1 Supplemental Figure 1. Mutational analysis of FL Igs. Variable region sequences from the expressed Ig of tumors from 467 FL patients were cloned and analyzed. (A) The number of mutations compared to closest match germline sequence for the heavy and light chain V genes. (B) The frequency of mutations in the heavy and light chain V genes calculated from the number of replacement (R; black bar) and silent (S; white bar) nucleotides exchanges per base pair in framework regions (FWR1, FWR2, and FWR3) and complementarity determining regions (CDR1 and CDR2). The R/S ratio for each region is indicated. Supplemental Figure 2. LC-MS/MS identification of the 236kD protein immunoprecipitated by tumor Ig 1152. 236 kDA protein band peptide sequences matching myoferlin are shown in bold and are underlined. Supplemental Figure 3. Nucleotide sequence alignment of molecular clones of IgH variable region from the follicular lymphoma tumor of patient 1152. Unique nucleotide sequences and number of times they were observed are indicated by alphabetic and numeric characters, respectively. Grey-shaded nucleotides indicate nucleotides present in the dominant clone, whereas mutations are specified in white. Silent and replacement mutations are represented by circles and squares, respectively. Framework regions (FWR1, FWR2, FWR3, and FWR4) and complementarity determining regions (CDR1, CDR2, and CDR3) are indicated.
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Supplemental Figure 1. Mutational analysis of FL Igs ... · Framework regions (FWR1, FWR2, FWR3, and FWR4) and complementarity determining regions (CDR1, CDR2, and CDR3) are indicated.
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Supplemental Figure 1. Mutational analysis of FL Igs. Variable region sequences
from the expressed Ig of tumors from 467 FL patients were cloned and analyzed. (A) The
number of mutations compared to closest match germline sequence for the heavy and
light chain V genes. (B) The frequency of mutations in the heavy and light chain V genes
calculated from the number of replacement (R; black bar) and silent (S; white bar)
nucleotides exchanges per base pair in framework regions (FWR1, FWR2, and FWR3)
and complementarity determining regions (CDR1 and CDR2). The R/S ratio for each
region is indicated.
Supplemental Figure 2. LC-MS/MS identification of the 236kD protein
immunoprecipitated by tumor Ig 1152. 236 kDA protein band peptide sequences
matching myoferlin are shown in bold and are underlined.
Supplemental Figure 3. Nucleotide sequence alignment of molecular clones of IgH
variable region from the follicular lymphoma tumor of patient 1152. Unique
nucleotide sequences and number of times they were observed are indicated by alphabetic
and numeric characters, respectively. Grey-shaded nucleotides indicate nucleotides
present in the dominant clone, whereas mutations are specified in white. Silent and
replacement mutations are represented by circles and squares, respectively. Framework
regions (FWR1, FWR2, FWR3, and FWR4) and complementarity determining regions
(CDR1, CDR2, and CDR3) are indicated.
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Supplemental Figure 4. Nucleotide sequences of IgΗ and Igλ of variable regions
from subclones derived from tumor 1152. Grey-shaded nucleotides indicate the
consensus sequence of the (A) IgΗ and (B, C) Igλ variable regions. Framework regions
(FWR1, FWR2, FWR3, and FWR4) and complementarity determining regions (CDR1,
CDR2, and CDR3) are indicated. (D) Graphical summary of mutations in both IgH and
Igλ differentiating the tumor subclones. 2E12, 6C12, 4B11, 1G2, and 1E9 were obtained
through rescue fusion of cells from the tumor biopsy of patient 1152; 1152 corresponds to
the recombinant tumor Ig from patient 1152. HN represents the hypothetical mature naïve
pre-malignant clone, based on the closest matched variable region germline genes. λRE
represents a predicted precursor that has undergone receptor editing of the light chain.
Number of mutations is indicated adjacent to connecting lines with number of
replacement mutations specified in parentheses. In bold are the locations of specific
replacement mutations; amino acid changes are indicated in parentheses.
Supplemental Figure 5. Igs from non-tumor B cells of patient 1152 exhibit different
HEP-2 staining and do not bind myoferlin. Two clones not originating from the tumor
were recovered in the rescue fusion of the tumor biopsy of patient 1152. (A) HEp-2 IFA
staining pattern of non-tumor Igs. Bars, 25µm. (B) Immunoblot for myoferlin
immunoprecipitations from lysate of 293T cells transfected with recombinant myoferlin-
HA construct by non-tumor Igs (NT1 and NT2) and Ig from tumor clone 6C12.
Supplemental Figure 6. Phenotypic Analysis of patient 1152 tumor biopsy. A single
cell suspension of the tumor biopsy of patient 1152 was analyzed by flow cytometry to
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characterize the tumor cell phenotype. FSC-A vs SSC-A was used to gate on singlets
followed by a live cell gate based on SSC-A vs FSC-A. CD3-CD20+ B cells were then
gated on and used in the analysis of tumor cell phenotype. In the two right-most columns,
plots are gated on CD3-CD20+ cells and the CD20 axis has been cropped and enlarged to
highlight differences between the CD20hi and CD20int populations. Tumor cells are IgGλ
and predominantly reside in the CD20hi population.
10 20 30 40 50 60 70C A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A G C C G C A C A G A C C C T C A C A C T G A C G T G C A C T T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T C A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G A T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A G C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C T
80 90 100 110 120 130 140 150G G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G A T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G A T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G A T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T T
160 170 180 190 200 210 220G G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G T C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C A A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C C
230 240 250 260 270 280 290 300G C C A A A A A T C A G G T A G T C C T C A C A A T A A C G A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G A A T AG C C A A A A A T C A G G T A G T C C T C A C A A T A A C G A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G A A T AG C C A A A A A T C A G G T A G T C C T C A C A A T A A C G A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A T T G T G C C C G A A T AG C C A A A A A T C A A G T A G T C C T C A C A A T A A C G A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G A A T AG C C A A A A A T C A G G T A G T C C T C A C A A T A A C G A A T A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G A G T AG C C A A A A A T C A G G T A G T C C T C A C A A T A A C G A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G A A T AG C C A A A A A T C A G G T A G T C C T C A C A A T A A C G A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G A A T AG C C A A A A A T C A A G T A G T C C T C A C A A T A A C G A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G C A T AG C C A A A A A T C A G G T A G T C C T C A C A A T A A C G A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G A A T AG T C A A A A A T C A G G T A G T C C T C A C A A T A A C G A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G A A T AG C C A A A A A T C A G G T A G T C C T C A C A A T A A C G A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G A A T AG C C A A A A A T C A G G T A G T C C T C A C A G T A A C G A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G A A T AG C C A A A A A T C A G G T A G T C C T C A C A A T A A C G A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G A G T AG C C A A A A A T C A G G T A G T C C T C A C A A T A A C G A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G A G T AG C C A A A A A T C A G G T A G T C C T C A C A A T A A C G A A C A T G G A G C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G T A T AG C C A A A A A T C A G G T A G T C C T C A C A A A A A C G A A T A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G A A T AG C C A A A A A T C A G G T A G T C C T C A C A C T A A C G A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G A A T AG C C A A A A A T C A G G T A G T C C T C A C A A T G A C G A A C G T G G A C C C T G T G G A C A C A G G C A C A T A T T A C T G T G C C C G A A T AG C C A A A A A T C A G A T A G T C C T C A C A A T A A C G G A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G T C C G A A T A
310 320 330 340 350 360G C G G T G A C C T T T G C G G G A C T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C T T T T G C G G G A G T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C T T T T G C G G G A G T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C C T T T G C G G G A C T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C T T T T G C G G G A A T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C C T T T G C G G G A G T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C C T T T G C G G G A C T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C C T T T G C G G G A G T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C T T T T G C G G G A G T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C C T T T G C G G G A C T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C T T T T G C G G G A G T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C C T T T G C G G G A C T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C T T T T G C G G G A G T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C T T T T G C G G G A G T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C T T T T G C G G G A G T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C C T T T G C G G G A C T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C T T T T G C G G G A G T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C T T T T G C G G G A G T T A C C A C A G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C C T T T G C G G G A G T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C A
10 20 30 40 50 60 70C A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T G A A A C C C A C A C A G A C C C T C A C A C T G A C C T G C A C C T T C T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A G C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C T G G T A A A A C C C G C A C A G A C C C T C A C A C T G A C G T G C A C C T T T T C TC A G G T C A C C T T G A G G G A G T C T G G T C C T G C G C A G G T G A A T C C C A C A C A G A C C C T C A C A C T G A C C T G C A C C T T C T C T
80 90 100 110 120 130 140 150G G G T T C T C A C T C A G C A C T A G T G G A A T G T G T G T G A G C T G G A T C C G T C A G C C C C C A G G G A A G G C C C T G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G G T T T T C A C T C T C C A C T C G T G G A A T G T G T G T C T C C T G G A T C C G T C A G T C C C C A G G G A A G G C C C C G G A G T G G C T TG G C T T C T C A C T C A C A A C T A A G G G A A T G T G T G T A A T T T G G A T C C G T C A G C C C C C A G G G A G G G C C C T G G A G T G G C T T
160 170 180 190 200 210 220G C A C T C A T T G A T T G G G A T G A T G A T A A A T A C T A C A G C A C A T C T C T G A A G A C C A G G C T C A C C A T C T C C A A G G A C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG G A C G C A T T G A C T G G G A T G A T G A T A A A T T C T A T A G T G C C T C T C T G A A G A G G A G A C T C A C C A T C T C C A A G G G C A C CG C G C G C A T T G A T T G G G A T G A T G A G A A G T A C T A T A G A A C A T C T C T G A A G A C C A G A C T C A C C A T C T C C A A G G A C A A C
230 240 250 260 270 280 290 300T C C A A A A A C C A G G T G G T C C T T A C A A T G A C C A A C A T G G A C C C T G T G G A C A C A G C C A C G T A T T A C T G T G C A C G G A T AG C C A A A A A T C A G G T A G T C C T C A C A A T A A C G A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G A A T AG C C A A A A A T C A G G T A G T C C T C A C A A T A A C G A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G A A T AG C C A A A A A T C A G G T A G T C C T C A C A A T A A C G A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G A A T AG C C A A A A A T C A G G T A G T C C T C A C A A T A A C G A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G T G C C C G A A T AG C C A A A A A T C A G G T A G T C C T C A C A A T A A C G A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T T C T G T G C C C G A A T AT C C A G A A A G C A A G T G G T C C T T A C A G T G G C C A A C A T G G A C C C T G T G G A C A C A G C C A C A T A T T A C T G C G C A C G A C T A
310 320 330 340 350 360 370G C G G T G A C G T T T G G G G G A G T T A C C A C C G T C G A C T A C T G G G G C C A G G G A A C C C T G G T C A C C G T C T C C T C AG C G G T G A C C T T T G C G G G A G T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C T T T T G C G G G A G T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C C T T T G C G G G A C T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C C T T T G C G G G A C T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AG C G G T G A C C T T T G C G G G A C T T A C C A C C G T C G A C T T T T G G G G C C A G G G A G C C C T G G T C A C C G T C T C C T C AA G G G T T T C A T T T G C G G G A G A T C C C G T C G T C G A T T A T T G G G G C C C G G G A A C C C T G G T C A C C G T C T C C T C A
10 20 30 40 50 60 70C A G A C T G T G G T G A C C C A G G A G C C A T C G T T C T C A G T G T C C C C T G G A G G G A C A G T C A C A C T C A C T T G T G G C T T G A G CC A G A C T G T G G T G A C C C A G G A A C C A T C G G T C T C A G T G T C C C C T G G A G G G A C A G T C A C A G T C A C T T G T G G C T T G A C GC A G A C T G T G G T G A C C C A G G A A C C A T C G G T G T C A G T G T C C C C T G G A G G G A C A G T C A C A G T C A C T T G T G G C T T G A C GC A G A C T G T G G T G A C C C A G G A A C C A T C G G T C T C A G T G T C C C C T G G A G G G A C A G T C A C A G T C A C T T G T G G C T T G A C GC A G A C T G T G G T G A C C C A G G A A C C A T C G G T C T C A G T G T C C C C T G G A G G G A C A G T C A C A G T C A C T T G T G G C T T G A C GC A G A C T G T G G T G A C C C A G G A A C C T T C G G T C T C A G T G T C C C C T G G A G G G A C A G T C A C A G T C A C T T G T G G C T T G A C G
80 90 100 110 120 130 140 150T C T G G C T C A G T C T C T A C T A G T T A C T A C C C C A G C T G G T A C C A G C A G A C C C C A G G C C A G G C T C C A C G C A C G C T C A T CT C G G G C T C A G T C T C T A C T T C T A A T T A T C C C A G T T G G T A C C A A C A G A C C C C A G G C C A G G C T C C A C G C A C T C T C A T TT C G G G C T C A G T C T C T A C T T C T A A T T A T C C C A G T T G G T A C C A A C A G A C C C C A G G C C A G G C T C C A C A C A C T C T C A T TT C G G G C T C A G T C T C T A C T T C T A A T T A T C C C A G T T G G T A C C A A C A G A C C C C A G G C C A G G C T C C A C G C A C T C T C A T TT C G G G C T C A G T C T C T A C T T C T A A T T A T C C C A G T T G G T A C C A A C A G A C C C C A G G C C A G G C T C C A C G C A C T C T C A T TT C G G G C T C A G T C T C T A C T T C T A A T T A T C C C A G T T G G T A C C A G C A G A C C C C A G G C C A G G C T C C A C G C A C T C T C A T T
160 170 180 190 200 210 220T A C A G C A C A A A C A C T C G C T C T T C T G G G G T C C C T G A T C G C T T C T C T G G C T C C A T C C T T G G G A A C A A A G C T G C C C T CT T C A A C A C T A A C A C T C G C T C T T C T G G G G T C C C T G A T C G C T T C T C T G G C T C C A T C C T T G G G A C C A A A G C T G C C C T TT T C A A C A C T A A C A C T C G C T C T T C T G G G G T C C C T G A T C G C T T C T C T G G C T C C A T C C T T G G G A C C A A A G C T G C C C T CT T C A A C A C T A A C A C T C G C T C T T C T G G G G T C C C T G A T C G C T T C T C T G G C T C C A T C C T T G G G A C C A A A G C T G C C C T TT T C A A C A C T A A C A C T C G C T C T T C T G G G G T C C C T G A T C G C T T C T C T G G C T C C A T C C T T G G G A C C A A A G C T G C C C T TT T C A A C A C T A A C A C T C G C T C T T C T G G G G T C C C T G A T C G C T T C T C T G G C T C C A T C C T T G G G A C C A A A G C T G C C C T T
230 240 250 260 270 280 290 300A C C A T C A C G G G G G C C C A G G C A G A T G A T G A A T C T G A T T A T T A C T G T G T G C T G T A T A T G G G T A G T G G C A T T T C T G T GA C C A T C A C G G G G G C C C A G G C A G A A G A T G A A T C C G A A T A T T A T T G T T T A T T G T A T A T G G G C A G T G G C A C T T C T G T GA C C A T C A C G G G G G C C C A G G C A G A A G A T G A A T C C G A A T A T T A T T G T T T A T T G T A T A T G G G C A G T G G C A C T T C T G T GA C C A T C A C G G G G G C C C A G G C A G A A G A T G A A T C C G A A T A T T A T T G T T T A T T G T A T A T G G G C A G T G G C A C T T C T G T GA C C A T C A C G G G G G C C C A G G C A G A A G A T G A A T C C G A A T A T T A T T G T T T A T T G T A T A T G G G C A G T G G C A C T T C T G T GA C C A T C A C G G G G G C C C A G G C A G A A G A T G A A T C C G A A T A T T A T T G T T T A T T G T A T A T G G G C A G T G G C A C T T C T G T G
310 320 330T T C G G A G G A G G C A C C C A G C T G A C C G T C C T CT T C G G A G G A G G C A C C C A G T T G A C C G T C C T AT T C G G A G G A G G C A C C C A C T T G A C C G T C C T CT T C G G A G G A G G C A C C C A G T T G A C C G T C C T CT T C G G A G G A G G C A C C C A G T T G A C C G T C C T CT T C G G A G G A G G C A C C C A G T T G A C C G T C C T C
GermlineClone 2E12
10 20 30 40 50 60 70C A G C C T G T G C T G A C T C A G C C A C C T T C T G C A T C A G C C T C C C T G G G A G C C T C G G T C A C A C T C A C C T G C A C C C T G A G CC A G C C T A T A T T G A G T C A G T C A C C T T C T A C A T C A G C T T C C C T G G G A G C C T C G G T C A C A C T C A C C T G C A C C C T G A A C
GermlineClone 2E12
80 90 100 110 120 130 140 150A G C G G C T A C A G T A A T T A T A A A G T G G A C T G G T A C C A G C A G A G A C C A G G G A A G G G C C C C C G A T T T G T G A T G C G A G T GA A C G A C T A C A G T A A T T A C A A A G T G G A C T G G T A T C A A C A G A G A C C A G G A A A G G G C C C C C G A T T T G T G A T G C G G G T G
GermlineClone 2E12
160 170 180 190 200 210 220G G C A C T G G T G G G A T T G T G G G A T C C A A G G G G G A T G G C A T C C C T G A T C G C T T C T C A G T C T T G G G C T C A G G C C T G A A TG A C A C T G G C G G A A T T G T G G G G T C G A A G G G G G A C G A C A T C C C T G A T C G C T T C T C A G T C T T G G G C T C A G G C C T G A A T
GermlineClone 2E12
230 240 250 260 270 280 290 300C G G T A C C T G A C C A T C A A G A A C A T C C A G G A A G A G G A T G A G A G T G A C T A C C A C T G T G G G G C A G A C C A T G G C A G T G G GC G T T C C C T G A C T A T C A A A A A C A T C C A A G A A G C A G A T G A G G C T G A C T A T G T T T G T G G G A C A T G T C T T G G C A G T G G G
GermlineClone 2E12
310 320 330 340A G C A A C T T C G T T G T G G T A T T C G G C G G A G G G A C C A A G C T G A C C G T C C TA G C A A C T T C G T T G T G A T T T T C G G C G G A G G G A C C A G G T T G A C C G T C C T