt 192
<210> 130
<211> 362
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (362)
<223> n = A,T,C or G
<400> 130
ccctttttta tggaatgagt agactgtatg tttgaanatt tanccacaac ctctttgaca 60
CA 02391369 2002-05-10
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48
tataatgacgcaacaaaaaggtgctgtttagtcctatggttcagtttatgcccctgacaa 120
gtttccattgtgttttgccgatcttctggctaatcgtggtatcctccatgttattagtaa 180
ttctgtattccattttgttaacgcctggtagatgtaacctgctangaggctaactttata 240
cttatttaaaagctcttattttgtggtcattaaaatggcaatttatgtgcagcactttat 300
tgcagcaggaagcacgtgtgggttggttgtaaagctctttgctaatcttaaaaagtaatg 360
gg 362
<210> 131
<211> 332
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(332)
<223> n = A,T,C or G
<400> 131
ctttttgaaagatcgtgtccactcctgtggacatcttgttttaatggagtttcccatgca 60
gtangactggtatggttgcagctgtccagataaaaacatttgaagagctccaaaatgaga 120
gttctcccaggttcgccctgctgctccaagtctcagcagcagcctcttttaggaggcatc 180
ttctgaactagattaaggcagcttgtaaatctgatgtgatttggtttattatccaactaa 240
cttccatctgttatcactggagaaagcccagactccccangacnggtacggattgtgggc 300
atanaaggattgggtgaagctggcgttgtggt 332
<210> 132
<211> 322
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (322)
<223> n = A,T,C or G
<400> 132
acttttgccattttgtatatataaacaatcttgggacattctcctgaaaactaggtgtcc 60
agtggctaagagaactcgatttcaagcaattctgaaaggaaaaccagcatgacacagaat 120
ctcaaattcccaaacaggggctctgtgggaaaaatgagggaggacctttgtatctcgggt 180
tttagcaagttaaaatgaanatgacaggaaaggcttatttatcaacaaagagaagagttg 240
ggatgcttctaaaaaaaactttggtagagaaaataggaatgctnaatcctagggaagcct 300
gtaacaatctacaattggtcca 322
<210> 133
<211> 278
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(278)
<223> n = A,T,C or G
<400> 133
acaagccttc acaagtttaa ctaaattggg attaatcttt ctgtanttat ctgcataatt 60
cttgtttttc tttccatctg gctcctgggt tgacaatttg tggaaacaac tctattgcta 120
ctatttaaaa aaaatcacaa atctttccct ttaagctatg ttnaattcaa actattcctg 180
ctattcctgt tttgtcaaag aaattatatt tttcaaaata tgtntatttg tttgatgggt 240
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
49
cccacgaaac actaataaaa accacagaga ccagcctg 278
<210> 134
<211> 121
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(121)
<223> n = A,.T,C or G
<400> 134
gtttanaaaa cttgtttagc tccatagagg aaagaatgtt aaactttgta ttttaaaaca 60
tgattctctg aggttaaact tggttttcaa atgttatttt tacttgtatt ttgcttttgg 120
t 121
<210> 135
<211> 350
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(350)
<223> n = A,T,C or G
<400> 135
acttanaaccatgcctagcacatcagaatccctcaaagaacatcagtataatcctatacc 60
atancaagtggtgactggttaagcgtgcgacaaaggtcagctggcacattacttgtgtgc 120
aaacttgatacttttgttctaagtaggaactagtatacagtncctaggantggtactcca 180
gggtgccccccaactcctgcagccgctcctctgtgccagnccctgnaaggaactttcgct 240
ccacctcaatcaagccctgggccatgctacctgcaattggctgaacaaacgtttgctgag 300
ttcccaaggatgcaaagcctggtgctcaactcctggggcgtcaactcagt 350
<210> 136
<211> 399
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(399)
<223> n = A,T,C or G
<400>
136
tgtaccgtgaagacgacagaagttgcatggcagggacagggcagggccgaggccagggtt 60
gctgtgattgtatccgaatantcctcgtgagaaaagataatgagatgacgtgagcagcct 120
gcagacttgtgtctgccttcaanaagccagacaggaaggccctgcctgccttggctctga 180
cctggcggccagccagccagccacaggtgggcttcttccttttgtggtgacaacnccaag 240
aaaactgcagaggcccagggtcaggtgtnagtgggtangtgaccataaaacaccaggtgc 300
tcccaggaacccgggcaaaggccatccccacctacagccagcatgcccactggcgtgatg 360
ggtgcaganggatgaagcagccagntgttctgctgtggt 399
<210> 137
<211> 165
<212> DNA
<213> Homo sapien
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
<220>
<221> misc_feature
<222> (1). .(165)
<223> n = A,T,C or G
<400> 137
actggtgtgg tngggggtga tgctggtggt anaagttgan gtgacttcan gatggtgtgt 60
ggaggaagtg tgtgaacgta gggatgtaga ngttttggcc gtgctaaatg agcttcggga 120
ttggctggtc ccactggtgg tcactgtcat tggtggggtt cctgt 165
<210> 138
<211> 338
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(338)
<223> n = A,T,C or G
<400>
138
actcactggaatgccacattcacaacagaatcagaggtctgtgaaaacattaatggctcc 60
ttaacttctccagtaagaatcagggacttgaaatggaaacgttaacagccacatgcccaa 120
tgctgggcagtctcccatgccttccacagtgaaagggcttgagaaaaatcacatccaatg 180
tcatgtgtttccagccacaccaaaaggtgcttggggtggagggctgggggcatananggt 240
cangcctcaggaagcctcaagttccattcagctttgccactgtacattccccatntttaa 300
aaaaactgatgccttttttttttttttttgtaaaattc 338
<210> 139
<211> 382
<212> DNA
<213> Homo sapien
<400> 139
gggaatcttggtttttggcatctggtttgcctatagccgaggccactttgacagaacaaa 60
gaaagggacttcgagtaagaaggtgatttacagccagcctagtgcccgaagtgaaggaga 120
attcaaacagacctcgtcattcctggtgtgagcctggtcggctcaccgcctatcatctgc 180
atttgccttactcaggtgctaccggactctggcccctgatgtctgtagtttcacaggatg 240
ccttatttgtcttctacaccccacagggccccctacttcttcggatgtgtttttaataat 300
gtcagctatgtgccccatcctccttcatgccctccctccctttcctaccactgctgagtg 360
gcctggaacttgtttaaagtgt 382
<210> 140
<211> 200
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (200)
<223> n = A,T,C or G
<400> 140
accaaanctt ctttctgttg tgttngattt tactataggg gtttngcttn ttctaaanat 60
acttttcatt taacancttt tgttaagtgt caggctgcac tttgctccat anaattattg 120
ttttcacatt tcaacttgta tgtgtttgtc tcttanagca ttggtgaaat cacatatttt 180
atattcagca taaaggagaa 200
CA 02391369 2002-05-10
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51
<210> 141
<211> 335
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(335)
<223> n = A,T,C or G
<400>
141
actttattttcaaaacactcatatgttgcaaaaaacacatagaaaaataaagtttggtgg 60
gggtgctgactaaacttcaagtcacagacttttatgtgacagattggagcagggtttgtt 120
atgcatgtagagaacccaaactaatttattaaacaggatagaaacaggctgtctgggtga 180
aatggttctgagaaccatccaattcacctgtcagatgctgatanactagctcttcagatg 240
tttttctaccagttcagagatnggttaatgactanttccaatggggaaaaagcaagatgg 300
attcacaaaccaagtaattttaaacaaagacactt 335
<210> 142
<211> 459
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(459)
<223> n = A,T,C or G
<400> 142
accaggttaatattgccacatatatcctttccaattgcgggctaaacagacgtgtattta 60
gggttgtttaaagacaacccagcttaatatcaagagaaattgtgacctttcatggagtat 120
ctgatggagaaaacactgagttttgacaaatcttattttattcagatagcagtctgatca 180
'
cacatggtccaacaacactcaaataataaatcaaatatnatcagatgttaaagattggtc.240
ttcaaacatcatagccaatgatgccccgcttgcctataatctctccgacataaaaccaca 300
tcaacacctcagtggccaccaaaccattcagcacagcttccttaactgtgagctgtttga 360
agctaccagtctgagcactattgactatntttttcangctctgaatagctctagggatct 420
cagcangggtgggaggaaccagctcaaccttggcgtant 459
<210> 143
<211> 140
<212> DNA
<213> Homo sapien
<400> 143
acatttcctt ccaccaagtc aggactcctg gcttctgtgg gagttcttat cacctgaggg 60
aaatccaaac agtctctcct agaaaggaat agtgtcacca accccaccca tctccctgag 120
accatccgac ttccctgtgt 140
<210> 144
<211> 164
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(164)
<223> n = A,T,C or G
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
52
<400> 144
acttcagtaa caacatacaa taacaacatt aagtgtatat tgccatcttt gtcattttct 60
atctatacca ctctcccttc tgaaaacaan aatcactanc caatcactta tacaaatttg 120
aggcaattaa tccatatttg ttttcaataa ggaaaaaaag atgt 164
<210> 145
<211> 303
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(303)
<223> n = A,T,C or G
<400>
145
acgtagaccatccaactttgtatttgtaatggcaaacatccagnagcaattcctaaacaa 60
actggagggtatttatacccaattatcccattcattaacatgccctcctcctcaggctat 120
gcaggacagctatcataagtcggcccaggcatccagatactaccatttgtataaacttca 180
gtaggggagtccatccaagtgacaggtctaatcaaaggaggaaatggaacataagcccag 240
tagtaaaatnttgcttagctgaaacagccacaaaagacttaccgccgtggtgattaccat 300
caa 303
<210> 146
<211> 327
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(327)
<223> n = A,T,C or G
<400> 146
actgcagctcaattagaagtggtctctgactttcatcancttctccctgggctccatgac 60
actggcctggagtgactcattgctctggttggttgagagagctcctttgccaacaggcct 120
ccaagtcagggctgggatttgtttcctttccacattctagcaacaatatgctggccactt 180
cctgaacagggagggtgggaggagccagcatggaacaagctgccactttctaaagtagcc 240
agacttgcccctgggcctgtcacacctactgatgaccttctgtgcctgcaggatggaatg 300
taggggtgagctgtgtgactctatggt 327
<210> 147
<211> 173
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(173)
<223> n = A,T,C or G
<400> 147
acattgtttt tttgagataa agcattgana gagctctcct taacgtgaca caatggaagg 60
actggaacac atacccacat ctttgttctg agggataatt ttctgataaa gtcttgctgt 120
atattcaagc acatatgtta tatattattc agttccatgt ttatagccta gtt 173
<210> 148
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
53
<211> 477
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (477)
<223> n = A,T,C or G
<400>
148
acaaccactttatctcatcgaatttttaacccaaactcactcactgtgcctttctatcct 60
atgggatatattatttgatgctccatttcatcacacatatatgaataatacactcatact 120
gccctactacctgctgcaataatcacattcccttcctgtcctgaccctgaagccattggg 180
gtggtcctagtggccatcagtccangcctgcaccttgagcccttgagctccattgctcac 240
nccancccacctcaccgaccccatcctcttacacagctacctccttgctctctaacccca 300
tagattatntccaaattcagtcaattaagttactattaacactctacccgacatgtccag 360
caccactggtaagccttctccagccaacacacacacacacacacncacacacacacatat 420
ccaggcacaggctacctcatcttcacaatcacccctttaattaccatgctatggtgg 477
<210> 149
<211> 207
<212> DNA
<213> Homo sapien
<400> 149
acagttgtat tataatatca agaaataaac ttgcaatgag agcatttaag agggaagaac 60
taacgtattt tagagagcca aggaaggttt ctgtggggag tgggatgtaa ggtggggcct 120
gatgataaat aagagtcagc caggtaagtg ggtggtgtgg tatgggcaca gtgaagaaca 180
tttcaggcag agggaacagc agtgaaa 207
<210> 150
<211> 111
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(111)
<223> n = A,T,C or G
<400> 150
accttgattt cattgctgct ctgatggaaa cccaactatc taatttagct aaaacatggg 60
cacttaaatg tggtcagtgt ttggacttgt taactantgg catctttggg t 111
<210> 151
<211> 196
<212> DNA
<213> Homo sapien
<400> 151
agcgcggcag gtcatattga acattccaga tacctatcat tactcgatgc tgttgataac 60
agcaagatgg ctttgaactc agggtcacca ccagctattg gaccttacta tgaaaaccat 120
ggataccaac cggaaaaccc ctatcccgca cagcccactg tggtccccac tgtctacgag 180
gtgcatccgg ctcagt 196
<210> 152
<211> 132
<212> DNA
taggggtgagctgtgtgactctatggt 327
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
54
<213> Homo sapien
<400> 152
acagcacttt cacatgtaag aagggagaaa ttcctaaatg taggagaaag ataacagaac 60
cttccccttt tcatctagtg gtggaaacct gatgctttat gttgacagga atagaaccag 120
gagggagttt gt 132
<210> 153
<211> 285
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (285)
<223> n = A,T,C or G
<400> 153
acaanacccanganaggccactggccgtggtgtcatggcctccaaacatgaaagtgtcag 60
cttctgctcttatgtcctcatctgacaactctttaccatttttatcctcgctcagcagga 120
gcacatcaataaagtccaaagtcttggacttggccttggcttggaggaagtcatcaacac 180
cctggctagtgagggtgcggcgccgctcctggatgacggcatctgtgaagtcgtgcacca 240
gtctgcaggccctgtggaagcgccgtccacacggagtnaggaatt 285
<210> 154
<211> 333
<212> DNA
<213> Homo sapien
<400> 154
accacagtcctgttgggccagggcttcatgaccctttctgtgaaaagccatattatcacc 60
accccaaatttttccttaaatatctttaactgaaggggtcagcctcttgactgcaaagac 120
cctaagccggttacacagctaactcccactggccctgatttgtgaaattgctgctgcctg 180
attggcacaggagtcgaaggtgttcagctcccctcctccgtggaacgagactctgatttg 240
agtttcacaaattctcgggccacctcgtcattgctcctctgaaataaaatccggagaatg 300
gtcaggcctgtctcatccatatggatcttccgg 333
<210> 155
<211> 308
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(308)
<223> n = A,T,C or G
<400>
155
actggaaataataaaacccacatcacagtgttgtgtcaaagatcatcagggcatggatgg 60
gaaagtgctttgggaactgtaaagtgcctaacacatgatcgatgatttttgttataatat 120
ttgaatcacggtgcatacaaactctcctgcctgctcctcctgggccccagccccagcccc 180
atcacagctcactgctctgttcatccaggcccagcatgtagtggctgattcttcttggct 240
gcttttagcctccanaagtttctctgaagccaaccaaacctctangtgtaaggcatgctg 300
gccctggt 308
<210> 156
<211> 295
<212> DNA
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
<213> Homo sapien
<400> 156
accttgctcggtgcttggaacatattaggaactcaaaatatgagatgataacagtgccta 60
ttattgattactgagagaactgttagacatttagttgaagattttctacacaggaactga 120
gaataggagattatgtttggccctcatattctctcctatcctccttgcctcattctatgt 180
ctaatatattctcaatcaaataaggttagcataatcaggaaatcgaccaaataccaatat 240
aaaaccagatgtctatccttaagattttcaaatagaaaacaaattaacagactat 295
<210> 157
<211> 126
<212> DNA
<213> Homo sapien
<400> 157
acaagtttaa atagtgctgt cactgtgcat gtgctgaaat gtgaaatcca ccacatttct 60
gaagagcaaa acaaattctg tcatgtaatc tctatcttgg gtcgtgggta tatctgtccc 120
cttagt 126
<210> 158
<211> 442
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(442)
<223> n = A,T,C or G
<400>
158
acccactggtcttggaaacacccatccttaatacgatgatttttctgtcgtgtgaaaatg 60
aanccagcaggctgcccctagtcagtccttccttccagagaaaaagagatttgagaaagt 120
gcctgggtaattcaccattaatttcctcccccaaactctctgagtcttcccttaatattt 180
ctggtggttctgaccaaagcaggtcatggtttgttgagcatttgggatcccagtgaagta 240
natgtttgtagccttgcatacttagcccttcccacgcacaaacggagtggcagagtggtg 300
ccaaccctgttttcccagtccacgtagacagattcacagtgcggaattctggaagctgga 360
nacagacgggctctttgcagagccgggactctgaganggacatgagggcctctgcctctg 420
tgttcattctctgatgtcctgt 442
<210> 159
<211> 498
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(498)
<223> n = A,T,C or~G
<400> 159
acttccaggtaacgttgttgtttccgttgagcctgaactgatgggtgacgttgtaggttc 60
tccaacaagaactgaggttgcagagcgggtagggaagagtgctgttccagttgcacctgg 120
gctgctgtggactgttgttgattcctcactacggcccaaggttgtggaactggcanaaag 180
gtgtgttgttgganttgagctcgggcggctgtggtaggttgtgggctcttcaacaggggc 240
tgctgtggtgccgggangtgaangtgttgtgtcacttgagcttggccagctctggaaagt 300
antanattcttcctgaaggccagcgcttgtggagctggcangggtcantgttgtgtgtaa 360
cgaaccagtgctgctgtgggtgggtgtanatcctccacaaagcctgaagttatggtgtcn 420
tcaggtaanaatgtggtttcagtgtccctgggcngctgtggaaggttgtanattgtcacc 480
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
56
aagggaataa gctgtggt 498
<210> 160
<211> 380
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(380)
<223> n = A,T,C or G
<400>
160
acctgcatccagcttccctgccaaactcacaaggagacatcaacctctagacagggaaac 60
agcttcaggatacttccaggagacagagccaccagcagcaaaacaaatattcccatgcct 120
ggagcatggcatagaggaagctganaaatgtggggtctgaggaagccatttgagtctggc 180
cactagacatctcatcagccacttgtgtgaagagatgccccatgaccccagatgcctctc 240
ccacccttacctccatctcacacacttgagctttccactctgtataattctaacatcctg 300
gagaaaaatggcagtttgaccgaacctgttcacaacggtagaggctgatttctaacgaaa 360
cttgtagaatgaagcctgga 380
<210> 161
<211>-114
<212> DNA
<213> Homo sapien
<400> 161
actccacatc ccctctgagc aggcggttgt cgttcaaggt gtatttggcc ttgcctgtca 60
cactgtccac tggcccctta tccacttggt gcttaatccc tcgaaagagc atgt 114
<210> 162
<211> 177
<212> DNA
<213> Homo sapien
<400> 162
actttctgaa tcgaatcaaa tgatacttag tgtagtttta atatcctcat atatatcaaa 60
gttttactac tctgataatt ttgtaaacca ggtaaccaga acatccagtc atacagcttt 120
tggtgatata taacttggca ataacccagt ctggtgatac ataaaactac tcactgt 177
<210> 163
<211> 137
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(137)
<223> n = A,T,C or G
<400> 163
catttataca gacaggcgtg aagacattca cgacaaaaac gcgaaattct atcccgtgac 60
canagaaggc agctacggct actcctacat cctggcgtgg gtggccttcg cctgcacctt 120
catcagcggc atgatgt 137
<210> 164
<211> 469
<212> DNA
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
57
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (469)
<223> n = A,T,C or G
<400> 164
cttatcacaatgaatgttctcctgggcagcgttgtgatctttgccaccttcgtgacttta 60
tgcaatgcatcatgctatttcatacctaatgagggagttccaggagattcaaccaggaaa 120
tgcatggatctcaaaggaaacaaacacccaataaactcggagtggcagactgacaactgt 180
gagacatgcacttgctacgaaacagaaatttcatgttgcacccttgtttctacacctgtg 240
ggttatgacaaagacaactgccaaagaatcttcaagaaggaggactgcaagtatatcgtg 300
gtggagaagaaggacccaaaaaagacctgttctgtcagtgaatggataatctaatgtgct 360
tctagtaggcacagggctcccaggccaggcctcattctcctctggcctctaatagtcaat 420
gattgtgtagccatgcctatcagtaaaaagatntttgagcaaacacttt 469
<210> 165
<211> 195
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(195)
<223> n = A,T,C or G
<400> 165
acagtttttt atanatatcg acattgccgg cacttgtgtt cagtttcata aagctggtgg 60
atccgctgtc atccactatt ccttggctag agtaaaaatt attcttatag cccatgtccc 120
tgcaggccgc ccgcccgtag ttctcgttcc agtegtcttg gcacacaggg tgccaggact 180
tcctctgaga tgagt 195
<210> 166
<211> 383
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (383)
<223> n = A,T,C or G
<400> 166
acatcttagtagtgtggcacatcagggggccatcagggtcacagtcactcatagcctcgc 60
cgaggtcggagtccacaccaccggtgtaggtgtgctcaatcttgggcttggcgcccacct 120
ttggagaagggatatgctgcacacacatgtccacaaagcctgtgaactcgccaaagaatt 180
tttgcagaccagcctgagcaaggggcggatgttcagcttcagctcctccttcgtcaggtg 240
gatgccaacctcgtctanggtccgtgggaagctggtgtccacntcacctacaacctgggc 300
gangatcttataaagaggctccnagataaactccacgaaacttctctgggagctgctagt 360
nggggcctttttggtgaactttc 383
<210> 167
<211> 247
<212> DNA
<213> Homo sapien
<220>
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
58
<221> misc_feature
<222> (1) . . (247)
<223> n = A,T,C or G
<400> 167
acagagccagaccttggccataaatgaancagagattaagactaaaccccaagtcganat 60
tggagcagaaactggagcaagaagtgggcctggggctgaagtagagaccaaggccactgc 120
tatanccatacacagagccaactctcaggccaaggcnatggttggggcaganccagagac 180
tcaatctgantccaaagtggtggctggaacactggtcatgacanaggcagtgactctgac 240
tgangtc 247
<210> 168
<211> 273
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(273)
<223> n = A,T,C or G
<400> 168
acttctaagttttctagaagtggaaggattgtantcatcctgaaaatgggtttacttcaa 60
aatccctcanccttgttcttcacnactgtctatactganagtgtcatgtttccacaaagg 120
gctgacacctgagcctgnattttcactcatccctgagaagccctttccagtagggtgggc 180
aattcccaacttccttgccacaagcttcccaggctttctcccctggaaaactccagcttg 240
agtcccagatacactcatgggctgccctgggca 273
<210> 169
<211> 431
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(431)
<223> n = A,T,C or G
<400>
169
acagccttggcttccccaaactccacagtctcagtgcagaaagatcatcttccagcagtc 60
agctcagaccagggtcaaaggatgtgacatcaacagtttctggtttcagaacaggttcta 120
ctactgtcaaatgaccccccatacttcctcaaaggctgtggtaagttttgcacaggtgag 180
ggcagcagaaagggggtanttactgatggacaccatcttctctgtatactccacactgac 240
cttgccatgggcaaaggcccctaccacaaaaacaataggatcactgctgggcaccagctc 300
acgcacatcactgacaaccgggatggaaaaagaantgccaactttcatacatccaactgg 360
aaagtgatctgatactggattcttaattaccttcaaaagcttctgggggccatcagctgc 420
tcgaacactga 431
<210> 170
<211> 266
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(266)
<223> n = A,T,C or G
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
59
<400> 170
acctgtgggctgggctgttatgcctgtgccggctgctgaaagggagttcagaggtggagc 60
tcaaggagctctgcaggcattttgccaancctctccanagcanagggagcaacctacact 120
ccccgctagaaagacaccagattggagtcctgggagggggagttggggtgggcatttgat 180
gtatacttg-tcacctgaatgaangagccagagaggaangagacgaanatganattggcct 240
tcaaagctaggggtctggcaggtgga 266
<210> 171
<211> 1248
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(1248)
<223> n = A, T, C or G
<400> 171
ggcagccaaatcataaacggcgaggactgcagcccgcactcgcagccctggcaggcggca60
ctggtcatggaaaacgaattgttctgctcgggcgtcctggtgcatccgcagtgggtgctg120
tcagccgcacactgtttccagaagtgagtgcagagctcctacaccatcgggctgggcctg180
cacagtcttgaggccgaccaagagccagggagccagatggtggaggccagcctctccgta240
cggcacccagagtacaacagacccttgctcgctaacgacctcatgctcatcaagttggac300
gaatccgtgtccgagtctgacaccatccggagcatcagcattgcttcgcagtgccctacc360
gcggggaactcttgcctcgtttctggctggggtctgctggcgaacggcagaatgcctacc420
gtgctgcagtgcgtgaacgtgtcggtggtgtctgaggaggtctgcagtaagctctatgac480
ccgctgtaccaccccagcatgttctgcgccggcggagggcaagaccagaaggactcctgc540
aacggtgactctggggggcccctgatctgcaacgggtacttgcagggccttgtgtctttc600
ggaaaagccccgtgtggccaagttggcgtgccaggtgtctacaccaacctctgcaaattc660
actgagtggatagagaaaaccgtccaggccagttaactctggggactgggaacccatgaa720
attgacccccaaatacatcctgcggaaggaattcaggaatatctgttcccagcccctcct780
ccctcaggcccaggagtccaggcccccagcccctcctccctcaaaccaagggtacagatc840
cccagcccctcctccctcagacccaggagtccagaccccccagcccctcctccctcagac900
ccaggagtccagcccctcctccctcagacccaggagtccagaccccccagcccctcctcc960
ctcagacccaggggtccaggcccccaacccctcctccctcagactcagaggtccaagccc1020
ccaacccntcattccccagacccagaggtccaggtcccagcccctcntccctcagaccca1080
gcggtccaatgccacctagactntccctgtacacagtgcccccttgtggcacgttgaccc1140
aaccttaccagttggtttttcatttttngtccctttcccctagatccagaaataaagttt1200
aagagaagngcaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa 1248
<210> 172
<211> 159
<212> PRT
<213> Homo sapien
<220>
<221> VARIANT
<222> (1)...(159)
<223> Xaa = Any Amino Acid
<400> 172
Met Val Glu Ala Ser Leu Ser Val Arg His Pro Glu Tyr Asn Arg Pro
1 5 10 15
Leu Leu Ala Asn Asp Leu Met Leu Ile Lys Leu Asp Glu Ser Val Ser
20 25 30
Glu Ser Asp Thr Ile Arg Ser Ile Ser Ile Ala Ser Gln Cys Pro Thr
35 40 45
Ala Gly Asn Ser Cys Leu Val Ser Gly Trp Gly Leu Leu Ala Asn Gly
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
50 55 60
Arg Met Pro Thr Val Leu Gln Cys Val Asn Val Ser Val Val Ser Glu
70 75 80
Glu Val Cys Ser Lys Leu Tyr Asp Pro Leu Tyr His Pro Ser Met Phe
85 90 95
Cys Ala Gly Gly Gly Gln Xaa Gln Xaa Asp Ser Cys Asn Gly Asp Ser
100 105 110
Gly Gly Pro Leu Ile Cys Asn Gly Tyr Leu Gln Gly Leu Val Ser Phe
115 120 125
Gly Lys Ala Pro Cys Gly Gln Val Gly Val Pro Gly Val Tyr Thr Asn
130 135 140
Leu Cys Lys Phe Thr Glu Trp Ile Glu Lys Thr Val Gln Ala Ser
145 150 155
<210> 173
<211> 1265
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(1265)
<223> n = A,T,C or G
<400>
173
ggcagcccgcactcgcagccctggcaggcggcactggtcatggaaaacgaattgttctgc60
tcgggcgtcctggtgcatccgcagtgggtgctgtcagccgcacactgtttccagaactcc120
tacaccatcgggctgggcctgcacagtcttgaggccgaccaagagccagggagccagatg180
gtggaggccagcctctccgtacggcacccagagtacaacagacccttgctcgctaacgac240
ctcatgctcatcaagttggacgaatccgtgtccgagtctgacaccatccggagcatcagc300
attgcttcgcagtgccctaccgcggggaactcttgcctcgtttctggctggggtctgctg360
gcgaacggtgagctcacgggtgtgtgtctgccctcttcaaggaggtcctctgcccagtcg420
cgggggctgacccagagctctgcgtcccaggcagaatgcctaccgtgctgcagtgcgtga480
acgtgtcggtggtgtctgaggaggtctgcagtaagctctatgacccgctgtaccacccca540
gcatgttctgcgccggcggagggcaagaccagaaggactcctgcaacggtgactctgggg600
ggcccctgatctgcaacgggtacttgcagggccttgtgtctttcggaaaagccccgtgtg660
gccaagttggcgtgccaggtgtctacaccaacctctgcaaattcactgagtggatagaga720
aaaccgtccaggccagttaactctggggactgggaacccatgaaattgacccccaaatac780
atcctgcggaaggaattcaggaatatctgttcccagcccctcctccctcaggcccaggag840
tccaggcccccagcccctcctccctcaaaccaagggtacagatccccagcccctcctccc900
tcagacccaggagtccagaccccccagcccctcctccctcagacccaggagtccagcccc960
tcctccntcagacccaggagtccagaccccccagcccctcctccctcagacccaggggtt1020
gaggcccccaacccctcctccttcagagtcagaggtccaagcccccaacccctcgttccc1080
cagacccagaggtnnaggtcccagcccctcttccntcagacccagnggtccaatgccacc1140
tagattttccctgnacacagtgcccccttgtggnangttgacccaaccttaccagttggt1200
ttttcatttttngtccctttcccctagatccagaaataaagtttaagagangngcaaaaa1260
aaaaa 1265
<210> 174
<211> 1459
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(1459)
<223> n = A,T,C or G
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
61
<400>
174
ggtcagccgcacactgtttccagaagtgagtgcagagctcctacaccatcgggctgggcc 60
tgcacagtcttgaggccgaccaagagccagggagccagatggtggaggccagcctctccg 120
tacggcacccagagtacaacagacccttgctcgctaacgacctcatgctcatcaagttgg 180
acgaatccgtgtccgagtctgacaccatccggagcatcagcattgcttcgcagtgcccta 240
ccgcggggaactcttgcctcgtttctggctggggtctgctggcgaacggtgagctcacgg 300
gtgtgtgtctgccctcttcaaggaggtcctctgcccagtcgcgggggctgacccagagct 360
ctgcgtcccaggcagaatgcctaccgtgctgcagtgcgtgaacgtgtcggtggtgtctga 420
ngaggtctgcantaagctctatgacccgctgtaccaccccancatgttctgcgccggcgg 480
agggcaagaccagaaggactcctgcaacgtgagagaggggaaaggggagggcaggcgact 540
cagggaagggtggagaagggggagacagagacacacagggccgcatggcgagatgcagag 600
atggagagacacacagggagacagtgacaactagagagagaaactgagagaaacagagaa 660
ataaacacaggaataaagagaagcaaaggaagagagaaacagaaacagacatggggaggc 720
agaaacacacacacatagaaatgcagttgaccttccaacagcatggggcctgagggcggt 780
gacctccacccaatagaaaatcctcttataacttttgactccccaaaaacctgactagaa 840
atagcctactgttgacggggagccttaccaataacataaatagtcgatttatgcatacgt 900
tttatgcattcatgatatacctttgttggaattttttgatatttctaagctacacagttc 960
gtctgtgaatttttttaaattgttgcaactctcctaaaatttttctgatgtgtttattga 1020
aaaaatccaagtataagtggacttgtgcattcaaaccagggttgttcaagggtcaactgt 1080
gtacccagagggaaacagtgacacagattcatagaggtgaaacacgaagagaaacaggaa 1140
aaatcaagactctacaaagaggctgggcagggtggctcatgcctgtaatcccagcacttt 1200
gggaggcgaggcaggcagatcacttgaggtaaggagttcaagaccagcctggccaaaatg 1260
gtgaaatcctgtctgtactaaaaatacaaaagttagctggatatggtggcaggcgcctgt 1320
aatcccagctacttgggaggctgaggcaggagaattgcttgaatatgggaggcagaggtt 1380
gaagtgagttgagatcacaccactatactccagctggggcaacagagtaagactctgtct 1440
caaaaaaaaaaaaaaaaaa 1459
<210> 175
<21l> 1167
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(1167)
<223> n = A,T,C or G
<400> 175
gcgcagccctggcaggcggcactggtcatggaaaacgaattgttctgctcgggcgtcctg60
gtgcatccgcagtgggtgctgtcagccgcacactgtttccagaactcctacaccatcggg120
ctgggcctgcacagtcttgaggccgaccaagagccagggagccagatggtggaggccagc180
ctctccgtacggcacccagagtacaacagactcttgctcgctaacgacctcatgctcatc240
aagttggacgaatccgtgtccgagtctgacaccatccggagcatcagcattgcttcgcag300
tgccctaccgcggggaactcttgcctcgtntctggctggggtctgctggcgaacggcaga360
atgcctaccgtgctgcactgcgtgaacgtgtcggtggtgtctgaggangtctgcagtaag420
ctctatgacccgctgtaccaccccagcatgttctgcgccggcggagggcaagaccagaag480
gactcctgcaacggtgactctggggggcccctgatctgcaacgggtacttgcagggcctt540
gtgtctttcggaaaagccccgtgtggccaacttggcgtgccaggtgtctacaccaacctc600
tgcaaattcactgagtggatagagaaaaccgtccagnccagttaactctggggactggga660
acccatgaaattgacccccaaatacatcctgcggaangaattcaggaatatctgttccca720
gcccctcctccctcaggcccaggagtccaggcccccagcccctcctccctcaaaccaagg780
gtacagatccccagcccctcctccctcagacccaggagtccagaccccccagcccctcnt840
ccntcagacccaggagtccagcccctcctccntcagacgcaggagtccagaccccccagc900
ccntcntccgtcagacccaggggtgcaggcccccaacccctcntccntcagagtcagagg960
tccaagcccccaacccctcgttccccagacccagaggtncaggtcccagcccctcctccc1020
tcagacccagcggtccaatgccacctagantntccctgtacacagtgcccccttgtggca1080
ngttgacccaaccttaccagttggtttttcattttttgtccctttcccctagatccagaa1140
ataaagtntaagagaagcgcaaaaaaa 1167
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
62
<210> 176
<211> 205
<212> PRT
<213> Homo sapien
<220>
<221> VARIANT
<222> (1)...(205)
<223> Xaa = Any Amino Acid
<400> 176
Met Glu Asn Glu Leu Phe Cys Ser Gly Val Leu Val His Pro Gln Trp
1 5 10 15
Val Leu Ser Ala Ala His Cys Phe Gln Asn Ser Tyr Thr Ile Gly Leu
20 25 30
Gly Leu His Ser Leu Glu Ala Asp Gln Glu Pro Gly Ser Gln Met Val
35 40 45
Glu Ala Ser Leu Ser Val Arg His Pro Glu Tyr Asn Arg Leu Leu Leu
50 55 60
Ala Asn Asp Leu Met Leu Ile Lys Leu Asp Glu Ser Val Ser Glu Ser
65 70 75 80
Asp Thr Ile Arg Ser Ile Ser Ile Ala Ser Gln Cys Pro Thr Ala Gly
85 90 95
Asn Ser Cys Leu Val Ser Gly Trp Gly Leu Leu Ala Asn Gly Arg Met
100 105 110
Pro Thr Val Leu His Cys Val Asn Val Ser Val Val Ser Glu Xaa Val
115 120 125
Cys Ser Lys Leu Tyr Asp Pro Leu Tyr His Pro Ser Met Phe Cys Ala
130 135 140
Gly Gly Gly Gln Asp Gln Lys Asp Ser Cys Asn Gly Asp Ser Gly Gly
145 150 155 160
Pro Leu Ile Cys Asn Gly Tyr Leu Gln Gl.y Leu Val Ser Phe Gly Lys
165 170 175
Ala Pro Cys Gly Gln Leu Gly Val Pro Gly Val Tyr Thr Asn Leu Cys
180 185 190
Lys Phe Thr Glu Trp Ile Glu Lys Thr Val Gln Xaa Ser
195 200 205
<210> 177
<211> 1119
<212> DNA
<213> Homo sapien
<400>
177
gcgcactcgcagccctggcaggcggcactggtcatggaaaacgaattgttctgctcgggc 60
gtcctggtgcatccgcagtgggtgctgtcagccgcacactgtttccagaactcctacacc 120
atcgggctgggcctgcacagtcttgaggccgaccaagagccagggagccagatggtggag 180
gccagcctctccgtacggcacccagagtacaacagacccttgctcgctaacgacctcatg 240
ctcatcaagttggacgaatccgtgtccgagtctgacaccatccggagcatcagcattgct 300
tcgcagtgccctaccgcggggaactcttgcctcgtttctggctggggtctgctggcgaac 360
gatgctgtgattgccatccagtcccagactgtgggaggctgggagtgtgagaagctttcc 420
caaccctggcagggttgtaccatttcggcaacttccagtgcaaggacgtcctgctgcatc 480
ctcactgggtgctcactactgctcactgcatcacccggaacactgtgatcaactagccag 540
caccatagttctccgaagtcagactatcatgattactgtgttgactgtgctgtctattgt 600
actaaccatgccgatgtttaggtgaaattagcgtcacttggcctcaaccatcttggtatc 660
cagttatcctcactgaattgagatttcctgcttcagtgtcagccattcccacataatttc 720
tgacctacagaggtgagggatcatatagctcttcaaggatgctggtactcccctcacaaa 780
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
63
ttcatttctcctgttgtagtgaaaggtgcgccctctggagcctcccagggtgggtgtgca 840
ggtcacaatgatgaatgtatgatcgtgttcccattacccaaagcctttaaatccctcatg 900
ctcagtacaccagggcaggtctagcatttcttcatttagtgtatgctgtccattcatgca 960
accacctcaggactcctggattctctgcctagttgagctcctgcatgctgcctccttggg 1020
gaggtgagggagagggcccatggttcaatgggatctgtgc.agttgtaacacattaggtgc 1080
ttaataaacagaagctgtgatgttaaaaaaaaaaaaaaa 1119
<210> 178
<211> 164
<212> PRT
<213> Homo sapien
<220>
<221> VARIANT
<222> (1)...(164)
<223> Xaa = Any Amino Acid
<400> 178
Met Glu Asn Glu Leu Phe Cys Ser Gly Val Leu Val His Pro Gln Trp
1 5 10 15
Val Leu Ser Ala Ala His Cys Phe Gln Asn Ser Tyr Thr Ile Gly Leu
20 25 30
Gly Leu His Ser Leu Glu Ala Asp Gln Glu Pro Gly Ser Gln Met Val
35 40 45
Glu Ala Ser Leu Ser Val Arg His Pro Glu Tyr Asn Arg Pro Leu Leu
50 55 60
Ala Asn Asp Leu Met Leu Ile Lys Leu Asp Glu Ser Val Ser Glu Ser
65 70 75 80
Asp Thr Ile Arg Ser Ile Ser Ile Ala Ser Gln Cys Pro Thr Ala Gly
85 90 95
Asn Ser Cys Leu Val Ser Gly Trp Gly Leu Leu Ala Asn Asp Ala Val .
100 105 110
Ile Ala Ile Gln Ser Xaa Thr Val Gly Gly Trp Glu Cys Glu Lys Leu
115 120 125
Ser Gln Pro Trp Gln Gly Cys Thr Ile Ser Ala Thr Ser Ser Ala Arg
130 135 140
Thr Ser Cys Cys Ile Leu Thr Gly Cys Ser Leu Leu Leu Thr Ala Ser
145 150 155 160
Pro Gly Thr Leu
<210> 179
<211> 250
<212> DNA
<213> Homo sapien
<400> 179
ctggagtgccttggtgtttcaagcccctgcaggaagcagaatgcaccttctgaggcacct 60
ccagctgcccccggccgggggatgcgaggctcggagcacccttgcccggctgtgattgct 120
gccaggcactgttcatctcagcttttctgtccctttgctcccggcaagcgcttctgctga 180
aagttcatatctggagcctgatgtcttaacgaataaaggtcccatgctccacccgaaaaa 240
aaaaaaaaaa 250
<210> 180
<211> 202
<212> DNA
<213> Homo sapien
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
64
<400> lso
actagtccag tgtggtggaa ttccattgtg ttgggcccaa cacaatggct acctttaaca 60
tcacccagac cccgcccctg cccgtgcccc acgctgctgc taacgacagt atgatgctta 120
ctctgctact cggaaactat ttttatgtaa ttaatgtatg ctttcttgtt tataaatgcc 180
tgatttaaaa aaaaaaaaaa as 202
<210> 181
<211> 558
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(558)
<223> n = A,T,C or G
<400>
181
tccytttgktnaggtttkkgagacamccckagacctwaanctgtgtcacagacttcyngg 60
aatgtttaggcagtgctagtaatttcytcgtaatgattctgttattactttcctnattct 120
ttattcctctttcttctgaagattaatgaagttgaaaattgaggtggataaatacaaaaa 180
ggtagtgtgatagtataagtatctaagtgcagatgaaagtgtgttatatatatccattca 240
aaattatgcaagttagtaattactcagggttaactaaattactttaatatgctgttgaac 300
ctactctgttccttggctagaaaaaattataaacaggactttgttagtttgggaagccaa 360
attgataatattctatgttctaaaagttgggctatacataaattattaagaaatatggaw 420
ttttattcccaggaatatggkgttcattttatgaatattacscrggatagawgtwtgagt 480
aaaaycagttttggtwaataygtwaatatgtcmtaaataaacaakgctttgacttatttc.540
caaaaaaaaaaaaaaaaa 558
<210> 182
<211> 479
<212> DNA
<213> Homo sapien.
<220>
<221> misc_feature
<222> (1) . . (479)
<223> n = A,T,C or G
<400> 182
acagggwttkgrggatgctaagsccccrgarwtygtttgatccaaccctggcttwttttc 60
agaggggaaaatggggcctagaagttacagmscatytagytggtgcgmtggcacccctgg 120
cstcacacagastcccgagtagctgggactacaggcacacagtcactgaagcaggccctg 180
ttwgcaattcacgttgccacctccaacttaaacattcttcatatgtgatgtccttagtca 240
ctaaggttaaactttcccacccagaaaaggcaacttagataaaatcttagagtactttca 300
tactmttctaagtcctcttccagcctcactkkgagtcctmcytgggggttgataggaant 360
ntctcttggctttctcaataaartctctatycatctcatgtttaatttggtacgcatara 420
awtgstgaraaaattaaaatgttctggttymactttaaaaaraaaaaaaaaaaaaaaaa 479
<210> 183
<211> 384
<212> DNA
<213> Homo sapien
<400> 183
aggcgggagc agaagctaaa gccaaagccc aagaagagtg gcagtgccag cactggtgcc 60
agtaccagta ccaataacag tgccagtgcc agtgccagca ccagtggtgg cttcagtgct 120
ggtgccagcc tgaccgccac tctcacattt gggctcttcg ctggccttgg tggagctggt 180
gccagcacca gtggcagctc tggtgcctgt ggtttctcct acaagtgaga ttttagatat 240
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
tgttaatcct gccagtcttt ctcttcaagc cagggtgcat cctcagaaac ctactcaaca 300
cagcactcta ggcagccact atcaatcaat tgaagttgac actctgcatt aratctattt 360
gccatttcaa aaaaaaaaaa aaaa 384
<210> 184
<211> 496
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(496)
<223> n = A,T,C or G
<400> 184
accgaattgggaccgctggcttataagcgatcatgtyyntccrgtatkacctcaacgagc 60
agggagatcgagtctatacgctgaagaaatttgacccgatgggacaacagacctgctcag 120
cccatcctgctcggttctccccagatgacaaatactctsgacaccgaatcaccatcaaga 180
aacgcttcaaggtgctcatgacccagcaaccgcgccctgtcctctgagggtcccttaaac 240
tgatgtcttttctgccacctgttacccctcggagactccgtaaccaaactcttcggactg 300
tgagccctgatgcctttttgccagccatactctttggcatccagtctctcgtggcgattg 360
attatgcttgtgtgaggcaatcatggtggcatcacccataaagggaacacatttgacttt 420
tttttctcatattttaaattactacmagawtattwmagawwaaatgawttgaaaaactst 480
taaaaaaaaaaaaaaa 496
<210> 185
<211> 384
<212> DNA
<213> Homo sapien
<400> 185
gctggtagcctatggcgkggcccacggaggggctcctgaggccacggracagtgacttcc 60
caagtatcytgcgcsgcgtcttctaccgtccctacctgcagatcttcgggcagattcccc 120
aggaggacatggacgtggccctcatggagcacagcaactgytcgtcggagcccggcttct 180
gggcacaccctcctggggcccaggcgggcacctgcgtctcccagtatgccaactggctgg 240
tggtgctgctcctcgtcatcttcctgctcgtggccaacatcctgctggtcaacttgctca 300
ttgccatgttcagttacacattcggcaaagtacagggcaacagcgatctctactgggaag 360
gcgcagcgttaccgcctcatccgg 384
<210> 186
<211> 577
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (577)
<223> n = A,T,C or G
<400>
186
gagttagctcctccacaaccttgatgaggtcgtctgcagtggcctctcgcttcataccgc 60
tnccatcgtcatactgtaggtttgccaccacytcctggcatcttggggcggcntaatatt 120
ccaggaaactctcaatcaagtcaccgtcgatgaaacctgtgggctggttctgtcttccgc 180
tcggtgtgaaaggatctcccagaaggagtgctcgatcttccccacacttttgatgacttt 240
attgagtcgattctgcatgtccagcaggaggttgtaccagctctctgacagtgaggtcac 300
cagccctatcatgccgttgamcgtgccgaagarcaccgagccttgtgtgggggkkgaagt 360
ctcacccagattctgcattaccagagagccgtggcaaaagacattgacaaactcgcccag 420
gtggaaaaagamcamctcctggargtgctngccgctcctcgtcmgttggtggcagcgctw 480
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
66
tccttttgac acacaaacaa gttaaaggca ttttcagccc ccagaaantt gtcatcatcc 540
aagatntcgc acagcactna tccagttggg attaaat 577
<210> 187
<211> 534
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (534)
<223> n = A,T,C or G
<400>
187
aacatcttcctgtataatgctgtgtaatatcgatccgatnttgtctgstgagaatycatw 60
actkggaaaagmaacattaaagcctggacactggtattaaaattcacaatatgcaacact 120
ttaaacagtgtgtcaatctgctcccyynactttgtcatcaccagtctgggaakaagggta 180
tgccctattcacacctgttaaaagggcgctaagcatttttgattcaacatcttttttttt 240
gacacaagtccgaaaaaagcaaaagtaaacagttatyaatttgttagccaattcactttc 300
ttcatgggacagagccatytgatttaaaaagcaaattgcataatattgagcttygggagc 360
tgatatttgagcggaagagtagcctttctacttcaccagacacaactccctttcatattg 420
ggatgttnacnaaagtwatgtctctwacagatgggatgcttttgtggcaattctgttctg 480
aggatctcccagtttatttaccacttgcacaagaaggcgttttcttcctcaggc 534
<210> 188
<211> 761
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(761)
<223> n = A,T,C or G
<400> 188
agaaaccagtatctctnaaaacaacctctcataccttgtggacctaattttgtgtgcgtg 60
tgtgtgtgcgcgcatattatatagacaggcacatcttttttacttttgtaaaagcttatg 120
cctctttggtatctatatctgtgaaagttttaatgatctgccataatgtcttggggacct 180
ttgtcttctgtgtaaatggtactagagaaaacacctatnttatgagtcaatctagttngt 240
tttattcgacatgaaggaaatttccagatnacaacactnacaaactctccctkgackarg 300
ggggacaaagaaaagcaaaactgamcataaraaacaatwacctggtgagaarttgcataa 360
acagaaatwrggtagtatattgaarnacagcatcattaaarmgttwtkttwttctccctt 420
gcaaaaaacatgtacngacttcccgttgagtaatgccaagttgttttttttatnataaaa 480
cttgcccttcattacatgtttnaaagtggtgtggtgggccaaaatattgaaatgatggaa 540
ctgactgataaagctgtacaaataagcagtgtgcctaacaagcaacacagtaatgttgac 600
atgcttaattcacaaatgctaatttcattataaatgtttgctaaaatacactttgaacta 660
tttttctgtnttcccagagctgagatnttagattttatgtagtatnaagtgaaaaantac 720
gaaaataataacattgaagaaaaananaaaaaanaaaaaaa 761
<210> 189
<211> 482
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(482)
<223> n = A,T,C or G
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
67
<400>
189
tttttttttttttgccgatnctactattttattgcaggangtgggggtgtatgcaccgca 60
caccggggctatnagaagcaagaaggaaggagggagggcacagccccttgctgagcaaca 120
aagccgcctgctgccttctctgtctgtctcctggtgcaggcacatggggagaccttcccc 180
aaggcaggggccaccagtccaggggtgggaatacagggggtgggangtgtgcataagaag 240
tgataggcacaggccacccggtacagacccctcggctcctgacaggtngatttcgaccag 300
gtcattgtgccctgcccaggcacagcgtanatctggaaaagacagaatgctttccttttc 360
aaatttggctngtcatngaangggcanttttccaanttnggctnggtcttggtacncttg 420
gttcggcccagctccncgtccaaaaantattcacccnnctccnaattgcttgcnggnccc 480
cc 482
<210> 190
<211> 471
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (471)
<223> n = A,T,C or G
<400>
190
ttttttttttttttaaaacagtttttcacaacaaaatttattagaagaatagtggttttg 60
aaaactctcgcatccagtgagaactaccatacaccacattacagctnggaatgtnctcca 120
aatgtctggtcaaatgatacaatggaaccatr_caatcttacacatgcacgaaagaacaag 180
cgcttttgaca.tacaatgcacaaaaaaaaaaggggggggggaccacatggattaaaattt 240
taagtactcatcacatacattaagacacagttctagtccagtcnaaaatcagaactgcnt 300
tgaaaaatttcatgtatgcaatccaaccaaagaacttnattggtgatcatgantnctcta 360
ctacatcnaccttgatcattgccaggaacnaaaagttnaaancacncngtacaaaaanaa 420
tctgtaattnanttcaacctccgtacngaaaaatnttnnttatacactccc 471
<210> 191
<211> 402
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (402)
<223> n = A,T,C or G
<400> 191
gagggattgaaggtctgttctastgtcggmctgttcagccaccaactctaacaagttgct 60
gtcttccactcactgtctgtaagctttttaacccagacwgtatcttcataaatagaacaa 120
attcttcaccagtcacatcttctaggacctttttggattcagttagtataagctcttcca 180
cttcctttgttaagacttcatctggtaaagtcttaagttttgtagaaaggaattyaattg 240
ctcgttctctaacaatgtcctctccttgaagtatttggctgaacaacccacctaaagtcc 300
ctttgtgcatccattttaaatatacttaatagggcattgktncactaggttaaattctgc 360
aagagtcatctgtctgcaaaagttgcgttagtatatctgcca 402
<210> 192
<211> 601
<212> DNA
<213> Homo sapien
<220>
<221> mist feature
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
68
<222> (1)...(601)
<223> n = A, T, C or G
<400>
192
gagctcggatccaataatctttgtctgagggcagcacacatatncagtgccatggnaact 60
ggtctaccccacatgggagcagcatgccgtagntatataaggtcattccctgagtcagac 120
atgcytytttgaytaccgtgtgccaagtgctggtgattctyaacacacytccatcccgyt 180
cttttgtggaaaaactggcacttktctggaactagcargacatcacttacaaattcaccc 240
acgagacacttgaaaggtgtaacaaagcgaytcttgcattgctttttgtccctccggcac 300
cagttgtcaatactaacccgctggtttgcctccatcacatttgtgatctgtagctctgga 360
tacatctcctgacagtactgaagaacttcttcttttgtttcaaaagcarctcttggtgcc 420
tgttggatcaggttcccatttcccagtcygaatgttcacatggcatatttwacttcccac 480
aaaacattgcgatttgaggctcagcaacagcaaatcctgttccggcattggctgcaagag 540
cctcgatgtagccggccagcgccaaggcaggcgccgtgagccccaccagcagcagaagca 600
g 601
<210> 193
<211> 608
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(608)
<223> n = A,T,C or G
<400>
193
atacagcccanatcccaccacgaagatgcgcttgttgactgagaacctgatgcggtcact 60
ggtcccgctgtagccccagcgactctccacctgctggaagcggttgatgctgcactcytt 120
cccaacgcaggcagmagcgggsccggtcaatgaactccaytcgtggcttggggtkgacgg 180
tkaagtgcaggaagaggctgaccacctcgcggtccaccaggatgcccgactgtgcgggac 240
ctgcagcgaaactcctcgatggtcatgagcgggaagcgaatgaggcccagggccttgccc 300
agaaccttccgcctgttctctggcgtcacctgcagctgctgccgctgacactcggcctcg 360
gaccagcggacaaacggcrttgaacagccgcacctcacggatgcccagtgtgtcgcgctc 420
caggammgscaccagcgtgtccaggtcaatgtcggtgaagccctccgcgggtratggcgt 480
ctgcagtgtttttgtcgatgttctccaggcacaggctggccagctgcggttcatcgaaga 540
gtcgcgcctgcgtgagcagcatgaaggcgttgtcggctcgcagttcttcttcaggaactc 600
cacgcaat 608
<210> 194
<211> 392
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(392)
<223> n = A,T,C or G
<400> 194
gaacggctggaccttgcctcgcattgtgcttgctggcagggaataccttggcaagcagyt 60
ccagtccgagcagccccagaccgctgccgcccgaagctaagcctgcctctggccttcccc 120
tccgcctcaatgcagaaccagtagtgggagcactgtgtttagagttaagagtgaacactg 180
tttgattttacttgggaatttcctctgttatatagcttttcccaatgctaatttccaaac 240
aacaacaacaaaataacatgtttgcctgttaagttgtataaaagtaggtgattctgtatt 300
taaagaaaatattactgttacatatactgcttgcaatttctgtatttattgktnctstgg 360
aaataaatatagttattaaaggttgtcantcc 392
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
69
<210> 195
<211> 502
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(502)
<223> n = A,T,C or G
<400> 195
ccsttkgaggggtkaggkyccagttyccgagtggaagaaacaggccaggagaagtgcgtg 60
ccgagctgaggcagatgttcccacagtgacccccagagccstgggstatagtytctgacc 120
cctcncaaggaaagaccacsttctggggacatgggctggagggcaggacctagaggcacc 180
aagggaaggccccattccggggstgttccccgaggaggaagggaaggggctctgtgtgcc 240
ccccasgaggaagaggccctgagtcctgggatcagacaccccttcacgtgtatccccaca 300
caaatgcaagctcaccaaggtcccctctcagtccccttccstacaccctgamcggccact 360
gscscacacccacccagagcacgccacccgccatggggartgtgctcaaggartcgcngg 420
gcarcgtggacatctngtcccagaagggggcagaatctccaataganggactgarcmstt 480
gctnanaaaaaaaaanaaaaas 502
<210> 196
<211> 665
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(665)
<223> n = A,T,C or G
<400>
196
ggttacttggtttcattgccaccacttagtggatgtcatttagaaccattttgtctgctc 60
cctctggaagccttgcgcagagcggactttgtaattgttggagaataactgctgaatttt 120
wagctgtttkgagttgattsgcaccactgcacccacaacttcaatatgaaaacyawttga 180
actwatttattatcttgtgaaaagtataacaatgaaaattttgttcatactgtattkatc 240
aagtatgatgaaaagcaawagatatatattcttttattatgttaaattatgattgccatt 300
attaatcggcaaaatgtggagtgtatgttcttttcacagtaatatatgccttttgtaact 360
tcacttggttattttattgtaaatgarttacaaaattcttaatttaagaraatggtatgt 420
watatttatttcattaatttctttcctkgtttacgtwaattttgaaaagawtgcatgatt 480
tcttgacagaaatcgatcttgatgctgtggaagtagtttgacccacatccctatgagttt 540
ttcttagaatgtataaaggttgtagcccatcnaacttcaaagaaaaaaatgaccacatac 600
tttgcaatcaggctgaaatgtggcatgctnttctaattccaactttataaactagcaaan 660
aagtg 665
<210> 197
<211> 492
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (492)
<223> n = A,T,C or G
<400> 197
ttttnttttt ttttttttgc aggaaggatt ccatttattg tggatgcatt ttcacaatat 60
atgtttattg gagcgatcca ttatcagtga aaagtatcaa gtgtttataa natttttagg 120
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
7~
aaggcagattcacagaacatgctngtcngcttgcagttttacctcgtanagatnacagag 180
aattatagtcnaaccagtaaacnaggaatttacttttcaaaagattaaatccaaactgaa 240
caaaattctaccctgaaacttactccatccaaatattggaataanagtcagcagtgatac 300
attctcttctgaactttagattttctagaaaaatatgtaatagtgatcaggaagagctct 360
tgttcaaaagtacaacnaagcaatgttcccttaccataggccttaattcaaactttgatc 420
catttcactcccatcacgggagtcaatgctacctgggacacttgtattttgttcatnctg 480
ancntggcttas 492
<210> 198
<211> 478
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (478)
<223> n = A,T,C or G
<400> 198
tttnttttgnatttcantctgtannaantattttcattatgtttattanaaaaatatnaa 60
tgtntccacnacaaatcatnttacntnagtaagaggccanctacattgtacaacatacac 120
tgagtatattttgaaaaggacaagtttaaagtanacncatattgccgancatancacatt 180
tatacatggcttgattgatatttagcacagcanaaactgagtgagttaccagaaanaaat 240
natatatgtcaatcngatttaagatacaaaacagatcctatggtacatancatcntgtag 300
gagttgtggctttatgtttactgaaagtcaatgcagttcctgtacaaagagatggccgta 360
agcattctagtacctctactccatggttaagaatcgtacacttatgtttacatatgtnca 420
gggtaagaattgr_gttaagtnaanttatggagaggtccangagaaaaatttgatncaa 478
<210> 199
<211> 482
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (482)
<223> n = A,T,C or G
<400>
199
agtgacttgtcctccaacaaaaccccttgatcaagtttgtggcactgacaatcagaccta 60
'
tgctagttcctgtcatctattcgctactaaatgcagactggaggggaccaaaaaggggca 120
tcaactccagctggattattttggagcctgcaaatctattcctacttgtacggactttga 180
agtgattcagtttcctctacggatgagagactggctcaagaatatcctcatgcagcttta 240
tgaagccnactctgaacacgctggttatctnagatgagaancagagaaataaagtcnaga 300
aaatttacctggangaaaagaggctttnggctggggaccatcccattgaaccttctctta 360
anggactttaagaanaaactaccacatgtntgtngtatcctggtgccnggccgtttantg 420
aacntngacnncacccttntggaatanantcttgacngcntcctgaacttgctcctctgc 480
ga 482
<210> 200
<211> 270
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (270)
<223> n = A,T,C or G
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
71
<400> 200
cggccgcaagtgcaactccagctggggccgtgcggacgaagattctgccagcagttggtc 60
cgactgcgacgacggcggcggcgacagtcgcaggtgcagcgcgggcgcctggggtcttgc 120
aaggctgagctgacgccgcagaggtcgtgtcacgtcccacgaccttgacgccgtcgggga 180
cagccggaacagagcccggtgaangcgggaggcctcggggagcccctcgggaagggcggc 240
ccgagagatacgcaggtgcaggtggccgcc 270
<210> 201
<211> 419
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (419)
<223> n = A,T,C or G
<400>
201
ttttttttttttttggaatctactgcgagcacagcaggtcagcaacaagtttattttgca 60
gctagcaaggtaacagggtagggcatggttacatgttcaggtcaacttcctttgtcgtgg 120
ttgattggtttgtctttatgggggcggggtggggtaggggaaancgaagcanaantaaca 180
tggagtgggtgcaccctccctgtagaacctggttacnaaagcttggggcagttcacctgg 240
tctgtgaccgtcattttcttgacatcaatgttattagaagtcaggatatcttttagagag 300
tccactgtntctggagggagattagggtttcttgccaanatccaancaaaatccacntga 360
aaaagttggatgatncangtacngaataccganggcatanttctcatantcggtggcca 419
c210> 202
<211> 509
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(509)
<223> n = A,T,C or G
<400> 202
tttntttttttttttttttttttttttttttttttttttttttttttttttttttttttt 60
tggcacttaatccatttttatttcaaaatgtctacaaantttnaatncnccattatacng 120
gtnattttncaaaatctaaannttattcaaatntnagccaaantccttacncaaatnnaa 180
tacncncaaaaatcaaaaatatacntntctttcagcaaacttngttacataaattaaaaa 240
aatatatacggctggtgttttcaaagtacaattatcttaacactgcaaacatntttnnaa 300
ggaactaaaataaaaaaaaacactnccgcaaaggttaaagggaacaacaaattcntttta 360
caacancnncnattataaaaatcatatctcaaatcttaggggaatatatacttcacacng 420
ggatcttaacttttactncactttgtttatttttttanaaccattgtnttgggcccaaca 480
caatggnaatnccnccncnctggactagt 509
<210> 203
<211> 583
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(583)
<223> n = A,T,C or G
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
72
<400> 203
ttttttttttttttttttgacccccctcttataaaaaacaagttaccattttattttact 60
tacacatatttattttataattggtattagatattcaaaaggcagcttttaaaatcaaac 120
taaatggaaactgccttagatacataattcttaggaattagcttaaaatctgcctaaagt 180
gaaaatcttctctagctcttttgactgtaaatttttgactcttgtaaaacatccaaattc 240
atttttcttgtctttaaaattatctaatctttccattttttccctattccaagtcaattt 300
gcttctctagcctcatttcctagctcttatctactattagtaagtggcttttttcctaaa 360
agggaaaacaggaagaganaatggcacacaaaacaaacattttatattcatatttctacc 420
tacgttaataaaatagcattttgtgaagccagctcaaaagaaggcttagatccttttatg 480
tccattttagtcactaaacgatatcnaaagtgccagaatgcaaaaggtttgtgaacattt 540
attcaaaagctaatataagatatttcacatactcatctttctg 583
<210> 204
<211> 589
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (589)
<223> n = A,T,C or G
<400> 204
ttttttttntttttttttttttttttnctcttctttttttttganaatgaggatcgagtt 60
tttcactctctagatagggcatgaagaaaactcatctttccagctttaaaataacaatca 120
aatctcttatgctatatcatattttaagttaaactaatgagtcactggcttatcttctcc 180
tgaaggaaatctgttcattcttctcattcatatagttatatcaagtactaccttgcatat 240
tgagaggtttttcttctctatttacacatatatttccatgtgaatttgtatcaaaccttt 300
attttcatgcaaactagaaaataatgtnttcttttgcataagagaagagaacaatatnag 360
cattacaaaactgctcaaattgtttgttaagnttatccattataattagttnggcaggag 420
ctaatacaaatcacatttacngacnagcaataataaaactgaagtaccagttaaatatcc 480
aaaataattaaaggaacatttttagcctgggtataattagctaattcactttacaagcat 540
ttattnagaatgaattcacatgttattattccntagcccaacacaatgg 589
<210> 205
<211> 545
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(545)
<223> n = A,T,C or G
<400> 205
tttttnttttttttttcagtaataatcagaacaatatttatttttatatttaaaattcat 60
agaaaagtgccttacatttaataaaagtttgtttctcaaagtgatcagaggaattagata 120
tngtcttgaacaccaatattaatttgaggaaaatacaccaaaatacattaagtaaattat 180
ttaagatcatagagcttgtaagtgaaaagataaaatttgacctcagaaactctgagcatt 240
aaaaatccactattagcaaataaattactatggacttcttgctttaattttgtgatgaat 300
atggggtgtcactggtaaaccaacacattctgaaggatacattacttagtgatagattct 360
tatgtactttgctanatnacgtggatatgagttgacaagtttctctttcttcaatctttt 420
aaggggcngangaaatgaggaagaaaagaaaaggattacgcatactgttctttctatngg 480
aaggattagatatgtttcctttgccaatattaaaaaaataataatgtttactactagtga 540
aaccc 545
<210> 206
<211> 487
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
73
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(487)
<223> n = A,T,C or G
<400>
206
ttttttttttttttttagtcaagtttctnatttttattataattaaagtcttggtcattt 60
catttattagctctgcaacttacatatttaaattaaagaaacgttnttagacaactgtna 120
caatttataaatgtaaggtgccattattgagtanatatattcctccaagagtggatgtgt 180
cccttctcccaccaactaatgaancagcaacattagtttaattttattagtagatnatac 240
actgctgcaaacgctaattctcttctccatccccatgtngatattgtgtatatgtgtgag 300
ttggtnagaatgcatcancaatctnacaatcaacagcaagatgaagctaggcntgggctt 360
tcggtgaaaatagactgtgtctgtctgaatcaaatgatctgacctatcctcggtggcaag 420
aactcttcgaaccgcttcctcaaaggcngctgccacatttgtggcntctnttgcacttgt 480
ttcaaaa 487
<210> 207
<211> 332
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(332)
<223> n = A,T,C or G
<400> 207
tgaattggctaaaagactgcatttttanaactagcaactcttatttctttcctttaaaaa 60
tacatagcattaaatcccaaatcctatttaaagacctgacagcttgagaaggtcactact 120
gcatttataggaccttctggtggttct.gctgttacntttgaantctgacaatccttgana 180
atctttgcatgcagaggaggtaaaaggtattggattttcacagaggaanaacacagcgca 240
gaaatgaaggggccaggcttactgagcttgtccactggagggctcatgggtgggacatgg 300
aaaagaaggcagcctaggccctggggagccca 332
<210> 208
<211> 524
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(524)
<223> n = A,T,C or G
<400> 208
agggcgtggtgcggagggcgttactgttttgtctcagtaacaataaatacaaaaagactg 60
gttgtgttccggccccatccaaccacgaagttgatttctcttgtgtgcagagtgactgat 120
tttaaaggacatggagcttgtcacaatgtcacaatgtcacagtgtgaagggcacactcac 180
tcccgcgtgattcacatttagcaaccaacaatagctcatgagtccatacttgtaaatact 240
tttggcagaatacttnttgaaacttgcagatgataactaagatccaagatatttcccaaa 300
gtaaatagaagtgggtcataatattaattacctgttcacatcagcttccatttacaagtc 360
atgagcccagacactgacatcaaactaagcccacttagactcctcaccaccagtctgtcc 420
tgtcatcagacaggaggctgtcaccttgaccaaattctcaccagtcaatcatctatccaa 480
aaaccattacctgatccacttccggtaatgcaccaccttggtga 524
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
74
<210> 209
<211> 159
<212> DNA
<213> Homo sapien
<400> 209 '
gggtgaggaa atccagagtt gccatggaga aaattccagt gtcagcattc ttgctccttg 60
tggccctctc ctacactctg gccagagata ccacagtcaa acctggagcc aaaaaggaca 120
caaaggactc tcgacccaaa ctgccccaga ccctctcca 159
<210> 210
<211> 256
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(256)
<223> n = A,T,C or G
<400>
210
actccctggcagacaaaggcagaggagagagctctgttagttctgtgttgttgaactgcc 60
actgaatttctttccacttggactattacatgccanttgagggactaatggaaaaacgta 120
tggggagattttanccaatttangtntgtaaatggggagactggggcaggcgggagagat 180
ttgcagggtgnaaatggganggctggtttgttanatgaacagggacataggaggtaggca 240
ccaggatgctaaatca 256
<210> 211
<211> 264
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(264)
<223> n = A,T,C or G
<400> 211
acattgtttttttgagataaagcattgagagagctctccttaacgtgacacaatggaagg 60
actggaacacatacccacatctttgttctgagggataattttctgataaagtcttgctgt 120
atattcaagcacatatgttatatattattcagttccatgtttatagcctagttaaggaga 180
ggggagatacattcngaaagaggactgaaagaaatactcaagtnggaaaacagaaaaaga 240
aaaaaaggagcaaatgagaagcct 264
<210> 212
<211> 328
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(328)
<223> n = A,T,C or G
<400> 212
acccaaaaat ccaatgctga atatttggct tcattattcc canattcttt gattgtcaaa 60
ggatttaatg ttgtctcagc ttgggcactt cagttaggac ctaaggatgc cagccggcag 120
gtttatatat gcagcaacaa tattcaagcg cgacaacagg ttattgaact tgcccgccag 180
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
ttnaatttca ttcccattga cttgggatcc ttatcatcag ccagagagat tgaaaattta 240
cccctacnac tctttactct ctgganaggg ccagtggtgg tagctataag cttggccaca 300
tttttttttc ctttattcct ttgtcaga 328
<210> 213
<211> 250
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (250)
<223> n = A,T,C or G
<400> 213
acttatgagc agagcgacat atccnagtgt agactgaata aaactgaatt ctctccagtt 60
taaagcattg ctcactgaag ggatagaagt gactgccagg agggaaagta agccaaggct 120
cattatgcca aagganatat acatttcaat tctccaaact tcttcctcat tccaagagtt 180
ttcaatattt gcatgaacct gctgataanc catgttaana aacaaatatc tctctnacct 240
tctcatcggt 250
<210> 214
<211> 444
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(444)
<223> n = A,T,C or G
<400> 214
acccagaatccaatgctgaatatttggcttcattattcccagattctttgattgtcaaag 60
gatttaatgttgtctcagcttgggcacttcagttaggacctaaggatgccagccggcagg 120
tttatatatgcagcaacaatattcaagcgcgacaacaggttattgaacttgcccgccagt 180
tgaatttcattcccattgacttgggatccttatcatcagccanagagattgaaaatttac 240
ccctacgactctttactctctggagagggccagtggtggtagctataagcttggccacat 300
ttttttttcctttattcctttgtcagagatgcgattcatccatatgctanaaaccaacag 360
agtgacttttacaaaattcctataganattgtgaataaaaccttacctatagttgccatt 420
actttgctctccctaatatacctc 444
<210> 215
<211> 366
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (366)
<223> n = A,T,C or G
<400>
215
acttatgagcagagcgacatatccaagtgtanactgaataaaactgaattctctccagtt 60
taaagcattgctcactgaagggatagaagtgactgccaggagggaaagtaagccaaggct 120
cattatgccaaagganatatacatttcaattctccaaacttcttcctcattccaagagtt 180
ttcaatatttgcatgaacctgctgataagccatgttgagaaacaaatatctctctgacct 240
tctcatcggtaagcagaggctgtaggcaacatggaccatagcgaanaaaaaacttagtaa 300
tccaagctgttttctacactgtaaccaggtttccaaccaaggtggaaatctcctatactt 360
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
76
ggtgcc 366
<210> 216
<211> 260
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(260)
<223> n = A,T,C or G
<400> 216
ctgtataaacagaactccactgcangagggagggccgggccaggagaatctccgcttgtc 60
caagacaggggcctaaggagggtctccacactgctnntaagggctnttncatttttttat 120
taataaaaagtnnaaaaggcctcttctcaacttttttcccttnggctggaaaatttaaaa 180
atcaaaaatttcctnaagttntcaagctatcatatatactntatcctgaaaaagcaacat 240
aattcttccttccctccttt 260
<210> 217
<211> 262
<212> DNA
<213> Homo sapien
<220>
<221> mi.sc_feature
<222> (1). .(262)
<223> n = A,T,C or G
<400> 217
acctacgtgggtaagtttanaaatgttataatttcaggaanaggaacgcatataattgta 60
tcttgcctataattttctattttaataaggaaatagcaaattggggtggggggaatgtag 120
ggcattctacagtttgagcaaaatgcaattaaatgtggaaggacagcactgaaaaatttt 180
atgaataatctgtatgattatatgtctctagagtagatttataattagccacttacccta 240
atatccttcatgcttgtaaagt 262
<210> 218
<211> 205
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(205)
<223> n = A,T,C or G
<400> 218
accaaggtgg tgcattaccg gaantggatc aangacacca tcgtggccaa cccctgagca 60
cccctatcaa ctcccttttg tagtaaactt ggaaccttgg aaatgaccag gccaagactc 120
aggcctcccc agttctactg acctttgtcc ttangtntna ngtccagggt tgctaggaaa 180
anaaatcagc agacacaggt gtaaa 205
<210> 219
<211> 114
<212> DNA
<213> Homo sapien
<400> 219
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
77
tactgttttg tctcagtaac aataaataca aaaagactgg ttgtgttccg gccccatcca 60
accacgaagt tgatttctct tgtgtgcaga gtgactgatt ttaaaggaca tgga 114
<210> 220
<211> 93
<212> DNA
<213> Homo sapien
<400> 220
actagccagc acaaaaggca gggtagcctg aattgctttc tgctctttac atttctttta 60
aaataagcat ttagtgctca gtccctactg agt 93
<210> 221
<211> 167
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(167)
<223> n = A,T,C or G
<400> 221
actangtgca ggtgcgcaca aatatttgtc gatattccct tcatcttgga ttccatgagg 60
tcttttgccc agcctgtggc tctactgtag taagtttctg ctgatgagga gccagnatgc 120
cccccactac cttccctgac gctccccana aatcacccaa cctctgt 167
<210> 222
<211> 351
<212> DNA
<213> Homo sapien
<400> 222
agggcgtggtgcggagggcggtactgacctcattagtaggaggatgcattctggcacccc 60
gttcttcacctgtcccccaatccttaaaaggccatactgcataaagtcaacaacagataa 120
atgtttgctgaattaaaggatggatgaaaaaaattaataatgaatttttgcataatccaa 180
ttttctcttttatatttctagaagaagtttctttgagcctattagatcccgggaatcttt 240
taggtgagcatgattagagagcttgtaggttgcttttacatatatctggcatatttgagt 300
ctcgtatcaaaacaatagattggtaaaggtggtattattgtattgataagt 351
<210> 223
<211> 383
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(383)
<223> n = A,T,C or G
<400> 223
aaaacaaacaaacaaaaaaaacaattcttcattcagaaaaattatcttagggactgatat 60
tggtaattatggtcaatttaatwrtrttktggggcatttccttacattgtcttgacaaga 120
ttaaaatgtctgtgccaaaattttgtattttatttggagacttcttatcaaaagtaatgc 180
tgccaaaggaagtctaaggaattagtagtgttcccmtcacttgtttggagtgtgctattc 240
taaaagattttgatttcctggaatgacaattatattttaactttggtgggggaaanagtt 300
ataggaccacagtcttcacttctgatacttgtaaattaatcttttattgcacttgttttg 360
accattaagctatatgtttaaaa 383
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
78
<210> 224
<211> 320
<212> DNA
<213> Homo sapien
<400>
224
cccctgaaggcttcttgttagaaaatagtacagttacaaccaataggaacaacaaaaaga 60
aaaagtttgtgacattgtagtagggagtgtgtaccccttactccccatcaaaaaaaaaat 120
ggatacatggttaaaggataraagggcaatattttatcatatgttctaaaagagaaggaa 180
gagaaaatactactttctcraaatggaagcccttaaaggtgctttgatactgaaggacac 240
aaatgtggccgtccatcctcctttaragttgcatgacttggacacggtaactgttgcagt 300
tttaractcmgcattgtgac 320
<210> 225
<211> 1214
<212> DNA
<213> Homo sapien
<400> 225
gaggactgcagcccgcactcgcagccctggcaggcggcactggtcatggaaaacgaattg60
ttctgctcgggcgtcctggtgcatccgcagtgggtgctgtcagccgcacactgtttccag120
aactcctacaccatcgggctgggcctgcacagtcttgaggccgaccaagagccagggagc180
cagatggtggaggccagcctctccgtacggcacccagagtacaacagacccttgctcgct240
aacgacctcatgctcatcaagttggacgaatccgtgtccgagtctgacaccatccggagc300
atcagcattgcttcgcagtgccctaccgcggggaactcttgcctcgtttctggctggggt360
ctgctggcgaacggcagaatgcctaccgtgctgcagtgcgtgaacgtgtcggtggtgtct420
gaggaggtctgcagtaagctctatgacccgctgtaccaccccagcatgttctgcgccggc480
ggagggcaagaccagaaggactcctgcaacggtgactctggggggcccctgatctgcaac540
gggtacttgcagggccttgtgtctttcggaaaagccccgtgtggccaagttggcgtgcca600
ggtgtctacaccaacctctgcaaattcactgagtggatagagaaaaccgtccaggccagt660
taactctggggactgggaacccatgaaattgacccccaaatacatcctgcggaaggaatt720
caggaatatctgttcccagcccctcctccctcaggcccaggagtccaggcccccagcccc780
tcctccctcaaaccaagggtacagatccccagcccctcctccctcagacccaggagtcca840
gaccccccagcccctcctccctcagacccaggagtccagcccctcctccctcagacccag900
gagtccagaccccccagcccctcctccctcagacccaggggtccaggcccccaacccctc960
ctccctcagactcagaggtccaagcccccaacccctccttccccagacccagaggtccag1020
gtcccagcccctcctccctcagacccagcggtccaatgccacctagactctccctgtaca1080
cagtgcccccttgtggcacgttgacccaaccttaccagttggtttttcattttttgtccc1140
tttcccctagatccagaaataaagtctaagagaagcgcaaaaaaaaaaaaaaaaaaaaaa1200
aaaaaaaaaaaaaa 1214
<210> 226
<211> 119
<212> DNA
<213> Homo sapien
<400> 226
acccagtatg tgcagggaga cggaacccca tgtgacagcc cactccacca gggttcccaa 60
agaacctggc ccagtcataa tcattcatcc tgacagtggc aataatcacg ataaccagt 119
<210> 227
<211> 818
<212> DNA
<213> Homo sapien
<400> 227
acaattcata gggacgacca atgaggacag ggaatgaacc cggctctccc ccagccctga 60
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
79
tttttgctacatatggggtcccttttcattctttgcaaaaacactgggttttctgagaac 120
acggacggttcttagcacaatttgtgaaatctgtgtaraaccgggctttgcaggggagat 180
aattttcctcctctggaggaaaggtggtgattgacaggcagggagacagtgacaaggcta 240
gagaaagccacgctcggccttctctgaaccaggatggaacggcagacccctgaaaacgaa 300
gcttgtccccttccaatcagccacttctgagaacccccatctaacttcctactggaaaag 360
agggcctcctcaggagcagtccaagagttttcaaagataacgtgacaactaccatctaga 420
ggaaagggtgcaccctcagcagagaagccgagagcttaactctggtcgtttccagagaca 480
acctgctggctgtcttgggatgcgcccagcctttgagaggccactaccccatgaacttct 540
gccatccactggacatgaagctgaggacactgggcttcaacactgagttgtcatgagagg 600
gacaggctctgccctcaagccggctgagggcagcaaccactctcctcccctttctcacgc 660
aaagccattcccacaaatccagaccataccatgaagcaacgagacccaaacagtttggct 720
caagaggatatgaggactgtctcagcctggctttgggctgacaccatgcacacacacaag 780
gtccacttctaggttttcagcctagatgggagtcgtgt 818
<210> 228
<211> 744
<212> DNA
<213> Homo sapien
<400>
228
actggagacactgttgaacttgatcaagacccagaccaccccaggtctccttcgtgggat 60
gtcatgacgtttgacatacctttggaacgagcctcctccttggaagatggaagaccgtgt 120
tcgtggccgacctggcctctcctggcctgtttcttaagatgcggagtcacatttcaatgg 180
taggaaaagtggcttcgtaaaatagaagagcagtcactgtggaactaccaaatggcgaga 240
tgctcggtgcacattggggtgctttgggataaaagatttatgagccaactattctctggc 300
accagattctaggccagtttgttccactgaagcttttcccacagcagtccacctctgcag 360
gctggcagctgaatggcttgccggtggctctgtggcaagatcacactgagatcgatgggt 420
gagaaggctaggatgcttgtctagtgttcttagctgtcacgttggctccttccaggttgg 480
ccagacggtgttggccactcccttctaaaacacaggcgccctcctggtgacagtgacccg 540
ccgtggtatgccttggcccattccagcagtcccagttatgcatttcaagtttggggtttg 600
ttcttttcgttaatgttcctctgtgttgtcagctgtcttcatttcctgggctaagcagca 660
ttgggagat.gtggaccagagatccactccttaagaaccagtggcgaaagacactttcttt 720
cttcactctgaagtagctggtggt 744
<210> 229
<211> 300
<212> DNA
<213> Homo sapien
<400> 229
cgagtctggg ttttgtctat aaagtttgat ccctcctttt ctcatccaaa tcatgtgaac 60
cattacacat cgaaataaaa gaaaggtggc agacttgccc aacgccaggc tgacatgtgc 120
tgcagggttg ttgtttttta attattattg ttagaaacgt cacccacagt ccctgttaat 180
ttgtatgtga cagccaactc tgagaaggtc ctatttttcc acctgcagag gatccagtct 240
cactaggctc ctccttgccc tcacactgga gtctccgcca gtgtgggtgc ccactgacat 300
<210> 230
<211> 301
<212> DNA
<213> Homo sapien
<400> 230
cagcagaacaaatacaaatatgaagagtgcaaagatctcataaaatctatgctgaggaat 60
gagcgacagttcaaggaggagaagcttgcagagcagctcaagcaagctgaggagctcagg 120
caatataaagtcctggttcacactcaggaacgagagctgacccagttaagggagaagttg 180
cgggaagggagagatgcctccctctcattgaatgagcatctccaggccctcctcactccg 240
gatgaaccggacaagtcccaggggcaggacctccaagaaacagacctcggccgcgaccac 300
g 301
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
<210> 231
<211> 301
<212> DNA
<213> Homo sapien
<400>
231
gcaagcacgctggcaaatctctgtcaggtcagctccagagaagccattagtcattttagc 60
caggaactccaagtccacatccttggcaactggggacttgcgcaggttagccttgaggat 120
ggcaacacgggacttctcatcaggaagtgggatgtagatgagctgatcaagacggccagg 180
tctgaggatggcaggatcaatgatgtcaggccggttggtaccgccaatgatgaacacatt 240
tttttttgtggacatgccatccatttctgtcaggatctggttgatgactcggtcagcagc 300
c 301
<210> 232
<211> 301
<212> DNA
<213> Homo sapien
<400> 232
agtaggtatttcgtgagaagttcaacaccaaaactggaacatagttctccttcaagtgtt 60
ggcgacagcggggcttcctgattctggaatataactttgtgtaaattaacagccacctat 120
agaagagtccatctgctgtgaaggagagacagagaactctgggttccgtcgtcctgtcca 180
cgtgctgtaccaagtgctggtgccagcctgttacctgttctcactgaaaatctggctaat 240
gctcttgtgtatcacttctgattctgacaatcaatcaatcaatggcctagagcactgact 300
g 301
<210> 233
<211> 301
<212> DNA
<213> Homo sapien
<400> 233
atgactgacttcccagtaaggctctctaaggggtaagtaggaggatccacaggatttgag 60
atgctaaggccccagagatcgtttgatccaaccctcttattttcagaggggaaaatgggg 120
cctagaagttacagagcatctagctggtgcgctggcacccctggcctcacacagactccc 180
gagtagctgggactacaggcacacagtcactgaagcaggccctgttagcaattctatgcg 240
tacaaattaacatgagatgagtagagactttattgagaaagcaagagaaaatcctatcaa 300
c 301
<210> 234
<211> 301
<212> DNA
<213> Homo sapien
<400>
234
aggtcctacacatcgagactcatccatgattgatatgaatttaaaaattacaagcaaaga 60
cattttattcatcatgatgctttcttttgtttcttcttttcgttttcttctttttctttt 120
tcaatttcagcaacatacttctcaatttcttcaggatttaaaatcttgagggattgatct 180
cgcctcatgacagcaagttcaatgtttttgccacctgactgaaccacttccaggagtgcc 240
ttgatcaccagcttaatggtcagatcatctgcttcaatggcttcgtcagtatagttcttc 300
t 301
<210> 235
<211> 283
<212> DNA
<213> Homo sapien
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
81
<400> 235
tggggctgtgcatcaggcgggtttgagaaatattcaattctcagcagaagccagaatttg 60
aattccctcatcttttagggaatcatttaccaggtttggagaggattcagacagctcagg 120
tgctttcactaatgtctctgaacttctgtccctctttgttcatggatagtccaataaata 180
atgttatctttgaactgatgctcataggagagaatataagaactctgagtgatatcaaca 240
ttagggattcaaagaaatattagatttaagctcacactggtca 283
<210> 236
<211> 301
<212> DNA
<213> Homo sapien
<400>
236
aggtcctccaccaactgcctgaagcacggttaaaattgggaagaagtatagtgcagcata 60
aatacttttaaatcgatcagatttccctaacccacatgcaatcttcttcaccagaagagg 120
tcggagcagcatcattaataccaagcagaatgcgtaatagataaatacaatggtatatag 180
tgggtagacggcttcatgagtacagtgtactgtggtatcgtaatctggacttgggttgta 240
aagcatcgtgtaccagtcagaaagcatcaatactcgacatgaacgaatataaagaacacc 300
a 301
<210> 237
<211> 301
<212> DNA
<213> Homo sapien
<400> 237
cagtggtagtggtggtggacgtggcgttggtcgtggtgccttttttggtgcccgtcacaa 60
actcaatttttgttcgctcctttttggccttttccaatttgtccatctcaattttctggg 120
ccttggctaatgcctcatagtaggagtcctcagaccagccatggggatcaaacatatcct 180
ttgggtagttggtgccaagctcgtcaatggcacagaatggatcagcttctcgtaaatcta 240
gggttccgaaattctttcttcctttggataatgtagttcatatccattccctcctttatc 300
t 301
<210> 238
<211> 301
<212> DNA
<213> Homo sapien
<400> 238
gggcaggtttttttttttttttttttgatggtgcagacccttgctttatttgtctgactt 60
gttcacagttcagccccctgctcagaaaaccaacgggccagctaaggagaggaggaggca 120
ccttgagacttccggagtcgaggctctccagggttccccagcccatcaatcattttctgc 180
accccctgcctgggaagcagctccctggggggtgggaatgggtgactagaagggatttca 240
gtgtgggacccagggtctgttcttcacagtaggaggtggaagggatgactaatttcttta 300
t 301
<210> 239
<211> 239
<212> DNA
<213> Homo sapien
<400> 239
ataagcagct agggaattct ttatttagta atgtcctaac ataaaagttc acataactgc 60
ttctgtcaaa ccatgatact gagctttgtg acaacccaga aataactaag agaaggcaaa 120
cataatacct tagagatcaa gaaacattta cacagttcaa ctgtttaaaa atagctcaac 180
attcagccag tgagtagagt gtgaatgcca gcatacacag tatacaggtc cttcaggga 239
<210> 240
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
82
<211> 300
<212> DNA
<213> Homo sapien
<400> 240
ggtcctaatgaagcagcagcttccacattttaacgcaggtttacggtgatactgtccttt 60
gggatctgccctccagtggaaccttttaaggaagaagtgggcccaagctaagttccacat 120
gctgggtgagccagatgacttctgttccctggtcactttcttcaatggggcgaatggggg 180
ctgccaggtttttaaaatcatgcttcatcttgaagcacacggtcacttcaccctcctcac 240
gctgtgggtgtactttgatgaaaatacccactttgttggcctttctgaagctataatgtc 300
<210> 241
<211> 301
<212> DNA
<213> Homo sapien
<400>
241
gaggtctggtgctgaggtctctgggctaggaagaggagttctgtggagctggaagccaga 60
cctctttggaggaaactccagcagctatgttggtgtctctgagggaatgcaacaaggctg 120
ctcctccatgtattggaaaactgcaaactggactcaactggaaggaagtgctgctgccag 180
tgtgaagaaccagcctgaggtgacagaaacggaagcaaacaggaacagccagtcttttct 240
tcctcctcctgtcatacggtctctctcaagcatcctttgttgtcaggggcctaaaaggga 300
g 301
<210> 242
<211> 301
<212> DNA
<213> Homo sapien
<400>
242
ccgaggtcctgggatgcaaccaatcactctgtttcacgtgacttttatcaccatacaatt 60
tgtggcatttcctcattttctacattgtagaatcaagagtgtaaataaatgtatatcgat 120
gtcttcaagaatatatcattcctttttcactagaacccattcaaaatataagtcaagaat 180
cttaatatcaacaaatatatcaagcaaactggaaggcagaataactaccataatttagta 240
taagtacccaaagttttataaatcaaaagccctaatgataaccatttttagaattcaatc 300
a 301
<210> 243
<211> 301
<212> DNA
<213> Homo sapien
<400> 243
aggtaagtcccagtttgaagctcaaaagatctggtatgagcataggctcatcgacgacat 60
ggtggcccaagctatgaaatcagagggaggcttcatctgggcctgtaaaaactatgatgg 120
tgacgtgcagtcggactctgtggcccaagggtatggctctctcggcatgatgaccagcgt 180
gctggtttgtccagatggcaagacagtagaagcagaggctgcccacgggactgtaacccg 240
tcactaccgcatgttccagaaaggacaggagacgtccaccaatcccattgcttccatttt 300
t 301
<210> 244
<211> 300
<212> DNA
<213> Homo sapien
<400> 244
gctggtttgc aagaatgaaa tgaatgattc tacagctagg acttaacctt gaaatggaaa 60
gtcatgcaat cccatttgca ggatctgtct gtgcacatgc ctctgtagag agcagcattc 120
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
83
ccagggacct tggaaacagt tgacactgta aggtgcttgc tccccaagac acatcctaaa 180
aggtgttgta atggtgaaaa cgtcttcctt ctttattgcc ccttcttatt tatgtgaaca 240
actgtttgtc ttttgtgtat cttttttaaa ctgtaaagtt caattgtgaa aatgaatatc 300
<210> 245
<211> 301
<212> DNA
<213> Homo sapien
<400> 245
gtctgagtatttaaaatgttattgaaattatccccaaccaatgttagaaaagaaagaggt 60
tatatacttagataaaaaatgaggtgaattactatccattgaaatcatgctcttagaatt 120
aaggccaggagatattgtcattaatgtaracttcaggacactagagtatagcagccctat 180
gttttcaaagagcagagatgcaattaaatattgtttagcatcaaaaaggccactcaatac 240
agctaataaaatgaaagacctaatttctaaagcaattctttataatttacaaagttttaa 300
g 301
<210> 246
<211> 301
<212> DNA
<213> Homo sapien
<400> 246
ggtctgtcctacaatgcctgcttcttgaaagaagtcggcactttctagaatagctaaata 60
acctgggcttattttaaagaactatttgtagctcagattggttttcctatggctaaaata 120
agtgcttcttgtgaaaattaaataaaacagttaattcaaagccttgatatatgttaccac 180
taacaatcatactaaatatattttgaagtacaaagtttgacatgctctaaagtgacaacc 240
caaatgtgtcttacaaaacacgttcctaacaaggtatgctttacactaccaatgcagaaa 300
c 301
<210> 247
<211> 301
<212> DNA
<213> Homo sapien
<400> 247
aggtcctttggcagggctcatggatcagagctcaaactggagggaaaggcatttcgggta 60
gcctaagagggcgactggcggcagcacaaccaaggaaggcaaggttgtttcccccacgct 120
gtgtcctgtgttcaggtgcgacacacaatcctcatgggaacaggatcacccatgcgctgc 180
ccttgatgatcaaggttggggcttaagtggattaagggaggcaagttctgggttccttgc 240
cttttcaaaccatgaagtcaggctctgtatccctccttttcctaactgatattctaacta 300
a 301
<210> 248
<211> 301
<212> DNA
<213> Homo sapien
<400>
248
aggtccttggagatgccatttcagccgaaggactcttctwttcggaagtacaccctcact 60
attaggaagattcttaggggtaatttttctgaggaaggagaactagccaacttaagaatt 120
acaggaagaaagtggtttggaagacagccaaagaaataaaagcagattaaattgtatcag 180
gtacattccagcctgttggcaactccataaaaacatttcagattttaatcccgaatttag 240
ctaatgagactggatttttgttttttatgttgtgtgtcgcagagctaaaaactcagttcc 300
c 301
<210> 249
<211> 301
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
84
<212> DNA
<213> Homo sapien
<400>
249
gtccagaggaagcacctggtgctgaactaggcttgccctgctgtgaacttgcacttggag 60
ccctgacgctgctgttctccccgaaaaacccgaccgacctccgcgatctccgtcccgccc 120
ccagggagacacagcagtgactcagagctggtcgcacactgtgcctccctcctcaccgcc 180
catcgtaatgaattattttgaaaattaattccaccatcctttcagattctggatggaaag 240
actgaatctttgactcagaattgtttgctgaaaagaatgatgtgactttcttagtcattt 300
a 301
<210> 250
<211> 301
<212> DNA
<213> Homo sapien
<400>
250
ggtctgtgacaaggacttgcaggctgtgggaggcaagtgacccttaacactacacttctc 60
cttatctttattggcttgataaacataattatttctaacactagcttatttccagttgcc 120
cataagcacatcagtacttttctctggctggaatagtaaactaaagtatggtacatctac 180
ctaaaagactactatgtggaataatacatactaatgaagtattacatgatttaaagacta 240
caataaaaccaaacatgcttataacattaagaaaaacaataaagatacatgattgaaacc 300
a 301
<210> 251
<211> 301
<212> DNA
<213> Homo sapien
<400> 251
gccgaggtcctacatttggcccagtttccccctgcatcctctccagggcccctgcctcat 60
agacaacctcatagagcataggagaactggttgccctgggggcagggggactgtctggat 120
ggcaggggtcctcaaaaatgccactgtcactgccaggaaatgcttctgagcagtacacct 180
cattgggatcaatgaaaagcttcaagaaatcttcaggctcactctcttgaaggcccggaa 240
cctctggaggggggcagtggaatcccagctccaggacggatcctgtcgaaaagatatcct 300
c 301
<210> 252
<211> 301
<212> DNA
<213> Homo sapien
<400> 252
gcaaccaatcactctgtttcacgtgacttttatcaccatacaatttgtggcatttcctca 60
ttttctacattgtagaatcaagagtgtaaataaatgtatatcgatgtcttcaagaatata 120
tcattcctttttcactaggaacccattcaaaatataagtcaagaatcttaatatcaacaa 180
atatatcaagcaaactggaaggcagaataactaccataatttagtataagtacccaaagt 240
tttataaatcaaaagccctaatgataaccatttttagaattcaatcatcactgtagaatc 300
a 301
<210> 253
<211> 301
<212> DNA
<213> Homo sapien
<400> 253
ttccctaaga agatgttatt ttgttgggtt ttgttccccc tccatctcga ttctcgtacc 60
caactaaaaa aaaaaaataa agaaaaaatg tgctgcgttc tgaaaaataa ctccttagct 120
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
tggtctgatt gttttcagac cttaaaatat aaacttgttt cacaagcttt aatccatgtg 180
gatttttttt cttagagaac cacaaaacat aaaaggagca agtcggactg aatacctgtt 240
tccatagtgc ccacagggta ttcctcacat tttctccata ggaaaatgct ttttcccaag 300
g 301
<210> 254
<211> 301
<212> DNA
<213> Homo sapien
<400>
254
cgctgcgcctttcccttgggggaggggcaaggccagagggggtccaagtgcagcacgagg 60
aacttgaccaattcccttgaagcgggtgggttaaaccctgtaaatgggaacaaaatcccc 120
ccaaatctcttcatcttaccctggtggactcctgactgtagaattttttggttgaaacaa 180
gaaaaaaataaagctttggacttttcaaggttgcttaacaggtactgaaagactggcctc 240
acttaaactgagccaggaaaagctgcagatttattaatgggtgtgttagtgtgcagtgcc 300
t 301
<210> 255
<211> 302
<212> DNA
<213> Homo sapien
<400> 255
agctttttttttttttttttttttttttttttcattaaaaaatagtgctctttattataa 60
attactgaaatgtttcttttctgaatataaatataaatatgtgcaaagtttgacttggat 120
tgggattttgttgagttcttcaagcatctcctaataccctcaagggcctgagtagggggg 180
aggaaaaaggactggaggtggaatctttataaaaaacaagagtgattgaggcagattgta 240
aacattattaaaaaacaagaaacaaacaaaaaaatagagaaaaaaaccaccccaacacac 300
as 302
<210> 256
<211> 301
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (301)
<223> n = A,T,C or G
<400> 256
gttccagaaaacattgaaggtggcttcccaaagtctaactagggataccccctctagcct 60
aggaccctcctccccacacctcaatccaccaaaccatccataatgcacccagataggccc 120
acccccaaaagcctggacaccttgagcacacagttatgaccaggacagactcatctctat 180
aggcaaatagctgctggcaaactggcattacctggtttgtggggatgggggggcaagtgt 240
gtggcctctcggcctggttagcaagaacattcagggtaggcctaagttantcgtgttagt 300
t 301
<210> 257
<211> 301
<212> DNA
<213> Homo sapien
<400> 257
gttgtggagg aactctggct tgctcattaa gtcctactga ttttcactat cccctgaatt 60
tccccactta tttttgtctt tcactatcgc aggccttaga agaggtctac ctgcctccag 120
tcttacctag tccagtctac cccctggagt tagaatggcc atcctgaagt gaaaagtaat 180
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
86
gtcacattac tcccttcagt gatttcttgt agaagtgcca atccctgaat gccaccaaga 240
tcttaatctt cacatcttta atcttatctc tttgactcct ctttacaccg gagaaggctc 300
c 301
<210> 258
<211> 301
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (301)
<223> n = A,T,C or G
<400>
258
cagcagtagtagatgccgtatgccagcacgcccagcactcccaggatcagcaccagcacc 60
aggggcccagccaccaggcgcagaagcaagataaacagtaggctcaagaccagagccacc 120
cccagggcaacaagaatccaataccaggactgggcaaaatcttcaaagatcttaacactg 180
atgtctcgggcattgaggctgtcaataanacgctgatcccctgctgtatggtggtgtcat 240
tggtgatccctgggagcgccggtggagtaacgttggtccatggaaagcagcgcccacaac 300
t 301
<210> 259
<211> 301
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(301)
<223> n = A,T,C or G
<400> 259
tcatatatgcaaacaaatgcagactangcctcaggcagagactaaaggacatctcttggg 60
gtgtcctgaagtgatttggacccctgagggcagacacctaagtaggaatcccagtgggaa 120
gcaaagccataaggaagcccaggattccttgtgatcaggaagtgggccaggaaggtctgt 180
tccagctcacatctcatctgcatgcagcacggaccggatgcgcccactgggtcttggctt 240
ccctcccatcttctcaagcagtgtccttgttgagccatttgcatccttggctccaggtgg 300
c 301
<210> 260
<211> 301
<212> DNA
<213> Homo sapien
<400> 260
ttttttttctccctaaggaaaaagaaggaacaagtctcataaaaccaaataagcaatggt 60
aaggtgtcttaacttgaaaaagattaggagtcactggtttacaagttataattgaatgaa 120
agaactgtaacagccacagttggccatttcatgccaatggcagcaaacaacaggattaac 180
tagggcaaaataaataagtgtgtggaagccctgataagtgcttaataaacagactgattc 240
actgagacatcagtacctgcccgggcggccgctcgagccgaattctgcagatatccatca 300
c 301
<210> 261
<211> 301
<212> DNA
<213> Homo sapien
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
87
<400>
261
aaatattcgagcaaatcctgtaactaatgtgtctccataaaaggctttgaactcagtgaa 60
tctgcttccatccacgattctagcaatgacctctcggacatcaaagctcctcttaaggtt 120
agcaccaactattccatacaattcatcagcaggaaataaaggctcttcagaaggttcaat 180
ggtgacatccaatttcttctgataatttagattcctcacaaccttcctagttaagtgaag 240
ggcatgatgatcatccaaagcccagtggtcacttactccagactttctgcaatgaagatc 300
a 301
<210> 262
<211> 301
<212> DNA
<213> Homo sapien
<400> 262
gaggagagcctgttacagcatttgtaagcacagaatactccaggagtatttgtaattgtc 60
tgtgagcttcttgccgcaagtctctcagaaatttaaaaagatgcaaatccctgagtcacc 120
cctagacttcctaaaccagatcctctggggctggaacctggcactctgcatttgtaatga 180
gggctttctggtgcacacctaattttgtgcatctttgccctaaatcctggattagtgccc 240
catcattacccccacattataatgggatagattcagagcagatactctccagcaaagaat 300
C 301
<210> 263
<211> 301
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(301)
<223> n = A,T,C or G
<400> 263
tttagcttgtggtaaatgactcacaaaactgattttaaaatcaagttaatgtgaattttg 60
aaaattactacttaatcctaattcacaataacaatggcattaaggtttgacttgagttgg 120
ttcttagtattatttatggtaaataggctcttaccacttgcaaataactggccacatcat 180
taatgactgacttcccagtaaggctctctaaggggtaagtangaggatccacaggatttg 240
agatgctaaggccccagagatcgtttgatccaaccctcttattttcagaggggaaaatgg 300
g 301
<210> 264
<211> 301
<212> DNA
<213> Homo sapien
<400>
264
aaagacgttaaaccactctactaccacttgtggaactctcaaagggtaaatgacaaascc 60
aatgaatgactctaaaaacaatatttacatttaatggtttgtagacaataaaaaaacaag 120
gtggatagatctagaattgtaacattttaagaaaaccatascatttgacagatgagaaag 180
ctcaattatagatgcaaagttataactaaactactatagtagtaaagaaatacatttcac 240
acccttcatataaattcactatcttggcttgaggcactccataaaatgtatcacgtgcat 300
a 301
<210> 265
<211> 301
<212> DNA
<213> Homo sapien
<400> 265
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
88
tgcccaagttatgtgtaagtgtatccgcacccagaggtaaaactacactgtcatctttgt 60
cttcttgtgacgcagtatttcttctctggggagaagccgggaagtcttctcctggctcta 120
catattcttggaagtctctaatcaacttttgttccatttgtttcatttcttcaggaggga 180
ttttcagtttgtcaacatgttctctaacaacacttgcccatttctgtaaagaatccaaag 240
cagtccaaggctttgacatgtcaacaaccagcataactagagtatccttcagagatacgg 300
c 301
<210> 266
<211> 301
<212> DNA
<213> Homo sapien
<400> 266
taccgtctgcccttcctcccatccaggccatctgcgaatctacatgggtcctcctattcg 60
acaccagatcactctttcctctacccacaggcttgctatgagcaagagacacaacctcct 120
ctcttctgtgttccagcttcttttcctgttcttcccaccccttaagttctattcctgggg 180
atagagacaccaatacccataacctctctcctaagcctccttataacccagggtgcacag 240
cacagactcctgacaactggtaaggccaatgaactgggagctcacagctggctgtgcctg 300
a 301
<210> 267
<211> 301
<212> DNA
<213> Homo sapien
<400> 267
aaagagcacaggccagctcagcctgccctggccatctagactcagcctggctccatgggg 60
gttctcagtgctgagtccatccaggaaaagctcacctagaccttctgaggctgaatcttc 120
atcctcacaggcagcttctgagagcctgatattcctagccttgatggtctggagtaaagc 180
ctcattctgattcctctccttcttttctttcaagttggctttcctcacatccctctgttc 240
aattcgcttcagcttgtctgctttagccctcatttccagaagcttcttctctttggcatc 300
t 301
<210> 268
<211> 301
<212> DNA
<213> Homo sapien
<400>
268
aatgtctcactcaactacttcccagcctaccgtggcctaattctgggagttttcttctta 60
gatcttgggagagctggttcttctaaggagaaggaggaaggacagatgtaactttggatc 120
tcgaagaggaagtctaatggaagtaattagtcaacggt.ccttgtttagactcttggaata 180
tgctgggtggctcagtgagcccttttggagaaagcaagtattattcttaaggagtaacca 240
cttcccattgttctactttctaccatcatcaattgtatattatgtattctttggagaact 300
a 301
<210> 269
<211> 301
<212> DNA
<213> Homo sapien
<400> 269
taacaatatacactagctatctttttaactgtccatcattagcaccaatgaagattcaat 60
aaaattacctttattcacacatctcaaaacaattctgcaaattcttagtgaagtttaact 120
atagtcacagaccttaaatattcacattgttttctatgtctactgaaaataagttcacta 180
cttttctggatattctttacaaaatcttattaaaattcctggtattatcacccccaatta 240
tacagtagcacaaccaccttatgtagtttttacatgatagctctgtagaagtttcacatc 300
t 301
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
89
<210> 270
<211> 301
<212> DNA
<213> Homo sapien
<400>
270
cattgaagagcttttgcgaaacatcagaacacaagtgcttataaaattaattaagcctta 60
cacaagaatacatattccttttatttctaaggagttaaacatagatgtagctgatgtgga 120
gagcttgctggtgcagtgcatattggataacactattcatggccgaattgatcaagtcaa 180
ccaactccttgaactggatcatcagaagaagggtggtgcacgatatactgcactagataa 240
tggaccaaccaactaaattctctcaccaggctgtatcagtaaactggcttaacagaaaac 300
a 301
<210> 271
<211> 301
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(301)
<223> n = A,T,C or G
<400> 271
aaaaggttctcataagattaacaatttaaataaatatttgatagaacattctttctcatt 60
tttatagctcatctttagggttgatattcagttcatgcttcccttgctgttcttgatcca 120
gaaLtgcaatcacttcatcagcctgtattcgctccaattctctataaagtgggtccaagg 180
tgaaccacagagccacagcacacctctttcccttggtgactgccttcaccccatganggt 240
tctctcctccagatganaactgatcatgcgcccacattttgggttttatagaagcagtca 300
c 301
<210> 272
<211> 301
<212> DNA
<213> Homo sapien
<400> 272
~
taaattgctaagccacagataacaccaatcaaatggaacaaatcactgtcttcaaatgtc 60
ttatcagaaaaccaaatgagcctggaatcttcataatacctaaacatgccgtatttagga 120
tccaataattccctcatgatgagcaagaaaaattctttgcgcacccctcctgcatccaca 180
gcatcttctccaacaaatataaccttgagtggcttcttgtaatctatgttctttgttttc 240
ctaaggacttccattgcatctcctacaatattttctctacgcaccactagaattaagcag 300
g 301
<210> 273
<211> 301
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (301)
<223> n = A,T,C or G
<400> 273
acatgtgtgt atgtgtatct ttgggaaaan aanaagacat cttgtttayt atttttttgg 60
agagangctg ggacatggat aatcacwtaa tttgctayta tyactttaat ctgactygaa 120
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
gaaccgtcta aaaataaaat ttaccatgtc dtatattcct tatagtatgc ttatttcacc 180
ttytttctgt ccagagagag tatcagtgac ananatttma gggtgaamac atgmattggt 240
gggacttnty tttacngagm accctgcccg sgcgccctcg makcngantt ccgcsananc 300
t 301
<210> 274
<211> 301
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(301)
<223> n = A,T,C or G
<400>
274
cttatatactctttctcagaggcaaaagaggagatgggtaatgtagacaattctttgagg 60
aacagtaaatgattattagagagaangaatggaccaaggagacagaaattaacttgtaaa 120
tgattctctttggaatctgaatgagatcaagaggccagctttagcttgtggaaaagtcca 180
tctaggtatggttgcattctcgtcttcttttctgcagtagataatgaggtaaccgaaggc 240
aattgtgcttcttttgataagaagctttcttggtcatatcaggaaattccaganaaagtc 300
c 301
<210> 275
<211> 301
<2:12> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(301)
<223> n = A,T,C or G
<400> 275
tcggtgtcagcagcacgtggcattgaacattgcaatgtggagcccaaaccacagaaaatg 60
gggtgaaattggccaactttctattaacttatgttggcaattttgccaccaacagtaagc 120
tggcccttctaataaaagaaaattgaaaggtttctcactaaacggaattaagtagtggag 180
tcaagagactcccaggcctcagcgtacctgcccgggcggccgctcgaagccgaattctgc 240
agatatccatcacactggcggncgctcgancatgcatctagaaggnccaattcgccctat 300
a 301
<210> 276
<211> 301
<212> DNA
<213> Homo sapien
<400> 276
tgtacacatactcaataaataaatgactgcattgtggtattattactatactgattatat 60
ttatcatgtgacttctaattagaaaatgtatccaaaagcaaaacagcagatatacaaaat 120
taaagagacagaagatagacattaacagataaggcaacttatacattgagaatccaaatc 180
caatacatttaaacatttgggaaatgagggggacaaatggaagccagatcaaatttgtgt 240
aaaactattcagtatgtttcccttgcttcatgtctgagaaggctctccttcaatggggat 300
g 301
<210> 277
<211> 301
<212> DNA
<213> Homo sapien
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
91
<2zo>
<221> misc_feature
<222> (1). .(301)
<223> n = A,T,C or G
<400>
277
tttgttgatgtcagtattttattacttgcgttatgagtgctcacctgggaaattctaaag 60
atacagaggacttggaggaagcagagcaactgaatttaatttaaaagaaggaaaacattg 120
gaatcatggcactcctgatactttcccaaatcaacactctcaatgccccaccctcgtcct 180
caccatagtggggagactaaagtggccacggatttgccttangtgtgcagtgcgttctga 240
gttcnctgtcgattacatctgaccagtctcctttttccgaagtccntccgttcaatcttg 300
c 301
<210> 278
<211> 301
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(301)
<223> n = A,T,C or G
<400> 278
taccactacactccagcctgggcaacagagcaagacctgtctcaaagcataaaatggaat 60
aacatatcaaatgaaacagggaaaatgaagctgacaatttatggaagccagggcttgtca 120
cagtctctactgttattatgcattacctgggaatttatataagcccttaataataatgc~~180
aatgaacatctcatgtgtgctcacaatgttctggcactattataagtgcttcacaggttt 24U
tatgtgttcttcgtaactttatggantaggtactcggccgcgaacacgctaagccgaatt 300
c 301
<210> 279
<211> 301
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (301)
<223> n = A,T,C or G
<400> 279
aaagcaggaatgacaaagcttgcttttctggtatgttctaggtgtattgtgacttttact 60
gttatattaattgccaatataagtaaatatagattatatatgtatagtgtttcacaaagc 120
ttagacctttaccttccagccaccccacagtgcttgatatttcagagtcagtcattggtt 180
atacatgtgtagttccaaagcacataagctagaanaanaaatatttctagggagcactac 240
catctgttttcacatgaaatgccacacacatagaactccaacatcaatttcattgcacag 300
a 301
<210> 280
<211> 301
<212> DNA
<213> Homo sapien
<400> 280
ggtactggag ttttcctccc ctgtgaaaac gtaactactg ttgggagtga attgaggatg 60
tagaaaggtg gtggaaccaa attgtggtca atggaaatag gagaatatgg ttctcactct 120
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
92
tgagaaaaaa acctaagatt agcccaggta gttgcctgta acttcagttt ttctgcctgg 180
gtttgatata gtttagggtt ggggttagat taagatctaa attacatcag gacaaagaga 240
cagactatta actccacagt taattaagga ggtatgttcc atgtttattt gttaaagcag 300
t 301
<210> 281
<211> 301
<212> DNA
<213> Homo sapien
<400> 281
aggtacaagaaggggaatgggaaagagctgctgctgtggcattgttcaacttggatattc 60
gccgagcaatccaaatcctgaatgaaggggcatcttctgaaaaaggagatctgaatctca 120
atgtggtagcaatggctttatcgggttatacggatgagaagaactccctttggagagaaa 180
tgtgtagcacactgcgattacagctaaataacccgtatttgtgtgtcatgtttgcatttc 240
tgacaagtgaaacaggatcttacgatggagttttgtatgaaaacaaagttgcagtacctc 3.00
g 301
<210> 282
<211> 301
<212> DNA
<213> Homo sapien
<400> 282
caggtactac agaattaaaa tactgacaag caagtagttt cttggcgtgc acgaattgca 60
tccagaaccc aaaaattaag aaattcaaaa agacattttg tgggcacctg ctagcacaga 120
agcgcagaag caaagcccag gcagaaccat gctaacctta cagctcagcc tgcacagaag 180
cgcagaagca aagcccaggc agaaccatgc taaccttaca gctcagcctg cacagaagcg 240
cagaagcaaa gcccaggcag aacatgctaa ccttacagct cagcctgcac agaagcacag 300
a 301
<210> 283
<211> 301
<212> DNA
<213> Homo sapien
<400> 283
atctgtatacggcagacaaactttataragtgtagagaggtgagcgaaaggatgcaaaag 60
cactttgagggctttataataatatgctgcttgaaaaaaaaaatgtgtagttgatactca 120
gtgcatctccagacatagtaaggggttgctctgaccaatcaggtgatcattttttctatc 180
acttcccaggttttatgcaaaaattttgttaaattctataatggtgatatgcatctttta 240
ggaaacatatacatttttaaaaatctattttatgtaagaactgacagacgaatttgcttt 300
g 301
<210> 284
<211> 301
<212> DNA
<213> Homo sapien
<400>
284
caggtacaaaacgctattaagtggcttagaatttgaacatttgtggtctttatttacttt 60
gcttcgtgtgtgggcaaagcaacatcttccctaaatatatattaccaagaaaagcaagaa 120
gcagattaggtttttgacaaaacaaacaggccaaaagggggctgacctggagcagagcat 180
ggtgagaggcaaggcatgagagggcaagtttgttgtggacagatctgtgcctactttatt 240
actggagtaaaagaaaacaaagttcattgatgtcgaaggatatatacagtgttagaaatt 300
a 301
<210> 285
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
93
<211> 301
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (301)
<223> n = A,T,C or G
<400> 285
acatcaccat gatcggatcc cccacccatt atacgttgta tgtttacata aatactcttc 60
aatgatcatt agtgttttaa aaaaaatact gaaaactcct tctgcatccc aatctctaac 120
caggaaagca aatgctattt acagacctgc aagccctccc tcaaacnaaa ctatttctgg 180
attaaatatg tctgacttct tttgaggtca cacgactagg caaatgctat ttacgatctg 240
caaaagctgt ttgaagagtc aaagccccca tgtgaacacg atttctggac cctgtaacag 300
t 301
<210> 286
<211> 301
<212> DNA
<213> Homo sapien
<400>
286
taccactgcattccagcctgggtgacagagtgagactccgtctccaaaaaaaactttgct 60
tgtatattatttttgccttacagtggatcattctagtaggaaaggacagtaagatttttt 120
atcaaaatgtgtcatgccagtaagagatgttatattcttttctcatttcttccccaccca 180
aaaataagctaccatatagcttataagtctcaaatttttgccttttactaaaatgtgatt 240
gtttctgttcattgtgtatgcttcatcacctatattaggcaaattccattttttcccttg 300
t 301
<210> 287
<211> 301
<212> DNA
<213> Homo sapien
<400> 287
tacagatctgggaactaaatattaaaaatgagtgtggctggatatatggagaatgttggg 60
cccagaaggaacgtagagatcagatattacaacagctttgttttgagggttagaaatatg 120
aaatgatttggttatgaacgcacagtttaggcagcagggccagaatcctgaccctctgcc 180
ccgtggttatctcctccccagcttggctgcctcatgttatcacagtattccattttgttt 240
gttgcatgtcttgtgaagccatcaagattttctcgtctgttttcctctcattggtaatgc 300
t 301
<210> 288
<211> 301
<212> DNA
<213> Homo sapien
<400> 288
gtacacctaactgcaaggacagctgaggaatgtaatgggcagccgcttttaaagaagtag 60
agtcaataggaagacaaattccagttccagctcagtctgggtatctgcaaagctgcaaaa 120
gatctttaaagacaatttcaagagaatatttccttaaagttggcaatttggagatcatac 180
aaaagcatctgcttttgtgatttaatttagctcatctggccactggaagaatccaaacag 240
tctgccttaattttggatgaatgcatgatggaaattcaataatttagaaagttaaaaaaa 300
a 301
<210> 289
<211> 301
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
94
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(301)
<223> n = A,T,C or G
<400> 289
ggtacactgtttccatgttatgtttctacacattgctacctcagtgctcctggaaactta 60
gcttttgatgtctccaagtagtccaccttcatttaactctttgaaactgtatcatctttg 120
ccaagtaagagtggtggcctatttcagctgctttgacaaaatgactggctcctgacttaa 180
cgttctataaatgaatgtgctgaagcaaagtgcccatggtggcggcgaanaagagaaaga 240
tgtgttttgttttggactctctgtggtcccttccaatgctgtgggtttccaaccagngga 300
a 301
<210> 290
<211> 301
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (301)
<223> n = A,T,C or G
<400>
290
acactgagctcttcttgataaatatacagaatgcttggcatatacaagattctatactac 60
tgactgatctgttcatttctctcacagctcttacccccaaaagcttttccaccctaagtg 120
ttctgacctccttttctaatcacagtagggatagaggcaganccacctacaatgaacatg 180
gagttctatcaagaggcagaaacagcacagaatcccagttttaccattcgctagcagtgc 240
tgccttgaacaaaaacatttctccatgtctcattttcttcatgcctcaagtaacagtgag 300
a 301
<210> 291
<211> 301
<212> DNA
<213> Homo sapien
<400> 291
caggtaccaatttcttctatcctagaaacatttcattttatgttgttgaaacataacaac 60
tatatcagctagattttttttctatgctttacctgctatggaaaatttgacacattctgc 120
tttactcttttgtttataggtgaatcacaaaatgtatttttatgtattctgtagttcaat 180
agccatggctgtttacttcatttaatttatttagcataaagacattatgaaaaggcctaa 240
acatgagcttcacttccccactaactaattagcatctgttatttcttaaccgtaatgcct 300
a 301
<210> 292
<211> 301
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (301)
<223> n = A,T,C or G
<400> 292
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
accttttagt agtaatgtct aataataaat aagaaatcaa ttttataagg tccatatagc 60
tgtattaaat aatttttaag tttaaaagat aaaataccat cattttaaat gttggtattc 120
aaaaccaaag natataaccg aaaggaaaaa cagatgagac ataaaatgat ttgcnagatg 180
ggaaatatag tasttyatga atgttnatta aattccagtt ataatagtgg ctacacactc 240
tcactacaca cacagacccc acagtcctat atgccacaaa cacatttcca taacttgaaa 300
a 301
<210> 293
<211> 301
<212> DNA
<213> Homo sapien
<400> 293
ggtaccaagtgctggtgccagcctgttacctgttctcactgaaaagtctggctaatgctc 60
ttgtgtagtcacttctgattctgacaatcaatcaatcaatggcctagagcactgactgtt 120
aacacaaacgtcactagcaaagtagcaacagctttaagtctaaatacaaagctgttctgt 180
gtgagaattttttaaaaggctacttgtataataacccttgtcatttttaatgtacctcgg 240
ccgcgaccacgctaagccgaattctgcagatatccatcacactggcggccgctcgagcat 300
g 301
<210> 294
<211> 301
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1)...(301)
<223> n = A,T,C or G
<400> 294
tgacccataacaatatacactagctatctttttaactgtccatcattagcaccaatgaag 60
attcaataaaattacctttattcacacatctcaaaacaattctgcaaattcttagtgaag 120
tttaactatagtcacagancttaaatattcacattgttttctatgtctactgaaaataag 180
ttcactacttttctgggatattctttacaaaatcttattaaaattcctggtattatcacc 240
cccaattatacagtagcacaaccaccttatgtagtttttacatgatagctctgtagaggt 300
t 301
<210> 295
<211> 305
<212> DNA
<213> Homo sapien
<400> 295
gtactctttctctcccctcctctgaatttaattctttcaacttgcaatttgcaaggatta 60
cacatttcactgtgatgtatattgtgttgcaaaaaaaaaagtgtctttgtttaaaattac 120
ttggtttgtgaatccatcttgctttttccccattggaactagtcattaacccatctctga 180
actggtagaaaaacrtctgaagagctagtctatcagcatctgacaggtgaattggatggt 240
tctcagaaccatttcacccagacagcctgtttctatcctgtttaataaattagtttgggt 300
tctct 305
<210> 296
<211> 301
<212> DNA
<213> Homo sapien
<400> 296
aggtactatg ggaagctgct aaaataatat ttgatagtaa aagtatgtaa tgtgctatct 60
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
96
cacctagtagtaaactaaaa ataaactgaaactttatggaatctgaagttattttccttg 120
attaaatagaattaataaac caatatgaggaaacatgaaaccatgcaatctactatcaac 180
tttgaaaaagtgattgaacg aaccacttagctttcagatgatgaacactgataagtcatt 240
tgtcattactataaatttta aaatctgttaataagatggcctatagggaggaaaaagggg 300
c 301
<210> 297
<211> 300
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(300)
<223> n = A,T,C or G
<400> 297
actgagttttaactggacgccaagcaggcaaggctggaaggttttgctctctttgtgcta 60
aaggttttgaaaaccttgaaggagaatcattttgacaagaagtacttaagagtctagaga 120
acaaagangtgaaccagctgaaagctctcgggggaancttacatgtgttgttaggcctgt 180
tccatcattgggagtgcactggccatccctcaaaatttgtctgggctggcctgagtggtc 240
accgcacctcggccgcgaccacgctaagccgaattctgcagatatccatcacactggcgg .300
<210> 298
<211> 301
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(301)
<223> n = A,T,C or G
<400>
298
tatggggtttgtcacccaaaagctgatgctgagaaaggcctccctggggcccctcccgcg 60
ggcatctgagagacctggtgttccagtgtttctggaaatgggtcccagtgccgccggctg 120
tgaagctctcagatcaatcacgggaagggcctggcggtggtggccacctggaaccaccct 180
gtcctgtctgtttacatttcactaycaggttttctctgggcattacnatttgttccccta 240
caacagtgacctgtgcattctgctgtggcctgctgtgtctgcaggtggctctcagcgagg 300
t 301
<210> 299
<211> 301
<212> DNA
<213> Homo sapien
<400> 299
gttttgagacggagtttcactcttgttgcccagactggactgcaatggcagggtctctgc 60
tcactgcaccctctgcctcccaggttcgagcaattctcctgcctcagcctcccaggtagc 120
tgggattgcaggctcacgccaccatacccagctaatttttttgtatttttagtagagacg 180
gagtttcgccatgttggccagctggtctcaaactcctgacctcaagcgacctgcctgcct 240
cggcctcccaaagtgctggaattataggcatgagtcaacacgcccagcctaaagatattt 300
t 301
<210> 300
<211> 301
<212> DNA
<213> Homo sapien
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
97
<400> 300
attcagttttatttgctgccccagtatctgtaaccaggagtgccacaaaatcttgccaga 60
tatgtcccacacccactgggaaaggctcccacctggctacttcctctatcagctgggtca 120
gctgcattccacaaggttctcagcctaatgagtttcactacctgccagtctcaaaactta 180
gtaaagcaagaccatgacattcccccacggaaatcagagtttgccccaccgtcttgttac 240
tataaagcctgcctctaacagtccttgcttcttcacaccaatcccgagcgcatcccccat 300
g 301
<210> 301
<211> 301
<212> DNA
<213> Homo sapien
<400> 301
ttaaatttttgagaggataaaaaggacaaataatctagaaatgtgtcttcttcagtctgc 60
agaggaccccaggtctccaagcaaccacatggtcaagggcatgaataattaaaagttggt 120
gggaactcacaaagaccctcagagctgagacacccacaacagtgggagctcacaaagacc 180
ctcagagctgagacacccacaacagtgggagctcacaaagaccctcagagctgagacacc 240
cacaacagcacctcgttcagctgccacatgtgtgaataaggatgcaatgtccagaagtgt 300
t 301
<210> 302
<211> 301
<212> DNA
<213> Homo sapien
<400> 302
aggtacacatttagcttgtggtaaatgactcacaaaactgattttaaaatcaagttaatg 60
tgaattttgaaaattactacttaatcctaattcacaataacaatggcattaaggtttgac 120
ttgagttggttcttagtattatttatggtaaataggctcttaccacttgcaaataactgg 180
ccacatcattaatgactgacttcccagtaaggctctctaaggggtaagtaggaggatcca 240
caggatttgagatgctaaggccccagagatcgtttgatccaaccctcttattttcagagg 300
.
g 301
<210> 303
<211> 301
<212> DNA
<213> Homo sapien
<400>
303
aggtaccaactgtggaaataggtagaggatcattttttctttccatatcaactaagttgt 60
atattgttttttgacagtttaacacatcttcttctgtcagagattctttcacaatagcac 120
tggctaatggaactaccgcttgcatgttaaaaatggtggtttgtgaaatgatcataggcc 180
agtaacgggtatgtttttctaactgatcttttgctcgttccaaagggacctcaagacttc 240
catcgattttatatctggggtctagaaaaggagttaatctgttttccctcataaattcac 300
c 301
<210> 304
<211> 301
<212> DNA
<213> Homo sapien
<400> 304
acatggatgt tattttgcag actgtcaacc tgaatttgta tttgcttgac attgcctaat 60
tattagtttc agtttcagct tacccacttt ttgtctgcaa catgcaraas agacagtgcc 120
ctttttagtg tatcatatca ggaatcatct cacattggtt tgtgccatta ctggtgcagt 180
gactttcagc cacttgggta aggtggagtt ggccatatgt ctccactgca aaattactga 240
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
98
ttttcctttt gtaattaata agtgtgtgtg tgaagattct ttgagatgag gtatatatct 300
c 301
<210> 305
<211> 301
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (301)
<223> n = A,T,C or G
<400>
305
gangtacagcgtggtcaaggtaacaagaagaaaaaaatgtgagtggcatcctgggatgag 60
cagggggacagacctggacagacacgttgtcatttgctgctgtgggtaggaaaatgggcg 120
taaaggaggagaaacagatacaaaatctccaactcagtattaaggtattctcatgcctag 180
aatattggtagaaacaagaatacattcatatggcaaataactaaccatggtggaacaaaa 240
ttctgggatttaagttggataccaangaaattgtattaaaagagctgttcatggaataag 300
a 301
<210> 306
<211> 8
<212> PRT
<213> Homo sapien
<400> 306
Val Leu Gly Trp Val Ala Glu Leu
1 5
<210> 307
<211> 637
<212> DNA
<213> Homo sapien
<400> 307
acagggratgaagggaaagggagaggatgaggaagcccccctggggatttggtttggtcc 60
ttgtgatcaggtggtctatggggcttatccctacaaagaagaatccagaaataggggcac 120
attgaggaatgatacttgagcccaaagagcattcaatcattgttttatttgccttmtttt 180
cacaccattggtgagggagggattaccaccctggggttatgaagatggttgaacacccca 240
cacatagcaccggagatatgagatcaacagtttcttagccatagagattcacagcccaga 300
gcaggaggacgcttgcacaccatgcaggatgacatgggggatgcgctcgggattggtgtg 360
aagaagcaaggactgttagaggcaggctttatagtaacaagacggtggggcaaactctga 420
tttccgtgggggaatgtcatggtcttgctttactaagttttgagactggcaggtagtgaa 480
actcattaggctgagaaccttgtggaatgcacttgacccasctgatagaggaagtagcca 540
ggtgggagcctttcccagtgggtgtgggacatatctggcaagattttgtggcactcctgg 600
ttacagatactggggcagcaaataaaactgaatcttg 637
<210> 308
<211> 647
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(647)
<223> n = A,T,C or G
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
99
<400>
308
acgattttcattatcatgtaaatcgggtcactcaaggggccaaccacagctgggagccac 60
tgctcaggggaaggttcatatgggactttctactgcccaaggttctatacaggatataaa 120
ggngcctcacagtatagatctggtagcaaagaagaagaaacaaacactgatctctttctg 180
ccacccctctgaccctttggaactcctctgaccctttagaacaagcctacctaatatctg 240
ctagagaaaagaccaacaacggcctcaaaggatctcttaccatgaaggtctcagctaatt 300
cttggctaagatgtgggttccacattaggttctgaatatggggggaagggtcaatttgct 360
cattttgtgtgtggataaagtcaggatgcccaggggccagagcagggggctgcttgcttt 420
gggaacaatggctgagcatataaccataggttatggggaacaaaacaacatcaaagtcac 480
tgtatcaattgccatgaagacttgagggacctgaatctaccgattcatcttaaggcagca 540
ggaccagtttgagtggcaacaatgcagcagcagaatcaatggaaacaacagaatgattgc 600
aatgtccttttttttctcctgcttctgacttgataaaaggggaccgt 647
<210> 309
<211> 460
<212> DNA
<213> Homo sapien
<400> 309
actttatagtttaggctggacattggaaaaaaaaaaaagccagaacaacatgtgatagat 60
aatatgattggctgcacacttccagactgatgaatgatgaacgtgatggactattgtatg 120
gagcacatcttcagcaagagggggaaatactcatcatttttggccagcagttgtttgatc 180
accaaacatcatgccagaatactcagcaaaccttcttagctcttgagaagtcaaagtccg 240
ggggaatttattcctggcaattttaattggactccttatgtgagagcagcggctacccag 300
ctggggtggtggagcgaacccgtcactagtggacatgcagtggcagagctcctggtaacc 360
acctagaggaatacacaggcacatgtgtgatgccaagcgtgacacctgtagcactcaaat 420
ttgtcttgtttttgtctttcggtgtgtaagattcttaagt 460
<210> 310
<211> 539
<212> DNA
<213> Homo sapien
<400>
310
acgggacttatcaaataaagataggaaaagaagaaaactcaaatattataggcagaaatg 60
ctaaaggttttaaaatatgtcaggattggaagaaggcatggataaagaacaaagttcagt 120
taggaaagagaaacacagaaggaagagacacaataaaagtcattatgtattctgtgagaa 180
gtcagacagtaagatttgtgggaaatgggttggtttgttgtatggtatgtattttagcaa 240
taatctttatggcagagaaagctaaaatcctttagcttgcgtgaatgatcacttgctgaa 300
ttcctcaaggtaggcatgatgaaggagggtttagaggagacacagacacaatgaactgac 360
ctagatagaaagccttagtatactcagctaggaatagtgattctgagggcacactgtgac 420
atgattatgtcattacatgtatggtagtgatggggatgataggaaggaagaacttatggc 480
atattttcacccccacaaaagtcagttaaatattgggacactaaccatccaggtcaaga 539
<210> 311
<211> 526
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(526)
<223> n = A,T,C or G
<400> 311
caaatttgag ccaatgacat agaattttac aaatcaagaa gcttattctg gggccatttc 60
ttttgacgtt ttctctaaac tactaaagag gcattaatga tccataaatt atattatcta 120
catttacagc atttaaaatg tgttcagcat gaaatattag ctacagggga agctaaataa 180
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
100
attaaacatggaataaagatttgtccttaaatataatctacaagaagactttgatatttg 240
tttttcacaagtgaagcattcttataaagtgtcataacctttttggggaaactatgggaa 300
aaaatggggaaactctgaagggttttaagtatcttacctgaagctacagactccataacc 360
tctctttacagggagctcctgcagcccctacagaaatgagtggctgagattcttgattgc 420
acagcaagagcttctcatctaaaccctttccctttttagtatctgtgtatcaagtataaa 480
agttctataaactgtagtntacttattttaatccccaaagcacagt 526
<210> 312
<211> 500
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (500)
<223> n = A,T,C or G
<400> 312
cctctctctccccaccccctgactctagagaactgggttttctcccagtactccagcaat 60
tcatttctgaaagcagttgagccactttattccaaagtacactgcagatgttcaaactct 120
ccatttctctttcccttccacctgccagttttgctgactctcaacttgtcatgagtgtaa 180
gcattaaggacattatgcttcttcgattctgaagacaggccctgctcatggatgactctg 240
gcttcttaggaaaatatttttcttccaaaatcagtaggaaatctaaacttatcccctctt 300
tgcagatgtctagcagcttcagacatttggttaagaacccatgggaaaaaaaaaaatcct 360
tgctaatgtggtttcctttgtaaaccangattcttatttgnctggtatagaatatcagct 420
ctgaacgtgtggtaaagatttttgtgtttgaatataggagaaatcagtttgctgaaaagt 480
tagtcttaattatctattgg 50.0
<210> 313
<211> 718
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(718)
<223> n = A,T,C or G
<400>
313
ggagatttgtgtggtttgcagccgagggagaccaggaagatctgcatggtgggaaggacc 60
tgatgatacagaggtgagaaataagaaaggctgctgactttaccatctgaggccacacat 120
ctgctgaaatggagataattaacatcactagaaacagcaagatgacaatataatgtctaa 180
gtagtgacatgtttttgcacatttccagcccttttaaatatccacacacacaggaagcac 240
aaaaggaagcacagagatccctgggagaaatgcccggccgccatcttgggtcatcgatga 300
gcctcgccctgtgcctgntcccgcttgtgagggaaggacattagaaaatgaattgatgtg 360
ttccttaaaggatggcaggaaaacagatcctgttgtggatatttatttgaacgggattac 420
agatttgaaatgaagtcacaaagtgagcattaccaatgagaggaaaacagacgagaaaat 480
cttgatggttcacaagacatgcaacaaacaaaatggaatactgtgatgacacgagcagcc 540
aactggggaggagataccacggggcagaggtcaggattctggccctgctgcctaactgtg 600
cgttataccaatcatttctatttctaccctcaaacaagctgtngaatatctgacttacgg 660
ttcttntggcccacattttcatnatccaccccntcnttttaannttantccaaantgt 718
<210> 314
<211> 358
<212> DNA
<213> Homo sapien
<400> 314
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
101
gtttatttacattacagaaaaaacatcaagacaatgtatactatttcaaatatatccata 60
cataatcaaatatagctgtagtacatgttttcattggtgtagattaccacaaatgcaagg 120
caacatgtgtagatctcttgtcttattcttttgtctataatactgtattgtgtagtccaa 180
gctctcggtagtccagccactgtgaaacatgctccctttagattaacctcgtggacgctc 240
ttgttgtattgctgaactgtagtgccctgtattttgcttctgtctgtgaattctgttgct 300
tctggggcatttccttgtgatgcagaggaccaccacacagatgacagcaatctgaatt 358
<210> 315
<211> 341
<212> DNA
<213> Homo sapien
<400> 315
taccacctccccgctggcactgatgagccgcatcaccatggtcaccagcaccatgaaggc 60
ataggtgatgatgaggacatggaatgggcccccaaggatggtctgtccaaagaagcgagt 120
gacccccattctgaagatgtctggaacctctaccagcaggatgatgatagccccaatgac 180
agtcaccagctccccgaccagccggatatcgtccttaggggtcatgtaggcttcctgaag 240
tagcttctgctgtaagagggtgttgtcccgggggctcgtgcggttattggtcctgggctt 300
gagggggcggtagatgcagcacatggtgaagcagatgatgt 341
<210> 316
<211> 151
<212> DNA
<213> Homo sapien
<400> 316
agact.gggca agactcttac gccccacact gcaatttggt cttgttgccg tatccattta 60
tgtgggcctt tctcgagttt ctgattataa acaccactgg agcgatgtgt tgactggact 120
cattcaggga gctctggttg caatattagt t 151
<210> 317
<211> 151
<212> DNA
<213> Homo sapien
<400> 317
agaactagtg gatcctaatg aaatacctga aacatatatt ggcatttatc aatggctcaa 60
atcttcattt atctctggcc ttaaccctgg ctcctgaggc tgcggccagc agatcccagg 120
ccagggctct gttcttgcca cacctgcttg a 151
<210> 318
<211> 151
<212> DNA
<213> Homo sapien
<400> 318
actggtggga ggcgctgttt agttggctgt tttcagaggg gtctttcgga gggacctcct 60
gctgcaggct ggagtgtctt tattcctggc gggagaccgc acattccact gctgaggctg 120
tgggggcggt ttatcaggca gtgataaaca t 151
<210> 319
<211> 151
<212> DNA
<213> Homo sapien
<400> 319
aactagtgga tccagagcta taggtacagt gtgatctcag ctttgcaaac acattttcta 60
catagatagt actaggtatt aatagatatg taaagaaaga aatcacacca ttaataatgg 120
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
102
taagattggg tttatgtgat tttagtgggt a 151
<210> 320
<211> 150
<212> DNA
<213> Homo sapien
<400> 320 '
aactagtgga tccactagtc cagtgtggtg gaattccatt gtgttggggt tctagatcgc 60
gagcggctgc cctttttttt tttttttttg ggggggaatt tttttttttt aatagttatt 120
gagtgttcta cagcttacag taaataccat 150
<210> 321
<211> 151
<212> DNA
<213> Homo sapien
<400> 321
agcaactttg tttttcatcc aggttatttt aggcttagga tttcctctca cactgcagtt 60
tagggtggca ttgtaaccag ctatggcata ggtgttaacc aaaggctgag taaacatggg 120
tgcctctgag aaatcaaagt cttcatacac t 151
<210> 322
<211> 151
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(151)
<223> n = A,T,C or G
<400> 322
atccagcatc ttctcctgtt tcttgccttc ctttttcttc ttcttasatt ctgcttgagg 60
tttgggcttg gtcagtttgc cacagggctt ggagatggtg acagtcttct ggcattcggc 120
attgtgcagg gctcgcttca nacttccagt t 151
<210> 323
<211> 151
<212> DNA
'<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(151)
<223> n = A,T,C or G
<400> 323
tgaggacttg tkttcttttt ctttattttt aatcctctta ckttgtaaat atattgccta 60
nagactcant tactacccag tttgtggttt twtgggagaa atgtaactgg acagttagct 120
gttcaatyaa aaagacactt ancccatgtg g 151
<210> 324
<211> 461
<212> DNA
<213> Homo sapien
<220>
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
103
<221> misc_feature
<222> (1). .(461)
<223> n = A,T,C or G
<400>
324
acctgtgtggaatttcagctttcctcatgcaaaaggattttgtatccccggcctacttga 60
agaagtggtcagctaaaggaatccaggttgttggttggactgttaatacctttgatgaaa 120
agagttactacgaatcccatcttggttccagctatatcactgacagcatggtagaagact 180
gcgaacctcacttctagactttcacggtgggacgaaacgggttcagaaactgccaggggc 240
ctcatacagggatatcaaaataccctttgtgctacccaggccctggggaatcaggtgact 300
cacacaaatgcaatagttggtcactgcatttttacctgaaccaaagctaaacccggtgtt 360
gccaccatgcaccatggcatgccagagttcaacactgttgctcttgaaaattgggtctga 420
aaaaacgcacaagagcccctgccctgccctagctgangcac 461
<210> 325
<211> 400
<212> DNA
<213> Homo sapien
<400> 325
acactgtttccatgttatgtttctacacattgctacctcagtgctcctggaaacttagct 60
tttgatgtctccaagtagtccaccttcatttaactctttgaaactgtatcatctttgcca 120
agtaagagtggtggcctatttcagctgctttgacaaaatgactggctcctgacttaacgt 180
tctataaatgaatgtgctgaagcaaagtgcccatggtggcggcgaagaagagaaagatgt 240
gttttgttttggactctctgtggtcccttccaatgctgtgggtttccaaccaggggaagg 300
gtcccttttgcattgccaagtgccataaccatgagcactacgctaccatggttctgcctc 360
ctggccaagcaggctggtttgcaagaatgaaatgaatgat 400
<210> 326
<211> 1215
<212> DNA
<213> Homo sapien
<400>
326
ggaggactgcagcccgcactcgcagccctggcaggcggcactggtcatggaaaacgaatt60
gttctgctcgggcgtcctggtgcatccgcagtgggtgctgtcagccgcacactgtttcca120
gaactcctacaccatcgggctgggcctgcacagtcttgaggccgaccaagagccagggag180
ccagatggtggaggccagcctctccgtacggcacccagagtacaacagacccttgctcgc240
taacgacctcatgctcatcaagttggacgaatccgtgtccgagtctgacaccatccggag300
catcagcattgcttcgcagtgccctaccgcggggaactcttgcctcgtttctggctgggg360
tctgctggcgaacggcagaatgcctaccgtgctgcagtgcgtgaacgtgtcggtggtgtc420
tgaggaggtctgcagtaagctctatgacccgctgtaccaccccagcatgttctgcgccgg480
cggagggcaagaccagaaggactcctgcaacggtgactctggggggcccctgatctgcaa540
cgggtacttgcagggccttgtgtctttcggaaaagccccgtgtggccaagttggcgtgcc600
aggtgtctacaccaacctctgcaaattcactgagtggatagagaaaaccgtccaggccag660
ttaactctggggactgggaacccatgaaattgacccccaaatacatcctgcggaaggaat720
tcaggaatatctgttcccagcccctcctccctcaggcccaggagtccaggcccccagccc780
ctcctccctcaaaccaagggtacagatccccagcccctcctccctcagacccaggagtcc840
agaccccccagcccctcctccctcagacccaggagtccagcccctcctccctcagaccca900
ggagtccagaccccccagcccctcctccctcagacccaggggtccaggcccccaacccct960
cctccctcagactcagaggtccaagcccccaacccctccttccccagacccagaggtcca1020
ggtcccagcccctcctccctcagacccagcggtccaatgccacctagactctccctgtac1080
acagtgcccccttgtggcacgttgacccaaccttaccagttggtttttcattttttgtcc1140
ctttcccctagatccagaaataaagtctaagagaagcgcaaaaaaaaaaaaaaaaaaaaa1200
aaaaaaaaaaaaaaa 1215
<210> 327
<211> 220
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
104
<212> PRT
<213> Homo sapien
<400> 327
Glu Asp Cys Ser Pro His Ser Gln Pro Trp Gln Ala Ala Leu Val Met
1 5 10 15
Glu Asn Glu Leu Phe Cys Ser Gly Val Leu Val His Pro Gln Trp Val
20 25 30
Leu Ser Ala Ala His Cys Phe Gln Asn Ser Tyr Thr Ile Gly Leu Gly
35 40 45
Leu His Ser Leu Glu Ala Asp Gln Glu Pro Gly Ser Gln Met Val Glu
50 55 60
Ala Ser Leu Ser Val Arg His Pro Glu Tyr Asn Arg Pro Leu Leu Ala
65 70 75 80
Asn Asp Leu Met Leu Ile Lys Leu Asp Glu Ser Val Ser Glu Ser Asp
85 90 95
Thr Ile Arg Ser Ile Ser Ile Ala Ser Gln Cys Pro Thr Ala Gly Asn
100 105 110
Ser Cys Leu Val Ser Gly Trp Gly Leu Leu Ala Asn Gly Arg Met Pro
115 120 125
Thr Val Leu Gln Cys Val Asn Val Ser Val Val Ser Glu Glu Val Cys
130 135 140
Ser Lys Leu Tyr Asp Pro Leu Tyr His Pro Ser Met Phe Cys Ala Gly
145 150 155 160
Gly Gly Gln Asp Gln Lys Asp Ser Cys Asn Gly Asp Ser Gly Gly Pro
165 170 175
Leu Ile Cys Asn Gly Tyr Leu Gln Gly Leu Val Ser Phe Gly Lys Ala
180 185 190
Pro Cys Gly Gln Val Gly Val Pro Gly Val Tyr Thr Asn Leu Cys Lys
195 200 205
Phe Thr Glu Trp Ile Glu Lys Thr Val Gln Ala Ser
210 215 220
<210> 328
<211> 234
<212> DNA
<213> Homo sapien
<400> 328
cgctcgtctc tggtagctgc agccaaatca taaacggcga ggactgcagc ccgcactcgc 60
agccctggca ggcggcactg gtcatggaaa acgaattgtt ctgctcgggc gtcctggtgc 120
atccgcagtg ggtgctgtca gccacacact gtttccagaa ctcctacacc atcgggctgg 180
gcctgcacag tcttgaggcc gaccaagagc cagggagcca gatggtggag gcca 234
<210> 329
<211> 77
<212> PRT
<213> Homo sapien
<400> 329
Leu Val Ser Gly Ser Cys Ser Gln Ile Ile Asn Gly Glu Asp Cys Ser
1 5 10 15
Pro His Ser Gln Pro Trp Gln Ala Ala Leu Val Met Glu Asn Glu Leu
20 25 30
Phe Cys Ser Gly Val Leu Val His Pro Gln Trp Val Leu Ser Ala Thr
35 40 45
His Cys Phe Gln Asn Ser Tyr Thr Ile Gly Leu Gly Leu His Ser Leu
50 55 60
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
105
Glu Ala Asp Gln Glu Pro Gly Ser Gln Met Val Glu Ala
65 70 75
<210> 330
<211> 70
<212> DNA
<213> Homo sapien
<400> 330
cccaacacaa tggcccgatc ccatccctga ctccgccctc aggatcgctc gtctctggta 60
gctgcagcca 70
<210> 331
<211> 22
<212> PRT
<213> Homo sapien
<400> 331
Gln His Asn Gly Pro Ile Pro Ser Leu Thr Pro Pro Ser Gly Ser Leu
1 5 10 15
Val Ser Gly Ser Cys Ser
<210> 332
<211> 2507
<212> DNA
<213> Homo sapien
<400>
332
tggtgccgctgcagccggcagagatggttgagctcatgttcccgctgttgctcctccttc60
tgcccttccttctgtatatggctgcgccccaaatcaggaaaatgctgtccagtggggtgt120
gtacatcaactgttcagcttcctgggaaagtagttgtggtcacaggagctaatacaggta180
tcgggaaggagacagccaaagagctggctcagagaggagctcgagtatatttagcttgcc240
gggatgtggaaaagggggaattggtggccaaagagatccagaccacgacagggaaccagc300
aggtgttggtgcggaaactggacctgtctgatactaagtctattcgagcttttgctaagg360
gcttcttagctgaggaaaagcacctccacgttttgatcaacaatgcaggagtgatgatgt420
gtccgtactcgaagacagcagatggctttgagatgcacataggagtcaaccacttgggtc480
acttcctcctaacccatctgctgctagagaaactaaaggaatcagccccatcaaggatag540
taaatgtgtcttccctcgcacatcacctgggaaggatccacttccataacctgcagggcg600
agaaattctacaatgcaggcctggcctactgtcacagcaagctagccaacatcctcttca660
cccaggaactggcccggagactaaaaggctctggcgttacgacgtattctgtacaccctg720
gcacagtccaatctgaactggttcggcactcatctttcatgagatggatgtggtggcttt780
tctcctttttcatcaagactcctcagcagggagcccagaccagcctgcactgtgccttaa840
cagaaggtcttgagattctaagtgggaatcatttcagtgactgtcatgtggcatgggtct900
ctgcccaagctcgtaatgagactatagcaaggcggctgtgggacgtcagttgtgacctgc960
tgggcctcccaatagactaacaggcagtgccagttggacccaagagaagactgcagcaga1020
ctacacagtacttcttgtcaaaatgattctccttcaaggttttcaaaacctttagcacaa1080
agagagcaaaaccttccagccttgcctgcttggtgtccagttaaaactcagtgtactgcc1140
agattcgtctaaatgtctgtcatgtccagatttactttgcttctgttactgccagagtta1200
ctagagatatcataataggataagaagaccctcatatgacctgcacagctcattttcctt1260
ctgaaagaaactactacctaggagaatctaagctatagcagggatgatttatgcaaattt1320
gaactagcttctttgttcacaattcagttcctcccaaccaaccagtcttcacttcaagag1380
ggccacactgcaacctcagcttaacatgaataacaaagactggctcaggagcagggcttg1440
cccaggcatggtggatcaccggaggtcagtagttcaagaccagcctggccaacatggtga1500
aaccccacctctactaaaaattgtgtatatctttgtgtgtcttcctgtttatgtgtgcca1560
agggagtattttcacaaagttcaaaacagccacaataatcagagatggagcaaaccagtg1620
ccatccagtctttatgcaaatgaaatgctgcaaagggaagcagattctgtatatgttggt1680
aactacccaccaagagcacatgggtagcagggaagaagtaaaaaaagagaaggagaatac1740
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
106
tggaagataatgcacaaaatgaagggactagttaaggattaactagccctttaaggatta1800
actagttaaggattaatagcaaaagayattaaatatgctaacatagctatggaggaattg1860
agggcaagcacccaggactgatgaggtcttaacaaaaaccagtgtggcaaaaaaaaaaaa1920
aaaaaaaaaaaaaaatcctaaaaacaaacaaacaaaaaaaacaattcttcattcagaaaa1980
attatcttagggactgatattggtaattatggtcaatttaataatattttggggcatttc2040
cttacattgtcttgacaagattaaaatgtctgtgccaaaattttgtattttatttggaga2100
cttcttatcaaaagtaatgctgccaaaggaagtctaaggaattagtagtgttcccatcac2160
ttgtttggagtgtgctattctaaaagattttgatttcctggaatgacaattatattttaa2220
ctttggtgggggaaagagttataggaccacagtcttcacttctgatacttgtaaattaat2280
cttttattgcacttgttttgaccattaagctatatgtttagaaatggtcattttacggaa2340
aaattagaaaaattctgataatagtgcagaataaatgaattaatgttttacttaatttat2400
attgaactgtcaatgacaaataaaaattctttttgattattttttgttttcatttaccag2460
aataaaaacgtaagaattaaaagtttgattacaaaaaaaaaaaaaaa 2507
<210> 333
<211> 3030
<212> DNA
<213> Homo sapien
<400>
333
gcaggcgacttgcgagctgggagcgatttaaaacgctttggattcccccggcctgggtgg60
ggagagcgagctgggtgccccctagattccccgcccccgcacctcatgagccgaccctcg120
gctccatggagcccggcaattatgccaccttggatggagccaaggatatcgaaggcttgc180
tgggagcgggaggggggcggaatctggtcgcccactcccctctgaccagccacccagcgg240
cgcctacgctgatgcctgctgtcaactatgcccccttggatctgccaggctcggcggagc300
cgccaaagcaatgccacccatgccctggggtgccccaggggacgtccccagctcccgtgc360
cttatggttactttggaggcgggtactactcctgccgagtgtcccggagctcgctgaaac420
cctgtgcccaggcagccaccctggccgcgtaccccgcggagactcccacggccggggaag480
agtaccccagycgccccactgagtttgccttctatccgggatatccgggaacctaccagc540
ctatggccagttacctggacgtgtctgtggtgcagactctgggtgctcctggagaaccgc600
gacatgactccctgttgcctgtggacagttaccagtcttgggctctcgctggtggctgga660
acagccagatgtgttgccagggagaacagaacccaccaggtcccttttggaaggcagcat720
ttgcagactccagcgggcagcaccctcctgacgcctgcgcctttcgtcgcggccgcaaga780 -
aacgcattccgtacagcaaggggcagttgcgggagctggagcgggagtatgcggctaaca840
agttcatcaccaaggacaagaggcgcaagatctcggcagccaccagcctctcggagcgcc900
agattaccatctggtttcagaaccgccgggtcaaagagaagaaggttctcgccaaggtga960
agaacagcgctaccccttaagagatctccttgcctgggtgggaggagcgaaagtgggggt1020
gtcctggggagaccaggaacctgccaagcccaggctggggccaaggactctgctgagagg1080
cccctagagacaacacccttcccaggccactggctgctggactgttcctcaggagcggcc1140
tgggtacccagtatgtgcagggagacggaaccccatgtgacagcccactccaccagggtt1200
cccaaagaacctggcccagtcataatcattcatcctgacagtggcaataatcacgataac1260
cagtactagctgccatgatcgttagcctcatattttctatctagagctctgtagagcact1320
ttagaaaccgctttcatgaattgagctaattatgaataaatttggaaggcgatccctttg1380
cagggaagctttctctcagacccccttccattacacctctcaccctggtaacagcaggaa1440
gactgaggagaggggaacgggcagattcgttgtgtggctgtgatgtccgtttagcatttt1500
tctcagctgacagctgggtaggtggacaattgtagaggctgtctcttcctccctccttgt1560
ccaccccatagggtgtacccactggtcttggaagcacccatccttaatacgatgattttt1620
ctgtcgtgtgaaaatgaagccagcaggctgcccctagtcagtccttccttccagagaaaa1680
agagatttgagaaagtgcctgggtaattcaccattaatttcctcccccaaactctctgag1740
tcttcccttaatatttctggtggttctgaccaaagcaggtcatggtttgttgagcatttg1800
ggatcccagtgaagtagatgtttgtagccttgcatacttagcccttcccaggcacaaacg1860
gagtggcagagtggtgccaaccctgttttcccagtccacgtagacagattcacagtgcgg1920
aattctggaagctggagacagacgggctctttgcagagccgggactctgagagggacatg1980
agggcctctgcctctgtgttcattctctgatgtcctgtacctgggctcagtgcccggtgg2040
gactcatctcctggccgcgcagcaaagccagcgggttcgtgctggtccttcctgcacctt2100
aggctgggggtggggggcctgccggcgcattctccacgattgagcgcacaggcctgaagt2160
ctggacaacccgcagaaccgaagctccgagcagcgggtcggtggcgagtagtggggtcgg2220
tggcgagcagttggtggtgggccgcggccgccactacctcgaggacatttccctcccgga2280
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
107
gccagctctcctagaaaccccgcggcggccgccgcagccaagtgtttatggcccgcggtc 2340
gggtgggatcctagccctgtctcctctcctgggaaggagtgagggtgggacgtgacttag 2400
acacctacaaatctatttaccaaagaggagcccgggactgagggaaaaggccaaagagtg 2460
tgagtgcatgcggactgggggttcaggggaagaggacgaggaggaggaagatgaggtcga 2520
tttcctgatttaaaaaatcgtccaagccccgtggtccagcttaaggtcctcggttacatg 2580
cgccgctcagagcaggtcactttctgccttccacgtcctccttcaaggaagccccatgtg 2640
ggtagctttcaatatcgcaggttcttactcctctgcctctataagctcaaacccaccaac 2700
gatcgggcaagtaaaccccctccctcgccgacttcggaactggcgagagttcagcgcaga 2760
tgggcctgtggggagggggcaagatagatgagggggagcggcatggtgcggggtgacccc 2820
ttggagagaggaaaaaggccacaagaggggctgccaccgccactaacggagatggccctg 2880
gtagagacctttgggggtctggaacctctggactccccatgctctaactcccacactctg 2940
ctatcagaaacttaaacttgaggattttctctgtttttcactcgcaataaaytcagagca 3000
aacaaaaaaaaaaaaaaaaaaaaactcgag 3030
<210> 334
<211> 2417
<212> DNA
<213> Homo sapien
<400>
334
ggcggccgctctagagctagtgggatcccccgggctgcacgaattcggcacgagtgagtt60
ggagttttacctgtattgttttaatttcaacaagcctgaggactagccacaaatgtaccc120
agtttacaaatgaggaaacaggtgcaaaaaggttgttacctgtcaaaggtcgtatgtggc180
agagccaagatttgagcccagttatgtctgatgaacttagcctatgctctttaaacttct240
gaatgctgaccattgaggatatctaaacttagatcaattgcattttccctccaagactat300
ttacttatcaatacaataataccacctttaccaatctattgttttgatac.gagactcaaa360
tatgccagatatatgtaaaagcaacctacaagctctctaatcatgctcacctaaaagatt420
cccgggatctaataggctcaaagaaacttcttctagaaatataaaagagaaaattggatt480
atgcaaaaattcattattaatttttttcatccatcctttaattcagcaaacatttatctg540
ttgttgactttatgcagtatggccttttaaggattgggggacaggtgaagaacggggtgc600
cagaatgcatcctcctactaatgaggtcagtacacatttgcattttaaaatgccctgtcc660
agctgggcatggtggatcatgcctgtaatctcaacattggaaggccaaggcaggaggatt720
gcttcagcccaggagttcaagaccagcctgggcaacatagaaagaccccatctctcaatc780
aatcaatcaatgccctgtctttgaaaataaaactctttaagaaaggtttaatgggcaggg840
tgtggtagctcatgcctataatacagcactttgggaggctgaggcaggaggatcacttta900
gcccagaagttcaagaccagcctgggcaacaagtgacacctcatctcaattttttaataa960
aatgaatacatacataaggaaagataaaaagaaaagtttaatgaaagaatacagtataaa1020
acaaatctcttggacctaaaagtatttttgttcaagccaaatattgtgaatcacctctct1080
gtgttgaggatacagaatatctaagcccaggaaactgagcagaaagttcatgtactaact1140
aatcaacccgaggcaaggcaaaaatgagactaactaatcaatccgaggcaaggggcaaat1200
tagacggaacctgactctggtctattaagcgacaactttccctctgttgtatttttcttt1260
tattcaatgtaaaaggataaaaactctctaaaactaaaaacaatgtttgtcaggagttac1320
aaaccatgaccaactaattatggggaatcataaaatatgactgtatgagatcttgatggt1380
ttacaaagtgtacccactgttaatcactttaaacattaatgaacttaaaaatgaatttac1440
ggagattggaatgtttctttcctgttgtattagttggctcaggctgccataacaaaatac1500
cacagactgggaggcttaagtaacagaaattcatttctcacagttctgggggctggaagt1560
ccacgatcaaggtgcaggaaaggcaggcttcattctgaggcccctctcttggctcacatg1620
tggccaccctcccactgcgtgctcacatgacctctttgtgctcctggaaagagggtgtgg1680
gggacagagggaaagagaaggagagggaactctctggtgtctcgtctttcaaggacccta1740
acctgggccactttggcccaggcactgtggggtggggggttgtggctgctctgctctgag1800
tggccaagataaagcaacagaaaaatgtccaaagctgtgcagcaaagacaagccaccgaa1860
cagggatctgctcatcagtgtggggacctccaagtcggccaccctggaggcaagccccca1920
cagagcccatgcaaggtggcagcagcagaagaagggaattgtccctgtccttggcacatt1980
cctcaccgacctggtgatgctggacactgcgatgaatggtaatgtggatgagaatatgat2040
ggactcccagaaaaggagacccagctgctcaggtggctgcaaatcattacagccttcatc2100
ctggggaggaactgggggcctggttctgggtcagagagcagcccagtgagggtgagagct2160
acagcctgtcctgccagctggatccccagtcccggtcaaccagtaatcaaggctgagcag2220
atcaggcttcccggagctggtcttgggaagccagccctggggtgagttggctcctgctgt2280
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
108
ggtactgaga caatattgtc ataaattcaa tgcgcccttg tatccctttt tcttttttat 2340
ctgtctacat ctataatcac tatgcatact agtctttgtt agtgtttcta ttcmacttaa 2400
tagagatatg ttatact 2417
<210> 335
<211> 2984
<212> DNA
<213> Homo sapien
<400>
335
atccctccttccccactctcctttccagaaggcacttggggtcttatctgttggactctg 60
aaaacacttcaggcgcccttccaaggcttccccaaacccctaagcagccgcagaagcgct 120
cccgagctgccttctcccacactcaggtgatcgagttggagaggaagttcagccatcaga 180
agtacctgtcggcccctgaacgggcccacctggccaagaacctcaagctcacggagaccc 240
aagtgaagatatggttccagaacagacgctataagactaagcgaaagcagctctcctcgg 300
agctgggagacttggagaagcactcctctttgccggccctgaaagaggaggccttctccc 360
gggcctccctggtctccgtgtataacagctatccttactacccatacctgtactgcgtgg 420
gcagctggagcccagctttttggtaatgccagctcaggtgacaaccattatgatcaaaaa 480
ctgccttccccagggtgtctctatgaaaagcacaaggggccaaggtcagggagcaagagg 540
tgtgcacaccaaagctattggagatttgcgtggaaatctcasattcttcactggtgagac 600
aatgaaacaacagagacagtgaaagttttaatacctaagtcattcccccagtgcatactg 660
taggtcattttttttgcttctggctacctgtttgaaggggagagagggaaaatcaagtgg 720
tattttccagcactttgtatgattttggatgagctgtacacccaaggattctgttctgca 780
actccatcctcctgtgtcactgaatatcaactctgaaagagcaaacctaacaggagaaag 840
gacaaccaggatgaggatgtcaccaactgaattaaacttaagtccagaagcctcctgttg 900
gccttggaatatggccaaggctctctctgtccctgtaaaagagaggggcaaatagagagt 960
ctccaagagaacgccctcatgctcagcacatatttgcatgggagggggagatgggtggga 1020
ggagatgaaaatatcagcttttcttattcctttttattccttttaaaatggtatgccaac 1080
ttaagtatttacagggtggcccaaatagaacaagatgcactcgctgtgattttaagacaa 1140
gctgtataaacagaactccactgcaagagggggggccgggccaggagaatctccgcttgt 1200
ccaagacaggggcctaaggagggtctccacactgctgctaggggctgttgcattttttta 1260
ttagtagaaagtggaaaggcctcttctcaacttttttcccttgggctggagaatttagaa 1320
tcagaagtttcctggagttttcaggctatcatatatactgtatcctgaaaggcaacataa 1380
ttcttccttccctccttttaaaattttgtgttcctttttgcagcaattactcactaaagg 1440
gcttcattttagtccagatttttagtctggctgcacctaacttatgcctcgcttatttag 1500
cccgagatctggtctttttttttttttttttttttccgtctccccaaagctttatctgtc 1560
ttgactttttaaaaaagtttgggggcagattctgaattggctaaaagacatgcattttta 1620
aaactagcaactcttatttctttcctttaaaaatacatagcattaaatcccaaatcctat 1680
ttaaagacctgacagcttgagaaggtcactactgcatttataggaccttctggtggttct 1740
gctgttacgtttgaagtctgacaatccttgagaatctttgcatgcagaggaggtaagagg 1800
tattggattttcacagaggaagaacacagcgcagaatgaagggccaggcttactgagctg 1860
tccagtggagggctcatgggtgggacatggaaaagaaggcagcctaggccctggggagcc 1920
cagtccactgagcaagcaagggactgagtgagccttttgcaggaaaaggctaagaaaaag 1980
gaaaaccattctaaaacacaacaagaaactgtccaaatgctttgggaactgtgtttattg 2040
cctataatgggtccccaaaatgggtaacctagacttcagagagaatgagcagagagcaaa 2100
ggagaaatctggctgtccttccattttcattctgttatctcaggtgagctggtagagggg 2160
agacattagaaaaaaatgaaacaacaaaacaattactaatgaggtacgctgaggcctggg 2220
agtctcttgactccactacttaattccgtttagtgagaaacctttcaattttcttttatt 2280
agaagggccagcttactgttggtggcaaaattgccaacataagttaatagaaagttggcc 2340
aatttcaccccattttctgtggtttgggctccacattgcaatgttcaatgccacgtgctg 2400
ctgacaccgaccggagtactagccagcacaaaaggcagggtagcctgaattgctttctgc 2460
tctttacatttcttttaaaataagcatttagtgctcagtccctactgagtactctttctc 2520
tcccctcctctgaatttaattctttcaacttgcaatttgcaaggattacacatttcactg 2580
tgatgtatattgtgttgcaaaaaaaaaaaaaagtgtctttgtttaaaattacttggtttg 2640
tgaatccatcttgctttttccccattggaactagtcattaacccatctctgaactggtag 2700
aaaaacatctgaagagctagtctatcagcatctgacaggtgaattggatggttctcagaa 2760
ccatttcacccagacagcctgtttctatcctgtttaataaattagtttgggttctctaca 2820
tgcataacaaaccctgctccaatctgtcacataaaagtctgtgacttgaagtttagtcag 2880
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
109
cacccccacc aaactttatt tttctatgtg ttttttgcaa catatgagtg ttttgaaaat 2940
aaagtaccca tgtctttatt agaaaaaaaa aaaaaaaaaa aaaa 2984
<210> 336
<211> 147
<212> PRT
<213> Homo sapien
<400> 336
Pro Ser Phe Pro Thr Leu Leu Ser Arg Arg His Leu Gly Ser Tyr Leu
1 5 10 15
Leu Asp Ser Glu Asn Thr Ser Gly Ala Leu Pro Arg Leu Pro.Gln Thr
20 25 30
Pro Lys Gln Pro Gln Lys Arg Ser Arg Ala Ala Phe Ser His Thr Gln
35 40 45
Val Ile Glu Leu Glu Arg Lys Phe Ser His Gln Lys Tyr Leu Ser Ala
50 55 60
Pro Glu Arg Ala His Leu Ala Lys Asn Leu Lys Leu Thr Glu Thr Gln
65 70 75 80
Val Lys Ile Trp Phe Gln Asn Arg Arg Tyr Lys Thr Lys Arg Lys Gln
85 90 95
Leu Ser Ser Glu Leu Gly Asp Leu Glu Lys His Ser Ser Leu Pro Ala
100 105 110
Leu Lys Glu Glu Ala Phe Ser Arg Ala Ser Leu Val Ser Val Tyr Asn
115 120 125
Ser Tyr Pro Tyr Tyr Pro Tyr Leu Tyr Cys Val Gly Ser Trp Ser Pro
130 135 140
Ala Phe Trp
145
<210> 337
<211> 9
<212> PRT
<213> Homo sapien
<400> 337
Ala Leu Thr Gly Phe Thr Phe Ser Ala
1 5
<210> 338
<211> 9
<212> PRT
<213> Homo sapien
<400> 338
Leu Leu Ala Asn Asp Leu Met Leu Ile
1 5
<210> 339
<211> 318
<212> PRT
<213> Homo sapien
<400> 339
Met Val Glu Leu Met Phe Pro Leu Leu Leu Leu Leu Leu Pro Phe Leu
1 5 10 15
Leu Tyr Met Ala Ala Pro Gln Ile Arg Lys Met Leu Ser Ser Gly Val
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
110
20 25 30
Cys Thr Ser Thr Val Gln Leu Pro Gly Lys Val Val Val Val Thr Gly
35 40 45
Ala Asn Thr Gly Ile Gly Lys Glu Thr Ala Lys Glu Leu Ala Gln Arg
50 55 60
Gly Ala Arg Val Tyr Leu Ala Cys Arg Asp Val Glu Lys Gly Glu Leu
65 70 75 80
Val Ala Lys Glu Ile Gln Thr Thr Thr Gly Asn Gln Gln Val Leu Val
85 90 95
Arg Lys Leu Asp Leu Ser Asp Thr Lys Ser Ile Arg Ala Phe Ala Lys
100 105 110
Gly Phe Leu Ala Glu Glu Lys His Leu His Val Leu Ile Asn Asn Ala
115 120 125
Gly Val Met Met Cys Pro Tyr Ser Lys Thr Ala Asp Gly Phe Glu Met
130 135 140
His Ile Gly Val Asn His Leu Gly His Phe Leu Leu Thr His Leu Leu
145 150 155 160
Leu Glu Lys Leu Lys Glu Ser Ala Pro Ser Arg Ile Val Asn Val Ser
165 170 175
Ser Leu Ala His His Leu Gly Arg Ile His Phe His Asn Leu Gln Gly
180 185 190
Glu Lys Phe Tyr Asn Ala Gly Leu Ala Tyr Cys His Ser Lys Leu Ala
195 200 205
Asn Ile Leu Phe Thr Gln Glu Leu Ala Arg Arg Leu Lys Gly Ser Gly
210 215 220
Val Thr Thr Tyr Ser Val His Pro Gly Thr Val Gln Ser Glu Leu Val
225 230 235 240
Arg His Ser Ser Phe Met Arg Trp Met Trp Trp Leu Phe Ser Phe Phe
245 250 255
Ile Lys Thr Pro Gln Gln Gly Ala Gln Thr Ser Leu His Cys Ala Leu
260 265 270
Thr Glu Gly Leu Glu Ile Leu Ser Gly Asn His Phe Ser Asp Cys His
275 280 285
Val Ala Trp Val Ser Ala Gln Ala Arg Asn Glu Thr Ile Ala Arg Arg
290 295 300
Leu Trp Asp Val Ser Cys Asp Leu Leu Gly Leu Pro Ile Asp
305 310 315
<210> 340
<211> 483
<212> DNA
<213> Homo sapien
<400>
340
gccgaggtctgccttcacacggaggacacgagactgcttcctcaagggctcctgcctgcc 60
tggacactggtgggaggcgctgtttagttggctgttttcagaggggtctttcggagggac 120
ctcctgctgcaggctggagtgtctttattcctggcgggagaccgcacattccactgctga 180
ggttgtgggggcggtttatcaggcagtgataaacataagatgtcatttccttgactccgg 240
ccttcaattttctctttggctgacgacggagtccgtggtgtcccgatgtaactgacccct 300
gctccaaacgtgacatcactgatgctcttctcgggggtgctgatggcccgcttggtcacg 360
tgctcaatctcgccattcgactcttgctccaaactgtatgaagacacctgactgcacgtt 420
ttttctgggcttccagaatttaaagtgaaaggcagcactcctaagctccgactccgatgc 480
ctg 483
<210> 341
<211> 344
<212> DNA
<213> Homo sapien
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
111
<400> 341
ctgctgctgagtcacagatttcattataaatagcctccctaaggaaaatacactgaatgc 60
tatttttactaaccattctatttttatagaaatagctgagagtttctaaaccaactctct 120
gctgccttacaagtattaaatattttacttctttccataaagagtagctcaaaatatgca 180
attaatttaataatttctgatgatggttttatctgcagtaatatgtatatcatctattag 240
aatttacttaatgaaaaactgaagagaacaaaatttgtaaccactagcacttaagtactc 300
ctgattcttaacattgtctttaatgaccacaagacaaccaacag 344
<210> 342
<211> 592
<212> DNA
<213> Homo sapien
<400> 342
acagcaaaaaagaaactgagaagcccaatytgctttcttgttaacatccacttatccaac 60
caatgtggaaacttcttatacttggttccattatgaagttggacaattgctgctatcaca 120
cctggcaggtaaaccaatgccaagagagtgatggaaaccattggcaagactttgttgatg 180
accaggattggaattttataaaaatattgttgatgggaagttgctaaagggtgaattact 240
tccctcagaagagtgtaaagaaaagtcagagatgctataatagcagctattttaattggc 300
aagtgccactgtggaaagagttcctgtgtgtgctgaagttctgaagggcagtcaaattca 360
tcagcatgggctgtttggtgcaaatgcaaaagcacaggtctttttagcatgctggtctct 420
cccgtgtccttatgcaaataatcgtcttcttctaaatttctcctaggcttcattttccaa 480
agttcttcttggtttgtgatgtcttttctgctttccattaattctataaaatagtatggc 540
ttcagccacccactcttcgccttagcttgaccgtgagtctcggctgccgctg 592
<210> 343
<211> 382
<212> DNA
<213> Homo sapien
<400>
343
ttcttgacctcctcctccttcaagctcaaacaccacctcccttattcaggaccggcactt 60
cttaatgtttgtggctttctctccagcctctcttaggaggggtaatggtggagttggcat 120
cttgtaactctcctttctcctttcttcccctttctctgcccgcctttcccatcctgctgt 180
agacttcttgattgtcagtctgtgtcacatccagtgattgttttggtttctgttcccttt 240
ctgactgcccaaggggctcagaaccccagcaatcccttcctttcactaccttcttttttg 300
ggggtagttggaagggactgaaattgtggggggaaggtaggaggcacatcaataaagagg 360
aaaccaccaagctgaaaaaaas 382
<210> 344
<211> 536
<212> DNA
<213> Homo sapien
<400>
344
ctgggcctgaagctgtagggtaaatcagaggcaggcttctgagtgatgagagtcctgaga 60
caataggccacataaacttggctggatggaacctcacaataaggtggtcacctcttgttt 120
gtttagggggatgccaaggataaggccagctcagttatatgaagagaagcagaacaaaca 180
agtctttcagagaaatggatgcaatcagagtgggatcccggtcacatcaaggtcacactc 240
caccttcatgtgcctgaatggttgccaggtcagaaaaatccaccccttacgagtgcggct 300
tcgaccctatatcccccgcccgcgtccctttctccataaaattcttcttagtagctatta 360
ccttcttattatttgatctagaaattgccctccttttacccctaccatgagccctacaaa 420
caactaacctgccactaatagttatgtcatccctcttattaatcatcatcctagccctaa 480
gtctggcctatgagtgactacaaaaaggattagactgagccgaataacaaaaaaaa 536
<210> 345
<211> 251
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
112
<212> DNA
<213> Homo sapien
<400> 345
accttttgaggtctctctcaccacctccacagccaccgtcaccgtgggatgtgctggatg 60
tgaatgaagcccccatctttgtgcctcctgaaaagagagtggaagtgtccgaggactttg 120
gcgtgggccaggaaatcacatcctacactgcccaggagccagacacatttatggaacaga 180
aaataacatatcggatttggagagacactgccaactggctggagattaatccggacactg 240
gtgccatttcc 251
<210> 346
<211> 282
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (282)
<223> n = A,T,C or G
<400> 346
cgcgtctctg acactgtgat catgacaggg gttcaaacag aaagtgcctg ggccctcctt 60
ctaagtcttg ttaccaaaaa aaggaaaaag aaaagatctt ctcagttaca aattctggga 120
agggagacta tacctggctc ttgccctaag tgagaggtct tccctcccgc accaaaaaat 180
agaaaggctt tctatttcac tggcccaggt agggggaagg agagtaactt tgagtctgtg 240
ggtctcattt cccaaggtgc cttcaatgct catnaaaacc as 282
<210> 347
<211> 201
<212> DNA
<213> Homo sapien
<220>
<221> misr__feature
<222> (1). .(201)
<223> n = A,T,C or G
<400> 347
acacacataa tattataaaa tgccatctaa ttggaaggag ctttctatca ttgcaagtca 60
taaatataac ttttaaaana ntactancag cttttaccta ngctcctaaa tgcttgtaaa 120
tctgagactg actggaccca cccagaccca gggcaaagat acatgttacc atatcatct.t 180
tataaagaat ttttttttgt c 201
<210> 348
<211> 251
<212> DNA
<213> Homo sapien
<400>
348
ctgttaatcacaacatttgtgcatcacttgtgccaagtgagaaaatgttctaaaatcaca 60
agagagaacagtgccagaatgaaactgaccctaagtcccaggtgcccctgggcaggcaga 120
aggagacactcccagcatggaggagggtttatcttttcatcctaggtcaggtctacaatg 180
ggggaaggttttattatagaactcccaacagcccacctcactcctgccacccacccgatg 240
gccctgcctcc 251
<210> 349
<211> 251
<212> DNA
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
113
<213> Homo sapien
<400> 349
taaaaatcaa gccatttaat tgtatctttg aaggtaaaca atatatggga gctggatcac 60
aacccctgag gatgccagag ctatgggtcc agaacatggt gtggtattat caacagagtt 120
cagaagggtc tgaactctac gtgttaccag agaacataat gcaattcatg cattccactt 180
agcaattttg taaaatacca gaaacagacc ccaagagtct ttcaagatga ggaaaattca 240
actcctggtt t 251
<210> 350
<211> 908
<212> DNA
<213> Homo sapien
<400> 350
ctggacactttgcgagggcttttgctggctgctgctgctgcccgtcatgctactcatcgt 60
agcccgcccggtgaagctcgctgctttccctacctccttaagtgactgccaaacgcccac 120
cggctggaattgctctggttatgatgacagagaaaatgatctcttcctctgtgacaccaa 180
cacctgtaaatttgatggggaatgtttaagaattggagacactgtgacttgcgtctgtca 240
gttcaagtgcaacaatgactatgtgcctgtgtgtggctccaatggggagagctaccagaa 300
tgagtgttacctgcgacaggctgcatgcaaacagcagagtgagatacttgtggtgtcaga 360
aggatcatgtgccacagtccatgaaggctctggagaaactagtcaaaaggagacatccac 420
ctgtgatatttgccagtttggtgcagaatgtgacgaagatgccgaggatgtctggtgtgt 480
gtgtaatattgactgttctcaaaccaacttcaatcccctctgcgcttctgatgggaaatc 540
ttatgataatgcatgccaaatcaaagaagcatcgtgtcagaaacaggagaaaattgaagt 600
catgtctttgggtcgatgtcaagataacacaactacaactactaagtctgaagatgggca 660
ttatgcaagaacagattatgcagagaatgctaacaaattagaagaaagtgccagagaaca 720
ccacataccttgtccggaacattacaatggcttctgcatgcatgggaagtgtgagcattc 780
tatcaatatgcaggagccatcttgcaggtgtgatgctggttatactggacaacactgtga 840
aaaaaaggactacagtgttctatacgttgttcccggtcctgtacgatttcagtatgtctt 900
aatcgcag 908
<210> 351
<211> 472
<212> DNA
<213> Homo sapien
<400> 351
ccagttatttgcaagtggtaagagcctatttaccataaataatactaagaaccaactcaa 60
gtcaaaccttaatgccattgttattgtgaattaggattaagtagtaattttcaaaattca 120
cattaacttgattttaaaatcagwtttgygagtcatttaccacaagctaaatgtgtacac 180
tatgataaaaacaaccattgtattcctgtttttctaaacagtcctaatttctaacactgt 240
atatatccttcgacatcaatgaactttgttttcttttactccagtaataaagtaggcaca 300
gatctgtccacaacaaacttgccctctcatgccttgcctctcaccatgctctgctccagg 360
tcagcccccttttggcctgtttgttttgtcaaaaacctaatctgcttcttgcttttcttg 420
gtaatatatatttagggaagatgttgctttgcccacacacgaagcaaagtas 472
<210> 352
<211> 251
<212> DNA
<213> Homo sapien
<400>
352
ctcaaagctaatctctcgggaatcaaaccagaaaagggcaaggatcttaggcatggtgga 60
tgtggataaggccaggtcaatggctgcaagcatgcagagaaagaggtacatcggagcgtg 120
caggctgcgttccgtccttacgatgaagaccacgatgcagtttccaaacattgccactac 180
atacatggaaaggagggggaagccaacccagaaatgggctttctctaatcctgggatacc 240
aataagcacaa 251
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
114
<210> 353
<211> 436
<212> DNA
<213> Homo sapien
<400> 353
ttttttttttttttttttttttttttacaacaatgcagtcatttatttattgagtatgtg 60
cacattatggtattattactatactgattatatttatcatgtgacttctaattaraaaat 120
gtatccaaaagcaaaacagcagatatacaaaattaaagagacagaagatagacattaaca 180
gataaggcaacttatacattgacaatccaaatccaatacatttaaacatttgggaaatga 240
gggggacaaatggaagccaratcaaatttgtgtaaaactattcagtatgtttcccttgct 300
tcatgtctgaraaggctctcccttcaatggggatgacaaactccaaatgccacacaaatg 360
ttaacagaatactagattcacactggaacgggggtaaagaagaaattattttctataaaa 420
gggctcctaatgtagt 436
<210> 354
<211> 854
<212> DNA
<213> Homo sapien
<400>
354
ccttttctagttcaccagttttctgcaaggatgctggttagggagtgtctgcaggaggag 60
caagtctgaaaccaaatctaggaaacataggaaacgagccaggcacagggctggtgggcc 120
atcagggaccaccctttgggttgatattttgcttaatctgcatcttttgagtaagatcat 180
ctggcagtagaagctgttctccaggtacatttctctagctcatgtacaaaaacatcctga 240
aggactttgtcaggtgccttgctaaaagccagatgcgttcggcacttccttggtctgagg 300
ttaattgcacacctacaggcactgggctcatgctttcaagtattttgtcctcactttagg 360
gtgagtgaaagatccccattataggagcacttgggagagatcatataaaagctgactctt .
' 420
gagtacatgcagtaatggggtagatgtgtgtggtgtgtcttcattcctgcaagggtgctt 480
gttagggagtgtttccaggaggaacaagtctgaaaccaatcatgaaataaatggtaggtg 540
tgaactggaaaactaattcaaaagagagatcgtgatatcagtgtggttgatacaccttgg 600
caatatggaaggctctaatttgcccatatttgaaataataattcagctttttgtaataca 660
aaataacaaaggattgagaatcatggtgtctaatgtataaaagacccaggaaacataaat 720
atatcaactgcataaatgtaaaatgcatgtgacccaagaaggccccaaagtggcagacaa 780
cattgtacccattttcccttccaaaatgtgagcggcgggcctgctgctttcaaggctgtc 840
acacgggatgtcag 854
<210> 355
<211> 676
<212> DNA
<213> Homo sapien
<400> 355
gaaattaagtatgagctaaattccctgttaaaacctctaggggtgacagatctcttcaac 60
caggtcaaagctgatctttctggaatgtcaccaaccaagggcctatatttatcaaaagcc 120
atccacaagtcatacctggatgtcagcgaagagggcacggaggcagcagcagccactggg 180
gacagcatcgctgtaaaaagcctaccaatgagagctcagttcaaggcgaaccaccccttc 240
ctgttctttataaggcacactcataccaacacgatcctattctgtggcaagcttgcctct 300
ccctaatcagatggggttgagtaaggctcagagttgcagatgaggtgcagagacaatcct 360
gtgactttcccacggccaaaaagctgttcacacctcacgcacctctgtgcctcagtttgc 420
tcatctgcaaaataggtctaggatttcttccaaccatttcatgagttgtgaagctaaggc 480
tttgttaatcatggaaaaaggtagacttatgcagaaagcctttctggctttcttatctgt 540
ggtgtctcatttgagtgctgtccagtgacatgatcaagtcaatgagtaaaattttaaggg 600
attagattttcttgacttgtatgtatctgtgagatcttgaataagtgacctgacatctct 660
gcttaaagaaaaccag 676
<210> 356
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
115
<211> 574
<212> DNA
<213> Homo sapien
<400>
356
tttttttttttttttcaggaaaacattctcttactttatttgcatctcagcaaaggttct 60
catgtggcacctgactggcatcaaaccaaagttcgtaggccaacaaagatgggccactca 120
caagcttcccatttgtagatctcagtgcctatgagtatctgacacctgttcctctcttca 180
gtctcttagggaggcttaaatctgtctcaggtgtgctaagagtgccagcccaaggkggtc 240
aaaagtccacaaaactgcagtctttgctgggatagtaagccaagcagtgcctggacagca 300
gagttcttttcttgggcaacagataaccagacaggactctaatcgtgctcttattcaaca 360
ttcttctgtctctgcctagactggaataaaaagccaatctctctcgtggcacagggaagg 420
agatacaagctcgtttacatgtgatagatctaacaaaggcatctaccgaagtctggtctg 480
gatagacggcacagggagctcttaggtcagcgctgctggttggaggacattcctgagtcc 540
agctttgcagcctttgtgcaacagtactttccca 574
<210> 357
<211> 393
<212> DNA
<213> Homo sapien
<400> 357
tttttttttttttttttttttttttttttttacagaatataratgctttatcactgkact 60
taatatggkgkcttgttcactatacttaaaaatgcaccactcataaatatttaattcagc ~
120
aagccacaaccaaracttgattttatcaacaaaaacccctaaatataaacggsaaaaaag 180
atagatataattattccagtttttttaaaacttaaaaratattccattgccgaattaara 240
araarataagtgttatatggaaagaagggcattcaagcacactaaaraaacctgaggkaa 300
gcataatctgtacaaaattaaactgtcctttttggcattttaacaaatttgcaacgktct 360
tttttr_tctttttctgtttttttttttttttac 393
<210> 358
<211> 630
<212> DNA
<213> Homo sapien
<400>
358
acagggtaaacaggaggatccttgctctcacggagcttacattctagcaggaggacaata 60
ttaatgtttataggaaaatgatgagtttatgacaaaggaagtagatagtgttttacaaga 120
gcatagagtagggaagctaatccagcacagggaggtcacagagacatccctaaggaagtg 180
gagtttaaactgagagaagcaagtgcttaaactgaaggatgtgttgaagaagaagggaga 240
gtagaacaatttgggcagagggaaccttatagaccctaaggtgggaaggttcaaagaact 300
gaaagagagctagaacagctggagccgttctccggtgtaaagaggagtcaaagagataag 360
attaaagatgtgaagattaagatcttggtggcattcagggattggcacttctacaagaaa 420
tcactgaagggagtaatgtgacattacttttcacttcaggatggccattctaactccagg 480
gggtagactggactaggtaagactggaggcaggtagacctcttctaaggcctgcgatagt 540
gaaagacaaaaataagtggggaaattcaggggatagtgaaaatcagtaggacttaatgag 600
caagccagaggttcctccacaacaaccagt 630
<210> 359
<211> 620
<212> DNA
<213> Homo sapien
<400> 359
acagcattcc aaaatataca tctagagact aarrgtaaat gctctatagt gaagaagtaa 60
taattaaaaa atgctactaa tatagaaaat ttataatcag aaaaataaat attcagggag 120
ctcaccagaa gaataaagtg ctctgccagt tattaaagga ttactgctgg tgaattaaat 180
atggcattcc ccaagggaaa tagagagatt cttctggatt atgttcaata tttatttcac 240
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
116
aggattaactgttttaggaacagatataaagcttcgccacggaagagatggacaaagcac 300
aaagacaacatgataccttaggaagcaacactaccctttcaggcataaaatttggagaaa 360
tgcaacattatgcttcatgaataatatgtagaaagaaggtctgatgaaaatgacatcctt 420
aatgtaagataactttataagaattctgggtcaaataaaattctttgaagaaaacatcca 480
aatgtcattgacttatcaaatactatcttggcatataacctatgaaggcaaaactaaaca 540
aacaaaaagctcacaccaaacaaaaccatcaacttattttgtattctataacatacgaga 600
ctgtaaagatgtgacagtgt 620
<210> 360
<211> 431
<212> DNA
<213> Homo sapien
<400>
360
aaaaaaaaaaagccagaacaacatgtgatagataatatgattggctgcacacttccagac 60
tgatgaatgatgaacgtgatggactattgtatggagcacatcttcagcaagagggggaaa 120
tactcatcatttttggccagcagttgtttgatcaccaaacatcatgccagaatactcagc 180
aaaccttcttagctcttgagaagtcaaagtccgggggaatttattcctggcaattttaat 240
tggactccttatgtgagagcagcggctacccagctggggtggtggagcgaacccgtcact 300
agtggacatgcagtggcagagctcctggtaaccacctagaggaatacacaggcacatgtg 360
tgatgccaagcgtgacacctgtagcactcaaatttgtcttgtttttgtctttcggtgtgt 420
agattcttagt 431
<210> 361
<211> 351
<212> DNA
<213> Homo sapien
<400> 361
acactgatttccgatcaaaagaatcatcatctttaccttgacttttcagggaattactga60
actttcttctcagaagatagggcacagccattgccttggcctcacttgaagggtctgcat120
ttgggtcctctggtctcttgccaagtttcccagccactcgagggagaaatatcgggaggt180
ttgacttcctccggggctttcccgagggcttcaccgtgagccctgcggccctcagggctg.240
caatcctggattcaatgtctgaaacctcgctctctgcctgctggacttctgaggccgtca'300
ctgccactctgtcctccagctctgacagctcctcatctgtggtcctgttgt 351
<210> 362
<211> 463
<212> DNA
<213> Homo sapien
<400> 362
acttcatcaggccataatgggtgcctcccgtgagaatccaagcacctttggactgcgcga 60
tgtagatgagccggctgaagatcttgcgcatgcgcggcttcagggcgaagttcttggcgc 120
ccccggtcacagaaatgaccaggttgggtgttttcaggtgccagtgctgggtcagcagct 180
cgtaaaggatttccgcgtccgtgtcgcaggacagacgtatatacttccctttcttcccca 240
gtgtctcaaactgaatatccccaaaggcgtcggtaggaaattccttggtgtgtttcttgt 300
agttccatttctcactttggttgatctgggtgccttccatgtgctggctctgggcatagc 360
cacacttgcacacattctccctgataagcacgatggtgtggacaggaaggaaggatttca 420
ttgagcctgcttatggaaactggtattgttagcttaaatagac 463
<210> 363
<211> 653
<212> DNA
<213> Homo sapien
<220>
<221> misc feature
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
117
<222> (1)...(653)
<223> n = A,T,C or G
<400> 363
acccccgagtncctgnctggcatactgngaacgaccaacgacacacccaagctcggcctc 60
ctcttggngattctgggtgacatcttcatgaatggcaaccgtgccagwgaggctgtcctc 120
tgggaggcactacgcaagatgggactgcgtcctggggtgagacatcctctccttggagat 180
ctaacgaaacttctcacctatgagttgtaaagcagaaatacctgnactacagacgagtgc 240
ccaacagcaaccccccggaagtatgagttcctctrgggcctccgttcctaccatgagasc 300
tagcaagatgnaagtgttgagantcattgcagaggttcagaaaagagacccntcgtgact 360
ggtctgcacagttcatggaggctgcagatgaggccttggatgctctggatgctgctgcag 420
ctgaggccgaagcccgggctgaagcaagaacccgcatgggaattggagatgaggctgtgt 480
ntgggccctggagctgggatgacattgagtttgagctgctgacctgggatgaggaaggag 540
attttggagatccntggtccagaattccatttaccttctgggccagataccaccagaatg 600
cccgctccagattccctcagacctttgccggtcccattattggtcstggtggt 653
<210> 364
<211> 401
<212> DNA
<213> Homo sapien
<400>
364
actagaggaaagacgttaaaccactctactaccacttgtggaactctcaaagggtaaatg 60
acaaagccaatgaatgactctaaaaacaatatttacatttaatggtttgtagacaataaa 120
aaaacaaggtggatagatctagaattgtaacattttaagaaaaccatagcatttgacaga 180
tgagaaagctcaattatagatgcaaagttataactaaactactatagtagtaaagaaata 240
catttcacacccttcatataaattcactatcttggcttgaggcactccataaaatgtatc 300
acgtgcatagtaaatctttatatttgctatggcgttgcactagaggacttggactgcaac 360
aagtggatgcgcggaaaatgaaatcttcttcaatagcccag 401,
<210> 365
<211> 356
<212> DNA
<213> Homo sapien
<400>
365
ccagtgtcatatttgggcttaaaatttcaagaagggcacttcaaatggctttgcatttgc 60
atgtttcagtgctagagcgtaggaatagaccctggcgtccactgtgagatgttcttcagc 120
taccagagcatcaagtctctgcagcaggtcattcttgggtaaagaaatgacttccacaaa 180
ctctccatcccctggctttggcttcggccttgcgttttcggcatcatctccgttaatggt 240
gactgtcacgatgtgtatagtacagtttgacaagcctgggtccatacagaccgctggaga 300
acattcggcaatgtcccctttgtagccagtttcttcttcgagctcccggagagcag 356
<210> 366
<211> 1851
<212> DNA
<213> Homo sapien
<400> 366
tcatcaccattgccagcagcggcaccgttagtcaggttttctgggaatcccacatgagta 60
cttccgtgttcttcattcttcttcaatagccataaatcttctagctctggctggctgttt 120
tcacttcctttaagcctttgtgactcttcctctgatgtcagctttaagtcttgttctgga 180
ttgctgttttcagaagagatttttaacatctgtttttctttgtagtcagaaagtaactgg 240
caaattacatgatgatgactagaaacagcatactctctggccgtctttccagatcttgag 300
aagatacatcaacattttgctcaagtagagggctgactatacttgctgatccacaacata 360
cagcaagtatgagagcagttcttccatatctatccagcgcatttaaattcgcttttttct 420
tgattaaaaatttcaccacttgctgtttttgctcatgtataccaagtagcagtggtgtga 480
ggccatgcttgttttttgattcgatatcagcaccgtataagagcagtgctttggccatta 540
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
118
atttatcttcattgtagacagcatagtgtagagtggtatttccatactcatctggaatat600
ttggatcagtgccatgttccagcaacattaacgcacattcatcttcctggcattgtacgg660
cctttgtcagagctgtcctctttttgttgtcaaggacattaagttgacatcgtctgtcca720
gcacgagttttactacttctgaattcccattggcagaggccagatgtagagcagtcctct780
tttgcttgtccctcttgttcacatccgtgtccctgagcatgacgatgagatcctttctgg840
ggactttaccccaccaggcagctctgtggagcttgtccagatcttctccatggacgtggt900
acctgggatccatgaaggcgctgtcatcgtagtctccccaagcgaccacgttgctcttgc960
cgctcccctgcagcaggggaagcagtggcagcaccacttgcacctcttgctcccaagcgt1020
cttcacagaggagtcgttgtggtctccagaagtgcccacgttgctcttgccgctccccct1080
gtccatccagggaggaagaaatgcaggaaatgaaagatgcatgcacgatggtatactcct1140
cagccatcaaacttctggacagcaggtcacttccagcaaggtggagaaagctgtccaccc1200
acagaggatgagatccagaaaccacaatatccattcacaaacaaacacttttcagccaga1260
cacaggtactgaaatcatgtcatctgcggcaacatggtggaacctacccaatcacacatc1320
aagagatgaagacactgcagtatatctgcacaacgtaatactcttcatccataacaaaat1380
aatataattttcctctggagccatatggatgaactatgaaggaagaactccccgaagaag1440
ccagtcgcagagaagccacactgaagctctgtcctcagccatcagcgccacggacaggar1500
tgtgtttcttccccagtgatgcagcctcaagttatcccgaagctgccgcagcacacggtg1560
gctcctgagaaacaccccagctcttccggtctaacacaggcaagtcaataaatgtgataa1620
tcacataaacagaattaaaagcaaagtcacataagcatctcaacagacacagaaaaggca1680
tttgacaaaatccagcatccttgtatttattgttgcagttctcagaggaaatgcttctaa1740
cttttccccatttagtattatgttggctgtgggcttgtcataggtggtttttattacttt1800
aaggtatgtcccttctatgcctgttttgctgagggttttaattctcgtgcc 1851
<210> 367
<211> 668
<212> DNA
<213> Homo sapien
<400> 367
cttgagcttccaaatayggaagactggcccttacacasgtcaatgttaaaatgaatgcat 60
ttcagt.attttgaagataaaattrgtagatctataccttgttttttgattcgatatcagc 120.
accrtataagagcagtgctttggccattaatttatctttcattrtagacagcrtagtgya 180
gagtggtatttccatactcatctggaatatttggatcagtgccatgttccagcaacatta 240
acgcacattcatcttcctggcattgtacggcctgtcagtattagacccaaaaacaaatta 300
catatcttaggaattcaaaataacattccacagctttcaccaactagttatatttaaagg 360
agaaaactcatttttatgccatgtattgaaatcaaacccacctcatgctgatatagttgg 420
ctactgcatacctttatcagagctgtcctctttttgttgtcaaggacattaagttgacat 480
cgtctgtccagcaggagttttactacttctgaattcccattggcagaggccagatgtaga 540
gcagtcctatgagagtgagaagactttttaggaaattgtagtgcactagctacagccata 600
gcaatgattcatgtaactgcaaacactgaatagcctgctattactctgccttcaaaaaaa 660
aaaaaaaa 668
<210> 368
<211> 1512
<212> DNA
<213> Homo sapien
<400>
368
gggtcgcccagggggsgcgtgggctttcctcgggtgggtgtgggttttccctgggtgggg 60
tgggctgggctrgaatcccctgctggggttggcaggttttggctgggattgacttttytc 120
ttcaaacagattggaaacccggagttacctgctagttggtgaaactggttggtagacgcg 180
atctgttggctactactggcttctcctggctgttaaaagcagatggtggttgaggttgat 240
tccatgccggctgcttcttctgtgaagaagccatttggtctcaggagcaagatgggcaag 300
tggtgctgccgttgcttcccctgctgcagggagagcggcaagagcaacgtgggcacttct 360
ggagaccacgacgactctgctatgaagacactcaggagcaagatgggcaagtggtgccgc 420
cactgcttcccctgctgcagggggagtggcaagagcaacgtgggcgcttctggagaccac 480
gacgaytctgctatgaagacactcaggaacaagatgggcaagtggtgctgccactgcttc 540
ccctgctgcagggggagcrgcaagagcaaggtgggcgcttggggagactacgatgacagt 600
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
119
gccttcatggagcccaggtaccacgtccgtggagaagatctggacaagctccacagagct 660
gcctggtggggtaaagtccccagaaaggatctcatcgtcatgctcagggacactgacgtg 720
aacaagaaggacaagcaaaagaggactgctctacatctggcctctgccaatgggaattca 780
gaagtagtaaaactcstgctggacagacgatgtcaacttaatgtccttgacaacaaaaag 840
aggacagctctgayaaaggccgtacaatgccaggaagatgaatgtgcgttaatgttgctg 900
gaacatggcactgatccaaatattccagatgagtatggaaataccactctrcactaygct 960
rtctayaatgaagataaattaatggccaaagcactgctcttatayggtgctgatatcgaa 1020
tcaaaaaacaaggtatagatctactaattttatcttcaaaatactgaaatgcattcattt 1080
taacattgacgtgtgtaagggccagtcttccgtatttggaagctcaagcataacttgaat 1140
gaaaatattttgaaatgacctaattatctmagactttattttaaatattgttattttcaa 1200
agaagcattagagggtacagttttttttttttaaatgcacttctggtaaatacttttgtt 1260
gaaaacactgaatttgtaaaaggtaatacttactatttttcaatttttccctcctaggat 1320
ttttttcccctaatgaatgtaagatggcaaaatttgccctgaaataggttttacatgaaa 1380
actccaagaaaagttaaacatgtttcagtgaatagagatcctgctcctttggcaagttcc 1440
taaaaaacagtaatagatacgaggtgatgcgcctgtcagtggcaaggtttaagatatttc 1500
tgatctcgtgcc 1512
<210> 369
<211> 1853
<212> DNA
<213> Homo sapien
<400>
369
gggtcgcccagggggsgcgtgggctttcctcgggtgggtgtgggttttccctgggtgggg60
tgggctgggctrgaatcccctgctggggttggcaggttttggctgggattgacttttytc120
ttcaaacagattggaaacccggagttacctgctagttggtgaaactggttggtagacgcg180
atctgttggctactactggcttctcctggctgttaaaagcagatggtggttgaggttgat240
tccatgccggctgcttcttctgtgaagaagcr_atttggtctcaggagcaagatgggcaag300
tggtgctgccgttgcttcccctgctgcagggagagcggcaagagcaacgtgggcacttct360
ggagaccacgacgactctgctatgaagacactcaggagcaagatgggcaagtggtgccgc420
cactgcttcccctgctgcagggggagtggcaagagcaacgtgggcgcttctggagaccac480
gacgaytctgctatgaagacactcaggaacaagatgggcaagtggtgctgccactgcttc540
ccctgctgcagggggagcrgcaagagcaaggtgggcgcttggggagactacgatgacagy600
gccttcatggakcccaggtaccacgtccrtggagaagatctggacaagctccacagagct6'60
gcctggtggggtaaagtccccagaaaggatctcatcgtcatgctcagggacackgaygtg720
aacaagarggacaagcaaaagaggactgctctacatctggcctctgccaatgggaattca780
gaagtagtaaaactcstgctggacagacgatgtcaacttaatgtccttgacaacaaaaag840
aggacagctctgayaaaggccgtacaatgccaggaagatgaatgtgcgttaatgttgctg900
gaacatggcactgatccaaatattccagatgagtatggaaataccactctrcactaygct960
rtctayaatgaagataaattaatggccaaagcactgctcttatayggtgctgatatcgaa1020
tcaaaaaacaagcatggcctcacaccactgytacttggtrtacatgagcaaaaacagcaa1080
gtsgtgaaatttttaatyaagaaaaaagcgaatttaaaatgcrctggatagatatggaag1140
ractgctctcatacttgctgtatgttgtggatcagcaagtatagtcagccytctacttga1200
gcaaaatrttgatgtatcttctcaagatctggaaagacggccagagagtatgctgtttct1260
agtcatcatcatgtaatttgccagttactttctgactacaaagaaaaacagatgttaaaa1320
atctcttctgaaaacagcaatccagaacaagacttaaagctgacatcagaggaagagtca1380
caaaggcttaaaggaagtgaaaacagccagccagaggcatggaaacttttaaatttaaac1440
ttttggtttaatgttttttttttttgccttaataatattagatagtcccaaatgaaatwa1500
cctatgagactaggctttgagaatcaatagattctttttttaagaatcttttggctagga1560
gcggtgtctcacgcctgtaattccagcaccttgagaggctgaggtgggcagatcacgaga1620
tcaggagatcgagaccatcctggctaacacggtgaaaccccatctctactaaaaatacaa1680
aaacttagctgggtgtggtggcgggtgcctgtagtcccagctactcaggargctgaggca1740
ggagaatggcatgaacccgggaggtggaggttgcagtgagccgagatccgccactacact1800
ccagcctgggtgacagagcaagactctgtctcaaaaaaaaaaaaaaaaaaaaa 1853
<210> 370
<211> 2184
<212> DNA
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
120
<213> Homo sapien
<400>
370
ggcacgagaattaaaaccctcagcaaaacaggcatagaagggacataccttaaagtaata60
aaaaccacctatgacaagcccacagccaacataatactaaatggggaaaagttagaagca120
tttcctctgagaactgcaacaataaatacaaggatgctggattttgtcaaatgccttttc180
tgtgtctgttgagatgcttatgtgactttgcttttaattctgtttatgtgattatcacat240
ttattgacttgcctgtgttagaccggaagagctggggtgtttctcaggagccaccgtgtg300
ctgcggcagcttcgggataacttgaggctgcatcactggggaagaaacacaytcctgtcc360
gtggcgctgatggctgaggacagagcttcagtgtggcttctctgcgactggcttcttcgg420
ggagttcttccttcatagttcatccatatggctccagaggaaaattatattattttgtta480
tggatgaagagtattacgttgtgcagatatactgcagtgtcttcatctcttgatgtgtga540
ttgggtaggttccaccatgttgccgcagatgacatgatttcagtacctgtgtctggctga600
aaagtgtttgtttgtgaatggatattgtggtttctggatctcatcctctgtgggtggaca660
gctttctccaccttgctggaagtgacctgctgtccagaagtttgatggctgaggagtata720
ccatcgtgcatgcatctttcatttcctgcatttcttcctccctggatggacagggggagc780
ggcaagagcaacgtgggcacttctggagaccacaacgactcctctgtgaagacgcttggg840
agcaagaggtgcaagtggtgctgccactgcttcccctgctgcaggggagcggcaagagca900
acgtggtcgcttggggagactacgatgacagcgccttcatggatcccaggtaccacgtcc960
atggagaagatctggacaagctccacagagctgcctggtggggtaaagtccccagaaagg1020
atctcatcgtcatgctcagggacacggatgtgaacaagagggacaagcaaaagaggactg1080
ctctacatctggcctctgccaatgggaattcagaagtagtaaaactcgtgctggacagac1140
gatgtcaacttaatgtccttgacaacaaaaagaggacagctctgacaaaggccgtacaat1200
gccaggaagatgaatgtgcgttaatgttgctggaacatggcactgatccaaatattccag1260
atgagtatggaaataccactctacactatgctgtctacaatgaagataaattaatggcca1320
aagcactgctcttatacggtgctgatatcgaatcaaaaaacaagcatggcctcacaccac1380
tgctacttggtatacatgagcaaaaacagcaagtggtgaaatttttaatcaagaaaaaag1440
cgaatttaaatgcgctggatagatatggaagaactgctctcatacttgctgtatgttgtg1500
gatcagcaagtatagtcagccctctacttgagcaaaatgttgatgtatcttctcaagatc1560
tggaaagacggccagagagtatgctgtttctagtcatcatcatgtaatttgccagttact1620
ttctgactacaaagaaaaacagatgttaaaaatctcttctgaaaacagcaatccagaaca1680
agacttaaagctgacatcagaggaagagtcacaaaggcttaaaggaagtgaaaacagcca1740
gccagaggcatggaaacttttaaatttaaacttttggtttaatgttttttttttttgcct1800
taataatattagatagtcccaaatgaaatwacctatgagactaggctttgagaatcaata1860
gattctttttttaagaatcttttggctaggagcggtgtctcacgcctgtaattccagcac1920
cttgagaggctgaggtgggcagatcacgagatcaggagatcgagaccatcctggctaaca1980
cggtgaaaccccatctctactaaaaatacaaaaacttagctgggtgtggtggcgggtgcc2040
tgtagtcccagctactcaggargctgaggcaggagaatggcatgaacccgggaggtggag2100
gttgcagtgagccgagatccgccactacactccagcctgggtgacagagcaagactctgt2160
ctcaaaaaaaaaaaaaaaaaaaaa 2184
<210> 371
<211> 1855
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(1855)
<223> n = A,T,C or G
<400> 371
tgcacgcatcggccagtgtctgtgccacgtacactgacgccccctgagatgtgcacgccg 60
cacgcgcacgttgcacgcgcggcagcggcttggctggcttgtaacggcttgcacgcgcac 120
gccgcccccgcataaccgtcagactggcctgtaacggcttgcaggcgcacgccgcacgcg 180
cgtaacggcttggctgccctgtaacggcttgcacgtgcatgctgcacgcgcgttaacggc 240
ttggctggcatgtagccgcttggcttggctttgcattytttgctkggctkggcgttgkty 300
tcttggattgacgcttcctccttggatkgacgtttcctccttggatkgacgtttcytyty 360
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
121
tcgcgttcctttgctggacttgaccttttytctgctgggtttggcattcctttggggtgg420
gctgggtgttttctccgggggggktkgcccttcctggggtgggcgtgggkcgcccccagg480
gggcgtgggctttccccgggtgggtgtgggttttcctggggtggggtgggctgtgctggg540
atccccctgctggggttggcagggattgacttttttcttcaaacagattggaaacccgga600
gtaacntgctagttggtgaaactggttggtagacgcgatctgctggtactactgtttctc660
ctggctgttaaaagcagatggtggctgaggttgattcaatgccggctgcttcttctgtga720
agaagccatttggtctcaggagcaagatgggcaagtggtgcgccactgcttcccctgctg780
cagggggagcggcaagagcaacgtgggcacttctggagaccacaacgactcctctgtgaa840
gacgcttgggagcaagaggtgcaagtggtgctgcccactgcttcccctgctgcaggggag900
cggcaagagcaacgtggkcgcttggggagactacgatgacagcgccttcatggakcccag960
gtaccacgtccrtggagaagatctggacaagctccacagagctgcctggtggggtaaagt1020
ccccagaaaggatctcatcgtcatgctcagggacactgaygtgaacaagarggacaagca1080
aaagaggactgctctacatctggcctctgccaatgggaattcagaagtagtaaaactcgt1140
gctggacagacgatgtcaacttaatgtccttgacaacaaaaagaggacagctctgacaaa1200
ggccgtacaatgccaggaagatgaatgtgcgttaatgttgctggaacatggcactgatcc1260
aaatattccagatgagtatggaaataccactctacactatgctgtctacaatgaagataa1320
attaatggccaaagcactgctcttatacggtgctgatatcgaatcaaaaaacaaggtata1380
gatctactaattttatcttcaaaatactgaaatgcattcattttaacattgacgtgtgta1440
agggccagtcttccgtatttggaagctcaagcataacttgaatgaaaatattttgaaatg1500
acctaattatctaagactttattttaaatattgttattttcaaagaagcattagagggta1560
cagttttttttttttaaatgcacttctggtaaatacttttgttgaaaacactgaatttgt1620
aaaaggtaatacttactatttttcaatttttccctcctaggatttttttcccctaatgaa1680
tgtaagatggcaaaatttgccctgaaataggttttacatgaaaactccaagaaaagttaa1740
acatgtttcagtgaatagagatcctgctcctttggcaagttcctaaaaaacagtaataga1800
tacgaggtgatgcgcctgtcagtggcaaggtttaagatatttctgatctcgtgcc 1855
<210> 372
<211> 1059
<212> DNA
<213> Homo sapien
<400> 372
gcaacgtgggcacttctggagaccacaacgactcctctgtgaagacgcttgggagcaaga60
ggtgcaagtggtgctgcccactgcttcccctgctgcaggggagcggcaagagcaacgtgg120
gcgcttgrggagactmcgatgacagygccttcatggagcccaggtaccacgtccgtggag180
aagatctggacaagctccacagagctgccctggtggggtaaagtccccagaaaggatctc240
atcgtcatgctcagggacactgaygtgaacaagarggacaagcaaaagaggactgctcta300
catctggcctctgccaatgggaattcagaagtagtaaaactcstgctggacagacgatgt360
caacttaatgtccttgacaacaaaaagaggacagctctgayaaaggccgtacaatgccag420
gaagatgaatgtgcgttaatgttgctggaacatggcactgatccaaatattccagatgag480
tatggaaataccactctrcactaygctrtctayaatgaagataaattaatggccaaagca540
ctgctcttatayggtgctgatatcgaatcaaaaaacaaggtatagatctactaattttat600
cttcaaaatactgaaatgcattcattttaacattgacgtgtgtaagggccagtcttccgt660
atttggaagctcaagcataacttgaatgaaaatattttgaaatgacctaattatctaaga720
ctttattttaaatattgttattttcaaagaagcattagagggtacagtttttttttttta780
aatgcacttctggtaaatacttttgttgaaaacactgaatttgtaaaaggtaatacttac840
tatttttcaatttttccctcctaggatttttttcccctaatgaatgtaagatggcaaaat900
ttgccctgaaataggttttacatgaaaactccaagaaaagttaaacatgtttcagtgaat960
agagatcctgctcctttggcaagttcctaaaaaacagtaatagatacgaggtgatgcgcc1020
tgtcagtggcaaggtttaagatatttctgatctcgtgcc 1059
<210> 373
<211> 1155
<212> DNA
<213> Homo sapien
<400> 373
atggtggttg aggttgattc catgccggct gcctcttctg tgaagaagcc atttggtctc 60
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
122
aggagcaagatgggcaagtggtgctgccgttgcttcccctgctgcagggagagcggcaag120
agcaacgtgggcacttctggagaccacgacgactctgctatgaagacactcaggagcaag180
atgggcaagtggtgccgccactgcttcccctgctgcagggggagtggcaagagcaacgtg240
ggcgcttctggagaccacgacgactctgctatgaagacactcaggaacaagatgggcaag300
tggtgctgccactgcttcccctgctgcagggggagcggcaagagcaaggtgggcgcttgg360
ggagactacgatgacagtgccttcatggagcccaggtaccacgtccgtggagaagatctg420
gacaagctccacagagctgcctggtggggtaaagtccccagaaaggatctcatcgtcatg480
ctcagggacactgacgtgaacaagaaggacaagcaaaagaggactgctctacatctggcc540
tctgccaatgggaattcagaagtagtaaaactcctgctggacagacgatgtcaacttaat600
gtccttgacaacaaaaagaggacagctctgataaaggccgtacaatgccaggaagatgaa660
tgtgcgttaatgttgctggaacatggcactgatccaaatattccagatgagtatggaaat720
accactctgcactacgctatctataatgaagataaattaatggccaaagcactgctctta780
tatggtgctgatatcgaatcaaaaaacaagcatggcctcacaccactgttacttggtgta840
catgagcaaaaacagcaagtcgtgaaattt~ttaatcaagaaaaaagcgaatttaaatgca900
ctggatagatatggaaggactgctctcatacttgctgtatgttgtggatcagcaagtata960
gtcagccttctacttgagcaaaatattgatgtatcttctcaagatctatctggacagacg1020
gccagagagtatgctgtttctagtcatcatcatgtaatttgccagttactttctgactac1080
aaagaaaaacagatgctaaaaatctcttctgaaaacagcaatccagaaaatgtctcaaga1140
accagaaataaataa 1155
<210> 374
<211> 2000
<212> DNA
<213> Homo sapien
<400> 374
atggtggttgaggttgattccatgccggctgcctcttctgtgaagaagccatttggtctc60
aggagcaagatgggcaagtggtgctgccgttgcttcccctgctgcagggagagcggcaag120
agcaacgtgggcacttctggagaccacgacgactctgctatgaagacactcaggagcaag180
atgggcaagtggtgccgccactgcttcccctgctgcagggggagtggcaagagcaacgtg240 .
ggcgcttctggagaccacgacgactctgctatgaagacactcaggaacaagatgggcaag300
tggtgctgccactgcttcccctgctgcagggggagcggcaagagcaaggtgggcgcttgg360
ggagactacgatgacagtgccttcatggagcccaggtaccacgtccgtggagaagatctg420
gacaagctccacagagctgcctggtggggtaaagtccccagaaaggatctcatcgtcatg480
ctcagggacactgacgtgaacaagaaggacaagcaaaagaggactgctctacatctggcc540
tctgccaatgggaattcagaagtagtaaaactcctgctggacagacgatgtcaacttaat600
gtccttgacaacaaaaagaggacagctctgataaaggccgtacaatgccaggaagatgaa660
tgtgcgttaatgttgctggaacatggcactgatccaaatattccagatgagtatggaaat720
accactctgcactacgctatctataatgaagataaattaatggccaaagcactgctctta780
tatggtgctgatatcgaatcaaaaaacaagcatggcctcacaccactgttacttggtgta840
catgagcaaaaacagcaagtcgtgaaatttttaatcaagaaaaaagcgaatttaaatgca900
ctggatagatatggaaggactgctctcatacttgctgtatgttgtggatcagcaagtata960
gtcagccttctacttgagcaaaatattgatgtatcttctcaagatctatctggacagacg1020
gccagagagtatgctgtttctagtcatcatcatgtaatttgccagttactttctgactac1080
aaagaaaaacagatgctaaaaatctcttctgaaaacagcaatccagaacaagacttaaag1140
ctgacatcagaggaagagtcacaaaggttcaaaggcagtgaaaatagccagccagagaaa1200
atgtctcaagaaccagaaataaataaggatggtgatagagaggttgaagaagaaatgaag1260
aagcatgaaagtaataatgtgggattactagaaaacctgactaatggtgtcactgctggc1320
aatggtgataatggattaattcctcaaaggaagagcagaacacctgaaaatcagcaattt1380
cctgacaacgaaagtgaagagtatcacagaatttgcgaattagtttctgactacaaagaa1440
aaacagatgccaaaatactcttctgaaaacagcaacccagaacaagacttaaagctgaca1500
tcagaggaagagtcacaaaggcttgagggcagtgaaaatggccagccagagctagaaaat1560
tttatggctatcgaagaaatgaagaagcacggaagtactcatgtcggattcccagaaaac1620
ctgactaatggtgccactgctggcaatggtgatgatggattaattcctccaaggaagagc1680
agaacacctgaaagccagcaatttcctgacactgagaatgaagagtatcacagtgacgaa1740
caaaatgatactcagaagcaattttgtgaagaacagaacactggaatattacacgatgag1800
attctgattcatgaagaaaagcagatagaagtggttgaaaaaatgaattctgagctttct1860
cttagttgtaagaaagaaaaagacatcttgcatgaaaatagtacgttgcgggaagaaatt1920
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gccatgctaa gactggagct agacacaatg aaacatcaga gccagctaaa aaaaaaaaaa 1980
aaaaaaaaaa aaaaaaaaaa 2000
<210> 375
<211> 2040
<212> DNA
<213> Homo sapien
<400>
375
atggtggttgaggttgattccatgccggctgcctcttctgtgaagaagccatttggtctc60
aggagcaagatgggcaagtggtgctgccgttgcttcccctgctgcagggagagcggcaag120
agcaacgtgggcacttctggagaccacgacgactctgctatgaagacactcaggagcaag180
atgggcaagtggtgccgccactgcttcccctgctgcagggggagtggcaagagcaacgtg240
ggcgcttctggagaccacgacgactctgctatgaagacactcaggaacaagatgggcaag300
tggtgctgccactgcttcccctgctgcagggggagcggcaagagcaaggtgggcgcttgg360
ggagactacgatgacagtgccttcatggagcccaggtaccacgtccgtggagaagatctg420
gacaagctccacagagctgcctggtggggtaaagtccccagaaaggatctcatcgtcatg480
ctcagggacactgacgtgaacaagaaggacaagcaaaagaggactgctctacatctggcc540
tctgccaatgggaattcagaagtagtaaaactcctgctggacagacgatgtcaacttaat600
gtccttgacaacaaaaagaggacagctctgataaaggccgtacaatgccaggaagatgaa660
tgtgcgttaatgttgctggaacatggcactgatccaaatattccagatgagtatggaaat720
accactctgcactacgctatctataatgaagataaattaatggccaaagcactgctctta780
tatggtgctgatatcgaatcaaaaaacaagcatggcctcacaccactgttacttggtgta840
catgagcaaaaacagcaagtcgtgaaatttttaatcaagaaaaaagcgaatttaaatgca900
ctggatagatatggaaggactgctctcatacttgctgtatgttgtggatcagcaagtata960 .
gtcagccttctacttgagcaaaatattgatgtatcttctcaagatctatctggacagacg1020
gccagagagtatgctgtttctagtcatcatcatgtaatttgccagttactttctgactac1080
aaagaaaaacagatgctaaaaatctcttctgaaaacagcaatccagaacaagacttaaag1140
ctgacatcagaggaagagtcacaaaggttcaaaggcagtgaaaatagccagccagagaaa1200
atgtctcaagaaccagaaataaataaggatggtgatagagaggttgaagaagaaatgaag1260
aagcatgaaagtaataatgtgggattactagaaaacctgactaatggtgtcactgctggc1320
aatggtgataatggattaattcctcaaaggaagagcagaacacctgaaaatcagcaattt1380
ccrgacaacgaaagtgaagagtatcacagaatttgcgaattagtttctgactacaaagaa1440 .,
aaacagatgccaaaatactcttctgaaaacagcaacccagaacaagacttaaagctgaca1500 ,
tcagaggaagagtcacaaaggcttgagggcagtgaaaatggccagccagagaaaagatct1560
caagaaccagaaataaataaggatggtgatagagagctagaaaattttatggctatcgaa1620
gaaatgaagaagcacggaagtactcatgtcggattcccagaaaacctgactaatggtgcc1680
actgctggcaatggtgatgatggattaattcctccaaggaagagcagaacacctgaaagc1740
cagcaatttcctgacactgagaatgaagagtatcacagtgacgaacaaaatgatactcag1800
aagcaattttgtgaagaacagaacactggaatattacacgatgagattctgattcatgaa1860
gaaaagcagatagaagtggttgaaaaaatgaattctgagctttctcttagttgtaagaaa1920
gaaaaagacatcttgcatgaaaatagtacgttgcgggaagaaattgccatgctaagactg1980
gagctagacacaatgaaacatcagagccagctaaaaaaaaaaaaaaaaaaaaaaaaaaaa2040
<210> 376
<211> 329
<212> PRT
<213> Homo sapien
<400> 376
Met Asp Ile Val Val Ser Gly Ser His Pro Leu Trp Val Asp Ser Phe
1 5 10 15
Leu His Leu Ala Gly Ser Asp Leu Leu Ser Arg Ser Leu Met Ala Glu
20 25 30
Glu Tyr Thr Ile Val His Ala Ser Phe Ile Ser Cys Ile Ser Ser Ser
35 40 45
Leu Asp Gly Gln Gly Glu Arg Gln Glu Gln Arg Gly His Phe Trp Arg
50 55 60
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Pro Gln Arg Leu Leu Cys Glu Asp Ala Trp Glu Gln Glu Val Gln Val
65 70 75 80
Val Leu Pro Leu Leu Pro Leu Leu Gln Gly Ser Gly Lys Ser Asn Val
85 90 95
Val Ala Trp Gly Asp Tyr Asp Asp Ser Ala Phe Met Asp Pro Arg Tyr
100 105 110
His Val His Gly Glu Asp Leu Asp Lys Leu His Arg Ala Ala Trp Trp
115 120 125
Gly Lys Val Pro Arg Lys Asp Leu Ile Val Met Leu Arg Asp Thr Asp
130 135 140
Val Asn Lys Arg Asp Lys Gln Lys Arg Thr Ala Leu His Leu Ala Ser
145 150 155 160
Ala Asn Gly Asn Ser Glu Val Val Lys Leu Val Leu Asp Arg Arg Cys
165 170 175
Gln Leu Asn Val Leu Asp Asn Lys Lys Arg Thr Ala Leu Thr Lys Ala
180 185 190
Val Gln Cys Gln Glu Asp Glu Cys Ala Leu Met Leu Leu Glu His Gly
195 200 205
Thr Asp Pro Asn Ile Pro Asp Glu Tyr Gly Asn Thr Thr Leu His Tyr
210 215 220
Ala Val Tyr Asn Glu Asp Lys Leu Met Ala Lys Ala Leu Leu Leu Tyr
225 230 235 240
Gly Ala Asp Ile Glu Ser Lys Asn Lys His Gly Leu Thr Pro Leu Leu
245 250 255
Leu Gly Ile His Glu Gln Lys Gln Gln Val Val Lys Phe Leu Ile Lys
260 265 270
Lys Lys Ala Asn Leu Asn Ala Leu Asp Arg Tyr Gly Arg Thr Ala Leu
275 280 285
Ile Leu Ala Val Cys Cys Gly Ser Ala Ser Ile Val Ser Pro Leu Leu
290 295 300
Glu Gln Asn Val Asp Val Ser Ser Gln Asp Leu Glu Arg Arg Pro Glu
305 310 315 320
Ser Met Leu Phe 'Leu Val Ile Ile Met
325
<210> 377
<211> 148
<212> PRT
<213> Homo sapien
<220>
<221> VARIANT
<222> (1)...(148)
<223> Xaa = Any Amino Acid
<400> 377
Met Thr Xaa Pro Ser Trp Ser Pro Gly Thr Thr Ser Val Glu Lys Ile
1 5 10 15
Trp Thr Ser Ser Thr Glu Leu Pro Trp Trp Gly Lys Val Pro Arg Lys
20 25 30
Asp Leu Ile Val Met Leu Arg Asp Thr Asp Val Asn Lys Xaa Asp Lys
35 40 45
Gln Lys Arg Thr Ala Leu His Leu Ala Ser Ala Asn Gly Asn Ser Glu
50 55 60
Val Val Lys Leu Xaa Leu Asp Arg Arg Cys Gln Leu Asn Val Leu Asp
65 70 75 80
Asn Lys Lys Arg Thr Ala Leu Xaa Lys Ala Val Gln Cys Gln Glu Asp
85 90 95
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Glu Cys Ala Leu Met Leu Leu Glu His Gly Thr Asp Pro Asn Ile Pro
100 105 110
Asp Glu Tyr Gly Asn Thr Thr Leu His Tyr Ala Xaa Tyr Asn Glu Asp
115 120 125
Lys Leu Met Ala Lys Ala Leu Leu Leu Tyr Gly Ala Asp Ile Glu Ser
130 135 140
Lys Asn Lys Val
145
<210> 378
<211> 1719
<212> PRT
<213> Homo sapien
<400> 378
Met Val Val Glu Val Asp Ser Met Pro Ala Ala Ser Ser Val Lys Lys
1 5 10 15
Pro Phe Gly Leu Arg Ser Lys Met Gly Lys Trp Cys Cys Arg Cys Phe
20 25 30
Pro Cys Cys Arg Glu Ser Gly Lys Ser Asn Val Gly Thr Ser Gly Asp
35 40 45
His Asp Asp Ser Ala Met Lys Thr Leu Arg Ser Lys Met Gly Lys Trp
50 55 60
Cys Arg His Cys Phe Pro Cys Cys Arg Gly Ser Gly Lys Ser Asn.Val
65 70 75 80
Gly Ala Ser Gly Asp His Asp Asp Ser Ala Met Lys Thr Leu Arg Asn
85 90 95
Lys Met Gly Lys Trp Cys Cys His Cys Phe Pro Cys Cys Arg Gly Ser
100 105 110
Gly Lys Ser Lys Val Gly Ala Trp Gly Asp Tyr Asp Asp Ser Ala Phe
115 120 125
Met Glu Pro Arg Tyr His Val Arg Gly Glu Asp Leu Asp Lys Leu His
130 135 140
Arg Ala Ala Trp Trp Gly Lys Val Pro Arg Lys Asp Leu Ile Val Met
145 150 155 160
Leu Arg Asp Thr Asp Val Asn Lys Lys Asp Lys Gln Lys Arg Thr Ala
165 170 175
Leu His Leu Ala Ser Ala Asn Gly Asn Ser Glu Val Val Lys Leu Leu
180 185 190
Leu Asp Arg Arg Cys Gln Leu Asn Val Leu Asp Asn Lys Lys Arg Thr
195 200 205
Ala Leu Ile Lys Ala Val Gln Cys Gln Glu Asp Glu Cys Ala Leu Met
210 215 220
Leu Leu Glu His Gly Thr Asp Pro Asn Ile Pro Asp Glu Tyr Gly Asn
225 230 235 240
Thr Thr Leu His Tyr Ala Ile Tyr Asn Glu Asp Lys Leu Met Ala Lys
245 250 255
Ala Leu Leu Leu Tyr Gly Ala Asp Ile Glu Ser Lys Asn Lys His Gly
260 265 270
Leu Thr Pro Leu Leu Leu Gly Val His Glu Gln Lys Gln Gln Val Val
275 280 285
Lys Phe Leu Ile Lys Lys Lys Ala Asn Leu Asn Ala Leu Asp Arg Tyr
290 295 300
Gly Arg Thr Ala Leu Ile Leu Ala Val Cys Cys Gly Ser Ala Ser Ile
305 310 315 320
Val Ser Leu Leu Leu Glu Gln Asn Ile Asp Val Ser Ser Gln Asp Leu
325 330 335
Ser Gly Gln Thr Ala Arg Glu Tyr Ala Val Ser Ser His His His Val
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340 345 350
Ile Cys Gln Leu Leu Ser Asp Tyr Lys Glu Lys Gln Met Leu Lys Ile
355 360 365
Ser Ser Glu Asn Ser Asn Pro Glu Asn Val Ser Arg Thr Arg Asn Lys
370 375 380
Pro Arg Thr His Met Val Val Glu Val Asp Ser Met Pro Ala Ala Ser
385 390 395 400
Ser Val Lys Lys Pro Phe Gly Leu Arg Ser Lys Met Gly Lys Trp Cys
405 410 415
Cys Arg Cys Phe Pro Cys Cys Arg Glu Ser Gly Lys Ser Asn Val Gly
420 425 430
Thr Ser Gly Asp His Asp Asp Ser Ala Met Lys Thr Leu Arg Ser Lys
435 440 445
Met Gly Lys Trp Cys Arg His Cys Phe Pro Cys Cys Arg Gly Ser Gly
450 455 460
Lys Ser Asn Val Gly Ala Ser Gly Asp His Asp Asp Ser Ala Met Lys
465 470 475 480
Thr Leu Arg Asn Lys Met Gly Lys Trp Cys Cys His Cys Phe Pro Cys
485 490 495
Cys Arg Gly Ser Gly Lys Ser Lys Val Gly Ala Trp Gly Asp Tyr Asp
500 505 510
Asp Ser Ala Phe Met Glu Pro Arg Tyr His Val Arg Gly Glu Asp Leu
515 520 525
Asp Lys Leu His Arg Ala Ala Trp Trp Gly Lys Val Pro Arg Lys Asp
530 535 540
Leu Tle Val Met Leu Arg Asp Thr Asp Val Asn Lys Lys Asp Lys Gln
545 550 555 560
Lys Arg Thr Ala Leu His Leu Ala Ser Ala Asn Gly Asn Ser Glu Val
565 570 575
Val Lys Leu Leu Leu Asp Arg Arg Cys Gln Leu Asn Val Leu Asp Asn
580 585 590
Lys Lys Arg Thr Ala Leu Ile Lys Ala Val Gln Cys Gln Glu Asp Glu
595 600 605
Cys Ala Leu Met Leu Leu Glu His Gly Thr Asp Pro Asn Ile Pro Asp
610 615 620
Glu Tyr Gly Asn Thr Thr Leu His Tyr Ala Ile Tyr Asn Glu Asp Lys
625 630 635 640
Leu Met Ala Lys Ala Leu Leu Leu Tyr Gly Ala Asp Ile Glu Ser Lys
645 650 655
Asn Lys His Gly Leu Thr Pro Leu Leu Leu Gly Val His Glu Gln Lys
660 665 670
Gln Gln Val Val Lys Phe Leu Ile Lys Lys Lys Ala Asn Leu Asn Ala
675 680 685
Leu Asp Arg Tyr Gly Arg Thr Ala Leu Ile Leu Ala Val Cys Cys Gly
690 695 700
Ser Ala Ser Ile Val Ser Leu Leu Leu Glu Gln Asn Ile Asp Val Ser
705 710 715 720
Ser Gln Asp Leu Ser Gly Gln Thr Ala Arg Glu Tyr Ala Val Ser Ser
725 730 735
His His His Val Ile Cys Gln Leu Leu Ser Asp Tyr Lys Glu Lys Gln
740 745 750
Met Leu Lys Ile Ser Ser Glu Asn Ser Asn Pro Glu Gln Asp Leu Lys
755 760 765
Leu Thr Ser Glu Glu Glu Ser Gln Arg Phe Lys Gly Ser Glu Asn Ser
770 775 780
Gln Pro Glu Lys Met Ser Gln Glu Pro Glu Ile Asn Lys Asp Gly Asp
785 790 795 800
Arg Glu Val Glu Glu Glu Met Lys Lys His Glu Ser Asn Asn Val Gly
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805 810 815
Leu Leu Glu Asn Leu Thr Asn Gly Val Thr Ala Gly Asn Gly Asp Asn
820 825 830
Gly Leu Ile Pro Gln Arg Lys Ser Arg Thr Pro Glu Asn Gln Gln Phe
835 840 845
Pro Asp Asn Glu Ser Glu Glu Tyr His Arg Ile Cys Glu Leu Val Ser
850 855 860
Asp Tyr Lys Glu Lys Gln Met Pro Lys Tyr Ser Ser Glu Asn Ser Asn
865 870 875 880
Pro Glu Gln Asp Leu Lys Leu Thr Ser Glu Glu Glu Ser Gln Arg Leu
885 890 895
Glu Gly Ser Glu Asn Gly Gln Pro Glu Leu Glu Asn Phe Met Ala Ile
900 905 910
Glu Glu Met Lys Lys His Gly Ser Thr His Val Gly Phe Pro Glu Asn
915 920 925
Leu Thr Asn Gly Ala Thr Ala Gly Asn Gly Asp Asp Gly Leu Ile Pro
930 935 940
Pro Arg Lys Ser Arg Thr Pro Glu Ser Gln Gln Phe Pro Asp Thr Glu
945 950 955 960
Asn Glu Glu Tyr His Ser Asp Glu Gln Asn Asp Thr Gln Lys Gln Phe
965 970 975
Cys Glu Glu Gln Asn Thr Gly Ile Leu His Asp Glu Ile Leu Ile His
980 985 990
Glu GIu Lys Gln Ile Glu Val Val Giu Lys Met Asn Ser Glu Leu Ser
995 1000 1005
Leu Ser Cys Lys Lys Glu Lys Asp Ile Leu His Glu Asn Ser Thr Leu
1010 1015 1020
Arg Glu Glu Ile Ala Met Leu Arg Leu Glu Leu Asp Thr Met .Lys His
1025 1030 1035 1040
Gln Ser Gln Leu, Pro Arg Thr His Met Val Val Glu Val Asp Ser Met
1045 1050 1055
Pro Ala Ala Ser Ser Val Lys Lys Pro Phe Gly Leu Arg Ser Lys Met
1060 1065 1070
Gly Lys Trp Cys Cys Arg Cys Phe Pro Cys Cys Arg Glu Ser Gly Lys
1075 1080 1085
Ser Asn Val Gly Thr Ser Gly Asp His Asp Asp Ser Ala Met Lys Thr
1090 1095 1100
Leu Arg Ser Lys Met Gly Lys Trp Cys Arg His Cys Phe Pro Cys Cys
1105 1110 1115 1120
Arg Gly Ser Gly Lys Ser Asn Val Gly Ala Ser Gly Asp His Asp Asp
1125 1130 1135
Ser Ala Met Lys Thr Leu Arg Asn Lys Met Gly Lys Trp Cys Cys His
1140 1145 1150
Cys Phe Pro Cys Cys Arg Gly Ser Gly Lys Ser Lys Val Gly Ala Trp
1155 1160 1165
Gly Asp Tyr Asp Asp Ser Ala Phe Met Glu Pro Arg Tyr,His Val Arg
1170 1175 1180
Gly Glu Asp Leu Asp Lys Leu His Arg Ala Ala Trp Trp Gly Lys Val
1185 1190 1195 1200
Pro Arg Lys Asp Leu Ile Val Met Leu Arg Asp Thr Asp Val Asn Lys
1205 1210 1215
Lys Asp Lys Gln Lys Arg Thr Ala Leu His Leu Ala Ser Ala Asn Gly
1220 1225 1230
Asn Ser Glu Val Val Lys Leu Leu Leu Asp Arg Arg Cys Gln Leu Asn
1235 1240 1245
Val Leu Asp Asn Lys Lys Arg Thr Ala Leu Ile Lys Ala Val Gln Cys
1250 1255 1260
Gln Glu Asp Glu Cys Ala Leu Met Leu Leu Glu His Gly Thr Asp Pro
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1265 1270 1275 1280
Asn Ile Pro Asp Glu Tyr Gly Asn Thr Thr Leu His Tyr Ala Ile Tyr
1285 1290 1295
Asn Glu Asp Lys Leu Met Ala Lys Ala Leu Leu Leu Tyr Gly Ala Asp
1300 1305 1310
Ile Glu Ser Lys Asn Lys His Gly Leu Thr Pro Leu Leu Leu Gly Val
1315 1320 1325
His Glu Gln Lys Gln Gln Val Val Lys Phe Leu Ile Lys Lys Lys Ala
1330 1335 1340
Asn Leu Asn Ala Leu Asp Arg Tyr Gly Arg Thr Ala Leu Ile Leu Ala
1345 1350 1355 1360
Val Cys Cys Gly Ser Ala Ser Ile Val Ser Leu Leu Leu Glu Gln Asn
1365 1370 1375
Ile Asp Val Ser Ser Gln Asp Leu Ser Gly Gln Thr Ala Arg Glu Tyr
1380 1385 1390
Ala Val Ser Ser His His His Val Ile Cys Gln Leu Leu Ser Asp Tyr
1395 1400 1405
Lys Glu Lys Gln Met Leu Lys Ile Ser Ser Glu Asn Ser Asn Pro Glu
1410 1415 1420
Gln Asp Leu Lys Leu Thr Ser Glu Glu Glu Ser Gln Arg Phe Lys Gly
1425 1430 1435 1440
Ser Glu Asn Ser Gln Pro Glu Lys Met Ser Gln Glu Pro Glu Ile Asn
1445 1450 1455
Lys Asp Gly Asp Arg Glu Val Glu Glu Glu Met Lys Lys His Glu Ser
1460 1465 1470
Asn Asn Val Gly Leu Leu Glu Asn Leu Thr .Asn ~~ly Val Thr Ala Gly
1475 1480 1485
Asn Gly Asp Asn Gly Leu Ile Pro Gln Arg Lys Ser Arg Thr Pro Glu
1490 1495 1500
Asn Gln Gln Phe.Pro Asp Asn Glu Ser Glu Glu Tyr His Arg Ile Cys
1505 1510 1515 1520
Glu Leu Val Ser Asp Tyr Lys Glu Lys Gln Met Pro Lys Tyr Ser Ser
1525 1530 1535
Glu Asn Ser Asn Pro Glu Gln Asp Leu Lys Leu Thr Ser Glu Glu Glu ..
1540 1545 1550
Ser Gln Arg Leu Glu Gly Ser Glu Asn Gly Gln Pro Glu Lys Arg Ser
1555 1560 1565
Gln Glu Pro Glu Ile Asn Lys Asp Gly Asp Arg Glu Leu Glu Asn Phe
1570 1575 1580
Met Ala Ile Glu Glu Met Lys Lys His Gly Ser Thr His Val Gly Phe
1585 1590 1595 1600
Pro Glu Asn Leu Thr Asn Gly Ala Thr Ala Gly Asn Gly Asp Asp Gly
1605 1610 1615
Leu Ile Pro Pro Arg Lys Ser Arg Thr Pro Glu Ser Gln Gln Phe Pro
1620 1625 1630
Asp Thr Glu Asn Glu Glu Tyr His Ser Asp Glu Gln Asn Asp Thr Gln
1635 1640 1645
Lys Gln Phe Cys Glu Glu Gln Asn Thr Gly Ile Leu His Asp Glu Ile
1650 1655 1660
Leu Ile His Glu Glu Lys Gln Ile Glu Val Val Glu Lys Met Asn Ser
1665 1670 1675 1680
Glu Leu Ser Leu Ser Cys Lys Lys Glu Lys Asp Ile Leu His Glu Asn
1685 1690 1695
Ser Thr Leu Arg Glu Glu Ile Ala Met Leu Arg Leu Glu Leu Asp Thr
1700 1705 1710
Met Lys His Gln Ser Gln Leu
1715
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<210> 379
<211> 656
<212> PRT
<213> Homo sapien
<400> 379
Met Val Val Glu Val Asp Ser Met Pro Ala Ala Ser Ser Val Lys Lys
1 5 10 15
Pro Phe Gly Leu Arg Ser Lys Met Gly Lys Trp Cys Cys Arg Cys Phe
20 25 30
Pro Cys Cys Arg Glu Ser Gly Lys Ser Asn Val Gly Thr Ser Gly Asp
35 40 45
His Asp Asp Ser Ala Met Lys Thr Leu Arg Ser Lys Met Gly Lys Trp
50 55 60
Cys Arg His Cys Phe Pro Cys Cys Arg Gly Ser Gly Lys Ser Asn Val
65 70 75 80
Gly Ala Ser Gly Asp His Asp Asp Ser Ala Met Lys Thr Leu Arg Asn
85 90 95
Lys Met Gly Lys Trp Cys Cys His Cys Phe Pro Cys Cys Arg Gly Ser
100 105 110
Gly Lys Ser Lys Val Gly Ala Trp Gly Asp Tyr Asp Asp Ser Ala Phe
115 120 125
Met Glu Pro Arg Tyr His Val Arg Gly Glu Asp Leu Asp Lys Leu His
130 135 140
Arg Ala Ala Trp Trp Gly Lys Val Pro Arg Lys Asp Leu Ile Val Met
145 150 155 160
Leu Arg Asp Thr Asp Val Asn Lys Lys Asp Lys Gln Lys Arg Thr Ala
165 170 175
Leu His Leu Ala Ser Ala Asn Gly Asn Ser Glu Val Val Lys Leu Leu
180 185 190
Leu Asp Arg Arg Cys Gln Leu Asn Val Leu Asp Asn Lys Lys Arg Thr
195 200 205
Ala Leu Ile Lys Ala Val Gln Cys Gln Glu Asp Glu Cys Ala Leu Met
210 215 220
Leu Leu Glu His Gly Thr Asp Pro Asn Ile Pro Asp Glu Tyr Gly Asn
225 230 235 240
Thr Thr Leu His Tyr Ala Ile Tyr Asn Glu Asp Lys Leu Met Ala Lys
245 250 255
Ala Leu Leu Leu Tyr Gly Ala Asp Ile Glu Ser Lys Asn Lys His Gly
260 265 270
Leu Thr Pro Leu Leu Leu Gly Val His Glu Gln Lys Gln Gln Val Val
275 280 285
Lys Phe Leu Ile Lys Lys Lys Ala Asn Leu Asn Ala Leu Asp Arg Tyr
290 295 300
Gly Arg Thr Ala Leu Ile Leu Ala Val Cys Cys Gly Ser Ala Ser Ile
305 310 315 320
Val Ser Leu Leu Leu Glu Gln Asn Ile Asp Val Ser Ser Gln Asp Leu
325 330 335
Ser Gly Gln Thr Ala Arg Glu Tyr Ala Val Ser Ser His His His Val
340 345 350
Ile Cys Gln Leu Leu Ser Asp Tyr Lys Glu Lys Gln Met Leu Lys Ile
355 360 365
Ser Ser Glu Asn Ser Asn Pro Glu Gln Asp Leu Lys Leu Thr Ser Glu
370 375 380
Glu Glu Ser Gln Arg Phe Lys Gly Ser Glu Asn Ser Gln Pro Glu Lys
385 390 395 400
Met Ser Gln Glu Pro Glu Ile Asn Lys Asp Gly Asp Arg Glu Val Glu
405 410 415
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Glu Glu Met Lys Lys His Glu Ser Asn Asn Val Gly Leu Leu Glu Asn
420 425 430
Leu Thr Asn Gly Val Thr Ala Gly Asn Gly Asp Asn Gly Leu Ile Pro
435 440 445
Gln Arg Lys Ser Arg Thr Pro Glu Asn Gln Gln Phe Pro Asp Asn Glu
450 455 460
Ser Glu Glu Tyr His Arg Ile Cys Glu Leu Val Ser Asp Tyr Lys Glu
465 470 475 480
Lys Gln Met Pro Lys Tyr Ser Ser Glu Asn Ser Asn Pro Glu Gln Asp
485 490 495
Leu Lys Leu Thr Ser Glu Glu Glu Ser Gln Arg Leu Glu Gly Ser Glu
500 505 510
Asn Gly Gln Pro Glu Leu Glu Asn Phe Met Ala Ile Glu Glu Met Lys
515 520 525
Lys His Gly Ser Thr His Val Gly Phe Pro Glu Asn Leu Thr Asn Gly
530 535 540
Ala Thr Ala Gly Asn Gly Asp Asp Gly Leu Ile Pro Pro Arg Lys Ser
545 550 555 560
Arg Thr Pro Glu Ser Gln Gln Phe Pro Asp Thr Glu Asn Glu Glu Tyr
565 570 575
His Ser Asp Glu Gln Asn Asp Thr Gln Lys Gln Phe Cys Glu Glu Gln
580 585 590
Asn Thr Gly Ile Leu His Asp Glu Ile Leu Ile His Glu Glu Lys Gln
595 600 605
Ile Glu Val Val Glu Lys Met Asn Ser Glu Leu Ser Leu Ser Cys Lys
610 615 620
Lys Glu Lys Asp Ile Leu His Glu Asn Ser Thr Leu Arg Glu Glu Ile
625 630 635 640
Ala Met Leu Arg Leu Glu Leu Asp Thr Met Lys His Gln Ser Gln Leu
645 650 655
<210> 380
<211> 671
<212> PRT
<213> Homo sapien
<400> 380
Met Val Val Glu Val Asp Ser Met Pro Ala Ala Ser Ser Val Lys Lys
1 5 10 15
Pro Phe Gly Leu Arg Ser Lys Met Gly Lys Trp Cys Cys Arg Cys Phe
20 25 30
Pro Cys Cys Arg Glu Ser Gly Lys Ser Asn Val Gly Thr Ser Gly Asp
35 40 45
His Asp Asp Ser Ala Met Lys Thr Leu Arg Ser Lys Met Gly Lys Trp
50 55 60
Cys Arg His Cys Phe Pro Cys Cys Arg Gly Ser Gly Lys Ser Asn Val
65 ~ 70 75 80
Gly Ala Ser Gly Asp His Asp Asp Ser Ala Met Lys Thr Leu Arg Asn
85 90 95
Lys Met Gly Lys Trp Cys Cys His Cys Phe Pro Cys Cys Arg Gly Ser
100 105 110
Gly Lys Ser Lys Val Gly Ala Trp Gly Asp Tyr Asp Asp Ser Ala Phe
115 120 125
Met Glu Pro Arg Tyr His Val Arg Gly Glu Asp Leu Asp Lys Leu His
130 135 140
Arg Ala Ala Trp Trp Gly Lys Val Pro Arg Lys Asp Leu Ile Val Met
145 150 155 160
Leu Arg Asp Thr Asp Val Asn Lys Lys Asp Lys Gln Lys Arg Thr Ala
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165 170 175
Leu His Leu Ala Ser Ala Asn Gly Asn Ser Glu Val Val Lys Leu Leu
180 185 190
Leu Asp Arg Arg Cys Gln Leu Asn Val Leu Asp Asn Lys Lys Arg Thr
195 200 205
Ala Leu Ile Lys Ala Val Gln Cys Gln Glu Asp Glu Cys Ala Leu Met
210 215 220
Leu Leu Glu His Gly Thr Asp Pro Asn Ile Pro Asp Glu Tyr Gly Asn
225 230 235 240
Thr Thr Leu His Tyr Ala Ile Tyr Asn Glu Asp Lys Leu Met Ala Lys
245 250 255
Ala Leu Leu Leu Tyr Gly Ala Asp Ile Glu Ser Lys Asn Lys His Gly
260 265 270
Leu Thr Pro Leu Leu Leu Gly Val His Glu Gln Lys Gln Gln Val Val
275 280 285
Lys Phe Leu Ile Lys Lys Lys Ala Asn Leu Asn Ala Leu Asp Arg Tyr
290 295 300
Gly Arg Thr Ala Leu Ile Leu Ala Val Cys Cys Gly Ser Ala Ser Ile
305 310 315 320
Val Ser Leu Leu Leu Glu Gln Asn Ile Asp Val Ser Ser Gln Asp Leu
325 330 335
Ser Gly Gln Thr Ala Arg Glu Tyr Ala Val Ser Ser His His His Val
340 345 350
Ile Cys Gln Leu Leu Ser Asp Tyr Lys Glu Lys Gln Met Leu Lys Ile
355 360 365
Ser Ser Glu Asn Ser Asn Pro Glu Gln Asp Leu Lys Leu Thr Ser Glu
370 375 380
Glu Glu Ser Gln Arg Phe Lys Gly Ser Glu Asn Ser Gln Pro Glu Lys
385 390 395 400
Met Ser Gln Glu Pro Glu Ile Asn Lys Asp Gly Asp Arg Glu Val Glu
405 410 415
Glu Glu Met Lys Lys His Glu Ser Asn Asn Val Gly Leu Leu Glu Asn
420 425 430
Leu Thr Asn Gly Val Thr Ala Gly Asn Gly Asp Asn Gly Leu Ile Pro
435 440 445
Gln Arg Lys Ser Arg Thr Pro Glu Asn Gln Gln Phe Pro Asp Asn Glu
450 455 460
Ser Glu Glu Tyr His Arg Ile Cys Glu Leu Val Ser Asp Tyr Lys Glu
465 470 475 480
Lys Gln Met Pro Lys Tyr Ser Ser Glu Asn Ser Asn Pro Glu Gln Asp
485 490 495
Leu Lys Leu Thr Ser Glu Glu Glu Ser Gln Arg Leu Glu Gly Ser Glu
500 505 510
Asn Gly Gln Pro Glu Lys Arg Ser Gln Glu Pro Glu Ile Asn Lys Asp
515 520 525
Gly Asp Arg Glu Leu Glu Asn Phe Met Ala Ile Glu Glu Met Lys Lys
530 535 540
His Gly Ser Thr His Val Gly Phe Pro Glu Asn Leu Thr Asn Gly Ala
545 550 555 560
Thr Ala Gly Asn Gly Asp Asp Gly Leu Ile Pro Pro Arg Lys Ser Arg
565 570 575
Thr Pro Glu Ser Gln Gln Phe Pro Asp Thr Glu Asn Glu Glu Tyr His
580 585 590
Ser Asp Glu Gln Asn Asp Thr Gln Lys Gln Phe Cys Glu Glu Gln Asn
595 600 605
Thr Gly Ile Leu His Asp Glu Ile Leu Ile His Glu Glu Lys Gln Ile
610 615 620
Glu Val Val Glu Lys Met Asn Ser Glu Leu Ser Leu Ser Cys Lys Lys
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
132
625 630 635 640
Glu Lys Asp Ile Leu His Glu Asn Ser Thr Leu Arg Glu Glu Ile Ala
645 650 655
Met Leu Arg Leu Glu Leu Asp Thr Met Lys His Gln Ser Gln Leu
660 665 670
<210> 381
<211> 251
<212> DNA
<213> Homo sapien
<400> 381
ggagaagcgt ctgctggggc aggaaggggt ttccctgccc tctcacctgt ccctcaccaa 60
ggtaacatgc ttcccctaag ggtatcccaa cccaggggcc tcaccatgac ctctgagggg 120
ccaatatccc aggagaagca ttggggagtt gggggcaggt gaaggaccca ggactcacac 180
atcctgggcc tccaaggcag aggagagggt cctcaagaag gtcaggagga aaatccgtaa 240
caagcagtca g 251
<210> 382
<211> 3279
<212> DNA
<213> Homo Sapiens
<400> 382
cttcctgcag cccccatgct ggtgaggggc acgggcagga acagtggacc caacatggaa 60
atgctggagg gtgtcaggaa gtgatcgggc tctggggcag ggaggagggg tggggagtgt 120
cactgggagg ggacatcctg cagaaggtag gagtgagcaa acacccgctg caggggaggg 180
gagagccctg cggcacctgg gggagcagag ggagcagcac ctgcccaggc ctgggaggag 240
gggcctggag ggcgtgagga ggagcgaggg ggctgcatgg ctggagtgag ggatcagggg 300
cagggcgcga gatggcctca cacagggaag agagggcccc tcctgcaggg cctcacctgg 360
gccacaggag gacactgctt ttcctctgag gagtcaggag ctgtggatgg tgctggacag 420
aagaaggaca gggcctggct caggtgtcca gaggctgtcg ctggcttccc tttgggatca 480
gactgcaggg agggagggcg gcagggttgt ggggggagtg acgatgagga tgacctgggg 540
gtggctccag gccttgcccc tgcctgggcc ctcacccagc ctccctcaca gtctcctggc 600
cctcagtctc tcccctccac tccatcctcc atctggcctc agtgggtcat tctgatcact 660
gaactgacca tacccagccc tgcccacggc cctccatggc tccccaatgc cctggagagg 720
ggacatctag tcagagagta gtcctgaaga ggtggcctct gcgatgtgcc tgtgggggca 780
gcatcctgca gatggtcccg gccctcatcc tgctgacctg tctgcaggga ctgtcctcct 840
ggaccttgcc ccttgtgcag gagctggacc ctgaagtccc ctccccatag gccaagactg 900
gagccttgtt ccctctgttg gactccctgc ccatattctt gtgggagtgg gttctggaga 960
catttctgtc tgttcctgag agctgggaat tgctctcagt catctgcctg cgcggttctg 1020
agagatggag ttgcctaggc agttattggg gccaatcttt ctcactgtgt ctctcctcct 1080
ttacccttag ggtgattctg ggggtccact tgtctgtaat ggtgtgcttc aaggtatcac 1140
atcatggggc cctgagccat gtgccctgcc tgaaaagcct gctgtgtaca ccaaggtggt 1200
gcattaccgg aagtggatca aggacaccat cgcagccaac ccctgagtgc ccctgtccca 1260
cccctacctc tagtaaattt aagtccacct cacgttctgg catcacttgg cctttctgga 1320
tgctggacac ctgaagcttg gaactcacct ggccgaagct cgagcctcct gagtcctact 1380
gacctgtgct ttctggtgtg gagtccaggg ctgctaggaa aaggaatggg cagacacagg 1440
tgtatgccaa tgtttctgaa atgggtataa tttcgtcctc tccttcggaa cactggctgt 1500
ctctgaagac ttctcgctca gtttcagtga ggacacacac aaagacgtgg gtgaccatgt 1560
tgtttgtggg gtgcagagat gggaggggtg gggcccaccc tggaagagtg gacagtgaca 1620
caaggtggac actctctaca gatcactgag gataagctgg agccacaatg catgaggcac 1680
acacacagca aggttgacgc tgtaaacata gcccacgctg tcctgggggc actgggaagc 1740
ctagataagg ccgtgagcag aaagaagggg aggatcctcc tatgttgttg aaggagggac 1800
tagggggaga aactgaaagc tgattaatta caggaggttt gttcaggtcc cccaaaccac 1860
cgtcagattt gatgatttcc tagcaggact tacagaaata aagagctatc atgctgtggt 1920
ttattatggt ttgttacatt gataggatac atactgaaat cagcaaacaa aacagatgta 1980
tagattagag tgtggagaaa acagaggaaa acttgcagtt acgaagactg gcaacttggc 2040
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
133
tttactaagt tttcagactg gcaggaagtc aaacctatta ggctgaggac cttgtggagt 2100
gtagctgatc cagctgatag aggaactagc caggtggggg cctttccctt tggatggggg 2160
gcatatccga cagttattct ctccaagtgg agacttacgg acagcatata attctccctg 2220
caaggatgta tgataatatg tacaaagtaa ttccaactga ggaagctcac ctgatcctta 2280
gtgtccaggg tttttactgg gggtctgtag gacgagtatg gagtacttga ataattgacc 2340
tgaagtcctc agacctgagg ttccctagag ttcaaacaga tacagcatgg tccagagtcc 2400
cagatgtaca aaaacaggga ttcatcacaa atcccatctt tagcatgaag ggtctggcat 2460
ggcccaaggc cccaagtata tcaaggcact tgggcagaac atgccaagga atcaaatgtc 2520
atctcccagg agttattcaa gggtgagccc tttacttggg atgtacaggc tttgagcagt 2580
gcagggctgc tgagtcaacc ttttattgta caggggatga gggaaaggga gaggatgagg 2640
aagcccccct ggggatttgg tttggtcttg tgatcaggtg gtctatgggg ctatccctac 2700
aaagaagaat ccagaaatag gggcacattg aggaatgata ctgagcccaa agagcattca 2760
atcattgttt tatttgcctt cttttcacac cattggtgag ggagggatta ccaccctggg 2820
gttatgaaga tggttgaaca ccccacacat agcaccggag atatgagatc aacagtttct 2880
tagccataga gattcacagc ccagagcagg aggacgctgc acaccatgca ggatgacatg 2940
ggggatgcgc tcgggattgg tgtgaagaag caaggactgt tagaggcagg ctttatagta 3000
acaagacggt ggggcaaact ctgatttccg tgggggaatg tcatggtctt gctttactaa 3060
gttttgagac tggcaggtag tgaaactcat taggctgaga accttgtgga atgcagctga 3120
cccagctgat agaggaagta gccaggtggg agcctttccc agtgggtgtg ggacatatct 3180
ggcaagattt tgtggcactc ctggttacag atactggggc agcaaataaa actgaatctt 3240
gttttcagac cttaaaaaaa aaaaaaaaaa aaaagtttt 3279
<210> 383
<211> 154
<212> PRT
<213> Homo Sapiens
<400> 383
Met Ala Gly Val Arg Asp G1n Gly Gln Gly Ala Arg Trp Pro His Thr
10 15
Gly Lys Arg Gly Pro Leu Leu Gln Gly Leu Thr Trp Ala Thr Gly Gly
20 25 30
His Cys Phe Ser Ser Glu Glu Ser Gly Ala Val Asp Gly Ala Gly Gln
35 40 45
Lys Lys Asp Arg Ala Trp Leu Arg Cys Pro Glu Ala Val Ala Gly Phe
50 55 60
Pro Leu Gly Ser Asp Cys Arg Glu Gly Gly Arg Gln Gly Cys Gly Gly
65 70 75 80
Ser Asp Asp Glu Asp Asp Leu Gly Val Ala Pro Gly Leu Ala Pro Ala
85 90 95
Trp Ala Leu Thr Gln Pro Pro Ser Gln Ser Pro Gly Pro Gln Ser Leu
100 105 110
Pro Ser Thr Pro Ser Ser Ile Trp Pro Gln Trp Val Ile Leu Ile Thr
115 120 125
Glu Leu Thr Ile Pro Ser Pro Ala His Gly Pro Pro Trp Leu Pro Asn
130 135 140
Ala Leu Glu Arg Gly His Leu Val Arg Glu
145 150
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
i34
<210> 384
<211> 557
<212> DNA
<213> Homo sapiens
<400> 384
ggatcctcta gagcggccgc ctactactac taaattcgcg gccgcgtcga cgaagaagag 60
aaagatgtgt tttgttttgg actctctgtg gtcccttcca atgctgtggg tttccaacca 120
ggggaagggt cccttttgca ttgccaagtg ccataaccat gagcactact ctaccatggt 180
tctgcctcct ggccaagcag gctggtttgc aagaatgaaa tgaatgattc tacagctagg 240
acttaacctt gaaatggaaa gtcttgcaat cccatttgca ggatccgtct gtgcacatgc 300
ctctgtagag agcagcattc ccagggacct tggaaacagt tggcactgta aggtgcttgc 360
tccccaagac acatcctaaa aggtgttgta atggtgaaaa cgtcttcctt ctttattgcc 420
ccttcttatt tatgtgaaca actgtttgtc tttttttgta tcttttttaa actgtaaagt 480
tcaattgtga aaatgaatat catgcaaata aattatgcga tttttttttc aaagtaaaaa 540
aaaaaaaaaa aaaaaaa 557
<210> 385
<211> 337
<212> DNA
<213> Homo sapiens
<400> 385
ttcccaggtg atgtgcgagg gaagacacat ttactatcct tgatggggct gattccttta 60
gtttctctag cagcagatgg gttaggagga agtgacccaa. gtggttgact cctatgtgca 120
tctcaaagcc atctgctgtc ttcgagtacg gacacatcat cactcctgca ttgttgatca 180
aaacgtggag gtgcttttcc tcagctaaga agcccttagc aaaagctcga atagacttag 240
tatcagacag gtccagtttc cgcaccaaca cctgctggtt ccctgtcgtg gtctggatct 300
ctttggccac caattccccc ttttccacat cccggca 337
<210> 386
<211> 300
<212> DNA
<213> Homo sapiens
<400> 386
gggcccgcta ccggcccagg ccccgcctcg cgagtcctcc tccccgggtg cctgcccgca 60
gcccgctcgg cccagagggt gggcgcgggg ctgcctctac cggctggcgg ctgtaactca 120
gcgaccttgg cccgaaggct ctagcaagga cccaccgacc ccagccgcgg cggcggcggc 180
gcggactttg cccggtgtgt ggggcggagc ggactgcgtg tccgcggacg ggcagcgaag 240
atgttagcct tcgctgccag gaccgtggac cgatcccagg gctgtggtgt aacctcagcc 300
<210> 387
<211> 537
<212> DNA
<213> Homo sapiens
<400> 387
gggccgagtc gggcaccaag ggactctttg caggcttcct tcctcggatc atcaaggctg 60
ccccctcctg tgccatcatg atcagcacct atgagttcgg caaaagcttc ttccagaggc 120
tgaaccagga ccggcttctg ggcggctgaa aggggcaagg aggcaaggac cccgtctctc 180
ccacggatgg ggagagggca ggaggagacc cagccaagtg ccttttcctc agcactgagg 240
gagggggctt gtttcccttc cctcccggcg acaagctcca gggcagggct gtccctctgg 300
gcggcccagc acttcctcag acacaacttc ttcctgctgc tccagtcgtg gggatcatca 360
cttacccacc ccccaagttc aagaccaaat cttccagctg cccccttcgt gtttccctgt 420
gtttgctgta gctgggcatg tctccaggaa ccaagaagcc ctcagcctgg tgtagtctcc 480
ctgacccttg ttaattcctt aagtctaaag atgatgaact tcaaaaaaaa aaaaaaa 537
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
135
<210> 388
<211> 520
<212> DNA
<213> Homo Sapiens
<400> 388
aggataattt ttaaaccaat caaatgaaaa aaacaaacaa acaaaaaagg aaatgtcatg 60
tgaggttaaa ccagtttgca ttcccctaat gtggaaaaag taagaggact actcagcact 120
gtttgaagat tgcctcttct acagcttctg agaattgtgt tatttcactt gccaagtgaa 180
ggaccccctc cccaacatgc cccagcccac ccctaagcat ggtcccttgt caccaggcaa 240
ccaggaaact gctacttgtg gacctcacca gagaccagga gggtttggtt agctcacagg 300
acttccccca ccccagaaga ttagcatccc atactagact catactcaac tcaactaggc 360
tcatactcaa ttgatggtta ttagacaatt ccatttcttt ctggttatta taaacagaaa 420
atctttcctc ttctcattac cagtaaaggc tcttggtatc tttctgttgg aatgatttct 480
atgaacttgt cttattttaa tggtgggttt tttttctggt 520
<210> 389
<211> 365
<212> DNA
<213> Homo Sapiens
<400> 389
cgttgcccca gtttgacaga aggaaaggcg gagcttattc aaagtctaga gggagtggag 60
gagttaaggc tggatttcag atctgcctgg ttccagccgc agtgtgccct ctgctccccc 120
aacgactttc caaataatct caccagcgcc ttccagctca ggcgtcctag aagcgtcttg 180
aagcctatgg ccagctgtct ttgtgttccc tctcacccgc ctgtcctcac agctgagact 240
cccaggaaac cttcagacta cctt.cctctg ccttcagcaa ggggcgttgc ccacattctc 300
tgagggtcag tggaagaacc tagactccca ttgctagagg tagaaagggg aagggtgctg 360
gggag 365
<210> 390
<211> 221
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1) . . (221)
<223> n = A,T,C or G
<400> 390
tgcctctcca tcctggcccc gacttctctg tcaggaaagt ggggatggac cccatctgca 60
tacacggntt ctcatgggtg tggaacatct ctgcttgcgg tttcaggaag gcctctggct 120
gctctangag tctgancnga ntcgttgccc cantntgaca naaggaaagg cggagcttat 180
tcaaagtcta gagggagtgg aggagttaag gctggatttc a 221
<210> 391
<211> 325
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(325)
<223> n = A,T,C or G
<400> 391
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
136
tggagcaggt cccgaggcct ccctagagcc tggggccgac tctgtgncga tgcangcttt 60
ctctcgcgcc cagcctggag ctgctcctgg catctaccaa caatcagncg aggcgagcag 120
tagccagggc actgctgcca acagccagtc cnnataccat catgtnaccc ggtgngctct 180
naanttngat ntccanagcc ctacccatcn tagttctgct ctcccaccgg ntaccagccc 240
cactgcccag gaatcctaca gccagtaccc tgtcccgacg tctctaccta ccagtacgat 300
gagacctccg gctactacta tgacc 325
<210> 392
<211> 277
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1) . . (277)
<223> n = A,T,C or G
<400> 392
atattgttta actccttcct ttatatcttt taacattttc atggngaaag gttcacatct 60
agtctcactt nggcnagngn ctcctacttg agtctcttcc ccggcctgnn ccagtngnaa 120
antaccanga accgncatgn cttaanaacn ncctggtttn tgggttnntc aatgactgca 180
tgcagtgcac caccctgtcc actacgtgat gctgtaggat taaagtctca cagtgggcgg 240
ctgaggatac agcgccgcgt cctgtgttgc tggggaa 277
<210> 393
<211> 566
<212> DNA
<213> Homo Sapiens
<400> 333
actagtccag tgtggtggaa ttcgcggccg cgtcgacgga caggtcagct gtctggctca 60
gtgatctaca ttctgaagtt gtctgaaaat gtcttcatga ttaaattcag cctaaacgtt 120
ttgccgggaa cactgcagag acaatgctgt gagtttccaa ccttagccca tctgcgggca 180
gagaaggtct agtttgtcca tcagcattat catgatatca ggactggtta cttggttaag 240
gaggggtcta ggagatctgt cccttttaga gacaccttac ttataatgaa gtatttggga 300
gggtggtttt caaaagtaga aatgtcctgt attccgatga tcatcctgta aacattttat 360
catttattaa tcatccctgc ctgtgtctat tattatattc atatctctac gctggaaact 420
ttctgcrtca atgtttactg tgcctttgtt tttgctagtt tgtgttgttg aaaaaaaaaa 480
cattctctgc ctgagtttta atttttgtcc aaagttattt taatctatac aattaaaagc 540
ttttgcctat caaaaaaaaa aaaaaa 566
<210> 394
<211> 384
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1). .(384)
<223> n = A,T,C or G
<400> 394
gaacatacat gtcccggcac ctgagctgca gtctgacatc atcgccatca cgggcctcgc 60
tgcaaattng gaccgggcca aggctggact gctggagcgt gtgaaggagc tacaggccna 120
gcaggaggac cgggctttaa ggagttttaa gctgagtgtc actgtagacc ccaaatacca 180
tcccaagatt atcgggagaa agggggcagt aattacccaa atccggttgg agcatgacgt 240
gaacatccag tttcctgata aggacgatgg gaaccagccc caggaccaaa ttaccatcac 300
agggtacgaa aagaacacag aagctgccag ggatgctata ctgagaattg tgggtgaact 360
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
137
tgagcagatg gtttctgagg acgt 384
<210> 395
<211> 399
<212> DNA
<213> Homo Sapiens
<400> 395
ggcaaaactg tgtgacctca ataagacctc gcagatccaa ggtcaagtat cagaagtgac 60
tctgaccttg gactccaaga cctacatcaa cagcctggct atattagatg atgagccagt 120
tatcagaggt ttcatcattg cggaaattgt ggagtctaag gaaatcatgg cctctgaagt 180
attcacgtct ttccagtacc ctgagttctc tatagagttg cctaacacag gcagaattgg 240
ccagctactt gtctgcaatt gtatcttcaa.gaataccctg gccatccctt tgactgacgt 300
caagttctct ttggaaagcc tgggcatctc ctcactacag acctctgacc atgggacggt 360
gcagcctggt gagaccatcc aatcccaaat aaaatgcac 399
<210> 396
<211> 403
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(403)
<223> n = A,T,C or G
<400> 396
tggagttntc agtgcaaaca agccataaag cttcagtagc aaattactgt ctcacagaaa 60
gacattttca acttctgctc cagctgctga taaaacaaat catgtgttta gcttgactcc 120
agacaaggac aacctgttcc ttcat'aactc tctagagaaa aaaaggagtt gttagtagat 180
actaaaaaaa gtggatgaat aatctggata tttttcctaa aaagattcct tgaaacacat 240
taggaaaatg gagggcctta tgatcagaat gctagaatta gt.ccattgtg ctgaagcagg 300
gtttagggga gggagtgagg gataaaagaa ggaaaaaaag aagagtgaga aaacctattt 360
atcaaagcag gtgctatcac tcaatgttag gccctgctct ttt 403
<210> 397
<211> 100
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(100)
<223> n = A,T,C or G
<400> 397
actagtncag tgtggtggaa ttcgcggccg cgtcgaccta naanccatct ctatagcaaa 60
tccatccccg ctcctggttg gtnacagaat gactgacaaa 100
<210> 398
<211> 278
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(278)
<223> n = A,T,C or G
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
138
<400> 398
gcggccgcgt cgacagcagt tccgccagcg ctcgcccctg ggtggggatg tgctgcacgc 60
ccacctggac atctggaagt cagcggcctg gatgaaagag cggacttcac ctggggcgat 120
tcactactgt gcctcgacca gtgaggagag ctggaccgac agcgaggtgg actcatcatg 180
ctccgggcag cccatccacc tgtggcagtt cctcaaggag ttgctactca agccccacag 240
ctatggccgc ttcattangt ggctcaacaa ggagaagg 278
<210> 399
<211> 298
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(298)
<223> n = A,T,C or G
<400> 399
acggaggtgg aggaagcgnc cctgggatcg anaggatggg tcctgncatt gaccncctcn 60
ggggtgccng catggagcgc atgggcgcgg gcctgggcca cggcatggat cgcgtgggct 120
ccgagatcga gcgcatgggc ctggtcatgg accgcatggg ctccgtggag cgcatgggct 180
ccggcattga gcgcatgggc ccgctgggcc tcgaccacat ggcctccanc attgancgca 240
tgggccagac catggagcgc attggctctg gcgtggagcn catgggtgcc ggcatggg 298
<210> 400
<211> 548
<212> DNA
<213> Homo Sapiens
<400> 400
acatcaacta cttcctcatt ttaaggtatg gcagttccct tcatcccctt ttcctgcctt 60
gtacatgtac atgtatgaaa tttccttctc ttaccgaact ctctccacac atcacaaggt 120
caaagaacca cacgcttaga agggtaagag ggcaccctat gaaatgaaat ggtgatttct 180
tgagtctctt ttttccacgt ttaaggggcc atggcaggac ttagagttgc gagttaagac 240
tgcagagggc tagagaatta tttcatacag gctttgaggc cacccatgtc acttatcccg 300
tataccctct caccatcccc ttgtctactc tgatgccccc aagatgcaac tgggcagcta 360
gttggcccca taattctggg cctttgttgt ttgttttaat tacttgggca tcccaggaag 420
ctttccagtg atctcctacc atgggccccc ctcctgggat caagcccctc ccaggccctg 480
tccccagccc ctcctgcccc agcccacccg cttgccttgg tgctcagccc tcccattggg 540
agcaggtt 548
<210> 401
<211> 355
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(355)
<223> n = A,T,C or G
<400> 401
actgtttcca tgttatgttt ctacacattg ctacctcagt gctcctggaa acttagcttt 60
tgatgtctcc aagtagtcca ccttcattta actctttgaa actgtatcat ctttgccaag 120
taagagtggt ggcctatttc agctgctttg acaaaatgac tggctcctga cttaacgttc 180
tataaatgaa tgtgctgaag caaagtgccc atggtggcgg cgaagaagan aaagatgtgt 240
tttgttttgg actctctgtg gtcccttcca atgctgnggg tttccaacca ggggaagggt 300
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
139
cccttttgca ttgccaagtg ccataaccat gagcactact ctaccatggn tctgc 355
<210> 402
<211> 407
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(407)
<223> n = A,T,C or G
<400> 402
atggggcaag ctggataaag aaccaagacc cactggagta tgctgtcttc aagaaaccca 60
tctcacatgc ggtggcatac ataggctcaa aataaaggaa tggagaaaaa tatttcaagc 120
aaatggaaaa cagaaaaaag caggtgttgc actcctactt tctgacaaaa cagactatgc 180
gaataaagat aaaaaagaga aggacattac aaaggtggtc ctgacctttg ataaatctca 240
ttgcttgata ccaacctggg ctgttttaat tgcccaaacc aaaaggataa tttgctgagg 300
ttgtggagct tctcccctgc agagagtccc tgatctccca aaatttggtt gagatgtaag 360
gntgattttg ctgacaactc cttttctgaa gttttactca tttccaa 407
<210> 403
<211> 303
<2i2> DNA
<213> Homo Sapiens
<220>
<221> misc feature
<222> (1) .. (303)
<223> n = A,T,C or G
<4U0> 403
cagtatttat agccnaactg aaaagctagt agcaggcaag~ tctcaaatcc aggcaccaaa 60
tcctaagcaa gagccatggc atggtgaaaa tgcaaaagga gagtctggcc aatctacaaa 120 .
tagagaacaa gacctactca gtcatgaaca aaaaggcaga caccaacatg gatctcatgg 180
gggattggat attgtaatta tagagcagga agatgacagt gatcgtcatt tggcacaaca 240
tcttaacaac gaccgaaacc cattatttac ataaacctcc attcggtaac catgttgaaa 300
gga 303
<210> 404
<211> 225
<212> DNA
<213> Homo Sapiens
<400> 404
aagtgtaact tttaaaaatt tagtggattt tgaaaattct tagaggaaag taaaggaaaa 60
attgttaatg cactcattta cctttacatg gtgaaagttc tctcttgatc ctacaaacag 120
acattttcca ctcgtgtttc catagttgtt aagtgtatca gatgtgttgg gcatgtgaat 180
ctccaagtgc ctgtgtaata aataaagtat ctttatttca ttcat 225
<210> 405
<211> 334
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1). .(334)
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
140
<223> n = A,T,C or G
<400> 405
gagctgttat actgtgagtt ctactaggaa atcatcaaat ctgagggttg tctggaggac 60
ttcaatacac ctccccccat agtgaatcag cttccagggg gtccagtccc tctccttact 120
tcatccccat cccatgccaa aggaagaccc tccctccttg gctcacagcc ttctctaggc 180
ttcccagtgc ctccaggaca gagtgggtta tgttttcagc tccatccttg ctgtgagtgt 240
ctggtgcggt tgtgcctcca gcttctgctc agtgcttcat ggacagtgtc cagcccatgt 300
cactctccac tctctcanng tggatcccac ccct 334
<210> 406
<211> 216
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1). .(216)
<223> n = A,T,C or G
<400> 406
tttcatacct aatgagggag ttganatnac atnnaaccag gaaatgcatg gatctcaang 60
gaaacaaaca cccaataaac tcggagtggc agactgacaa ctgtgagaca tgcacttgct 120
acnaaacaca aatttnatgt tgcacccttg tttctacacc tgtgggttat gacaaagaca 180
actgccaaag aatnttcaag aaggaggact gccant 216
<210> 407
<211> 413
<212> DNA
<213> Homo sapiens
<400> 407
gctgacttgc tagtatcatc tgcattcatt gaagcacaag aacttcatgc cttgactcat 60
gtaaatgcaa taggattaaa aaataaattt gatatcacat ggaaacagac aaaaaatatt 120
gtacaacatt gcacccagtg tcagattcta cacctggcca ctcaggaagc aagagttaat 180
cccagaggtc tatgtcctaa tgtgttatgg caaatggatg tcatgcacgt accttcattt 240
ggaaaattgt catttgtcca tgtgacagtt gatacttatt cacatttcat atgggcaacc 300
tgccagacag gagaaagtct tcccatgtta aaagacattt attatcttgt tttcctgtca 360
tgggagttcc agaaaaagtt aaaacagaca atgggccagg ttctgtagta aag 413
<210> 408
<211> 183
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1). .(183)
<223> n = A,T,C or G
<400> 408
ggagctngcc ctcaattcct ccatntctat gttancatat ttaatgtctt ttgnnattaa 60
tncttaacta gttaatcctt aaagggctan ntaatcctta actagtccct ccattgtgag 120
cattatcctt ccagtattcn ccttctnttt tatttactcc ttcctggcta cccatgtact 180
ntt 183
<210> 409
<211> 250
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
141
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(250)
<223> n = A,T,C or G
<400> 409
cccacgcatg ataagctctt tatttctgta agtcctgcta ggaaatcatc aaatctgacg 60
gtggtttggg ggacctgaac aaacctcctg taattaatca gctttcagtt tctcccccta 120
gtccctcctt caacaacata ggaggatcct ccccttcttt ctgctcacgg ccttatctag 180
gcttcccagt gcccccagga cagcgtgggc tatgtttaca gcgcntcctt gctggggggg 240
ggccntatgc 250
<210> 410
<211> 306
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(306)
<223> n = A,T,C or G
<400> 410
ggctggtttg caagaatgaa atgaatgatt ctacagctag gacttaacct tgaaatggaa 60
agtcttgcaa tcccatttgc aggatccgtc tgtgcacatg cctctgtaga gagcagcatt 120
cccagggacc ttggaaacag ttggcactgt aaggtgcttg ctccccaaga cacatcctaa 180
aaggtgttgt aatggtgaaa accgcttcct tctttattgc cccttcttat ttatgtgaac 240
nactggttgg ctttttttgn atctttttta aactggaaag ttcaattgng aaaatgaata 300
tcntgc 306
<210> 411
<211> 261
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(261)
<223> n = A,T,C or G
<400> 411
agagatattn cttaggtnaa agttcataga gttcccatga actatatgac tggccacaca 60
ggatcttttg tatttaagga ttctgagatt ttgcttgagc aggattagat aaggctgttc 120
tttaaatgtc tgaaatggaa cagatttcaa aaaaaaaccc cacaatctag ggtgggaaca 180
aggaaggaaa gatgtgaata ggctgatggg caaaaaacca atttacccat cagttccagc 240
cttctctcaa ggngaggcaa a . 261
<210> 412
<211> 241
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(241)
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
142
<223> n = A,T,C or G
<400> 412
gttcaatgtt acctgacatt tctacaacac cccactcacc gatgtattcg ttgcccagtg 60
ggaacatacc agcctgaatt tggaaaaaat aattgtgttt cttgcccagg aaatactacg 120
actgactttg atggctccac aaacataacc cagtgtaaaa acagaagatg tggaggggag 180
ctgggagatt tcactgggta cattgaattc ccaaactacc cangcaatta cccagccaac 240
a 241
<210> 413
<211> 231
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1). .(231)
<223> n = A,T,C or G
<400> 413
aactcttaca atccaagtga ctcatctgtg tgcttgaatc ctttccactg tctcatctcc 60
ctcatccaag tttctagtac cttctctttg ttgtgaagga taatcaaact gaacaacaaa 120
aagtttactc tcctcatttg gaacctaaaa actctcttct tcctgggtct gagggctcca 180
agaatccttg aatcanttct cagatcattg gggacaccan atcaggaacc t 231
<210> 414
<211> 234
<212> DNA
<213> Homo Sapiens
<400> 414
actgtccatg aagcactgag cagaagctgg aggcacaacg caccagacac tcacagcaag 60
gatggagctg aaaacataac ccactctgtc ctggaggcac tgggaagcct agagaaggct 120
gtgagccaag gagggagggt cttcctttgg catgggatgg ggatgaagta aggagaggga 180
ctggaccccc tggaagctga ttcactatgg ggggaggtgt attgaagtcc tcca 234
<210> 415
<211> 217
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(217)
<223> n = A,T,C or G
<400> 415
gcataggatt aagactgagt atcttttcta cattctttta actttctaag gggcacttct 60
caaaacacag accaggtagc aaatctccac tgctctaagg ntctcaccac cactttctca 120
cacctagcaa tagtagaatt cagtcctact tctgaggcca gaagaatggt tcagaaaaat 180
antggattat aaaaaataac aattaagaaa aataatc 217
<210> 416
<211> 213
<212> DNA
<213> Homo Sapiens
<220>
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
143
<221> misc_feature
<222> (1) . . (213)
<223> n = A,T,C or G
<400> 416
atgcatatnt aaagganact gcctcgcttt tagaagacat ctggnctgct ctctgcatga 60
ggcacagcag taaagctctt tgattcccag aatcaagaac tctccccttc agactattac 120
cgaatgcaag gtggttaatt gaaggccact aattgatgct caaatagaag gatattgact 180
atattggaac agatggagtc tctactacaa aag 213
<210> 417
<211> 303
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1) . . (303)
<223> n = A,T,C or G
<400> 417
nagtcttcag gcccatcagg gaagttcaca ctggagagaa gtcatacata tgtactgtat 60
gtgggaaagg ctttactctg agttcaaatc ttcaagccca tcagagagtc cacactggag 120
agaagccata caaatgcaat gagtgtggga agagcttcag gagggattcc cattatcaag 180
ttcatctagt ggtccacaca ggagagaaac cctataaatg tgagatatgt gggaagggct 240
tcantcaaag ttcgtatctt caaatccatc ngaaggncca cagtatanan aaacctttta 300
agt 303
<210> 418
<211> 328
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(328)
<223> n = A,T,C or G
<400> 418
tttttggcgg tggtggggca gggacgggac angagtctca ctctgttgcc caggctggag 60
tgcacaggca tgatctcggc tcactacaac ccctgcctcc catgtccaag cgattcttgt 120
gcctcagcct tccctgtagc tagaattaca ggcacatgcc accacaccca gctagttttt 180
gtatttttag tagagacagg gtttcaccat gttggccagg ctggtctcaa actcctnacc 240
tcagnggtca ggctggtctc aaactcctga cctcaagtga tctgcccacc tcagcctccc 300
aaagtgctan gattacaggc cgtgagcc 328
<210> 419
<211> 389
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1) . . (389)
<223> n = A,T,C or G
<400> 419
cctcctcaag acggcctgtg gtccgcctcc cggcaaccaa gaagcctgca gtgccatatg 60
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
144
acccctgagc catggactgg agcctgaaag gcagcgtaca ccctgctcct gatcttgctg 120
cttgtttcct ctctgtggct ccattcatag cacagttgtt gcactgaggc ttgtgcaggc 180
cgagcaaggc caagctggct caaagagcaa ccagtcaact ctgccacggt gtgccaggca 240
ccggttctcc agccaccaac ctcactcgct cccgcaaatg gcacatcagt tcttctaccc 300
taaaggtagg accaaagggc atctgctttt ctgaagtcct ctgctctatc agccatcacg 360
tggcagccac tcnggctgtg tcgacgcgg 389
<210> 420
<211> 408
<212> DNA
<213> Homo sapiens
<400> 420
gttcctccta actcctgcca gaaacagctc tcctcaacat gagagctgca cccctcctcc 60
tggccagggc agcaagcctt agccttggct tcttgtttct gctttttttc tggctagacc 120
gaagtgtact agccaaggag ttgaagtttg tgactttggt gtttcggcat ggagaccgaa 180
gtcccattga cacctttccc actgacccca taaaggaatc ctcatggcca caaggatttg 240
gccaactcac ccagctgggc atggagcagc attatgaact tggagagtat ataagaaaga 300
gatatagaaa attcttgaat gagtcctata aacatgaaca ggtttatatt cgaagcacag 360
acgttgaccg gactttgatg aagtgctatg acaaacctgg caagcccg 408
<210> 421
<211> 352
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1). .(352)
<223> n = A,T,C or G
<400> 421
gctcaaaaat ctttttactg atnggcatgg ctacacaatc attgactatt acggaggcca 60
gaggagaatg aggcctggcc tgggagccct gtgcctacta naagcacatt agattatcca 120
ttcactgaca gaacaggtct tttttgggtc cttcttctcc accacnatat acttgcagtc 180
ctccttcttg aagattcttt ggcagttgtc tttgtcataa cccacaggtg tagaaacaag 240
ggtgcaacat gaaatttctg tttcgtagca agtgcatgtc tcacaagttg gcangtctgc 300
cactccgagt ttattgggtg tttgtttcct ttgagatcca tgcatttcct gg 352
<210> 422
<211> 337
<212> DNA
<213> Homo sapiens
<400> 422
atgccaccat gctggcaatg cagcgggcgg tcgaaggcct gcatatccag cccaagctgg 60
cgatgatcga cggcaaccgt tgcccgaagt tgccgatgcc agccgaagcg gtggtcaagg 120
gcgatagcaa ggtgccggcg atcgcggcgg cgtcaatcct ggccaaggtc agccgtgatc 180
gtgaaatggc agctgtcgaa ttgatctacc cgggttatgg catcggcggg cataagggct 240
atccgacacc ggtgcacctg gaagccttgc agcggctggg gccgacgccg attcaccgac 300
gcttcttccg ccggtacggc tggcctatga aaattat 337
<210> 423
<211> 310
<212> DNA
<213> Homo sapiens
<220>
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
145
<221> misc_feature
<222> (1) . . (310)
<223> n = A,T,C or G
<400> 423
gctcaaaaat ctttttactg atatggcatg gctacacaat cattgactat tagaggccag 60
aggagaatga ggcctggcct gggagccctg tgcctactan aagcncatta gattatccat 120
tcactgacag aacaggtctt ttttgggtcc ttcttctcca ccacgatata cttgcagtcc 180
tccttcttga agattctttg gcagttgtct ttgtcataac ccacaggtgt anaaacaagg 240
gtgcaacatg aaatttctgt ttcgtagcaa gtgcatgtct cacagttgtc aagtctgccc 300
tccgagttta 310
<210> 424
<211> 370
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1). .(370)
<223> n = A,T,C or G
<400> 424
gctcaaaaat ctttttactg ataggcatgg ctacacaatc attgactatt agaggccaga 60
ggagaatgag gcctggcctg ggagccctgt gcctactaga agcacattag attatccatt 120
cactgacaga acaggtcttt tttgggtcct tcttctccac cacgatatac ttgcagtcct 180
ccttcttgaa gattctttgg cagttgtctt tgtcataacc cacaggtgta gaaacatcct 240
ggttgaatct cctggaactc cctcattagg tatgaaatag catgatgcat tgcataaagt 300
cacgaaggtg gcaaagatca caacgctgcc cagganaaca ttcattgtga taagcaggac 360
tccgtcgacg 370
<210> 425
<211> 216
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1). .(216)
<223> n = A,T,C or G
<400> 425
aattgctatn ntttattttg ccactcaaaa taattaccaa aaaaaaaaaa tnttaaatga 60
taacaacnca acatcaaggn aaananaaca ggaatggntg actntgcata aatnggccga 120
anattatcca ttatnttaag ggttgacttc aggntacagc acacagacaa acatgcccag 180
gaggntntca ggaccgctcg atgtnttntg aggagg 216
<210> 426
<211> 596
<212> DNA
<213> Homo sapiens
<400> 426
cttccagtga ggataaccct gttgccccgg gccgaggttc tccattaggc tctgattgat 60
tggcagtcag tgatggaagg gtgttctgat cattccgact gccccaaggg tcgctggcca 120
gctctctgtt ttgctgagtt ggcagtagga cctaatttgt taattaagag tagatggtga 180
gctgtccttg tattttgatt aacctaatgg ccttcccagc acgactcgga ttcagctgga 240
gacatcacgg caacttttaa tgaaatgatt tgaagggcca ttaagaggca cttcccgtta 300
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
146
ttaggcagtt catctgcact gataacttct tggcagctga gctggtcgga gctgtggccc 360
aaacgcacac ttggcttttg gttttgagat acaactctta atcttttagt catgcttgag 420
ggtggatggc cttttcagct ttaacccaat ttgcactgcc ttggaagtgt agccaggaga 480
atacactcat atactcgtgg gcttagaggc cacagcagat gtcattggtc tactgcctga 540
gtcccgctgg tcccatccca ggaccttcca tcggcgagta cctgggagcc cgtgct 596
<210> 427
<211> 107
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(107)
<223> n = A,T,C or G
<400> 427
gaagaattca agttaggttt attcaaaggg cttacngaga atcctanacc caggncccag 60
cccgggagca gccttanaga gctcctgttt gactgcccgg ctcagng 107
<210> 428
<211> 38
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1) . . (38)
<223> n = A,T,C or G
<400> 428
gaacttccna anaangactt tattcactat tttacatt 38
<210> 429
<211> 544
<212> DNA
<213> Homo Sapiens
<400> 429
ctttgctgga cggaataaaa gtggacgcaa gcatgacctc ctgatgaggg cgctgcattt 60
attgaagagc ggctgcagcc ctgcggttca gattaaaatc cgagaattgt atagacgccg 120
atatccacga actcttgaag gactttctga tttatccaca atcaaatcat cggttttcag 180
tttggatggt ggctcatcac ctgtagaacc tgacttggcc gtggctggaa tccactcgtt 240
gccttccact tcagttacac ctcactcacc atcctctcct gttggttctg tgctgcttca 300
agatactaag cccacatttg agatgcagca gccatctccc ccaattcctc ctgtccatcc 360
tgatgtgcag ttaaaaaatc tgccctttta tgatgtcctt gatgttctca tcaagcccac 420
gagtttagtt caaagcagta ttcagcgatt tcaagagaag ttttttattt ttgctttgac 480
acctcaacaa gttagagaga tatgcatatc cagggatttt ttgccaggtg gtaggagaga 540
ttat 544
<210> 430
<211> 507
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(507)
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
147
<223> n = A,T,C or G
<400> 430
cttatcncaa tggggctccc aaacttggct gtgcagtgga aactccgggg gaattttgaa 60
gaacactgac acccatcttc caccccgaca ctctgattta attgggctgc agtgagaaca 120
gagcatcaat ttaaaaagct gcccagaatg ttntcctggg cagcgttgtg atctttgccn 180
ccttcgtgac tttatgcaat gcatcatgct atttcatacc taatgaggga gttccaggag 240
attcaaccag gatgtttcta cncctgtggg ttatgacaaa gacaactgcc aaagaatntt 300
caagaaggag gactgcaagt atatcgtggt ggagaagaag gacccaaaaa agacctgttc 360
tgtcagtgaa tggataatct aatgtgcttc tagtaggcac agggctccca ggccaggcct 420
cattctcctc tggcctctaa tagtcaatga ttgtgtagcc atgcctatca gtaaaaagat 480
ttttgagcaa aaaaaaaaaa aaaaaaa 507
<210> 431
<211> 392
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1) . . (392)
<223> n = A,T,C or G
<400> 431
gaaaattcag aatggataaa aacaaatgaa gtacaaaata tttcagattt acatagcgat 60
aaacaagaaa gcacttatca ggaggactta caaatggaag tacactctan aaccatcatc 120
tatcatggct aaar_gtgaga ttagcacagc tgtattattt gtacattgca aacacctaga 180
aagagatggg aaacaaaatc ccaggagttt tgtgtgtgga gtcctgggtt ttccaacaga 240
catcattcca gcattctgag attagggnga ttggggatca ttctggagtt ggaatgttca 300
acaaaagtga tgttgttagg taaaatgtac aacttctgga tctatgcaga cattgaaggt 360
gcaatgagtc tggcttttac tctgctgttt ct 392
<210> 432
<211> 387
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(387)
<223> n = A,T,C or G
<400> 432
ggtatccnta cataatcaaa tatagctgta gtacatgttt tcattggngt agattaccac 60
aaatgcaagg caacatgtgt agatctcttg tcttattctt ttgtctataa tactgtattg 120
ngtagtccaa gctctcggna gtccagccac tgngaaacat gctcccttta gattaacctc 180
gtggacnctn ttgttgnatt gtctgaactg tagngccctg tattttgctt ctgtctgnga 240
attctgttgc ttctggggca tttccttgng atgcagagga ccaccacaca gatgacagca 300
atctgaattg ntccaatcac agctgcgatt aagacatact gaaatcgtac aggaccggga 360
acaacgtata gaacactgga gtccttt 387
<210> 433
<211> 281
<212> DNA
<213> Homo Sapiens
<220>
<221> misc feature
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
148
<222> (1)...(281)
<223> n = A,T,C or G
<400> 433
ttcaactagc anagaanact gcttcagggn gtgtaaaatg aaaggcttcc acgcagttat 60
ctgattaaag aacactaaga gagggacaag gctagaagcc gcaggatgtc tacactatag 120
caggcnctat ttgggttggc tggaggagct gtggaaaaca tggagagatt ggcgctggag 180
atcgccgtgg ctattcctcn ttgntattac accagngagg ntctctgtnt gcccactggt 240
tnnaaaaccg ntatacaata atgatagaat aggacacaca t 281
<210> 434
<211> 484
<212> DNA
<213> Homo Sapiens
<400> 434
ttttaaaata agcatttagt gctcagtccc tactgagtac tctttctctc ccctcctctg 60
aatttaattc tttcaacttg caatttgcaa ggattacaca tttcactgtg atgtatattg 120
tgttgcaaaa aaaaaaaagt gtctttgttt aaaattactt ggtttgtgaa tccatcttgc 180
tttttcccca ttggaactag tcattaaccc atctctgaac tggtagaaaa acatctgaag 240
agctagtcta tcagcatctg acaggtgaat tggatggttc tcagaaccat ttcacccaga 300
cagcctgttt ctatcctgtt taataaatta gtttgggttc tctacatgca taacaaaccc 360
tgctccaatc tgtcacataa aagtctgtga cttgaagttt agtcagcacc cccaccaaac 420
tttatttttc tatgtgtttt ttgcaacata tgagtgtttt gaaaataaag tacccatgtc 480
ttta 484
<210> 435
<211> 424
<212> DNA
<213> Homo Sapiens
<400> 435
gcgccgctca gagcaggtca ctttctgcct tccacgtcct ccttcaagga agccccatgt 60
gggtagcttt caatatcgca ggttcttact cctctgcctc tataagctca aacccaccaa 120
cgatcgggca agtaaacccc ctccctcgcc gacttcggaa ctggcgagag ttcagcgcag 180
atgggcctgt ggggaggggg caagatagat gagggggagc ggcatggtgc ggggtgaccc 240
cttggagaga ggaaaaaggc cacaagaggg gctgccaccg ccactaacgg agatggccct 300
ggtagagacc tttgggggtc tggaacctct ggactcccca tgctctaact cccacactct 360
gctatcagaa acttaaactt gaggattttc tctgtttttc actcgcaata aattcagagc 420
aaac 424
<210> 436
<211> 667
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(667)
<223> n = A,T,C or G
<400> 436
accttgggaa nactctcaca atataaaggg tcgtagactt tactccaaat tccaaaaagg 60
tcctggccat gtaatcctga aagttttccc aaggtagcta taaaatcctt ataagggtgc 120
agcctcttct ggaattcctc tgatttcaaa gtctcactct caagttcttg aaaacgaggg 180
cagttcctga aaggcaggta tagcaactga tcttcagaaa gaggaactgt gtgcaccggg 240
atgggctgcc agagtaggat aggattccag atgctgacac cttctggggg aaacagggct 300
gccaggtttg tcatagcact catcaaagtc cggtcaacgt ctgtgcttcg aatataaacc 360
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
149
tgttcatgtt tataggactc attcaagaat tttctatatc tctttcttat atactctcca 420
agttcataat gctgctccat gcccagctgg gtgagttggc caaatccttg tggccatgag 480
gattccttta tggggtcagt gggaaaggtg tcaatgggac ttcggtctcc atgccgaaac 540
accaaagtca caaacttcaa ctccttggct agtacacttc ggtctagcca gaaaaaaagc 600
agaaacaaga agccaaggct aaggcttgct gccctgccag gaggaggggt gcagctctca 660
tgttgag 667
<210> 437
<211> 693
<212> DNA
<213> Homo Sapiens
<400> 437
ctacgtctca accctcattt ttaggtaagg aatcttaagt ccaaagatat taagtgactc 60
acacagccag gtaaggaaag ctggattggc acactaggac tctaccatac cgggttttgt 120
taaagctcag gttaggaggc tgataagctt ggaaggaact tcagacagct ttttcagatc 180
ataaaagata attcttagcc catgttcttc tccagagcag acctgaaatg acagcacagc 240
aggtactcct ctattttcac ccctcttgct tctactctct ggcagtcaga cctgtgggag 300
gccatgggag aaagcagctc tctggatgtt tgtacagatc atggactatt ctctgtggac 360
catttctcca ggttacccta ggtgtcacta ttggggggac agccagcatc tttagctttc 420
atttgagttt ctgtctgtct tcagtagagg aaacttttgc tcttcacact tcacatctga 480
acacctaact gctgttgctc ctgaggtggt gaaagacaga tatagagctt acagtattta 540
tcctatttct aggcactgag ggctgtgggg taccttgtgg tgccaaaaca gatcctgttt 600
taaggacatg ttgcttcaga gatgtctgta actatctggg ggctctgttg gctctttacc 660
ctgcatcatg tgctctcttg gctgaaaatg acc 693
<210> 438
<211> 360
<212> DNA
<213> Homo Sapiens
<400> 438
ctgcttatca caatgaatgt tctcctgggc agcgttgtga tctttgccac cttcgtgact 60
ttatgcaatg catcatgcta tttcatacct aatgagggag ttccaggaga ttcaaccagg 120
atgtttctac acctgtgggt tatgacaaag acaactgcca aagaatcttc aagaaggagg 180
actgcaagta tatctggtgg agaagaagga cccaaaaaag acctgttctg tcagtgaatg 240
gataatctaa tgtgcttcta gtaggcacag ggctcccagg ccaggcctca ttctcctctg 300
gcctctaata gtcaataatt gtgtagccat gcctatcagt aaaaagattt ttgagcaaac 360
<210> 439
<211> 431
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(431)
<223> n = A,T,C or G
<400> 439
gttcctnnta actcctgcca gaaacagctc tcctcaacat gagagctgca cccctcctcc 60
tggccagggc agcaagcctt agccttggct tcttgtttct gctttttttc tggctagacc 120
gaagtgtact agccaaggag ttgaagtttg tgactttggt gtttcggcat ggagaccgaa 180
gtcccattga cacctttccc actgacccca taaaggaatc ctcatggcca caaggatttg 240
gccaactcac ccagctgggc atggagcagc attatgaact tggagagtat ataagaaaga 300
gatatagaaa attcttgaat gagtcctata aacatgaaca ggtttatatt cgaagcacag 360
acgttgaccg gactttgatg agtgctatga caaacctggc agcccgtcga cgcggccgcg 420
aatttagtag t 431
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
150
<210> 440
<211> 523
<212> DNA
<213> Homo Sapiens
<400> 440
agagataaag cttaggtcaa agttcataga gttcccatga actatatgac tggccacaca 60
ggatcttttg tatttaagga ttctgagatt ttgcttgagc aggattagat aaggctgttc 120
tttaaatgtc tgaaatggaa cagatttcaa aaaaaaaccc cacaatctag ggtgggaaca 180
aggaaggaaa gatgtgaata ggctgatggg caaaaaacca atttacccat cagttccagc 240
cttctctcaa ggagaggcaa agaaaggaga tacagtggag acatctggaa agttttctcc 300
actggaaaac tgctactatc tgtttttata tttctgttaa aatatatgag gctacagaac 360
taaaaattaa aacctctttg tgtcccttgg tcctggaaca tttatgttcc ttttaaagaa 420
acaaaaatca aactttacag aaagatttga tgtatgtaat acatatagca gctcttgaag 480
tatatatatc atagcaaata agtcatctga tgagaacaag cta 523
<210> 441
<211> 430
<212> DNA
<213> Homo Sapiens
<400> 441
gttcctccta actcctgcca gaaacagctc tcctcaacat gagagctgca cccctcctcc 60
tggccagggc agcaagcctt agccttggct tcttgtttct gctttttttc tggctagacc 120
gaagtgtact agccaaggag ttgaagtttg tgactttggt gtttcggcat ggagaccgaa 180
gtcccattga cacctttccc actgacccca taaaggaatc ctcatggcca caaggatttg 240
gccaactcac ccagctgggc atggaycagc attatgaact tggagagtat ataagaaaga 300
gatatagaaa attcttgaat gagtcctata aacatgaaca ggtttatatt cgaagcacag,360
acgttgaccg gactttgatg agtgctatga caaacctggc agcccgtcga cgcggccgcg 420
aatttagtag 430
<210> 442
<211> 362
<212> DNA
<213> Homo sapiens
<400> 442
ctaaggaatt agtagtgttc ccatcacttg tttggagtgt gctattctaa aagattttga 60
tttcctggaa tgacaattat attttaactt tggtggggga aagagttata ggaccacagt 120
cttcacttct gatacttgta aattaatctt ttattgcact tgttttgacc attaagctat 180
atgtttagaa atggtcattt tacggaaaaa ttagaaaaat tctgataata gtgcagaata 240
aatgaattaa tgttttactt aatttatatt gaactgtcaa tgacaaataa aaattctttt 300
tgattatttt ttgttttcat ttaccagaat aaaaactaag aattaaaagt ttgattacag 360
tc 362
<210> 443
<211> 624
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(624)
<223> n = A,T,C or G
<400> 443
tttttttttt gcaacacaat atacatcaca gtgaaatgtg taatccttgc aaattgcaag 60
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
151
ttgaaagaat taaattcaga ggaggggaga gaaagagtac tcagtaggga ctgagcacta 120
aatgcttatt ttaaaagaaa tgtaaagagc agaaagcaat tcaggctacc ctgccttttg 180
tgctggctag tactccggtc ggtgtcagca gcacgtggca ttgaacattg caatgtggag 240
cccaaaccac agaaaatggg gtgaaattgg ccaactttct attaacttgg cttcctgttt 300
tataaaatat tgtgaataat atcacctact tcaaagggca gttatgaggc ttaaatgaac 360
taacgcctac aaaacactta aacatagata acataggtgc aagtactatg tatctggtac 420
atggtaaaca tccttattat taaagtcaac gctaaaatga atgtgtgtgc atatgctaat 480
agtacagaga gagggcactt aaaccaacta agggcctgga gggaaggttt cctggaaaga 540
ngatgcttgt gctgggtcca aatcttggtc tactatgacc ttggccaaat tatttaaact 600
ttgtccctat ctgctaaaca gatc 624
<210> 444
<211> 425
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1) . . (425)
<223> n = A,T,C or G
<400> 444
gcacatcatt nntcttgcat tctttgagaa taagaagatc agtaaatagt tcagaagtgg 60
gaagctttgt ccaggcctgt gtgtgaaccc aatgttttgc ttagaaatag aacaagtaag 120
ttcattgcta tagcataaca caaaatttgc ataagtggtg gtcagcaaat ccttgaatgc 180
tgcttaatgt gagaggttgg taaaatcctt tgtgcaacac tctaactccc tgaatgtttt 240
gctgtgctgg gacctgtgca tgccagacaa ggccaagctg gctgaaagag caaccagcca 300
cctctgcaat ctgccacctc ctgctggcag gatttgtttt tgcatcctgt gaagagccaa 360
ggaggcacca gggcataagt gagtagactt atggtcgacg cggccgcgaa tttagtagta 420
gtaga 425
<210> 445
<21.1> 414
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1). .(414)
<223> n = A,T,C or G
<400> 445
catgtttatg nttttggatt actttgggca cctagtgttt ctaaatcgtc tatcattctt 60
ttctgttttt caaaagcaga gatggccaga gtctcaacaa actgtatctt caagtctttg 120
tgaaattctt tgcatgtggc agattattgg atgtagtttc ctttaactag catataaatc 180
tggtgtgttt cagataaatg aacagcaaaa tgtggtggaa ttaccatttg gaacattgtg 240
aatgaaaaat tgtgtctcta gattatgtaa caaataacta tttcctaacc attgatcttt 300
ggatttttat aatcctactc acaaatgact aggcttctcc tcttgtattt tgaagcagtg 360
tgggtgctgg attgataaaa aaaaaaaaag tcgacgcggc cgcgaattta gtag 414
<210> 446
<211> 631
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1). .(631)
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
152
<223> n = A,T,C or G
<400> 446
acaaattaga anaaagtgcc agagaacacc acataccttg tccggaacat tacaatggct 60
tctgcatgca tgggaagtgt gagcattcta tcaatatgca ggagccatct tgcaggtgtg 120
atgctggtta tactggacaa cactgtgaaa aaaaggacta cagtgttcta tacgttgttc 180
ccggtcctgt acgatttcag tatgtcttaa tcgcagctgt gattggaaca attcagattg 240
ctgtcatctg tgtggtggtc ctctgcatca caagggccaa actttaggta atagcattgg 300
actgagattt gtaaactttc caaccttcca ggaaatgccc cagaagcaac agaattcaca 360
gacagaagca aaatacaggg cactacagtt cagacaatac aacaagagcg tccacgaggt 420
taatctaaag ggagcatgtt tcacagtggc tggactaccg agagcttgga ctacacaata 480
cagtattata gacaaaagaa taagacaaga gatctacaca tgttgccttg catttgtggt 540
aatctacacc aatgaaaaca tgtactacag ctatatttga ttatgtatgg atatatttga 600
aatagtatac attgtcttga tgttttttct g 631
<210> 447
<211> 585
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1). .(585)
<223> n = A,T,C or G
<400> 447
ccttgggaaa antntcacaa tataaagggt cgtagacttt actccaaatt ccaaaaaggt 60
cctggccatg taatcctgaa agttttccca aggtagctat aaaatcctta taagggtgca 120
gcctcttctg gaattcctct gatttcaaag tctcactctc aagttcttga aaacgagggc 180
agttcctgaa aggcaggtat agcaactgat cttcagaaag aggaactgtg tgcaccggga 240
tgggctgcca gagtaggata ggattccaga tgctgacacc ttctggggga aacagggctg 300
ccaggtttgt catagcactc atcaaagtcc ggtcaacgtc tgtgcttcga atataaacct 360
gttcatgttt ataggactca ttcaagaatt ttctatatct ctttcttata tactctccaa 420
gttcataatg ctgctccatg cccagctggg tgagttggcc aaatccttgt ggccatgagg 480
attcctttat ggggtcagtg ggaaaggtgt caatgggact tcggtctcca tgccgaaaca 540
ccaaagtcac aaacttcaac tccttggcta gtacacttcg gtcta 585
<210> 448
<211> 93
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(93)
<223> n = A,T,C or G
<400> 448
tgctcgtggg tcattctgan nnccgaactg accntgccag ccctgccgan gggccnccat 60
ggctccctag tgccctggag agganggggc tag 93
<210> 449
<211> 706
<212> DNA
<213> Homo sapiens
<220>
<221> mist feature
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
153
<222> (1)...(706)
<223> n = A,T,C or G
<400> 449
ccaagttcat gctntgtgct ggacgctgga cagggggcaa aagcnnttgc tcgtgggtca 60
ttctgancac cgaactgacc atgccagccc tgccgatggt cctccatggc tccctagtgc 120
cctggagagg aggtgtctag tcagagagta gtcctggaag gtggcctctg ngaggagcca 180
cggggacagc atcctgcaga tggtcgggcg cgtcccattc gccattcagg ctgcgcaact 240
gttgggaagg gcgatcggtg cgggcctctt cgctattacg ccagctggcg aaagggggat 300
gtgctgcaag gcgattaagt tgggtaacgc cagggttttc ccagtcncga cgttgtaaaa 360
cgacggccag tgaattgaat ttaggtgacn ctatagaaga gctatgacgt cgcatgcacg 420
cgtacgtaag cttggatcct ctagagcggc cgcctactac tactaaattc gcggccgcgt 480
cgacgtggga tccncactga gagagtggag agtgacatgt gctggacnct gtccatgaag 540
cactgagcag aagctggagg cacaacgcnc cagacactca cagctactca ggaggctgag 600
aacaggttga acctgggagg tggaggttgc aatgagctga gatcaggccn ctgcncccca 660
gcatggatga cagagtgaaa ctccatctta aaaaaaaaaa aaaaaa 706
<210> 450
<211> 493
<212> DNA
<213> Homo Sapiens
<400> 450
gagacggagt gtcactctgt tgcccaggct ggagtgcagc aagacactgt ctaagaaaaa 60
acagttttaa aaggtaaaac aacataaaaa gaaatatcct atagtggaaa taagagagtc 120
aaatgaggct gagaacttta caaagggatc ttacagacat gtcgccaata tcactgcatg 180
agcctaagta taagaacaac ctttggggag aaaccatcat ttgacagtga ggtacaattc 240
caagtcaggt agtgaaatgg gtggaattaa actcaaatta atcctgccag ctgaaacgca 300
agagacactg tcagagagtt aaaaagtgag ttctatccat g~aggtgattc cacagtcttc 360
tcaagtcaac acatctgtga actcacagac caagttctta aaccactgtt caaactctgc 420
tacacatcag aatcacctgg agagctttac aaactcccat tgccgagggt cgacgcggcc 480
gcgaatttag tag 493
<210> 451
<211> 501
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1). .(501)
<223> n = A,T,C or G
<400> 451
gggcgcgtcc cattcgccat tcaggctgcg caactgttgg gaagggcgat cggtgcgggc 60
ctcttcgcta ttacgccagc tggcgaaagg gggatgtgct gcaaggcgat taagttgggt 120
aacgccaggg ttttcccagt cncgacgttg taaaacgacg gccagtgaat tgaatttagg 180
tgacnctata gaagagctat gacgtcgcat gcacgcgtac gtaagcttgg atcctctaga 240
gcggccgcct actactacta aattcgcggc cgcgtcgacg tgggatccnc actgagagag 300
tggagagtga catgtgctgg acnctgtcca tgaagcactg agcagaagct ggaggcacaa 360
cgcnccagac actcacagct actcaggagg ctgagaacag gttgaacctg ggaggtggag 420
gttgcaatga gctgagatca ggccnctgcn ccccagcatg gatgacagag tgaaactcca 480
tcttaaaaaa aaaaaaaaaa a 501
<210> 452
<211> 51
<212> DNA
<213> Homo Sapiens
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
154
<220>
<221> misc_feature
<222> (1). .(51)
<223> n = A,T,C or G
<400> 452
agacggtttc accnttacaa cnccttttag gatgggnntt ggggagcaag c 51
<210> 453
<211> 317
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<222> (1) . . (317)
<223> n = A,T,C or G
<400> 453
tacatcttgc tttttcccca ttggaactag tcattaaccc atctctgaac tggtagaaaa 60
acatctgaag agctagtcta tcagcatctg gcaagtgaat tggatggttc tcagaaccat 120
ttcacccana cagcctgttt ctatcctgtt taataaatta gtttgggttc tctacatgca 180
taacaaaccc tgctccaatc tgtcacataa aagtctgtga cttgaagttt antcagcacc 240
cccaccaaac tttatttttc tatgtgtttt ttgcaacata tgagtgtttt gaaaataagg 300
tacccatgtc tttatta 3l7 ,
<210> 454
<211> 231
<212> DNA
<213> Homo Sapiens
<400> 454
ttcgaggtac aatcaactct cagagtgtag tttccttcta tagatgagtc agcattaata 60 ='~
taagccacgc cacgctcttg aaggagtctt gaattctcct ctgctcactc agtagaacca 120
agaagaccaa attcttctgc atcccagctt gcaaacaaaa ttgttcttct aggtctccac 180
ccttcctttt tcagtgttcc aaagctcctc acaatttcat gaacaacagc t 231
<210> 455
<211> 231
<212> DNA
<213> Homo Sapiens
<400> 455
taccaaagag ggcataataa tcagtctcac agtagggttc accatcctcc aagtgaaaaa 60
cattgttccg aatgggcttt ccacaggcta cacacacaaa acaggaaaca tgccaagttt 120
gtttcaacgc attgatgact tctccaagga tcttcctttg gcatcgacca cattcagggg 180
caaagaattt ctcatagcac agctcacaat acagggctcc tttctcctct a 231
<210> 456
<211> 231
<212> DNA
<213> Homo Sapiens
<400> 456
ttggcaggta cccttacaaa gaagacacca taccttatgc gttattaggt ggaataatca 60
ttccattcag tattatcgtt attattcttg gagaaaccct gtctgtttac tgtaaccttt 120
tgcactcaaa ttcctttatc aggaataact acatagccac tatttacaaa gccattggaa 180
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
155
cctttttatt tggtgcagct gctagtcagt ccctgactga cattgccaag t 231
<210> 457
<211> 231
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1) . . (231)
<223> n = A,T,C or G
<400> 457
cgaggtaccc aggggtctga aaatctctnn tttantagtc gatagcaaaa ttgttcatca 60
gcattcctta atatgatctt gctataatta gatttttctc cattagagtt catacagttt 120
tatttgattt tattagcaat ct.ctttcaga agacccttga gatcattaag ctttgtatcc 180
agttgtctaa atcgatgcct catttcctct gaggtgtcgc tggcttttgt g 231
<210> 458
<211> 231
<212> DNA
<213> Homo Sapiens
<400> 458
aggtctggtt ccccccactt ccactcccct ctactctctc taggactggg ctgggccaag 60
agaagagggg tggttaggga agccgttgag acctgaagcc ccaccctcta ccttccttca 120
acaccctaac cttgggtaac agcatttgga attatcattt gggatgagta gaatttccaa 180
ggtcctgggt taggcatttt ggggggccag accccaggag aagaagattc t 231
<210> 459
<211> 231
<212> DNA
<213> Homo Sapiens
<400> 459
ggtaccgagg ctcgctgaca cagagaaacc ccaacgcgag gaaaggaatg gccagccaca 60
ccttcgcgaa acctgtggtg gc.ccaccagt cctaacggga caggacagag agacagagca 120
gccctgcact gttttccctc caccacagcc atcctgtccc tcattggctc tgtgctttcc 180
actatacaca gtcaccgtcc caatgagaaa caagaaggag caccctccac a 231
<210> 460
<211> 231
<212> DNA
<213> Homo Sapiens
<400> 460
gcaggtataa catgctgcaa caacagatgt gactaggaac ggccggtgac atggggaggg 60
cctatcaccc tattcttggg ggctgcttct tcacagtgat catgaagcct agcagcaaat 120
cccacctccc cacacgcaca cggccagcct ggagcccaca gaagggtcct cctgcagcca 180
gtggagcttg gtccagcctc cagtccaccc ctaccaggct taaggataga a 231
<210> 461
<211> 231
<212> DNA
<213> Homo Sapiens
<400> 461
cgaggtttga gaagctctaa tgtgcagggg agccgagaag caggcggcct agggagggtc 60
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
156
gcgtgtgctc cagaagagtg tgtgcatgcc agaggggaaa caggcgcctg tgtgtcctgg 120
gtggggttca gtgaggagtg ggaaattggt tcagcagaac caagccgttg ggtgaataag 180
agggggattc catggcactg atagagccct atagtttcag agctgggaat t 231
<210> 462
<211> 231
<212> DNA
<213> Homo sapiens
<400> 462
aggtaccctc attgtagcca tgggaaaatt gatgttcagt ggggatcagt gaattaaatg 60
gggtcatgca agtataaaaa ttaaaaaaaa aagacttcat gcccaatctc atatgatgtg 120
gaagaactgt tagagagacc aacagggtag tgggttagag atttccagag tcttacattt 180
tctagaggag gtatttaatt tcttctcact catccagtgt tgtatttagg a 231
<210> 463
<211> 231
<212> DNA
<213> Homo Sapiens
<400> 463
tactccagcc tggtgacaga gcgagaccct atcaccgccc cccaccccac caaaaaaaaa 60
actgagtaga caggtgtcct cttggcatgg taagtcttaa gtcccctccc agatctgtga 120
catttgacag gtgtcttttc ctctggacct cggtgtcccc atctgagtga gaaaaggcag 180
tggggaggtg gatcttccag tcgaagcggt atagaagccc gtgtgaaaag c 231
<210> 464
<211> 231
<212> DNA
<213> Homo Sapiens
<400> 464
gtactctaag attttatcta agttgccttt tctgggtggg aaagtttaac cttagtgact 60
aaggacatca catatgaaga atgtttaagt tggaggtggc aacgtgaatt gcaaacaggg 120
cctgcttcag tgactgtgtg cctgtagtcc cagctactcg ggagtctgtg tgaggccagg 180
ggtgccagcg caccagctag atgctctgta acttctaggc cccattttcc c 231
<210> 465
<211> 231
<212> DNA
<213> Homo Sapiens
<400> 465
catgttgttg tagctgtggt aatgctggct gcatctcaga cagggttaac ttcagctcct 60
gtggcaaatt agcaacaaat tctgacatca tatttatggt ttctgtatct ttgttgatga 120
aggatggcac aatttttgct tgtgttcata atatactcag attagttcag ctccatcaga 180
taaactggag acatgcagga cattagggta gtgttgtagc tctggtaatg a 231
<210> 466
<211> 231
<212> DNA
<213> Homo sapiens
<400> 466
caggtacctc tttccattgg atactgtgct agcaagcatg ctctccgggg tttttttaat 60
ggccttcgaa cagaacttgc cacataccca ggtataatag tttctaacat ttgcccagga 120
cctgtgcaat caaatattgt ggagaattcc ctagctggag aagtcacaaa gactataggc 180
aataatggag accagtccca caagatgaca accagtcgtt gtgtgcggct g 231
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
157
<210> 467
<211> 311
<212> DNA
<213> Homo sapiens
<400> 467
gtacaccctg gcacagtcca atctgaactg gttcggcact catctttcat gagatggatg 60
tggtggcttt tctccttttt catcaagact cctcagcagg gagcccagac cagcctgcac 120
tgtgccttaa cagaaggtct tgagattcta agtgggaatc atttcagtga ctgtcatgtg 180
gcatgggtct ctgcccaagc tcgtaatgag actatagcaa ggcggctgtg ggacgtcagt 240
tgtgacctgc tgggcctccc aatagactaa caggcagtgc cagttggacc caagagaaga 300
ctgcagcaga c ~ 311
<210> 468
<211> 3112
<212> DNA
<213> Homo Sapiens
<400> 468
cattgtgttg ggagaaaaac agaggggaga tttgtgtggc tgcagccgag ggagaccagg 60
aagatctgca tggtgggaag gacctgatga tacagagttt gataggagac aattaaaggc 120
tggaaggcac tggatgcctg atgatgaagt ggactttcaa actggggcac tactgaaacg 180
atgggatggc cagagacaca ggagatgagt tggagcaagc tcaataacaa agtggttcaa 240
cgaggacttg gaattgcatg gagctggagc tgaagtttag cccaattgtt tactagttga 300
gtgaatgtgg atgattggat gatcatttct catctctgag cctcaggttc cccatccata 360
aaatgggata cacagtatga tctataaagt gggatatagt atgatctact tcactgggtt 420
atttgaagga tgaattgaga taatttattt caggtgccta gaacaatgcc cagattagta 480
catttggtgg aactgagaaa tggcataaca ccaaatttaa tatatgtcag atgttactat 540
gattatcatt caatctcata gttttgtcat ggcccaattt atcctcactt gtgcctcaac 600
aaattgaact gttaacaaag gaatctctgg tcctgggtaa tggctgagca ccactgagca 660
tttccattcc agttggcttc ttgggtttgc tagctgcatc actagtcatc ttaaataaat 720
gaagttttaa catttctcca gtgatttttt tatctcacct ttgaagatac tatgttatgt 780
gattaaataa agaacttgag aagaacaggt ttcattaaac ataaaatcaa tgtagacgca 840 .
aattttctgg atgggcaata cttatgttca caggaaatgc tttaaaatat gcagaagata 900
attaaatggc aatggacaaa gtgaaaaact tagacttttt tttttttttt ggaagtatct 960
ggatgttcct tagtcactta aaggagaact gaaaaatagc agtgagttcc acataatcca 1020
acctgtgaga ttaaggctct ttgtggggaa ggacaaagat ctgtaaattt acagtttcct 1080
tccaaagcca acgtcgaatt ttgaaacata tcaaagctct tcttcaagac aaataatcta 1140
tagtacatct ttcttatggg atgcacttat gaaaaatggt ggctgtcaac atctagtcac 1200
tttagctctc aaaatggttc attttaagag aaagttttag aatctcatat ttattcctgt 1260
ggaaggacag cattgtggct tggactttat aaggtcttta ttcaactaaa taggtgagaa 1320
ataagaaagg ctgctgactt taccatctga ggccacacat ctgctgaaat ggagataatt 1380
aacatcacta gaaacagcaa gatgacaata taatgtctaa gtagtgacat gtttttgcac 1440
atttccagcc cctttaaata tccacacaca caggaagcac aaaaggaagc acagagatcc 1500
ctgggagaaa tgcccggccg ccatcttggg tcatcgatga gcctcgccct gtgcctggtc 1560
ccgcttgtga gggaaggaca ttagaaaatg aattgatgtg ttccttaaag gatgggcagg 1620
aaaacagatc ctgttgtgga tatttatttg aacgggatta cagatttgaa atgaagtcac 1680
aaagtgagca ttaccaatga gaggaaaaca gacgagaaaa tcttgatggc ttcacaagac 1740
atgcaacaaa caaaatggaa tactgtgatg acatgaggca gccaagctgg ggaggagata 1800
accacggggc agagggtcag gattctggcc ctgctgccta aactgtgcgt tcataaccaa 1860
atcatttcat atttctaacc ctcaaaacaa agctgttgta atatctgatc tctacggttc 1920
cttctgggcc caacattctc catatatcca gccacactca tttttaatat ttagttccca 1980
gatctgtact gtgacctttc tacactgtag aataacatta ctcattttgt tcaaagaccc 2040
ttcgtgttgc tgcctaatat gtagctgact gtttttccta aggagtgttc tggcccaggg 2100
gatctgtgaa caggctggga agcatctcaa gatctttcca gggttatact tactagcaca 2160
cagcatgatc attacggagt gaattatcta atcaacatca tcctcagtgt ctttgcccat 2220
actgaaattc atttcccact tttgtgccca ttctcaagac ctcaaaatgt cattccatta 2280
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
158
atatcacagg attaactttt ttttttaacc tggaagaatt caatgttaca tgcagctatg 2340
ggaatttaat tacatatttt gttttccagt gcaaagatga ctaagtcctt tatccctccc 2400
ctttgtttga ttttttttcc agtataaagt taaaatgctt agccttgtac tgaggctgta 2460
tacagccaca gcctctcccc atccctccag ccttatctgt catcaccatc aacccctccc 2520
atgcacctaa acaaaatcta acttgtaatt ccttgaacat gtcaggcata cattattcct 2580
tctgcctgag aagctcttcc ttgtctctta aatctagaat gatgtaaagt tttgaataag 2640
ttgactatct tacttcatgc aaagaaggga cacatatgag attcatcatc acatgagaca 2700
gcaaatacta aaagtgtaat ttgattataa gagtttagat aaatatatga aatgcaagag 2760
ccacagaggg aatgtttatg gggcacgttt gtaagcctgg gatgtgaagc aaaggcaggg 2820
aacctcatag tatcttatat aatatacttc atttctctat ctctatcaca atatccaaca 2880
agcttttcac agaattcatg cagtgcaaat ccccaaaggt aacctttatc catttcatgg 2940
tgagtgcgct ttagaatttt ggcaaatcat actggtcact tatctcaact ttgagatgtg 3000
tttgtccttg tagttaattg aaagaaatag ggcactcttg tgagccactt tagggttcac 3060
tcctggcaat aaagaattta caaagagcaa aaaaaaaaaa aaaaaaaaaa as 3112
<210> 469
<211> 2229
<212> DNA
<213> Homo sapiens
<400> 469
agctctttgt aaattcttta ttgccaggag tgaaccctaa agtggctcac aagagtgccc 60
tatttctttc aattaactac aaggacaaac acatctcaaa gttgagataa gtgaccagta 120
tgatttgcca aaattctaaa gcgcactcac catgaaatgg ataaaggtta cctttgggga 180
tttgcactgc atgaattctg tgaaaagctt gttggatatt gtgatagaga tagagaaatg 240
aagtatatta tataagatac tatgaggttc cctgcctttg cttcacatcc caggcttaca 300
a.acgtgcccc ataaacattc cctctgtggc tcttgcattt catatattta,tctaaactct 360
tataatcaaa tacactttta gtatttgctg tctcatgtga tgatgaatct catatgtgtc 420
ccttctttgc atgaagtaag atagtcaact tattcaaaac tttacatcat tctagattta 480
agagacaagg aagagcttct caggcagaag gaataatgta tgcctgacat gttcaaggaa 540
ttacaagtta gattttgttt aggtgcatgg gaggggttga tggtgatgac agataaggct 600
ggagggatgg ggagaggctg tggctgtata cagcctcagt acaaggctaa gcattttaac 660
tttatactgg aaaaaaaatc aaacaaaggg gagggataaa ggacttagtc atctttgcac 720
tggaaaacaa aatatgtaat taaattccca tagctgcatg taacattgaa ttcttccagg 780 ',~'w
ttaaaaaaaa agttaatcct gtgatattaa tggaatgaca ttttgaggtc ttgagaatgg 840
gcacaaaagt gggaaatgaa tttcagtatg ggcaaagaca ctgaggatga tgttgattag 900
ataattcact ccgtaatgat catgctgtgt gctagtaagt ataaccctgg aaagatcttg 960
agatgcttcc cagcctgttc acagatcccc tgggccagaa cactccttag gaaaaacagt 1020
cagctacata ttaggcagca acacgaaggg tctttgaaca aaatgagtaa tgttattcta 1080
cagtgtagaa aggtcacagt acagatctgg gaactaaata ttaaaaatga gtgtggctgg 1140
atatatggag aatgttgggc ccagaaggaa ccgtagagat cagatattac aacagctttg 1200
ttttgagggt tagaaatatg aaatgatttg gttatgaacg cacagtttag gcagcagggc 1260
cagaatcctg accctctgcc ccgtggttat ctcctcccca gcttggctgc ctcatgtcat 1320
cacagtattc cattttgttt gttgcatgtc ttgtgaagcc atcaagattt tctcgtctgt 1380
tttcctctca ttggtaatgc tcactttgtg acttcatttc aaatctgtaa tcccgttcaa 1440
ataaatatcc acaacaggat ctgttttcct gcccatcctt taaggaacac atcaattcat 1500
tttctaatgt ccttccctca caagcgggac caggcacagg gcgaggctca tcgatgaccc 1560
aagatggcgg ccgggcattt ctcccaggga tctctgtgct tccttttgtg cttcctgtgt 1620
gtgtggatat ttaaaggggc tggaaatgtg caaaaacatg tcactactta gacattatat 1680
tgtcatcttg ctgtttctag tgatgttaat tatctccatt tcagcagatg tgtggcctca 1740
gatggtaaag tcagcagcct ttcttatttc tcacctggaa atacatacga ccatttgagg 1800
agacaaatgg caaggtgtca gcataccctg aacttgagtt gagagctaca cacaatatta 1860
ttggtttccg agcatcacaa acaccctctc tgtttcttca ctgggcacag aattttaata 1920
cttatttcag tgggctgttg gcaggaacaa atgaagcaat ctacataaag tcactagtgc 1980
agtgcctgac acacaccatt ctcttgaggt cccctctaga gatcccacag gtcatatgac 2040
ttcttgggga gcagtggctc acacctgtaa tcccagcact ttgggaggct gaggcaggtg 2100
ggtcacctga ggtcaggagt tcaagaccag cctggccaat atggtgaaac cccatctcta 2160
ctaaaaatac aaaaattagc tgggcgtgct ggtgcatgcc tgtaatccca gccccaacac 2220
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
159
aatggaatt 2229
<210> 470
<211> 2426
<212> DNA
<213> Homo sapiens
<400> 470
gtaaattctt tattgccagg agtgaaccct aaagtggctc acaagagtgc cctatttctt 60
tcaattaact acaaggacaa acacatctca aagttgagat aagtgaccag tatgatttgc 120
caaaattcta aagcgcactc accatgaaat ggataaaggt tacctttggg gatttgcact 180
gcatgaattc tgtgaaaagc ttgttggata ttgtgataga gatagagaaa tgaagtatat 240
tatataagat actatgaggt tccctgcctt tgcttcacat cccaggctta caaacgtgcc 300
ccataaacat tccctctgtg gctcttgcat ttcatatatt tatctaaact cttataatca 360
aattacactt ttagtatttg ctgtctcatg tgatgatgaa tctcatatgt gtcccttctt 420
tgcatgaagt aagatagtca acttattcaa aactttacat cattctagat ttaagagaca 480
aggaagagct tctcaggcag aaggaataat gtatgcctga catgttcaag gaattacaag 540
ttagattttg tttaggtgca tgggaggggt tgatggtgat gacagataag gctggaggga 600
tggggagagg ctgtggctgt atacagcctc agtacaaggc taagcatttt aactttatac 660
tggaaaaaaa atcaaacaaa ggggagggat aaaggactta gtcatctttg cactggaaaa 720
caaaatatgt aattaaattc ccatagctgc atgtaacatt gaattcttcc aggttaaaaa 780
aaaaagttaa tcctgtgata ttaatggaat gacattttga ggtcttgaga atgggcacaa 840
aagtgggaaa tgaatttcag tatgggcaaa gacactgagg atgatgttga ttagataatt 900
cactccgtaa tgatcatgct gtgtgctagt aagtataacc ctggaaagat cttgagatgc 960
ttcccagcct gttcacagat cccctgggcc agaacactcc ttaggaaaaa cagtcagcta 1020
catattaggc agcaacacga agggtctttg aacaaaatga gtaatgttat tctacagtgt 1080
agaaaggtca cagtacagat ctgggaacta aatattaaaa atgagtgtgg ctggatatat 1140
ggagaatgtt gggcccagaa ggaaccgtag agatcagata ttacaacagc tttgttttga :1200
gggttagaaa tatgaaatga tttggttatg aacgcacagt ttaggcagca gggccagaat 1260
cctgaccctc tgccccgtgg ttatctcctc cccagcttgg ctgcctcatg tcatcacagt 1320
attccatttt gtttgttgca tgtcttgtga agccatcaag attttctcgt ctgttttcct 1380
ctcattggta atgctcactt tgtgacttca tttcaaatct gtaatcccgt tcaaataaat 1440
atccacaaca ggatctgttt,tcctgcccat cctttaagga acacatcaat tcattttcta 1500 .
atgtccttcc ctcacaagcg ggaccaggca cagggcgagg ctcatcgatg acccaagatg 1560
gcggccgggc atttctccca gggatctctg tgcttccttt tgtgcttcct gtgtgtgtgg 1620
atatttaaag gggctggaaa tgtgcaaaaa catgtcacta cttagacatt atattgtcat 1680
cttgctgttt ctagtgatgt taattatctc catttcagca gatgtgtggc ctcagatggt 1740
aaagtcagca gcctttctta tttctcacct ggaaatacat acgaccattt gaggagacaa 1800
atggcaaggt gtcagcatac cctgaacttg agttgagagc tacacacaat attattggtt 1860
tccgagcatc acaaacaccc tctctgtttc ttcactgggc acagaatttt aatacttatt 1920
tcagtgggct gttggcagga acaaatgaag caatctacat aaagtcacta gtgcagtgcc 1980
tgacacacac cattctcttg aggtcccctc tagagatccc acaggtcata tgacttcttg 2040
gggagcagtg gctcacacct gtaatcccag cactttggga ggctgaggca ggtgggtcac 2100
ctgaggtcag gagttcaaga ccagcctggc caatatggtg aaaccccatc tctactaaaa 2160
atacaaaaat tagctgggcg tgctggtgca tgcctgtaat cccagctact tgggaggctg 2220
aggcaggaga attgctggaa catgggaggc ggaggttgca gtgagctgta attgtgccat 2280
tgcactcgaa cctgggcgac agagtggaac tctgtttcca aaaaacaaac aaacaaaaaa 2340
ggcatagtca gatacaacgt gggtgggatg tgtaaataga agcaggatat aaagggcatg 2400
gggtgacggt tttgcccaac acaatg 2426
<210> 471
<211> 812
<212> DNA
<213> Homo sapiens
<400> 471
gaacaaaatg agtaatgtta ttctacagtg tagaaaggtc acagtacaga tctgggaact 60
aaatattaaa aatgagtgtg gctggatata tggagaatgt tgggcccaga aggaaccgta 120
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
160
gagatcagat attacaacag ctttgttttg agggttagaa atatgaaatg atttggttat 180
gaacgcacag tttaggcagc agggccagaa tcctgaccct ctgccccgtg gttatctcct 240
ccccagcttg gctgcctcat gtcatcacag tattccattt tgtttgttgc atgtcttgtg 300
aagccatcaa gattttctcg tctgttttcc tctcattggt aatgctcact ttgtgacttc 360
atttcaaatc tgtaatcccg ttcaaataaa tatccacaac aggatctgtt ttcctgccca 420
tcctttaagg aacacatcaa ttcattttct aatgtccttc cctcacaagc gggaccaggc 480
acagggcgag gctcatcgat gacccaagat ggcggccggg catttctccc agggatctct 540
gtgcttcctt ttgtgcttcc tgtgtgtgtg gatatttaaa ggggctggaa atgtgcaaaa 600
acatgtcact acttagacat tatattgtca tcttgctgtt tctagtgatg ttaattatct 660
ccatttcagc agatgtgtgg cctcagatgg taaagtcagc agcctttctt atttctcacc 720
tctgtatcat caggtccttc ccaccatgca gatcttcctg gtctccctcg gctgcagcca 780
cacaaatctc ccctctgttt ttctgatgcc ag 812
<210> 472
<211> 515
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1) . . (515)
<223> n = A,T,C or G
<400> 472
acggagactt attttctgat attgtctgca tatgtatgtt tttaagagtc tggaaatagt 60
cttatgactt tcctatcatg cttattaata aataatacag cccagagaag atgaaaatgg 120
gttccagaat tattggtcct tgcagcccgg tgaatctcag caagaggaac caccaactga 180
caatcaggat attgaacctg gacaagagag agaaggaaca cctccgatcg aagaacgtaa 240
agtagaaggt gattgccagg aaatggatct ggaaaagact cggagtgagc gtggagatgg 300
ctctgatgta aaagagaaga ctccacctaa tcctaagcat gctaagacta aagaagcagg 360
agatgggcag ccataagtta aaaagaagac aagctgaagc tacacacatg gctgatgtca 420
cattgaaaat gtgactgaaa atttgaaaat tctctcaata aagtttgagt tttctctgaa 480
gaaaaaaaaa naaaaaaaaa aaanaaaaan aaaaa 515
<210> 473
<211> 5829
<212> DNA
<213> Homo Sapiens
<400> 473
cgcatgccgg ggaagcccaa gctggctcga agagccacca gccacctgtg caagggtggg 60
cctggaccag ttggaccagc caccaagctc acctactcaa ggaagcaggg atggccaggt 120
tgcaacagcc tgagtggctg ccacctgata gctgatggag cagaggcctg aggaaaatca 180
gatggcacat ttagctcttt aatggatctt aagttaattt ttctataaag cacatggcac 240
cagtccatgc ctcagagctc gtatggcact gcggaccaca gcaggccgag ttcccaggat 300
tgccatccag gggggccttc tgtagccctg gccagacctt gcagaggtgg ctgggtgctc 360
tttgagcgag ctcggcctcc ctggcatgca caggccccag gtactgacac gctgctctga 420
gtgagcttgt cctgccttgg ctgccaccta actgctgatg gagcagcggc cttaggaaaa 480
gcaaatggcg ctgtagccca actttagggt agaagaagat gtaccatgtc cggccgctag 540
ttggtgactg gtgcacctgc tcctggcgta cccttgcaga ggtgggtggt tgctctttgg 600
ccagcttggc cttgcctggc atgcacaagc ctcagtgcaa caactgtcct acaaatggag 660
acacagagag gaaacaagca gcgggctcag gagcagggtg tgtgctgcct ttggggctcc 720
agtccatgcc tcgggtcgta tggtactgca ggcttcttgg ttgccaagag gcggaccaca 780
ggccttcttg aggaggactt tacgttcaag tgcagaaagc agccaaaatt accatccatg 840
agactaagcc ttctgtggcc ctggcgagac ttaaaatttg tgccaaggca ggacaagctc 900
actcggagca gcgtgtcagt agctggggcc tatgcatgcc gggcagggcc gggctggctg 960
aaggagcaac cagccacctc tgcaagggtg cgcctagtgc aggcggagca tccaccacct 1020
cacccgctcg aggaagtggg gatggccagg ttcccacagc ctgagtgtct gccaccttat 1080
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
161
tgctgatgga gcagaggcct taagaaaagc agatggcact gtggccctac ctttagggtg 1140
gaagaagtga tgtacatgtc cggacgctaa ttggtgactg gtacaccggc tcctgctaca 1200
cctttgcaga ggtggctggt tgctctttga gccagcttgt ccttgcccgg catgcacaag 1260,
tttcagtgca acaactttgc cacaaatgga gccatataga ggaaacaaga agcaggttca 1320
ggagaagggt gtaccctgcc tttggggctc cagtccatgc ctcaggtgtc acatggcact 1380
gcgggcttct tggttgccag gaggcggacc acaggccatc ttggggagga ctttgtgttc 1440
aagtgcagaa agcagccagg attgccatcc agggggacct tctatagccc tggccaaacc 1500
ttgcaggggt gtctggttgc tctttgagcc ggcttggcct ccctggcatg cacgggcccc 1560
aggtgctggc acgctgctcc gagtgtgctt gtcctgcctt ggctgccacc tctgcggggg 1620
tgcgtctgga gggggtggac cggccaccaa ccttacccag tcaaggaagt ggatggccat 1680
gttcccacag cctgagtggc tgccacctga tggctgatgg agcaaaggcc ttaggaaaag 1740
cagatggccc ttggccctac ctttttgtta gaagaactga tgttccatgt cctgcagcga 1800
gtgaggttgg tggctgtgcc cccagctcct ggcgcgccct cgcagaggtg actggttgct 1860
ctttgggccc tcttggcctt gcccagcatg cacaagcctc agtgctacta ctgtgctaca 1920
aatggagcca tataggggaa acgagcagcc atctcaggag caaggtgtat gctgcctttg 1980
ggggctccag tccttgcctc aagggtctta tgtcactgtg ggcttcttgg ttgtcaagag 2040
gcagaccata ggccgtcttg agagggactt tatgttcaag tgcagaaagc agccaggatt 2100
gccaccctcg ggactctgcc ttctgtggcc ctggccaaac ttagaatttg gccgtagaca 2160
ggacaggctc acttggagta gcgtgtccgt agctggggtc tgtgcatgcc gggcaaggcc 2220
gggctggctc ggggagcaac cagccacctc tgcgggggtg cgcctggagc aggtggagca 2280
gccaccagct cacccactcc aggaagccgg ggtagccagg ttcccaaggc ctgagtgggt 2340
gccacctaat ggctgaagaa acagaggcct tgggaaaacc agatggcact gtggccctac 2400
ctttatggta gaagagctga tttagcctga ctggcagcgt gtggggttgg tggctggtct 2460
gcctgctgct ggcgcatccg tgcaaggatg gctggttgcc ctttgagcca gcttgccctt 2520
gcccggcatg cgcaagcctc agtgcaacaa ctgtgctgca aatggggcca tatagaggaa 2580
aggagcagct ggctctggag catggtgtgc actccctttg ggccttcagt ccatgtctca 2640 .
tgggtcgtat gacactgcgg gcttgttggt tgccaagagg cagaccacag gtcatcttga 2700
ggaggacttt atgttccagt ccagaaagca gccagtggta ccacccaggg gacttgtgct 2760
tctgtgccca ggccagacgt agaatttgac aaagtcagga cggtctcagt cagagcggcg 2820
tgtcggtccc cggggcctgt gcatgccggg cagggccggg ctggcttggg gagcaagcag 2880 t-
ccacctctgt taagggtgtg cctggagcag gtggagcagc caccaacctc acgcactgaa 2940
agaagcaggg atggccaggt tccaacatcc tgagtggctg ccacctgatg gctgatggag 3000
cagaggcctg aggaaaagca gatggcactg ctttgtagtg ctgttctttg tctctcttga 3060 . ..
tctttttcag ttaatgtctg ttttatcaga gactaggatt gcaaaccctg ctcttttttg 3120
ctttccattt gcttggtaaa tattcctcca tccctttatt ttaagcctat gtgtgtcttt 3180
gcacatgaga tgggtctcct gaatacagga caacaatggg tctttactct ttatccaact 3240
tgccagtctg tgtcttttaa ctggggcatt tagcccattt acatttaagt ttagtattgt 3300
tacatgtgaa atttatcctg tcatgatgtt gctagctttt tatttttccc attagtttgc 3360
agtttcttta tagtgtcaat ggtctttaca attcgatatg tttttgtagt ggctggtact 3420
ggtttttcct ttctacgttt agtgtctcct tcaggagctc ttgtaacaca agaatgtgga 3480
tttatttctt gtaaggtaaa tatgtggatt tatttcttgg gactgtattc tatggccttt 3540
accccaagaa tcattacttt ttaaaatgca attcaaatta gcataaaaca tttacagcct 3600
atggaaaggc ttgtggcatt agaatcctta tttataggat tattttgtgt ttttttgaga 3660
tatggtcttt gtcatcgagg cagaagtgcc gtggtttgat cataattcac cacagccctg 3720
aactcttgag tccaagccat ccttttgcct taatctccca accagttgga tctgcaggca 3780
taaggcatca tgcgtggcta attttttcac gttttttttt tttttttgtc gagattatgg 3840
tgtcactgtg ttgctctggc tgatctcaaa tgtttgacct caagggatct ttctgccacg 3900
gcctcctaaa gtgctaggat tatatgcatg atacaccatg cctattgtag agtattacat 3960
tattttcaaa gtcttattgt aagagccatt tattgccttt ggcctaaata actcaatata 4020
atatctctga aacttttttt tgacaaattt tggggcgtga tgatgagaga agggggtttg 4080
aaactttcta ataagagtta acttagagcc atttaagaaa ggaaaaaaca caaattatca 4140
gaaaaacaac agtaagatca agtgcaaaag ttctgtggca aagatgatga gagtaaagaa 4200
tatatgtttg tgactcatgg tggcttttac tttgttcttg aatttctgag tacgggttaa 4260
catttaaaga atctacatta tagataacat tttattgcaa gtaaatgtat ttcaaaattt 4320
gttattggtt ttgtatgaga ttattctcag cctacttcat tatcaagcta tattatttta 4380
ttaatgtagt tcgatgatct tacagcaaag ctgaaagctg tatcttcaaa atatgtctat 4440
ttgactaaaa agttattcaa caggagttat tatctataaa aaaaatacaa caggaatata 4500
aaaaacttga ggataaaaag atgttggaaa aagtaatatt aaatcttaaa aaacatatgg 4560
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
162
aaactacaca atggtgaaga cacattggtg aagtacaaaa atataaattg gatctagaag 4620
aaagggcaat gcaggcaata gaaaaattag tagaaatccc tttaaaggtt agtttgtaaa 4680
atcaggtaag tttatttata atttgctttc atttatttca ctgcaaatta tattttggat 4740
atgtatatat attgtgcttc ctctgcctgt cttacagcaa tttgccttgc agagttctag 4800
gaaaaaggtg gcatgtgttt ttactttcaa aatatttaaa tttccatcat tataacaaaa 4860
tcaatttttc agagtaatga ttctcactgt ggagtcattt gattattaag acccgttggc 4920
ataagattac atcctctgac tataaaaatc ctggaagaaa acctaggaaa tattcgtctg 4980
gacattgcac ttggcaatga atttatgggt aaccactgat ccacttccag tcactatcca 5040
tgagttttta tttccagata catgaaatca tatgagttga aactttcttt tgattgagca 5100
gtttggaaac cgtctttttg tagaatctgc aagtggatat ttggaaccct ttgaggccta 5160
tgctgaaaaa agaaatatct tcactacatg atgaccacca gcagcagctg gggaaaccag 5220
caccctgtgg aattccatac ggtgcataga atacatcctc ccttcagtcg gcttgggtca 5280
acttaggtca tgggccacct ggctgatagc agtttccaca gaaatgcttc aagatgaaag 5340
tggatgaccg ggccaccctc caccactgcc ctgtaagacc atgggacaca caggccacca 5400
gttcttttca tgtggtcatc ccctgttaga tgggagaaaa tacacctgcc tcatttttgt 5460
accttctgtg tgaacattcc acggcagact gtcgctaaat gtggatgaag aattgaatga 5520
atgaatgaat atgagagaaa atgaataaat ggttcagatc ctgggctgga aggctgtgta 5580
tgaggatggt gggtagagga gggtctgttt ttcttgcctt taagtcacta attgtcactt 5640
tggggcagga gcacaggctt tgaatgcaga ccgactggac tttaattctg gctttactag 5700
ttgtgattgt gtgaccttgt gaaagttact taaaccctct gtgcctgttt ctttatctgt 5760
aaaatggaga taataagatg tcaaaggact gtggtaagaa ttaaatgctt taaaaaaaaa 5820
aaaaaaaaa 5829
<210> 474
<211> 1594
<212> DNA
<213> Homo sapiens
<-400> 474
atttatggat cattaatgcc tctttagtag tttagagaaa acgtcaaaag aaatggcccc 60
agaataagct tcttgatttg taaaattcta tgtcattggc tcaaatttgt atagtatctc 120
aaaatataaa tatatagaca tctcagataa tatatttgaa atagcaaatt cctgttagaa 180
aataatagta cttaactaga tgagaataac aggtcgccat tatttgaatt gtctcctatt 240 .
cgtttttcat ttgttgtgtt actcatgttt tacttatgag ggatatatat aacttccact 300
gttttcagaa ttattgtatg cagtcagtat gagaatgcaa tttaagtttc cttgatgctt 360
tttcacactt ctattactag aaataagaat acagtaatat tggcaaagaa aattgaccag 420
ttcaataaaa ttttttagta aatctgattg aaaataaaca ttgcttatgg ctttcttaca 480
tcaatattgt tatgtcctag acaccttatc tgaaattacg gcttcaaaat tctaattatg 540
tgcaaatgtg taaaatatca atactttatg ttcaagctgg ggcctcttca ggcgtcctgg 600
gctgagagag aaagatgcta gctccgcaag ccggagaggg aacaccgcca cattgttaca 660
cggacacacc gccacgtgga cacatgacca gactcacatg tacagacaca cggagacatt 720
accacatgga gacaccgtca cacagtcaca cggacacact ggcatagtca catggacgga 780
cacacagaca tatggagaaa tcacatggac acaccaccac actatcacag ggacacagac 840
acacggagac atcaccacat ggacacactg tcacactacc acagggacac gagacatcac 900
actgtcacat ggacacacca tcacacacat gaacacaccg acacactgcc atatggacac 960
tggcacacac actgccacac tgtcacatgg acacacctcc acaccatcac accaccacac 1020
acactgcctg tggacacaag gacacacaga cactgtcaca cagatacaca aaacactgtc 1080
acacggagac atcaccatgc agatacacca ccactctggt gccgtctgaa ttaccctgct 1140
ggggggacag cagtggcata ctcatgccta agtgactggc tttcacccca gtagtgattg 1200
ccctccatca acactgccca ccccaggttg gggctacccc agcccatctt tacaaaacag 1260
ggcaaggtga actaatggag tgggtggagg agttggaaga aatcccagcg tcagtcaccg 1320
ggatagaatt cccaaggaac cctctttttg gaggatggtt tccatttctg gaggcgatct 1380
gccgacaggg tgaatgcctt cttgcttgtc ttctggggaa tcagagagag tccgttttgt 1440
ggtgggaaga gtgtggctgt gtactttgaa ctcctgtaaa ttctctgact catgtccaca 1500
aaaccaacag ttttgtgaat gtgtctggag gcaagggaag ggccactcag gatctatgtt 1560
gaagggaaga ggcctggggc tggagtattc gctt 1594
<210> 475
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
163
<211> 2414
<212> DNA
<213> Homo sapiens
<220>
<221> unsure
<222> (33)
<223> n=A,T,C or G
<400> 475
cccaacacaa tggctttata agaatgcttc acntgtgaaa aacaaatatc aaagtcttct 60
tgtagattat ttttaaggac aaatctttat tccatgttta atttatttag ctttccctgt 120
agctaatatt tcatgctgaa cacattttaa atgctgtaaa tgtagataat gtaatttatg 180
tatcattaat gcctctttag tagtttagag aaaacgtcaa aagaaatggc cccagaataa 240
gcttcttgat ttgtaaaatt ctatgtcatt ggctcaaatt tgtatagtat ctcaaaatat 300
aaatatatag acatctcaga taatatattt gaaatagcaa attcctgtta gaaaataata 360
gtacttaact agatgagaat aacaggtcgc cattatttga attgtctcct attcgttttt 420
catttgttgt gttactcatg ttttacttat ggggggatat atataacttc cgctgttttc 480
agaagtattg tatgcagtca gtatgagaat gcaatttaag tttccttgat gctttttcac 540
acttctatta ctagaaataa gaatacagta atattggcaa agaaaattga ccagttcaat 600
aaaatttttt-agtaaatctg attgaaaata aacattgctt atggctttct tacatcaata 660
ttgttatgtc ctagacacct tatctgaaat tacggcttca aaattctaat tatgtgcaaa 720
tgtgtaaaat atcaatactt tatgttcaag ctggggcctc ttcaggcgtc ctgggctgag 780
agagaaagat gctagctccg caagccgggg agggaacacc gccacattgt tacatggaca 840
caccgccacg tggacacatg accagactca catgtacaga cacacggaga cattaccaca 900
tggagacacc gtcacacagt cacacgagca cactggcata gtcacatgga cggacacaca 960
gacatatgga gaaatcacac tgacacacca ccacactatc acagggacac agacacacgg 1020
agacatcacc acatggacac actgtcacac taccacaggg acacgagaca tcacactgtc 1080
acatggacac accatcacac acatgaacac accgacacac tgccatatgg acactgccac 1140
acacactgcc acactgtcac atggacacac ctccatacca tcacaccacc acacacactg 1200
ccatgtggac acaaggacac acagacactg tcacacagat acacaaaaca ctgtcacacg 1260
gagacatcac catgcagata caccaccaca tggacatagc accagacact ctgccacaca 1320
gatacaccac cacacagaaa tgcggacaca ctgccacaca gacaccacca catcgttgcc 1380 -,.;.
acactttcat gtgtcagctg gcggtgtggg ccccacgact ctgggctcta atcgagaaat.1440 r
tacttggaca tatagtgaag gcaaaatttt tttttatttt ctgggtaacc aagcgcgact.1500
ctgtctcaaa aaaagaaaaa aaaagcaata tactgtgtaa tcgttgacag cataattcac 1560
tattatgtag atcggagagc agaggattct gaatgcatga acatatcatt aacatttcaa 1620
tacattactc ataattactg atgaactaaa gagaaaccaa gaaattatgg tgatagttat 1680
attgacctgg agaaatgtag acacaaaaga accgtaagat gagaaatgtg ttaacacagt 1740
ctataagggc atgcaagaat aaaaataggg gagaaaacag gagagttttt caagagcttt 1800
ctggtcatgt aagtcaactt gtatcggtta atttttaaaa ggtttattta catgcaataa 1860
actgcacata cttcaattgt acattttggt aattcttggc atttgtagct ctataaaacc 1920
agcaacatat taaaatagca aacatatcca ttacctttac caccaaagtt ttcttgtgtt 1980
ttttctactc actttttcct gcctatcccc ccatctcttc cacaggtaac cactgatcca 2040
cttccagtca ctatccatga gtttttattt ccaaatacat gaaatcatat gaatttctgg 2100
tttttcctgt tggagcccaa ggagcaaggg cagaatgagg aacatgatgt ttcttwccga 2160
cagttactca tgacgtctcc atccaggact gaggggggca tccttctcca tctaggactg 2220
ggggcatcct tctccatcca gtattggggg tcatccttct ccatccagta ttgggggtca 2280
tcctcctcca tccaggacct gaggggtgtc cttttctgcg cttccttgga tggcagtctt 2340
tcccttcatg tttatagtra cttaccatta aatcactgtg ccgttttttc ctaaaataaa 2400
aaaaaaaaaa aaaa 2414
<210> 476
<211> 3434
<212> DNA
<213> Homo sapiens
<400> 476
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
164
ctgtgctgca aatggggcca tatagaggaa aggagcagct ggctctggag catggtgtgc 60
actccctttg ggccttcagt ccatgtctca tgggtcgtat gacactgcgg gcttgttggt 120
tgccaagagg cagaccacag gtcatcttga ggaggacttt atgttccagt ccagaaagca 180
gccagtggta ccacccaggg gacttgtgct tctgtggccc aggccagacg tagaatttga 240
caaagtcagg acggtctcag tcagagcagc atgtcggtcc ccggggcctg tgcatgccgg 300
gcagggccag gctggcttaa ggagcaagca gccacctctg ttaggggtgt gcctggagca 360
ggtggagcag ccaccaacct cacgcactga aagaagcagg gatggccagg ttccaacatc 420
ctgagtggct gccacctgat ggctgatgga gcagaggcct gaggaaaagc agatggcact 480
gctttgtagt gctgttcttt gtctctcttg atctttttca gttaatgtct gttttatcag 540
agactaggat tgcaaaccct gctctttttt gctttccatt tgcttggtaa atattcctcc 600
atccctttat tttaagccta tgtgtgtctt tgcacatgag atgggtctcc tgaatacagg 660
acaacaatgg gtctttactc tttatccaac ttgccagtct gtgtctttta actggggcat 720
ttagcccatt tacatttaag tttagtattt gttacatgtg aaatttatcc tgtcatgatg 780
ttgctagctt tttatttttc ccattagttt gcagtttctt tatagtgtca atggtcttta 840
caattcgata tgtttttgta gtggctggta ctggtttttc ctttctacgt ttagtgtctc 900
cttcaggagc tcttgtaaca caagaatgtg gatttatttc ttgtaaggta aatatgtgga 960
tttattctgg gactgtattc tatggccttt accccaagaa tcattacttt ttaaaatgca 1020
attcaaatta gcataaaaca tttacagcct atggaaaggc ttgtggcatt agaatcctta 1080
tttataggat tattttgtgt ttttttgaga tatggtcttt gtcatcgagg cagaagtgcc 1140
gtggtttgat cataattcac cacagccctg aactcttgag tccaagccat ccttttgcct 1200
taatctccca accagttgga tctacaagca taaggcatca tgcgtggcta attttttcac 1260
gttttttttt tttttgtcga gattatggta tcactgtgtt gctctggctg atctcaaatg 1320
tttgacctca agggatcttt ctgccacagc ctcctaaagt gctaggatta tatgcatgat 1380
acaccatgcc tattgtagag tattacatta ttttcaaagt cttattgtaa gagccattta 1440
ttgcctttgg cctaaataac tcaatataat atctctgaaa cttttttttg acaaattttg 1500
gggcgtgatg atgagagaag ggggtttgaa actttctaat aagagttaac ttagagccat 1560
ttaagaaagg aaaaaacaca aattatcaga aaaacaacag taagatcaag tgcaaaagtt 1620
ctgtggcaaa gatgatgaga gtaaagaata tatgtttgtg actcatggtg gcttttactt 1680
tgttcttgaa tttctgagta cgggttaaca tttaaagaat ctacattata gataacattt 1740
tattgcaagt aaatgtattt caaaatttgt tattggtttt gtatgagatt attctcagcc 1800
tacttcatta tcaagctata ttattttatt aatgtagttc gatgatctta cagcaaagct 1860
gaaagctgta tcttcaaaat atgtctattt gactaaaaag ttattcaaca ggagttatta 1920
tctataaaaa aatacaacag gaatataaaa aacttgagga taaaaagatg ttggaaaaag 1980
taatattaaa tcttaaaaaa catatggaaa ctacacaatg gtgaagacac attggtgaag 2040
tacaaaaata taaattggat ctagaagaaa gggcaatgca ggcaatagaa aaattagtag 2100
aaatcccttt aaaggttagt ttgtaaaatc aggtaagttt atttataatt tgctttcatt 2160
tatttcactg caaattatat tttggatatg tatatatatt gtgcttcctc tgcctgtctt 2220 .
acagcaattt gccttgcaga gttctaggaa aaaggtggca tgtgttttta ctttcaaaat 2280
atttaaattt ccatcattat aacaaaatca atttttcaga gtaatgattc tcactgtgga 2340
gtcatttgat tattaagacc cgttggcata agattacatc ctctgactat aaaaatcctg 2400
gaagaaaacc taggaaatat tcgtctggac attgcacttg gcaatgaatt tatgggcgct 2460
ttggaatcct gcagatataa taatgataat taaacaaaac actcagagaa actgccaacc 2520
ctaggatgaa gtatattgtt actgtgcttt gggattaaaa taagtaacta cagtttatag 2580
aacttttata ctgatacaca gacactaaaa agggaaaggg tttagatgag aagctctgct 2640
atgcaatcaa gaatctcagc cactcatttc tgtaggggct gcaggagctc cctgtaaaga 2700
gaggttatgg agtctgtagc ttcaggtaag atacttaaaa cccttcagag tttctccatt 2760
ttttcccata gtttccccaa aaaggttatg acactttata agaatgcttc acttgtgaaa 2820
aacaaatatc aaagtcttct tgtagattat ttttaaggac aaatctttat tccatgttta 2880
atttatttag ctttccctgt agctaatatt tcatgctgaa cacattttaa atgctgtaaa 2940
tgtagataat gtaatttatg tatcattaat gcctctttag tagtttagag aaaacgtcaa 3000
aagaaatggc cccagaataa gcttcttgat ttgtaaaatt ctatgtcatt ggctcaaatt 3060
tgtatagtat ctcaaaatat aaatatatag acatctcaga taatatattt gaaatagcaa 3120
attcctgtta gaaaataata gtacttaact agatgagaat aacaggtcgc cattatttga 3180
attgtctcct attcgttttt catttgttgt gttactcatg ttttacttat ggggggatat 3240
atataacttc cgctgttttc agaagtattg tatgcagtca gtatgagaat gcaatttaag 3300.
tttccttgat gctttttcac acttctatta ctagaaataa gaatacagta atattggcaa 3360
agaaaattga ccagttcaat aaaatttttt agtaaatctg attgaaaata aaaaaaaaaa 3420
aaaaaaaaaa aaaa 3434
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
165
<210> 477
<211> 140
<212> PRT
<213> Homo Sapiens
<400> 477
Met Asp Gly His Thr Asp Ile Trp Arg Asn His Met Asp Thr Pro Pro
10 15
His Tyr His Arg Asp Thr Asp Thr Arg Arg His His His Met Asp Thr
20 25 30
Leu Ser His Tyr His Arg Asp Thr Arg His His Thr Val Thr Trp Thr
35 40 45
His His His Thr His Glu His Thr Asp Thr Leu Pro Tyr Gly His Trp
50 55 60
His Thr His Cys His Thr Val Thr Trp Thr His Leu His Thr Ile Thr
65 70 75 80
Pro Pro His Thr Leu Pro Val Asp Thr Arg Thr His Arg His Cys His
85 90 95
Thr Asp Thr Gln Asn Thr Val Thr Arg Arg His His His Ala Asp Thr
100 105 110
Pro Pro Leu Trp Cys Arg Leu Asn Tyr Pro Ala Gly Gly Thr Ala Val
115 120 125
Ala Tyr Ser Cys Leu Ser Asp Trp Leu Ser Pro Gln
130 135 140
<210> 478
<211> 143
<212> PRT
<213> Homo Sapiens
<400> 478
Met Tyr Arg His Thr Glu Thr Leu Pro His Gly Asp Thr Val Thr Gln
5 10 15
Ser His Gly His Thr Gly Ile Val Thr Trp Thr Asp Thr Gln Thr Tyr
20 25 30
Gly Glu Ile Thr Trp Thr His His His Thr Ile Thr Gly Thr Gln Thr
35 40 45
His Gly Asp Ile Thr Thr Trp Thr His Cys His Thr Thr Thr Gly Thr
50 55 60
Arg Asp Ile Thr Leu Ser His Gly His Thr Ile Thr His Met Asn Thr
65 70 75 80
Pro Thr His Cys His Met Asp Thr Gly Thr His Thr Ala Thr Leu Ser
85 90 95
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
166
His Gly His Thr Ser Thr Pro Ser His His His Thr His Cys Leu Trp
100 105 110
Thr Gln Gly His Thr Asp Thr Val Thr Gln Ile His Lys Thr Leu Ser
115 120 125
His Gly Asp Ile Thr Met Gln Ile His His His Ser Gly Ala Val
130 135 140
<210> 479
<211> 222
<212> PRT
<213> Homo sapiens
<400> 479
Met Tyr Arg His Thr Glu Thr Leu Pro His Gly Asp Thr Val Thr Gln
10 15
Ser His Glu His Thr Gly Ile Val Thr Trp Thr Asp Thr Gln Thr Tyr
20 25 30
Gly Glu Ile Thr Leu Thr His His His Thr Ile Thr Gly Thr Gln Thr
35 40 45
His Gly Asp Ile Thr Thr Trp Thr His Cys His Thr Thr Thr Gly Thr
50 55 60
Arg Asp Ile Thr Leu Ser His Gly His Thr Ile Thr His Met Asn Thr
65 70 75 80
Pro Thr His Cys His Met Asp Thr Ala Thr His Thr Ala 'rhr Leu Ser
85 90 95
His Gly His Thr Ser Ile Pro Ser His His His Thr His Cys His Val
100 105 110
Asp Thr Arg Thr His Arg His Cys His Thr Asp Thr Gln Asn Thr Val
115 120 125
Thr Arg Arg His His His Ala Asp Thr Pro Pro His Gly His Ser Thr
130 135 14U
Arg His Ser Ala Thr Gln Ile His His His Thr Glu Met Arg Thr His
145 150 155 160
Cys His Thr Asp Thr Thr Thr Ser Leu Pro His Phe His Val Ser Ala
165 170 175
Gly Gly Val Gly Pro Thr Thr Leu Gly Ser Asn Arg Glu Ile Thr Trp
180 185 190
Thr Tyr Ser Glu Gly Lys Ile Phe Phe Tyr Phe Leu Gly Asn Gln Ala
195 200 205
Arg Leu Cys Leu Lys Lys Arg Lys Lys Lys Gln Tyr Thr Val
210 215 220
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
167
<210> 480
<211> 144
<212> PRT
<213> Homo Sapiens
<400> 480
Met Glu Pro Tyr Arg Gly Asn Glu Gln Pro Ser Gln Glu Gln Gly Val
10 15
Cys Cys Leu Trp Gly Leu Gln Ser Leu Pro Gln Gly Ser Tyr Val Thr
20 25 30
Val Gly Phe Leu Val Val Lys Arg Gln Thr Ile Gly Arg Leu Glu Arg
35 40 45
Asp Phe Met Phe Lys Cys Arg Lys Gln Pro Gly Leu Pro Pro Ser Gly
50 55 60
Leu Cys Leu Leu Trp Pro Trp Pro Asn Leu Glu Phe Gly Arg Arg Gln
65 70 75 80
Asp Arg Leu Thr Trp Ser Ser Val Ser Val Ala Gly Val Cys Ala Cys
85 90 95
Arg Ala Arg Pro Gly Trp Leu Gly Glu Gln Pro Ala Thr Ser Ala Gly
100 105 110
Val Arg Leu Glu Gln Val Gl.u Gln Pro Pro Ala His Pro Leu Gln Glu .
115 120 125
Ala Gly Val Ala Arg Phe Pro Arg Pro Glu Trp Val Pro Pro Asn Gly
130 135 140
<210> 481
<211> 167
<212> PRT
<213> Homo sapiens
<400> 481
Met His Gly Pro Gln Val Leu Ala Arg Cys Ser Glu Cys Ala Cys Pro
5 10 15
Ala Leu Ala Ala Thr Ser Ala Gly Val Arg Leu Glu Gly Val Asp Arg
20 25 30
Pro Pro Thr Leu Pro Ser Gln Gly Ser Gly Trp Pro Cys Ser His Ser
35 40 45
Leu Ser Gly Cys His Leu Met Ala Asp Gly Ala Lys Ala Leu Gly Lys
50 55 60
Ala Asp Gly Pro Trp Pro Tyr Leu Phe Val Arg Arg Thr Asp Val Pro
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
168
65 70 75 80
Cys Pro Ala Ala Ser Glu Val Gly Gly Cys Ala Pro Ser Ser Trp Arg
85 90 95
Ala Leu Ala Glu Val Thr Gly Cys Ser Leu Gly Pro Leu Gly Leu Ala
100 105 110
Gln His Ala Gln Ala Ser Val Leu Leu Leu Cys Tyr Lys Trp Ser His
115 120 125
Ile Gly Glu Thr Ser Ser His Leu Arg Ser Lys Val Tyr Ala Ala Phe
130 135 140
Gly Gly Ser Ser Pro Cys Leu Lys Gly Leu Met Ser Leu Trp Ala Ser
145 150 155 160
Trp Leu Ser Arg Gly Arg Pro
165
<210> 482
<211> 143
<212> PRT
<213> Homo Sapiens
<4C0> 482
Met Glu Pro Tyr Arg Gly Asn Lys Lys Gln Val Gln Glu Lys Gly Val
10 15
Pro Cys Leu Trp Gly Ser Ser Pro Cys Leu Arg Cys His Met Ala Leu
20 25 30
Arg Ala Ser Trp Leu Pro Gl.y Gly Gly Pro Gln Ala Ile Leu Gly Arg
35 40 45
Thr Leu Cys Ser Ser Ala Glu Ser Ser Gln Asp Cys His Pro Gly Gly
50 55 60
Pro Ser Ile Ala Leu Ala Lys Pro Cys Arg Gly Val Trp Leu Leu Phe
65 70 75 80
Glu Pro Ala Trp Pro Pro Trp His Ala Arg Ala Pro Gly Ala Gly Thr
85 90 95
Leu Leu Arg Val Cys Leu Ser Cys Leu Gly Cys His Leu Cys Gly Gly
100 105 110
Ala Ser Gly Gly Gly Gly Pro Ala Thr Asn Leu Thr Gln Ser Arg Lys
115 120 125
Trp Met Ala Met Phe Pro Gln Pro Glu Trp Leu Pro Pro Asp Gly
130 135 140
<210> 483
<211> 143
<212> PRT
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
169
<213> Homo Sapiens
<400> 483
Met Glu Thr Gln Arg Gly Asn Lys Gln Arg Ala Gln Glu Gln Gly Val
10 15
Cys Cys Leu Trp Gly Ser Ser Pro Cys Leu Gly Ser Tyr Gly Thr Ala
20 25 30
Gly Phe Leu Val Ala Lys Arg Arg Thr Thr Gly Leu Leu Glu Glu Asp
35 40 45
Phe Thr Phe Lys Cys Arg Lys Gln Pro Lys Leu Pro Ser Met Arg Leu
50 55 60
Ser Leu Leu Trp Pro Trp Arg Asp Leu Lys Phe Val Pro Arg Gln Asp
65 70 75 80
Lys Leu Thr Arg Ser Ser Val Ser Val Ala Gly Ala Tyr Ala Cys Arg
85 90 95
Ala Gly Pro Gly Trp Leu Lys Glu Gin Pro Ala Thr Ser Ala Arg Val
100 105 110
Arg Leu Val Gln Ala Glu His Pro Pro Pro His Pro Leu Glu Glu Val
115 120 7_25
Gly Met Ala Arg Phe Pro Gln Pro Glu Cys Leu Pro Pro Tyr Cys
130 135 140
<210> 484
<211> 30
<212> PRT
<213> Homo Sapien
<400> 484
Thr Ala Ala Ser Asp Asn Phe Gln Leu Ser Gln Gly Gly Gln Gly Phe
.1 5 10 15
Ala Ile Pro Ile Gly Gln Ala Met Ala Ile Ala Gly Gln Ile
20 25 30
<210> 485
<211> 31
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 485
gggaagctta tcacctatgt gccgcctctg c 31
<210> 486
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
170
<223> Made in a lab
<400> 486
gcgaattctc acgctgagta tttggcc 27
<210> 487
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 487
cccgaattct tagctgccca tccgaacgcc ttcatc 36
<210> 488
<211> 33
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 488
gggaagcttc ttccccggct gcaccagctg tgc ~ 33
<210> 489
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 489
Met Asp Arg Leu Val Gln Arg Phe Gly Thr Arg Ala Val Tyr Leu Ala
1 5 10 15
Ser Val Ala
<210> 490
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 490
Tyr.Leu Ala Ser Val Ala Ala Phe Pro Val Ala Ala Gly Ala Thr Cys
1 5 10 15
Leu Ser His Ser
<210> 491
<211> 20
<212> PRT
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
171
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 491
Thr Cys Leu Ser His Ser Val Ala Val Val Thr Ala Ser Ala Ala Leu
1 5 10 15
Thr Gly Phe Thr
<210> 492
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 492
Ala Leu Thr Gly Phe Thr Phe Ser Ala Leu Gln Ile Leu Pro Tyr Thr
1 5 10 15
Leu Ala Ser Leu
<210> 493
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 493
Tyr Thr Leu Ala Ser Leu Tyr His Arg Glu Lys Gln Val Phe Leu Pro
1 5 10 15
Lys Tyr Arg Gly
<210> 494
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 494
Leu Pro Lys Tyr Arg Gly Asp Thr Gly Gly Ala Ser Ser Glu Asp Ser
1 5 10 15
Leu Met Ile Ser
2210> 495
<211> 20
<212> PRT
<213> Artificial Sequence
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
172
<220>
<223> Made in a lab
<400> 495
Asp Ser Leu Met Thr Ser Phe Leu Pro Gly Pro Lys Pro Gly Ala Pro
1 5 10 15
Phe Pro Asn Gly
<210> 496
<211> 21
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 496
Ala Pro Phe Pro Asn Gly His Val Gly Ala Gly Gly Ser Gly Leu Leu
1 5 10 15
Pro Pro Pro Pro Ala
<210> 497
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 497
Leu Leu Pro Pro Pro Pro Ala Leu Cys Gly Ala Ser Ala Cys Asp Val
1 5 10 15
Ser Val Arg Val
<210> 498
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 498
Asp Val Ser Val Arg Val Val Val Gly Glu Pro Thr Glu Ala Arg Val
1 5 10 15
Val Pro Gly Arg
<210> 499
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
173
<223> Made in a lab
<400> 499
Arg Val Val Pro Gly Arg Gly Ile Cys Leu Asp Leu Ala Ile Leu Asp
1 5 10 15
Ser Ala Phe Leu
<210> 500
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 500
Leu Asp Ser Ala Phe Leu Leu Ser Gln Val Ala Pro Ser Leu Phe Met
1 5 10 15
Gly Ser Ile Val
<210> 501
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 501
Phe Met Gly Ser Ile Val Gln Leu Ser Gln Ser Val Thr Ala Tyr Met
1 5 10 15
Val Ser Ala Ala
<210> 502
<211> 414
<212> DNA
<213> Homo Sapien
<220>
<221> misc_feature
<222> (1). .(414)
<223> n = A,T,C or G
<400>
502
caccatggagacaggcctgcgctggcttttcctggtcgctgtgctcaaaggtgtccaatg 60
tcagtcggtggaggagtccgggggtcgcctggtcacgcctgggacacctttgacantcac 120
ctgtagagtttttggaatngacctcagtagcaatgcaatgagctgggtccgccaggctcc 180
agggaaggggctggaatggatcggagccattgataattgtccacantacgcgacctgggc 240
gaaaggccgattnatnatttccaaaacctngaccacggtggatttgaaaatgaccagtcc 300
gacaaccgaggacacggccacctatttttgtggcagaatgaatactggtaatagtggttg 360
gaagaatatttggggcccaggcaccctggtcaccgtntcctcagggcaacctaa 414
<210> 503
<211> 379
<212> DNA
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
174
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(379)
<223> n = A,T,C or G
<400> 503
atncgatggtgcttggtcaaaggtgtccagtgtcagtcggtggaggagtccgggggtcgc 60
ctggtcacgcctgggacacccctgacactcacctgcaccgtntctggattngacatcagt 120
agctatggagtgagctgggtccgccaggctccagggaaggggctggnatacatcggatca 180
ttagtagtagtggtacattttacgcgagctgggcgaaaggccgattcaccatttccaaaa 240
cctngaccacggtggatttgaaaatcaccagtttgacaaccgaggacacggccacctatt 300
tntgtgccagaggggggtttaattataaagacatttggggcccaggcaccctggtcaccg 360
tntccttagggcaacctaa 379
<210> 504
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 504
Giy Phe Thr Asn Tyr Thr Asp Phe Glu Asp Ser Pro Tyr Phe Lys Glu
1 5 10 15
Asn Ser Ala
<210> 505
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 505
Lys Glu Asn Ser Ala Phe Pro Pro Phe Cys Cys Asn Asp Asn Val Thr
1 5 10 15
Asn Thr Ala Asn
<210> 506
<211> 407
<212> DNA
<213> Homo Sapien
<400> 506
atggagacaggcctgcgctggcttctcctggtcgctgcgctcaaaggtgtccagtgtcag 60
tcgctggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgc 120
accgtctctggattctccctcagtagcaatgcaatgatctgggtccgccaggctccaggg 180
aaggggctggaatacatcggatacattagttatggtggtagcgcatactacgcgagctgg 240
gtgaaaggccgattcaccatctccaaaacctcgaccacggtggatctgagaatgaccagt 300
ctgacaaccgaggacacggccacctatttctgtgccagaaatagtgattttagtggtatg 360
ttgtggggcccaggcaccctggtcaccgtctcctcagggcaacctaa 407
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
175
<210> 507
<211> 422
<212> DNA
<213> Homo Sapien
<400>
507
atggagacaggcctgcgctggcttctcctggtcgctgtgctcaaaggtgtccagtgtcag 60
tcggtggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgt 120
acagtctctggattctccctcagcaactacgacctgaactgggtccgccaggctccaggg 180
aaggggctggaatggatcgggatcattaattatgttggtaggacggactacgcgaactgg 240
gcaaaaggccggttcaccatctccaaaacctcgaccaccgtggatctcaagatcgccagt 300
ccgacaaccgaggacacggccacctatttctgtgccagagggtggaagtgcgatgagtct 360
ggtccgtgcttgcgcatctggggcccaggcaccctggtcaccgtctccttagggcaacct 420
as 422
<210> 508
<211> 411
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> (1). .(411)
<223> n = A,T,C or G
<400> 508
atggagacaggcctcgctggcttctcctggtcgctgtgctcaaaggtgtccagtgtcagt 60
cggtggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgca 120
cagtctctggaatcgacctcagtagctactgcatgagctgggtccgccaggctccaggga 180
aggggctggaatggatcggaatcattggtactcctggtgacacatactacgcgaggtggg 240
cgaaaggccgattcaccatctccaaaacctcgaccacggtgcatntgaaaatcnccagtc 300
cgacaaccgaggacacggccacctatttctgtgccagagatcttcgggatggtagtagta 360
ctggttattataaaatctggggcccaggcaccctggtcaccgtctccttgg 4.11
<210> 509
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 509
Leu Cys Lys Phe Thr Glu Trp Ile Glu Lys Thr Val Gln Ala Ser
1 5 10 15
<210> 510
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 510
Pro Glu Tyr Asn Arg Pro Leu Leu Ala Asn Asp Leu Met Leu Ile
1 5 10 15
CA 02391369 2002-05-10
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176
<210> 511
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 511
Tyr His Pro Ser Met Phe Cys Ala Gly Gly Gly Gln Asp Gln Lys
1 5 10 15
<210> 512
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 512
Asp Ser Gly Gly Pro Leu Ile Cys Asn Gly Tyr Leu Gln Gly Leu
1 5 10 15
<210> 513
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 513
Ala Pro Cys Gly Gln Val Gly Val Pro Asx Val Tyr Thr Asn Leu
1 5 10 15
<210> 514
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 514
Leu Cys Lys Phe Thr Glu Trp Ile Glu Lys Thr Val Gln Ala Ser
1 5 10 15
<210> 515
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
177
<400> 515
Met Val Glu Ala Ser Leu Ser Val Arg His Pro Glu Tyr Asn Arg
1 5 10 15
<210> 516
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 516
Val Ser Glu Ser Asp Thr Ile Arg Ser Ile Ser Ile Ala Ser Gln
1 5 10 15
<210> 517
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 517
Glu Val Cys Ser Lys Leu Tyr Asp Pro Leu Tyr His Pro Ser Met
1 5 10 15
<210> 518
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 518
Arg Ala Glu 'Pro Gly Thr Glu Ala Arg Arg His Tyr Asp Glu Gly
1 5 10 15
<210> 519
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 519
Arg Ala Glu Pro Gly Thr Glu Ala Arg Arg Asn Tyr Asp Glu Gly Cys
1 5 10 15
Gly
<210> 520
<211> 25
<212> PRT
<213> Artificial Sequence
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
178
<220>
<223> Made in a lab
<400> 520
Val Gly Glu Gly Leu Tyr Gln Gly Val Pro Arg Ala Glu Pro Gly Thr
1 5 10 15
Glu Ala Arg Arg His Tyr Asp Glu Gly
20 25
<210> 521
<211> 21
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 521
Ala Pro Phe Pro Asn Gly His Val Gly Ala Gly Gly Ser Gly Leu Leu
1 5 10 15
Pro Pro Pro Pro Ala
<210> 522
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 522
Leu Leu Val Val Pro Ala Ile Lys Lys Asp Tyr Gly Ser Gln Glu Asp '
1 5 10 15
Phe Thr Gln Val
<210> 523
<211> 254
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<220>
<221> VARIANT
<222> (1)...(254)
<223> Xaa = any amino acid
<400> 523
Met Ala Thr Ala Gly Asn Pro Trp Gly Trp Phe Leu Gly Tyr Leu Ile
1 5 10 15
Leu Gly Val Ala Gly Ser Leu Val Ser Gly Ser Cys Ser Gln Ile Ile
20 25 30
Asn Gly Glu Asp Cys Ser Pro His Ser Gln Pro Trp Gln Ala Ala Leu
35 40 45
CA 02391369 2002-05-10
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179
Val Met Glu Asn Glu Leu Phe Cys Ser Gly Val Leu Val His Pro Gln
50 55 60
Trp Val Leu Ser Ala Thr His Cys Phe Gln Asn Ser Tyr Thr Ile Gly
65 70 75 80
Leu Gly Leu His Ser Leu Glu Ala Asp Gln Glu Pro Gly Ser Gln Met
85 90 95
Val Glu Ala Ser Leu Ser Val Arg His Pro Glu Tyr Asn Arg Pro Leu
100 105 110
Leu Ala Asn Asp Leu Met Leu,Ile Lys Leu Asp Glu Ser Val Ser Glu
115 120 125
Ser Asp Thr Ile Arg Ser Ile Ser Ile Ala Ser Gln Cys Pro Thr Ala
130 135 140
Gly Asn Ser Cys Leu Val Ser Gly Trp Gly Leu Leu Ala Asn Gly Arg
145 150 155 160
Met Pro Thr Val Leu Gln Cys Val Asn Val Ser Val Val Ser Glu Glu
165 170 175
Val Cys Ser Lys Leu Tyr Asp Pro Leu Tyr His Pro Ser Met Phe Cys
180 185 190
Ala Gly Gly Gly Gln Xaa Gln Xaa Asp Ser Cys Asn Gly Asp Ser Gly
195 200 205
Gly Pro Leu Ile Cys Asn Gly Tyr Leu Gln Gly Leu Val Ser Phe Gly
210 215 220
Lys Ala Pro Cys Gly Gln Val Gly Val Pro Gly Val Tyr Thr Asn Leu
225 230 235 240
Cys Lys Phe Thr Glu Trp Ile Glu Lys Thr Val Gln Ala Ser
245 250
<210>
524
<211>
765
<212>
DNA
<213> sapien
Homo
<400>
524
atggccacagcaggaaatccctggggctggttcctggggtacctcatccttggtgtcgca'-60
ggatcgctcgtctctggtagctgcagccaaatcataaacggcgaggactgcagcccgcac120
tcgcagccctggcaggcggcactggtcatggaaaacgaattgttctgctcgggcgtcctg180
gtgcatccgcagtgggtgctgtcagccgcacactgtttccagaactcctacaccatcggg240
ctgggcctgcacagtcttgaggccgaccaagagccagggagccagatggtggaggccagc300
ctctccgtacggcacccagagtacaacagacccttgctcgctaacgacctcatgctcatc360
aagttggacgaatccgtgtccgagtctgacaccatccggagcatcagcattgcttcgcag420
tgccctaccgcggggaactcttgcctcgtttctggctggggtctgctggcgaacggcaga480
atgcctaccgtgctgcagtgcgtgaacgtgtcggtggtgtctgaggaggtctgcagtaag540
ctctatgacccgctgtaccaccccagcatgttctgcgccggcggagggcaagaccagaag600
gactcctgcaacggtgactctggggggcccctgatctgcaacgggtacttgcagggcctt660
gtgtctttcggaaaagccccgtgtggccaagttggcgtgccaggtgtctacaccaacctc720
tgcaaattcactgagtggatagagaaaaccgtccaggccagttaa 765
<210>
525
<211>
254
<212>
PRT
<213> sapien
Homo
<400>
525
Met Ala Ala Gly Leu Gly Leu Ile
Thr Asn Pro Tyr
Trp Gly
Trp Phe
1 5 10 15
Leu Gly Ala Gly Cys Ser Ile Ile
Val Ser Leu Gln
Val Ser
Gly Ser
20 25 30
Asn Gly Asp Cys Trp Gln Ala Leu
Glu Ser Pro Ala
His Ser
Gln Pro
CA 02391369 2002-05-10
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180
35 40 45
Val Met Glu Asn Glu Leu Phe Cys Ser Gly Val Leu Val His Pro Gln
50 55 60
Trp Val Leu Ser Ala Ala His Cys Phe Gln Asn Ser Tyr Thr Ile Gly
65 70 75 80
Leu Gly Leu His Ser Leu Glu Ala Asp Gln Glu Pro Gly Ser Gln Met
85 90 95
Val Glu Ala Ser Leu Ser Val Arg His Pro Glu Tyr Asn Arg Pro Leu
100 105 110
Leu Ala Asn Asp Leu Met Leu Ile Lys Leu Asp Glu Ser Val Ser Glu
115 120 125
Ser Asp Thr Ile Arg Ser Ile Ser Ile Ala Ser Gln Cys Pro Thr Ala
130 135 140
Gly Asn Ser Cys Leu Val Ser Gly Trp Gly Leu Leu Ala Asn Gly Arg
145 150 155 160
Met Pro Thr Val Leu Gln Cys Val Asn Val Ser Val Val Ser Glu Glu
165 170 175
Val Cys Ser Lys Leu Tyr Asp Pro Leu Tyr His Pro Ser Met Phe Cys
180 185 190
Ala Gly Gly Gly Gln Asp Gln Lys Asp Ser Cys Asn Gly Asp Ser Gly
195 200 205
Gly Pro Leu Ile Cys Asn Gly Tyr Leu Gln Gly Leu Val Ser Phe Gly
210 215 220
Lys Al.a Pro Cys Gly Gln Val Gly Val Pro Gly Val Tyr Thr Asn Leu
225 230 235 240
Cys Lys Phe Thr Glu Trp Ile Glu Lys Thr Val Gln Ala Ser
245 250
<210> 526
<211> 963
<212> DNA
<213> Homo Sapiens
<4b0> 526
atgagttcct gcaacttcac acatgccacc tttgtgctta ttggtatccc aggattagag 60
aaagcccatt tctgggttgg cttccccctc ctttccatgt atgtagtggc aatgtttgga 120
aactgcatcg tggtcttcat cgtaaggacg gaacgcagcc tgcacgctcc gatgtacctc 180
tttctctgca tgcttgcagc cattgacctg gccttatcca catccaccat gcctaagatc 240
cttgcccttt tctggtttga ttcccgagag attagctttg aggcctgtct tacccagatg 300
ttctttattc atgccctctc agccattgaa tccaccatcc tgctggccat ggcctttgac 360
cgttatgtgg ccatctgcca cccactgcgc catgctgcag tgctcaacaa tacagtaaca 420
gcccagattg gcatcgtggc tgtggtccgc ggatccctct tttttttccc actgcctctg 480
ctgatcaagc ggctggcctt ctgccactcc aatgtcctct cgcactccta ttgtgtccac 540
caggatgtaa tgaagttggc ctatgcagac actttgccca atgtggtata tggtcttact 600
gccattctgc tggtcatggg cgtggacgta atgttcatct ccttgtccta ttttctgata 660
atacgaacgg ttctgcaact gccttccaag tcagagcggg ccaaggcctt tggaacctgt 720
gtgtcacaca ttggtgtggt actcgccttc tatgtgccac ttattggcct ctcagttgta 780
caccgctttg gaaacagcct tcatcccatt gtgcgtgttg tcatgggtga catctacctg 840
ctgctgcctc ctgtcatcaa tcccatcatc tatggtgcca aaaccaaaca gatcagaaca 900
cgggtgctgg ctatgttcaa gatcagctgt gacaaggact tgcaggctgt gggaggcaag 960
tga 963
<210> 527
<211> 320
<212> PRT
<213> Homo sapiens
<400> 527
CA 02391369 2002-05-10
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181
Met Ser Ser Cys Asn Phe Thr His Ala Thr Phe Val Leu Ile Gly Ile
10 15
Pro Gly Leu Glu Lys Ala His Phe Trp Val Gly Phe Pro Leu Leu Ser
20 25 30
Met Tyr Val Val Ala Met Phe Gly Asn Cys Ile Val Val Phe Ile Val
35 40 45
Arg Thr Glu Arg Ser Leu His Ala Pro Met Tyr Leu Phe Leu Cys Met
50 55 60
Leu Ala Ala Ile Asp Leu Ala Leu Ser Thr Ser Thr Met Pro Lys Ile
65 70 75 80
Leu Ala Leu Phe Trp Phe Asp Ser Arg Glu Ile Ser Phe Glu Ala Cys
85 90 95
Leu Thr Gln Met Phe Phe Ile His Ala Leu Ser Ala Ile Glu Ser Thr
100 105 110
Ile Leu Leu Ala Met Ala Phe Asp Arg Tyr Val Ala Ile Cys His Pro
115 120 125
Leu Arg His Ala Ala Val Leu Asn Asn Thr Val Thr Ala Gln Ile Gly
130 135 140
Ile Val Ala Val Val Arg Gly Ser Leu Phe Phe Phe Pro Leu Pro Leu
145 150 155 160
Leu Ile Lys Arg Leu Ala Phe Cys His Ser Asn Val Leu Ser His Ser
1.65 170 175
Tyr Cys Val His Gln Asp Val Met Lys Leu Al.a Tyr Ala Asp Thr Leu
180 185 190
Pro Asn Val Val Tyr Gly Leu Thr Ala Ile Leu Leu Val Met Gly Val
195 200 205
Asp Val Met Phe Ile Ser Leu Ser Tyr Phe Leu Ile Ile Arg Thr Val
210 215 220
Leu Gln Leu Pro Ser Lys Ser Glu Arg Ala Lys Ala Phe Gly Thr Cys
225 230 235 240
Val Ser His Ile Gly Val Val Leu Ala Phe Tyr Val Pro Leu Ile Gly
245 250 255
Leu Ser Val Val His Arg Phe Gly Asn Ser Leu His Pro Ile Val Arg
260 265 270
Val Val Met Gly Asp Ile Tyr Leu Leu Leu Pro Pro Val Ile Asn Pro
275 280 285
Ile Ile Tyr Gly Ala Lys Thr Lys Gln Ile Arg Thr Arg Val Leu Ala
290 295 300
Met Phe Lys Ile Ser Cys Asp Lys Asp Leu Gln Ala Val Gly Gly Lys
CA 02391369 2002-05-10
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182
305 310 315 320
<210> 528
<211> 20
<212> DNA
<213> Homo Sapien
<400> 528
actatggtcc agaggctgtg 20
<210> 529
<211> 20
<212> DNA
<213> Homo Sapien
<400> 529
atcacctatg tgccgcctct 20
<210> 530
<211> 1852
<212> DNA
<213> Homo sapiens
<400> 530
ggcacgagaa ttaaaaccct cagcaaaaca ggcatagaag ggacatacct taaagtaata 60
aaaaccacct atgacaagcc cacagccaac ataatactaa atggggaaaa gttagaagca 120
tttcctctga gaactgcaac aataaataca aggatgctgg attttgtcaa atgccttttc 180
tgtgtctgtt gagatgctta tgtgactttg cttttaattc tgtttatgtg attatcacat 240
ttattgactt gcctgtgtta gaccggaaga gctggggtgt ttctcaggag ccaccgtgtg 300
ctgcggcagc ttcgggataa cttgaggctg catcactggg gaagaaacac aytcctgtcc 360
gtggcgctga tggctgagga cagagcttca gtgtggcttc tctgcgactg gcttcttcgg 420
ggagttcttc cttcatagtt catccatatg gctccagagg aaaattatat tattttgtta 480
tggatgaaga gtattacgtt gtgcagatat actgcagtgt cttcatctct tgatgtgtga 540
ttgggtaggt tccaccatgt tgccgcagat gacatgattt cagtacctgt gtctggctga 600
aaagtgtttg tttgtgaatg gatattgtgg tttctggatc tcatcctctg tgggtggaca 660
gctttctcca ccttgctgga agtgacctgc tgtccagaag tttgatggct gaggagtata 720
ccatcgtgca tgcatctttc atttcctgca tttcttcctc cctggatgga cagggggagc 780
ggcaagagca acgtgggcac ttctggagac cacaacgact cctctgtgaa gacgcttggg 840
agcaagaggt gcaagtggtg ctgccactgc ttcccctgct gcagggggag cggcaagagc 900
aacgtggtcg cttggggaga ctacgatgac agcgccttca tggatcccag gtaccacgtc 960
catggagaag atctggacaa gctccacaga gctgcctggt ggggtaaagt ccccagaaag 1020
gatctcatcg tcatgctcag ggacacggat gtgaacaaga gggacaagca aaagaggact 1080
gctctacatc tggcctctgc caatgggaat tcagaagtag taaaactcgt gctggacaga 1140
cgatgtcaac ttaatgtcct tgacaacaaa aagaggacag ctctgacaaa ggccgtacaa 1200
tgccaggaag atgaatgtgc gttaatgttg ctggaacatg gcactgatcc aaatattcca 1260
gatgagtatg gaaataccac tctacactat gctgtctaca atgaagataa attaatggcc 1320
aaagcactgc tcttatacgg tgctgatatc gaatcaaaaa acaagcatgg cctcacacca 1380
ctgctacttg gtatacatga gcaaaaacag caagtggtga aatttttaat caagaaaaaa 1440
gcgaatttaa atgcgctgga tagatatgga agaactgctc tcatacttgc tgtatgttgt 1500
ggatcagcaa gtatagtcag ccctctactt gagcaaaatg ttgatgtatc ttctcaagat 1560
ctggaaagac ggccagagag tatgctgttt ctagtcatca tcatgtaatt tgccagttac 1620
tttctgacta caaagaaaaa cagatgttaa aaatctcttc tgaaaacagc aatccagaac 1680
aagacttaaa gctgacatca gaggaagagt cacaaaggct taaaggaagt gaaaacagcc 1740
agccagagct agaagattta tggctattga agaagaatga agaacacgga agtactcatg 1800
tgggattccc agaaaacctg actaacggtg ccgctgctgg caatggtgat ga 1852
<210> 531
<211> 879
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
183
<212> DNA
<213> Homo Sapiens
<400> 531
atgcatcttt catttcctgc atttcttcct ccctggatgg acagggggag cggcaagagc 60
aacgtgggca cttctggaga ccacaacgac tcctctgtga agacgcttgg gagcaagagg 120
tgcaagtggt gctgccactg cttcccctgc tgcaggggga gcggcaagag caacgtggtc 180
gcttggggag actacgatga cagcgccttc atggatccca ggtaccacgt ccatggagaa 240
gatctggaca agctccacag agctgcctgg tggggtaaag tccccagaaa ggatctcatc 300
gtcatgctca gggacacgga tgtgaacaag agggacaagc aaaagaggac tgctctacat 360
ctggcctctg ccaatgggaa ttcagaagta gtaaaactcg tgctggacag acgatgtcaa 420
cttaatgtcc ttgacaacaa aaagaggaca gctctgacaa aggccgtaca atgccaggaa 480
gatgaatgtg cgttaatgtt gctggaacat ggcactgatc caaatattcc agatgagtat 540
ggaaatacca ctctacacta tgctgtctac aatgaagata aattaatggc caaagcactg 600
ctcttatacg gtgctgatat cgaatcaaaa aacaagcatg gcctcacacc actgctactt 660
ggtatacatg agcaaaaaca gcaagtggtg aaatttttaa tcaagaaaaa agcgaattta 720
aatgcgctgg atagatatgg aagaactgct ctcatacttg ctgtatgttg tggatcagca 780
agtatagtca gccctctact tgagcaaaat gttgatgtat cttctcaaga tctggaaaga 840
cggccagaga gtatgctgtt tctagtcatc atcatgtaa 879
<210> 532
<211> 292
<212> PRT
<213> Homo Sapiens
<400> 532
Met His Leu Ser Phe Pro Ala Phe Leu Pro Pro Trp Met Asp Arg Gly
10 15
Ser Gly Lys Ser Asn Val Gly Thr Ser Gly Asp His Asn Asp Ser Ser
20 25 30
Val Lys Thr Leu Gly Ser Lys Arg Cys Lys Trp Cys Cys His Cys Phe .-.
35 40 45
Pro Cys Cys Arg Gly Ser Gly Lys Ser Asn Val Val Ala Trp Gly Asp
50 55 60
Tyr Asp Asp Ser Ala Phe Met Asp Pro Arg Tyr His Val His Gly Glu
65 70 75 80
Asp Leu Asp Lys Leu His Arg Ala Ala Trp Trp Gly Lys Val Pro Arg
85 90 95
Lys Asp Leu Ile Val Met Leu Arg Asp Thr Asp Val Asn Lys Arg Asp
100 105 110
Lys Gln Lys Arg Thr Ala Leu His Leu Ala Ser Ala Asn Gly Asn Ser
115 120 125
Glu Val Val Lys Leu Val Leu Asp Arg Arg Cys Gln Leu Asn Val Leu
130 135 140
Asp Asn Lys Lys Arg Thr Ala Leu Thr Lys Ala Val Gln Cys Gln Glu
145 150 155 160
Asp Glu Cys Ala Leu Met Leu Leu Glu His Gly Thr Asp Pro Asn Ile
165 170 175
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
184
Pro Asp Glu Tyr Gly Asn Thr Thr Leu His Tyr Ala Val Tyr Asn Glu
180 185 190
Asp Lys Leu Met Ala Lys Ala Leu Leu Leu Tyr Gly Ala Asp Ile Glu
195 200 205
Ser Lys Asn Lys His Gly Leu Thr Pro Leu Leu Leu Gly Ile His Glu
210 215 220
Gln Lys Gln Gln Val Val Lys Phe Leu Ile Lys Lys Lys Ala Asn Leu
225 230 235 240
Asn Ala Leu Asp Arg Tyr Gly Arg Thr Ala Leu Ile Leu Ala Val Cys
245 250 255
Cys Gly Ser Ala Ser Ile Val Ser Pro Leu Leu Glu Gln Asn Val Asp
260 265 270
Val Ser Ser Gln Asp Leu Glu Arg Arg Pro Glu Ser Met Leu Phe Leu
275 280 285
Val Ile Ile Met
290
<210> 533
<211> 801
<212> DNA
<213> Homo Sapiens
<400> 533
atgtacaagc ttcagtgcaa caactgtgct acaaatggag ccacagagag gaaacaagca 60
gcaggctcag gagcagggta tgcgctgcct tcggctctcc aatccatgcc tcagggctcc 120 '.
tatgccactg cacgattctt ggttgccaag aggccaacca caggccatct tgagaaggag 180
tttatgttcc actgcagaaa gcagccagga tcaccatcca ggggacttgg tcttctgtgg 240
ccctggccag acatagaatt tgtgccaagg caggacaagc tcactcagag cagcgtgtta 300
gtacctcaaa tctgtgcgtg ccagacaagg ccaaactggc tcaatgagca accagccacc 360
tctgcagggg tgcgtctgga ggaggtggac cagccaccaa ccttacccag tcaaggaagt 420
ggatggccat gttcccacag cctgagtggc tgccacctga tggctgatat agcaaaggcc 480
ttaggaaaag cagatggccc ttggccctac ctttttgtta gaagaactga tgttccatgt 540
cctgcagcga gtgaggttgg tggctgtgcc cccagctcct ggcacaccct cgcagaggtg 600
actggttgct ctttgagccc tcttagcctt gcccagcatg cacaagcctc agtgctacta 660
ctgtgctaca aatggagcca tataggggaa acgagcagcc atctcaggag caaggtgtat 720
gctgcctttg ggggctccag tccttgcctc aagggtctta tgtcactgtg ggcttcttgg 780
ttgccaagag gcagaccata g 801
<210> 534
<211> 266
<212> PRT
<213> Homo Sapiens
<400> 534
Met Tyr Lys Leu Gln Cys Asn Asn Cys Ala Thr Asn Gly Ala Thr Glu
10 15
Arg Lys Gln Ala Ala Gly Ser Gly Ala Gly Tyr Ala Leu Pro Ser Ala
20 25 30
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
185
Leu Gln Ser Met Pro Gln Gly Ser Tyr Ala Thr Ala Arg Phe Leu Val
35 40 45
Ala Lys Arg Pro Thr Thr Gly His Leu Glu Lys Glu Phe Met Phe His
50 55 60
Cys Arg Lys Gln Pro Gly Ser Pro Ser Arg Gly Leu Gly Leu Leu Trp
65 70 75 80
Pro Trp Pro Asp Ile Glu Phe Val Pro Arg Gln Asp Lys Leu Thr Gln
85 90 95
Ser Ser Val Leu Val Pro Gln Ile Cys Ala Cys Gln Thr Arg Pro Asn
100 105 110
Trp Leu Asn Glu Gln Pro Ala Thr Ser Ala Gly Val Arg Leu Glu Glu
115 120 125
Val Asp Gln Pro Pro Thr Leu Pro Ser Gln Gly Ser Gly Trp Pro Cys
130 135 140
Ser His Ser Leu Ser Gly Cys His Leu Met Ala Asp Ile Ala Lys Ala
145 150 155 160
Leu Gly Lys Ala Asp Gly Pro Trp Pro Tyr Leu Phe Val Arg Arg Thr
165 170 175
Asp Val Pro Cys Pro Ala Ala Ser Glu Val Gly Gly Cys Ala Pro Ser
180 185 190
Ser Trp His Thr Leu Ala Glu Val Thr Gly Cys Ser Leu Ser Pro Leu
195 200 205
Ser Leu Ala Gln His Ala Gln Ala Ser Val Leu Leu Leu Cys Tyr Lys
210 215 220
Trp Ser His Ile Gly Glu Thr Ser Ser His Leu Arg Ser Lys Val Tyr
225 230 235 240
Ala Ala Phe Gly Gly Ser Ser Pro Cys Leu Lys Gly Leu Met Ser Leu
245 250 255
Trp Ala Ser Trp Leu Pro Arg Gly Arg Pro
260 265
<210> 535
<211> 6082
<212> DNA
<213> Homo Sapiens
<400> 535
cctccactat tacagcttat aggaaattac aatccacttt acaggcctca aaggttcatt 60
ctggccgagc ggacaggcgt ggcggccgga gccccagcat ccctgcttga ggtccaggag 120
cggagcccgc ggccactgcc gcctgatcag cgcgaccccg gcccgcgccc gccccgcccg 180
gcaagatgct gcccgtgtac caggaggtga agcccaaccc gctgcaggac gcgaacctct 240
gctcacgcgt gttcttctgg tggctcaatc ccttgtttaa aattggccat aaacggagat 300
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
186
tagaggaaga tgatatgtat tcagtgctgc cagaagaccg ctcacagcac cttggagagg 360
agttgcaagg gttctgggat aaagaagttt taagagctga gaatgacgca cagaagcctt 420
ctttaacaag agcaatcata aagtgttact ggaaatctta tttagttttg ggaattttta 480
cgttaattga ggaaagtgcc aaagtaatcc agcccatatt tttgggaaaa attattaatt 540
attttgaaaa ttatgatccc atggattctg tggctttgaa cacagcgtac gcctatgcca 600
cggtgctgac tttttgcacg ctcattttgg ctatactgca tcacttatat ttttatcacg 660
ttcagtgtgc tgggatgagg ttacgagtag ccatgtgcca tatgatttat cggaaggcac 720
ttcgtcttag taacatggcc atggggaaga caaccacagg ccagatagtc aatctgctgt 780
ccaatgatgt gaacaagttt gatcaggtga cagtgttctt acacttcctg tgggcaggac 840
cactgcaggc gatcgcagtg actgccctac tctggatgga gataggaata tcgtgccttg 900
ctgggatggc agttctaatc attctcctgc ccttgcaaag ctgttttggg aagttgttct 960
catcactgag gagtaaaact gcaactttca cggatgccag gatcaggacc atgaatgaag 1020
ttataactgg tataaggata ataaaaatgt acgcctggga aaagtcattt tcaaatctta 1080
ttaccaattt gagaaagaag gagatttcca agattctgag aagttcctgc ctcaggggga 1140
tgaatttggc ttcgtttttc agtgcaagca aaatcatcgt gtttgtgacc ttcaccacct 1200
acgtgctcct cggcagtgtg atcacagcca gccgcgtgtt cgtggcagtg acgctgtatg 1260
gggctgtgcg gctgacggtt accctcttct tcccctcagc cattgagagg gtgtcagagg 1320
caatcgtcag catccgaaga atccagacct ttttgctact. tgatgagata tcacagcgca 1380
accgtcagct gccgtcagat ggtaaaaaga tggtgcatgt gcaggatttt actgcttttt 1440
gggataaggc atcagagacc ccaactctac aaggcctttc ctttactgtc agacctggcg 1500
aattgttagc tgtggtcggc cccgtgggag cagggaagtc atcactgtta agtgccgtgc 1560
tcggggaatt ggccccaagt cacgggctgg tcagcgtgca tggaagaatt gcctatgtgt 1620
ctcagcagcc ctgggtgttc tcgggaactc tgaggagtaa tattttattt gggaagaaat 1680
acgaaaagga acgatatgaa aaagtcataa aggcttgtgc tctgaaaaag gatttacagc 1740
tgttggagga tggtgatctg actgtgatag gagatcgggg aaccacgctg agtggagggc 1800
agaaagcacg ggtaaacctt gcaagagcag tgtatcaaga tgctgacatc tatctcctgg 1860
acgatcctct cagtgcagta gatgcggaag ttagcagaca cttgttcgaa ctgtgtattt 1920
gtcaaatttt gcatgagaag atcacaattt tagtgactca tcagttgcag tacctcaaag 1980
ctgcaagtca gattctgata ttgaaagatg gtaaaatggt gcagaagggg acttacactg 2040
agtt.cctaaa atctggtata gattttggct cccttttaaa gaaggataat gaggaaagtg 21.00:
aacaacctcc agttccagga actcccacac taaggaatcg taccttctca gagtcttcgg 2160
tttggtctca acaatcttct agaccctcct tgaaagatgg tgctctggag agccaagata 2220
cagagaatgt cccagttaca ctatcagagg agaaccgttc tgaaggaaaa gttggttttc 2280-:
aggcctataa gaattacttc agagctggtg ctcactggat tgtcttcatt ttccttattc 2340's
tcctaaacac tgcagctcag gttgcctatg tgcttcaaga ttggtggctt tcatactggg 2400
caaacaaaca aagtatgcta aatgtcactg taaatggagg aggaaatgta accgagaagc 2460
tagatcttaa ctggtactta ggaatttatt caggtttaac tgtagctacc gttctttttg 2520
gcatagcaag atctctattg gtattctacg tccttgttaa ctcttcacaa actttgcaca 2580
acaaaatgtt tgagtcaatt ctgaaagctc cggtattatt ctttgataga aatccaatag 2640
gaagaatttt aaatcgtttc tccaaagaca ttggacactt ggatgatttg ctgccgctga 2700
cgtttttaga tttcatccag acattgctac aagtggttgg tgtggtctct gtggctgtgg 2760
ccgtgattcc ttggatcgca atacccttgg ttccccttgg aatcattttc atttttcttc 2820
ggcgatattt tttggaaacg tcaagagatg tgaagcgcct ggaatctaca actcggagtc 2880
cagtgttttc ccacttgtca tcttctctcc aggggctctg gaccatccgg gcatacaaag 2940
cagaagagag gtgtcaggaa ctgtttgatg cacaccagga tttacattca gaggcttggt 3000
tcttgttttt gacaacgtcc cgctggttcg ccgtccgtct ggatgccatc tgtgccatgt 3060
ttgtcatcat cgttgccttt gggtccctga ttctggcaaa aactctggat gccgggcagg 3120
ttggtttggc actgtcctat gccctcacgc tcatggggat gtttcagtgg tgtgttcgac 3180
aaagtgctga agttgagaat atgatgatct cagtagaaag ggtcattgaa tacacagacc 3240
ttgaaaaaga agcaccttgg gaatatcaga aacgcccacc accagcctgg ccccatgaag 3300
gagtgataat ctttgacaat gtgaacttca tgtacagtcc aggtgggcct ctggtactga 3360
agcatctgac agcactcatt aaatcacaag aaaaggttgg cattgtggga agaaccggag 3420
ctggaaaaag ttccctcatc tcagcccttt ttagattgtc agaacccgaa ggtaaaattt 3480
ggattgataa gatcttgaca actgaaattg gacttcacga tttaaggaag aaaatgtcaa 3540
tcatacctca ggaacctgtt ttgttcactg gaacaatgag gaaaaacctg gatcccttta 3600
atgagcacac ggatgaggaa ctgtggaatg ccttacaaga ggtacaactt aaagaaacca 3660
ttgaagatct tcctggtaaa atggatactg aattagcaga atcaggatcc aattttagtg 3720
ttggacaaag acaactggtg tgccttgcca gggcaattct caggaaaaat cagatattga 3780
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
187
ttattgatga agcgacggca aatgtggatc caagaactga tgagttaata caaaaaaaat 3840
ccgggagaaa tttgcccact gcaccgtgct aaccattgca cacagattga acaccattat 3900
tgacagcgac aagataatgg ttttagattc aggaagactg aaagaatatg atgagccgta 3960
tgttttgctg caaaataaag agagcctatt ttacaagatg gtgcaacaac tgggcaaggc 4020
agaagccgct gccctcactg aaacagcaaa acaggtatac ttcaaaagaa attatccaca 4080
tattggtcac actgaccaca tggttacaaa cacttccaat ggacagccct cgaccttaac 4140
tattttcgag acagcactgt gaatccaacc aaaatgtcaa gtccgttccg aaggcatttg 4200
ccactagttt ttggactatg taaaccacat tgtacttttt tttactttgg caacaaatat 4260
ttatacatac aagatgctag ttcatttgaa tatttctccc aacttatcca aggatctcca 4320
gctctaacaa aatggtttat ttttatttaa atgtcaatag ttgtttttta aaatccaaat 4380
cagaggtgca ggccaccagt taaatgccgt ctatcaggtt ttgtgcctta agagactaca 4440
gagtcaaagc tcatttttaa aggagtagga cagagttgtc acaggttttt gttgttgttt 4500
ttattgcccc caaaattaca tgttaatttc catttatatc agggattcta tttacttgaa 4560
gactgtgaag ttgccatttt gtctcattgt tttctttgac ataactagga tccattattt 4620
cccctgaagg cttcttgtta gaaaatagta cagttacaac caataggaac aacaaaaaga 4680
aaaagtttgt gacattgtag tagggagtgt gtacccctta ctccccatca aaaaaaaaaa 4740
tggatacatg gttaaaggat agaagggcaa tattttatca tatgttctaa aagagaagga 4800
agagaaaata ctactttctc aaaatggaag cccttaaagg tgctttgata ctgaaggaca 4860
caaatgtgac cgtccatcct cctttagagt tgcatgactt ggacacggta actgttgcag 4920
ttttagactc agcattgtga cacttcccaa gaaggccaaa cctctaaccg acattcctga 4980
aatacgtggc attattcttt tttggatttc tcatttatgg aaggctaacc ctctgttgac 5040
tgtaagcctt ttggtttggg ctgtattgaa atcctttcta aattgcatga ataggctctg 5100
ctaacgtgat gagacaaact gaaaattatt gcaagcattg actataatta tgcagtacgt 5160 -
tctcaggatg catccagggg ttcattttca tgagcctgtc caggttagtt tactcctgac 5220
cactaatagc attgtcattt gggctttctg ttgaatgaat caacaaacca caatacttcc 5280
tgggaccttt tgtactttat ttgaactatg agtctttaat ttttcctgat gatggtggct 5340'
gtaatatgtt gagttcagtt tactaaaggt tttactatta tggtttgaag tggagtctca 5400
tgacctctca gaataaggtg tcacctccct gaaattgcat atatgtatat agacatgcac 5460
acgtgtgcat ttgtttgtat acatatattt gtccttcgta tagcaagttt tttgctcatc 5520
agcagagagc aacagatgtt ttattgagtg aagccttaaa aagcacacac cacacacagc 5580
taactgccaa aatacattga ccgtagtagc tgttcaactc ctagtactta gaaatacacg 5640.:
tatggttaat gttcagtcca acaaaccaca cacagtaaat gtttattaat agtcatggtt 5'?00
cgtattttag gtgactgaaa ttgcaacagt gatcataatg aggtttgtta aaatgatagc 5760;...
tatattcaaa atgtctatat gtttatttgg acttttgagg ttaaagacag tcatataaac 5820='.
gtcctgtttc tgttttaatg ttatcataga attttttaat gaaactaaat tcaattgaaa 5880
taaatgatag ttttcatctc caaaaaaaaa aaaaaaaagg gcggccgctc gagtctagag 5940
ggcccgttta aacccgctga tcagcctcga ctgtgccttc tagttgccag ccatctgttg 6000
tttgcccctc ccccgtgcct tccttgaccc tggaaggtgc cactcccact gtcctttcct 6060
aataaaatga ggaaattgca tc 6082
<210> 536
<211> 6140
<212> DNA
<213> Homo Sapiens
<220>
<221> unsure
<222> (4535)
<223> n=A,T,C or G
<400> 536
cagtggcgca gtctcagctc actgcagcct ccacctcctg tgttcaagca gtcctcctgc 60
ctcagccacc agactagcag gtctcccccg cctctttctt ggaaggacac ttgccattgg 120
atttaggacc cacttggata atccaggatg atgtcttcac tccaacatcc tcagtttaat 180
tccatgtgca aatacccttt tcccaaataa cattcaattc tttaccagga aaggtggctc 240
aatcccttgt ttaaaattgg ccataaacgg agattagagg aagatgatat gtattcagtg 300
ctgccagaag accgctcaca gcaccttgga gaggagttgc aagggttctg ggataaagaa 360
gttttaagag ctgagaatga cgcacagaag ccttctttaa caagagcaat cataaagtgt 420
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
188
tactggaaat cttatttagt tttgggaatt tttacgttaa ttgaggaaag tgccaaagta 480
atccagccca tatttttggg aaaaattatt aattattttg aaaattatga tcccatggat 540
tctgtggctt tgaacacagc gtacgcctat gccacggtgc tgactttttg cacgctcatt 600
ttggctatac tgcatcactt atatttttat cacgttcagt gtgctgggat gaggttacga 660
gtagccatgt gccatatgat ttatcggaag gcacttcgtc ttagtaacat ggccatgggg 720
aagacaacca caggccagat agtcaatctg ctgtccaatg atgtgaacaa gtttgatcag 780
gtgacagtgt tcttacactt cctgtgggca ggaccactgc aggcgatcgc agtgactgcc 840
ctactctgga tggagatagg aatatcgtgc cttgctggga tggcagttct aatcattctc 900
ctgcccttgc aaagctgttt tgggaagttg ttctcatcac tgaggagtaa aactgcaact 960
ttcacggatg ccaggatcag gaccatgaat gaagttataa ctggtataag gataataaaa 1020
atgtacgcct gggaaaagtc attttcaaat cttattacca atttgagaaa gaaggagatt 1080
tccaagattc tgagaagttc ctgcctcagg gggatgaatt tggcttcgtt tttcagtgca 1140
agcaaaatca tcgtgtttgt gaccttcacc acctacgtgc tcctcggcag tgtgatcaca 1200
gccagccgcg tgttcgtggc agtgacgctg tatggggctg tgcggctgac ggttaccctc 1260
ttcttcccct cagccattga gagggtgtca gaggcaatcg tcagcatccg aagaatccag 1320
acctttttgc tacttgatga gatatcacag cgcaaccgtc agctgccgtc agatggtaaa 1380
aagatggtgc atgtgcagga ttttactgct ttttgggata aggcatcaga gaccccaact 1440
ctacaaggcc tttcctttac tgtcagacct ggcgaattgt tagctgtggt cggccccgtg 1500
ggagcaggga agtcatcact gttaagtgcc gtgctcgggg aattggcccc aagtcacggg 1560
ctggtcagcg tgcatggaag aattgcctat gtgtctcagc agccctgggt gttctcggga 1620
actctgagga gtaatatttt atttgggaag aaatacgaaa aggaacgata tgaaaaagtc 1680
ataaaggctt gtgctctgaa aaaggattta cagctgttgg aggatggtga tctgactgtg 1740
ataggagatc ggggaaccac gctgagtgga gggcagaaag cacgggtaaa ccttgcaaga 1800
gcagtgtatc aagatgctga catctatctc ctggacgatc ctctcagtgc agtagatgcg 1860
gaagttagca gacacttgtt cgaactgtgt atttgtcaaa ttttgcatga gaagatcaca 1920
attttagtga ctcatcagtt gcagtacctc aaagctgcaa gtcagattct gatattgaaa 1980
gatggtaaaa tggtgcagaa ggggacttac actgagttcc taaaatctgg tatagatttt 2040
ggctcccttt taaagaagga taatgaggaa agtgaacaac ctccagttcc aggaactccc 2100
acactaagga atcgtacctt ctcagagtct tcggttt_ggt ctcaacaatc ttctagaccc 2160
tccttgaaag atggtgctct ggagagccaa gatacagaga atgtcccagt tacactatca 2220
gaggagaacc gttctgaagg aaaagttggt tttcaggcct ataagaatta cttcagagct 2280.:.
ggtgctcact ggattgtctt cattttcctt attctcctaa acactgcagc tcaggttgcc 2340
tatgtgcttc aagattggtg gctttcatac tgggcaaaca aacaaagtat gctaaatgtc 2400~.-
actgtaaatg gaggaggaaa tgtaaccgag aagctagatc ttaactggta cttaggaatt 2460r
tattcaggtt taactgtagc taccgttctt tttggcatag caagatctct attggtattc 2520
tacgtccttg ttaactcttc acaaactttg cacaacaaaa tgtttgagtc aattctgaaa 2580
gctccggtat tattctttga tagaaatcca ataggaagaa ttttaaatcg tttctccaaa 2640
gacattggac acttggatga tttgctgccg ctgacgtttt tagatttcat ccagacattg 2700
ctacaagtgg ttggtgtggt ctctgtggct gtggccgtga ttccttggat cgcaataccc 2760
ttggttcccc ttggaatcat tttcattttt cttcggcgat attttttgga aacgtcaaga 2820
gatgtgaagc gcctggaatc tacaactcgg agtccagtgt tttcccactt gtcatcttct 2880
ctccaggggc tctggaccat ccgggcatac aaagcagaag agaggtgtca ggaactgttt 2940
gatgcacacc aggatttaca ttcagaggct tggttcttgt ttttgacaac gtcccgctgg 3000
ttcgccgtcc gtctggatgc catctgtgcc atgtttgtca tcatcgttgc ctttgggtcc 3060
ctgattctgg caaaaactct ggatgccggg caggttggtt tggcactgtc ctatgccctc 3120
acgctcatgg ggatgtttca gtggtgtgtt cgacaaagtg ctgaagttga gaatatgatg 3180
atctcagtag aaagggtcat tgaatacaca gaccttgaaa aagaagcacc ttgggaatat 3240
cagaaacgcc caccaccagc ctggccccat gaaggagtga taatctttga caatgtgaac 3300
ttcatgtaca gtccaggtgg gcctctggta ctgaagcatc tgacagcact cattaaatca 3360
caagaaaagg ttggcattgt gggaagaacc ggagctggaa aaagttccct catctcagcc 3420
ctttttagat tgtcagaacc cgaaggtaaa atttggattg ataagatctt gacaactgaa 3480
attggacttc acgatttaag gaagaaaatg tcaatcatac ctcaggaacc tgttttgttc 3540
actggaacaa tgaggaaaaa cctggatccc tttaatgagc acacggatga ggaactgtgg 3600
aatgccttac aagaggtaca acttaaagaa accattgaag atcttcctgg taaaatggat 3660
actgaattag cagaatcagg atccaatttt agtgttggac aaagacaact ggtgtgcctt 3720
gccagggcaa ttctcaggaa aaatcagata ttgattattg atgaagcgac ggcaaatgtg 3780
gatccaagaa ctgatgagtt aatacaaaaa aaaatccggg agaaatttgc ccactgcacc 3840
gtgctaacca ttgcacacag attgaacacc attattgaca gcgacaagat aatggtttta 3900
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gattcaggaa gactgaaaga atatgatgag ccgtatgttt tgctgcaaaa taaagagagc 3960
ctattttaca agatggtgca acaactgggc aaggcagaag ccgctgccct cactgaaaca 4020
gcaaaacaga gatggggttt caccatgttg gccaggctgg tctcaaactc ctgacctcaa 4080
gtgatccacc tgccttggcc tcccaaactg ctgagattac aggtgtgagc caccacgccc 4140
agcctgagta tacttcaaaa gaaattatcc acatattggt cacactgacc acatggttac 4200
aaacacttcc aatggacagc cctcgacctt aactattttc gagacagcac tgtgaatcca 4260
accaaaatgt caagtccgtt ccgaaggcat ttgccactag tttttggact atgtaaacca 4320
cattgtactt ttttttactt tggcaacaaa tatttataca tacaagatgc tagttcattt 4380
gaatatttct cccaacttat ccaaggatct ccagctctaa caaaatggtt tatttttatt 4440
taaatgtcaa tagtkgkttt ttaaaatcca aatcagaggt gcaggccacc agttaaatgc 4500
cgtctatcag gttttgtgcc ttaagagact acagnagtca gaagctcatt tttaaaggag 4560
taggacagag ttgtcacagg tttttgttgg tgtttktatt gcccccaaaa ttacatgtta 4620
atttccattt atatcagggg attctattta cttgaagact gtgaagttgc cattttgtct 4680
cattgttttc tttgacatam ctaggatcca ttatttcccc tgaaggcttc ttgkagaaaa 4740
tagtacagtt acaaccaata ggaactamca aaaagaaaaa gtttgtgaca ttgtagtagg 4800
gagtgtgtac cccttactcc ccatcaaaaa aaaaaatgga tacatggtta aaggatagaa 4860
gggcaatatt ttatcatatg ttctaaaaga gaaggaagag aaaatactac tttctcaaaa 4920
tggaagccct taaaggtgct ttgatactga aggacacaaa tgtgaccgtc catcctcctt 4980
tagagttgca tgacttggac acggtaactg ttgcagtttt agactcagca ttgtgacact 5040
tcccaagaag gccaaacctc taaccgacat tcctgaaata cgtggcatta ttcttttttg 5100
gatttctcat ttaggaaggc taaccctctg ttgamtgtam kccttttggt ttgggctgta 5160
ttgaaatcct ttctaaattg catgaatagg ctctgctaac cgtgatgaga caaactgaaa 5220
attattgcaa gcattgacta taattatgca gtacgttctc aggatgcatc caggggttca 5280
ttttcatgag cctgtccagg ttagtttact cctgaccact aatagcattg tcatttgggc 5340
tttctgttga atgaatcaac aaaccacaat acttcctggg accttttgta ctttatttga 5400
actatgagtc tttaattttt cctgatgatg gtggctgtaa tatgttgagt tcagtttact 5460 .
aaaggtttta ctattatggt ttgaagggag tctcatgacc tctcagaaaa ggtgcacctc 5520
cctgaaattg catatatgta tatagacatg cacacgtgtg catttgtttg tatacatata 5580
tttgtccttc gtatagcaag ttttttgctc atcagcagag agcaacagat gttttattga 5640
gtgaagcctt aaaaagcaca caccacacac agctaactgc caaaatacat tgaccgtagt 5700 <
agctgttcaa ctcctagtac ttagaaatac acgtatggtt aatgttcagt ccaacaaacc 5760 ~.
acacacagta aatgtttatt aatagtcatg gttcgtattt taggtgactg aaattgcaac 5820 '
agtgatcata atgaggtttg ttaaaatgat agctatattc aaaatgtcta tatgtttatt 5880 -...
tggacttttg aggttaaaga cagtcatata aacgtcctgt ttctgtttta atgttatcat 5940
agaatttttt aatgaaacta aattcaattg aaataaatga tagttttcat ctccaaaaaa 6000
aaaaaaaaag ggcggcccgc tcgagtctag agggcccggt ttaaacccgc tgatcagcct 6060
cgactgtgcc ttctagttgc cagccatctg ttgtttggcc ctcccccgtg ccttccttga 6120
ccctggaagg ggccactccc 6140
<210> 537
<211> 1228
<212> PRT
<213> Homo sapiens
<400> 537
Met Leu Pro Val Tyr Gln Glu Val Lys Pro Asn Pro Leu Gln Asp Ala
10 15
Asn Leu Cys Ser Arg Val Phe Phe Trp Trp Leu Asn Pro Leu Phe Lys
20 25 30
Ile Gly His Lys Arg Arg Leu Glu Glu Asp Asp Met Tyr Ser Val Leu
35 40 45
Pro Glu Asp Arg Ser Gln His Leu Gly Glu Glu Leu Gln Gly Phe Trp
50 55 60
Asp Lys Glu Val Leu Arg Ala Glu Asn Asp Ala Gln Lys Pro Ser Leu
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65 70 75 80
Thr Arg Ala Ile Ile Lys Cys Tyr Trp Lys Ser Tyr Leu Val Leu Gly
85 90 95
Ile Phe Thr Leu Ile Glu Glu Ser Ala Lys Val Ile Gln Pro Ile Phe
100 105 110
Leu Gly Lys Ile Ile Asn Tyr Phe Glu Asn Tyr Asp Pro Met Asp Ser
115 120 125
Val Ala Leu Asn Thr Ala Tyr Ala Tyr Ala Thr Val Leu Thr Phe Cys
130 135 140
Thr Leu Ile Leu Ala Ile Leu His His Leu Tyr Phe Tyr His Val Gln
145 150 155 160
~Cys Ala Gly Met Arg Leu Arg Val Ala Met Cys His Met Ile Tyr Arg
165 170 175
Lys Ala Leu Arg Leu Ser Asn Met Ala Met Gly Lys Thr Thr Thr Gly
180 185 190
Gln Ile Val Asn Leu Leu Ser Asn Asp Va1 Asn Lys Phe Asp Gln Val
195 200 205
Thr Val Phe Leu His Phe Leu Trp Ala Giy Pro Leu Gln Ala Ile Ala
210 215 220
Val Thr Ala Leu. Leu Trp Met Glu Ile Gly Ile Ser Cys Leu Ala Gly
225 230 235 240
Met Ala Val L,eu Ile Ile Leu Leu Pro Leu Gln Ser Cys Phe Gly Lys
245 250 255
Leu Phe Ser Ser Leu Arg Ser Lys Thr Ala Thr Phe Thr Asp Ala Arg
260 265 270
Ile Arg Thr Met Asn Glu Val Ile Thr Gly Ile Arg Ile Ile Lys Met
275 280 285
Tyr Ala Trp Glu Lys Ser Phe Ser Asn Leu Ile Thr Asn Leu Arg Lys
290 295 300
Lys Glu Ile Ser Lys Ile Leu Arg Ser Ser Cys Leu Arg Gly Met Asn
305 310 315 320
Leu Ala Ser Phe Phe Ser Ala Ser Lys Ile Ile Val Phe Val Thr Phe
325 330 335
Thr Thr Tyr Val Leu Leu Gly Ser Val Ile Thr Ala Ser Arg Val Phe
340 345 350
Val Ala Val Thr Leu Tyr Gly Ala Val Arg Leu Thr Val Thr Leu Phe
355 360 365
Phe Pro Ser Ala Ile Glu Arg Val Ser Glu Ala Ile Val Ser Ile Arg
370 375 380
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Arg Ile Gln Thr Phe Leu Leu Leu Asp Glu Ile Ser Gln Arg Asn Arg
385 390 395 400
Gln Leu Pro Ser Asp Gly Lys Lys Met Val His Val Gln Asp Phe Thr
405 410 415
Ala Phe Trp Asp Lys Ala Ser Glu Thr Pro Thr Leu Gln Gly Leu Ser
420 425 430
Phe Thr Val Arg Pro Gly Glu Leu Leu Ala Val Val Gly Pro Val Gly
435 440 445
Ala Gly Lys Ser Ser Leu Leu Ser Ala Val Leu Gly Glu Leu Ala Pro
450 455 460
Ser His Gly Leu Val Ser Val His Gly Arg Ile Ala Tyr Val Ser Gln
465 470 475 480
Gln Pro Trp Val Phe Ser Gly Thr Leu Arg Ser Asn Ile Leu Phe Gly
485 490 495
Lys Lys Tyr Glu Lys Glu Arg Tyr Gl.u L~ys Val Ile Lys Ala Cys Ala
500 505 510
Leu Lys Lys Asp Leu Gln Leu Leu Glu Asp Gly Asp Leu Thr Val Ile
515 520 525
Gly Asp Arg Gly Thr Thr Leu Ser Gly Gly Gln Lys Ala Arg Val Asn
530 535 540
Leu Ala Arg Ala Val Tyr Gln Asp Ala Asp Ile Tyr Leu Leu Asp Asp
545 550 555 560
Pro Leu Ser Ala Val Asp Ala Glu Val Ser Arg His Leu Phe Glu Leu
565 570 575
Cys Ile Cys Gln Ile Leu His Glu Lys Ile Thr Ile Leu Val Thr His
580 585 590
Gln Leu Gln Tyr Leu Lys Ala Ala Ser Gln Ile Leu Ile Leu Lys Asp
595 600 605
Gly Lys Met Val Gln Lys Gly Thr Tyr Thr Glu Phe Leu Lys Ser Gly
610 615 620
Ile Asp Phe Gly Ser Leu Leu Lys Lys Asp Asn Glu Glu Ser Glu Gln
625 630 635 640
Pro Pro Val Pro Gly Thr Pro Thr Leu Arg Asn Arg Thr Phe Ser Glu
645 650 655
Ser Ser Val Trp Ser Gln Gln Ser Ser Arg Pro Ser Leu Lys Asp Gly
660 665 670
Ala Leu Glu Ser Gln Asp Thr Glu Asn Val Pro Val Thr Leu Ser Glu
675 680 685
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Glu Asn Arg Ser Glu Gly Lys Val Gly Phe Gln Ala Tyr Lys Asn Tyr
690 695 700
Phe Arg Ala Gly Ala His Trp Ile Val Phe Ile Phe Leu Ile Leu Leu
705 710 715 720
Asn Thr Ala Ala Gln Val Ala Tyr Val Leu Gln Asp Trp Trp Leu Ser
725 730 735
Tyr Trp Ala Asn Lys Gln Ser Met Leu Asn Val Thr Val Asn Gly Gly
740 745 750
Gly Asn Val Thr Glu Lys Leu Asp Leu Asn Trp Tyr Leu Gly Ile Tyr
755 760 765
Ser Gly Leu Thr Val Ala Thr Val Leu Phe Gly Ile Ala Arg Ser Leu
770 775 780
Leu Val Phe Tyr Val Leu Val Asn Ser Ser Gln Thr Leu His Asn Lys
785 790 795 800
Met Phe Glu Ser Ile Leu Lys Ala Pro Val Leu Phe Phe Asp Arg Asn
805 810 815
Pro Ile Gly Arg Ile Leu Asn Arg Phe Ser Lys Asp Ile Gly His Leu
820 825 830
Asp Asp Leu Leu Pro Leu Thr Phe Leu Asp Phe Ile Gln Thr .Leu Leu
835 840 845
Gln Val Val Gly Val Val Ser Val Ala Val Ala Val Ile Pro Trp Ile
$5C 855 860
Ala Ile Pro Leu Val Pro Leu Gly Ile Iie Phe Ile Phe Leu Arg Arg
865 870 875 880
Tyr Phe Leu Glu Thr Ser Arg Asp Val Lys Arg Leu Glu Ser Thr Thr
885 890 895
Arg Ser Pro Val Phe Ser His Leu Ser Ser Ser Leu Gln Gly Leu Trp
900 905 910
Thr Ile Arg Ala Tyr Lys Ala Glu Glu Arg Cys Gln Glu Leu Phe Asp
915 920 925
Ala His Gln Asp Leu His Ser Glu Ala Trp Phe Leu Phe Leu Thr Thr
930 935 940
Ser Arg Trp Phe Ala Val Arg Leu Asp Ala Ile Cys Ala Met Phe Val
945 950 955 960
Ile Ile Val Ala Phe Gly Ser Leu Ile Leu Ala Lys Thr Leu Asp Ala
965 970 975
Gly Gln Val Gly Leu Ala Leu Ser Tyr Ala Leu Thr Leu Met Gly Met
980 985 990
Phe Gln Trp Cys Val Arg Gln Ser Ala Glu Val Glu Asn Met Met Ile
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995 1000 1005
Ser Val Glu Arg Val Ile Glu Tyr Thr Asp Leu Glu Lys Glu Ala Pro
1010 1015 1020
Trp Glu Tyr Gln Lys Arg Pro Pro Pro Ala Trp Pro His Glu Gly Val
1025 1030 1035 1040
Ile Ile Phe Asp Asn Val Asn Phe Met Tyr Ser Pro Gly Gly Pro Leu
1045 1050 1055
Val Leu Lys His Leu Thr Ala Leu Ile Lys Ser Gln Glu Lys Val Gly
1060 1065 1070
Ile Val Gly Arg Thr Gly Ala Gly Lys Ser Ser Leu Ile Ser Ala Leu
1075 1080 1085
Phe Arg Leu Ser Glu Pro Glu Gly Lys Ile Trp Ile Asp Lys Ile Leu
1090 1095 1100
Thr Thr Glu Ile Gly Leu His Asp Leu Arg Lys Lys Met Ser Ile Ile
1105 1110 1115 1120
Pro Gln Glu Pro Val Leu Phe Thr Gly Thr Met Arg Lys Asn Leu Asp
1125 1130 1135
Pro Phe Asn Glu His Thr Asp Glu Glu Leu Trp Asn Ala Leu Gln Glu
1140 1145 1150
Val Gln Leu Lys Glu Thr Ile Glu Asp Leu Pro Gly Lys Met Asp Thr
1155 1160 1165
Glu Leu Ala Glu Ser Gly Ser Asn Phe Ser Val Gly Gln Arg Gln Leu
1170 1175 11.80
Val Cys Leu Ala Arg Ala Ile Leu Arg Lys Asn Gln Ile Leu Ile Ile
1185 1190 1195 1200
Asp Glu Ala Thr Ala Asn Val Asp Pro Arg Thr Asp Glu Leu Ile Gln
1205 1210 1215
Lys Lys Ser Gly Arg Asn Leu Pro Thr Ala Pro Cys
1220 1225
<210> 538
<211> 1261
<212> PRT
<213> Homo Sapiens
<400> 538
Met Tyr Ser Val Leu Pro Glu Asp Arg Ser Gln His Leu Gly Glu Glu
10 15
Leu Gln Gly Phe Trp Asp Lys Glu Val Leu Arg Ala Glu Asn Asp Ala
20 25 30
Gln Lys Pro Ser Leu Thr Arg Ala Ile Ile Lys Cys Tyr Trp Lys Ser
35 40 45
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Tyr Leu Val Leu Gly Ile Phe Thr Leu Ile Glu Glu Ser Ala Lys Val
50 55 60
Ile Gln Pro Ile Phe Leu Gly Lys Ile Ile Asn Tyr Phe Glu Asn Tyr
65 70 75 80
Asp Pro Met Asp Ser Val Ala Leu Asn Thr Ala Tyr Ala Tyr Ala Thr
85 90 95
Val Leu Thr Phe Cys Thr Leu Ile Leu Ala Ile Leu His His Leu Tyr
100 105 110
Phe Tyr His Val Gln Cys Ala Gly Met Arg Leu Arg Val Ala Met Cys
115 120 125
His Met Ile Tyr Arg Lys Ala Leu Arg Leu Ser Asn Met Ala Met Gly
130 135 140
Lys Thr Thr Thr Gly Gln Ile Val Asn Leu Leu Ser Asn Asp Val Asn
145 150 155 160
Lys Phe Asp Gln Val Thr Val Phe Leu His Phe Leu Trp Ala Gly Pro
165 170 175
Leu Gln Ala Ile Ala Val Thr Ala Leu Leu Trp Met Glu Ile Gl.y Ile
180 185 190
Ser Cys Leu Ala Gly Met Ala Val Leu Ile Ile Leu Leu Pro Leu Gln
195 200 205
Ser Cys Phe Gly Lys Leu Phe Ser Ser Leu Arg Ser Lys Thr Ala Thr
210 215 220
Phe Thr Asp Ala Arg Ile Arg Thr Met Asn Glu Val Ile Thr Gly Ile
225 230 235 240
Arg Ile Ile Lys Met Tyr Ala Trp Glu Lys Ser Phe Ser Asn Leu Ile
245 250 255
Thr Asn Leu Arg Lys Lys Glu Ile Ser Lys Ile Leu Arg Ser Ser Cys
260 265 270
Leu Arg Gly Met Asn Leu Ala Ser Phe Phe Ser Ala Ser Lys Ile Ile
275 280 285
Val Phe Val Thr Phe Thr Thr Tyr Val Leu Leu Gly Ser Val Ile Thr
290 295 300
Ala Ser Arg Val Phe Val Ala Val Thr Leu Tyr Gly Ala Val Arg Leu
305 310 315 320
Thr Val Thr Leu Phe Phe Pro Ser Ala Ile Glu Arg Val Ser Glu Ala
325 330 335
Ile Val Ser Ile Arg Arg Ile Gln Thr Phe Leu Leu Leu Asp Glu Ile
340 345 350
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Ser Gln Arg Asn Arg Gln Leu Pro Ser Asp Gly Lys Lys Met Val His
355 360 365
Val Gln Asp Phe Thr Ala Phe Trp Asp Lys Ala Ser Glu Thr Pro Thr
370 375 380
Leu Gln Gly Leu Ser Phe Thr Val Arg Pro Gly Glu Leu Leu Ala Val
385 390 395 400
Val Gly Pro Val Gly Ala Gly Lys Ser Ser Leu Leu Ser Ala Val Leu
405 410 415
Gly Glu Leu Ala Pro Ser His Gly Leu Val Ser Val His Gly Arg Ile
420 425 430
Ala Tyr Val Ser Gln Gln Pro Trp Val Phe Ser Gly Thr Leu Arg Ser
435 440 445
Asn Ile Leu Phe Gly Lys Lys Tyr Glu Lys Glu Arg Tyr Glu Lys Val
450 455 460
Ile Lys Ala Cys Ala Leu Lys Lys Asp Leu Gln Leu Leu Glu Asp Gly
465 470 475 480
Asp Leu Thr Val Ile Gly Asp Arg Gly Thr Thr Leu Ser Gly Gly Gln
485 490 495
Lys Ala Arg Val Asn Leu Ala Arg Ala Val Tyr Gln Asp Ala Asp Ile
500 505 510
Tyr Leu Leu Asp Asp Pro Leu Ser Ala Val Asp Ala Glu Val Ser Arg
515 520 525
His heu Phe Glu Leu Cys Ile Cys Gln Ile Leu His Glu Lys Ile Thr
530 535 540
Ile Leu Val Thr His Gln Leu Gln Tyr Leu Lys Ala Ala Ser Gln Ile
545 550 555 560
Leu Ile Leu Lys Asp Gly Lys Met Val Gln Lys Gly Thr Tyr Thr Glu
565 570 575
Phe Leu Lys Ser Gly Ile Asp Phe Gly Ser Leu Leu Lys Lys Asp Asn
580 585 590
Glu Glu Ser Glu Gln Pro Pro Val Pro Gly Thr Pro Thr Leu Arg Asn
595 600 605
Arg Thr Phe Ser Glu Ser Ser Val Trp Ser Gln Gln Ser Ser Arg Pro
610 615 620
Ser Leu Lys Asp Gly Ala Leu Glu Ser Gln Asp Thr Glu Asn Val Pro
625 630 635 640
Val Thr Leu Ser Glu Glu Asn Arg Ser Glu Gly Lys Val Gly Phe Gln
645 650 655
Ala Tyr Lys Asn Tyr Phe Arg Ala Gly Ala His Trp Ile Val Phe Ile
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660 665 670
Phe Leu Ile Leu Leu Asn Thr Ala Ala Gln Val Ala Tyr Val Leu Gln
675 680 685
Asp Trp Trp Leu Ser Tyr Trp Ala Asn Lys Gln Ser Met Leu Asn Val
690 695 700
Thr Val Asn Gly Gly Gly Asn Val Thr Glu Lys Leu Asp Leu Asn Trp
705 710 715 720
Tyr Leu Gly Ile Tyr Ser Gly Leu Thr Val Ala Thr Val Leu Phe Gly
725 730 735
Ile Ala Arg Ser Leu Leu Val Phe Tyr Val Leu Val Asn Ser Ser Gln
740 745 750
Thr Leu His Asn Lys Met Phe Glu Ser Ile Leu Lys Ala Pro Val Leu
755 760 765
Phe Phe Asp Arg Asn Pro Ile Gly Arg Ile Leu Asn Arg Phe Ser Lys
770 775 780
Asp Ile Gly His Leu Asp Asp Leu Leu Pro Leu Thr Phe Leu Asp Phe
785 790 795 800
Ile Gln Thr Leu Leu Gln Val Val Gly Val Val Ser Val Ala Val Ala
805 810 815
Val Ile Pro Trp Ile Ala Ile Pro Leu Val Pro Leu Gly Ile Ile Phe
820 825 830
Ile Phe Leu Arg Arg Tyr Phe Leu Glu Thr Ser Arg Asp Val Lys Arg
835 840 845
Leu Glu Ser Thr Thr Arg Ser Pro Val Phe Ser His Leu Ser Ser Ser
850 855 860
Leu Gln Gly Leu Trp Thr Ile Arg Ala Tyr Lys Ala Glu Glu Arg Cys
865 870 875 880
Gln Glu Leu Phe Asp Ala His Gln Asp Leu His Ser Glu Ala Trp Phe
885 890 895
Leu Phe Leu Thr Thr Ser Arg Trp Phe Ala Val Arg Leu Asp Ala Ile
900 905 910
Cys Ala Met Phe Val Ile Ile Val Ala Phe Gly Ser Leu Ile Leu Ala
915 920 925
Lys Thr Leu Asp Ala Gly Gln Val Gly Leu Ala Leu Ser Tyr Ala Leu
930 935 940
Thr Leu Met Gly Met Phe Gln Trp Cys Val Arg Gln Ser Ala Glu Val
945 950 955 960
Glu Asn Met Met Ile Ser Val Glu Arg Val Ile Glu Tyr Thr Asp Leu
965 970 975
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Glu Lys Glu Ala Pro Trp Glu Tyr Gln Lys Arg Pro Pro Pro Ala Trp
980 985 990
Pro His Glu Gly Val Ile Ile Phe Asp Asn Val Asn Phe Met Tyr Ser
995 1000 1005
Pro Gly Gly Pro Leu Val Leu Lys His Leu Thr Ala Leu Ile Lys Ser
1010 1015 1020
Gln Glu Lys Val Gly Ile Val Gly Arg Thr Gly Ala Gly Lys Ser Ser
1025 1030 1035 1040
Leu Ile Ser Ala Leu Phe Arg Leu Ser Glu Pro Glu Gly Lys Ile Trp
1045 1050 1055
Ile Asp Lys Ile Leu Thr Thr Glu Ile Gly Leu His Asp Leu Arg Lys
1060 1065 1070
Lys Met Ser Ile Ile Pro Gln Glu Pro Val Leu Phe Thr Gly Thr Met
1075 1080 1085
Arg Lys Asn Leu Asp Pro Phe Asn Glu His Thr Asp Glu Glu Leu Trp
1090 1095 1100
Asn Ala Leu Gln Glu Val Gln Leu Lys Glu Thr Ile Glu Asp Leu Pro _
1105 1110 1115 1120
Gly Lys Met Asp Thr Glu Leu Ala Glu Ser Gly Ser Asn Phe Ser Val
1125 1130 1135
Gly Gln Arg Gln Leu Val Cys Leu Ala Arg Ala Ile Leu Arg hys Asn
1140 1145 1150
Gln Ile Leu Ile Ile Asp Glu Ala Thr Ala Asn Val Asp Pro Arg Thr
1155 1160 1165
Asp Glu Leu Ile Gln Lys Lys Ile Arg Glu Lys Phe Ala His Cys Thr
1170 1175 1180
Val Leu Thr Ile Ala His Arg Leu Asn Thr Ile Ile Asp Ser Asp Lys
1185 1190 1195 1200
Ile Met Val Leu Asp Ser Gly Arg Leu Lys Glu Tyr Asp Glu Pro Tyr
1205 1210 1215
Val Leu Leu Gln Asn Lys Glu Ser Leu Phe Tyr Lys Met Val Gln Gln
1220 1225 1230
Leu Gly Lys Ala Glu Ala Ala Ala Leu Thr Glu Thr Ala Lys Gln Arg
1235 1240 1245
Trp Gly Phe Thr Met Leu Ala Arg Leu Val Ser Asn Ser
1250 1255 1260
<210> 539
<211> 10
<212> PRT
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<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 539
Cys Leu Ser His Ser Val Ala Val Val Thr
1 5 10
<210> 540
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 540
Ala Val Val Thr Ala Ser Ala Ala Leu
1 5
<210> 541
<211> 14
<212> PRT
<213> Homo sapiens
<400> 541
Leu Ala Gly Leu Leu Cys Pro Asp Pro Arg Pro Leu Glu Leu
10
<210> 542
<211> 15
<212> PRT
<213> Homo sapiens
<400> 542
Thr Gln Val Val Phe Asp Lys Ser Asp Leu Ala Lys Tyr Ser Ala
5 10 15
<210> 543
<211> 12
<212> PRT
<213> Homo sapiens
<400> 543
Phe Met Gly Ser Ile Val Gln Leu Ser Gln Ser Val
5 10
<210> 544
<211> 18
<212> PRT
<213> Homo sapiens
<400> 544
Thr Tyr Val Pro Pro Leu Leu Leu Glu Val Gly Val Glu Glu Lys Phe
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10 15
Met Thr
<210> 545
<211> 18
<212> PRT
<213> Homo Sapiens
<400> 545
Met Asp Arg Leu Val Gln Arg Phe Gly Thr Arg Ala Val Tyr Leu Ala
5 10 15
Ser Val
<210> 546
<211> 29
<212> PRT
<213> Homo Sapiens
<400> 546
Phe Val Gly Glu Gly Leu Tyr Gln Gly Val Pro Arg Ala Glu Pro Gly
5 10 15
Thr Glu Ala Arg Arg His Tyr Asp Glu Gly Val Arg Met
20 25
<210> 547
<211> 58
<212> PRT
<213> Homo Sapiens
<400> 547
Val Ala Glu Glu Ala Ala Leu Gly Pro Thr Glu Pro Ala Glu Gly Leu
5 10 15
Ser Ala Pro Ser Leu Ser Pro His Cys Cys Pro Cys Arg Ala Arg Leu
20 25 30
Ala Phe Arg Asn Leu Gly Ala Leu Leu Pro Arg Leu His Gln Leu Cys
35 40 45
Cys Arg Met Pro Arg Thr Leu Arg Arg Leu
50 55
<210> 548
<211> 18
<212> PRT
<213> Homo Sapiens
<400> 548
Ile Asp Trp Asp Thr Ser Ala Leu Ala Pro Tyr Leu Gly Thr Gln Glu
CA 02391369 2002-05-10
WO 01/34802 PCT/US00/30904
200
10 15
Glu Cys
<210> 549
<211> 18
<212> PRT
<213> Homo sapiens
<400> 549
Leu Glu Ala Leu Leu Ser Asp Leu Phe Arg Asp Pro Asp His Cys Arg
5 10 15
Gln Ala
<210> 550
<211> 14
<212> PRT
<213> Homo sapiens
<400> 550
Ser Asp His Trp Arg Gly Arg Tyr Gly Arg Arg Arg Pro Phe
5 10
<210> 551
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in a lab
<400> 551
Phe Asp Lys Ser Asp Leu Ala Lys Tyr Ser Ala
1 5 10
