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*
Department of Pediatrics, Division of Basic Sciences, and
Division of Biostatistics, National Jewish Medical and Research Center, Denver, CO 80206; and
Department of Immunology, University of Colorado Health Sciences Center, Denver, CO 80262
Somatic mutations are not distributed randomly throughout Ab V
region genes. A sequence-specific target bias is revealed by a defined
hierarchy of mutability among di- and trinucleotide sequences located
within Ig intronic DNA. Here we report that the di- and trinucleotide
mutability preference pattern is shared by mouse intronic
JH and J
clusters and by human VH genes,
suggesting that a common mutation mechanism exists for all Ig V genes
of both species. Using di- and trinucleotide target preferences, we
performed a comprehensive analysis of human and murine germline V genes
to predict regional mutabilities. Heavy chain genes of both species
exhibit indistinguishable patterns in which complementarity-determining
region 1 (CDR1), CDR2, and framework region 3 (FR3) are predicted to be
more mutable than FR1 and FR2. This prediction is borne out by
empirical mutation data from nonproductively rearranged human
VH genes. Analysis of light chain genes in both species
also revealed a common, but unexpected, pattern in which FR2 is
predicted to be highly mutable. While our analyses of nonfunctional Ig
genes accurately predicts regional mutation preferences in
VH genes, observed relative mutability differences between
regions are more extreme than expected. This cannot be readily
accounted for by nascent mRNA secondary structure or by a supplemental
gene conversion mechanism that might favor nucleotide replacements in
CDR. Collectively, our data support the concept of a common mutation
mechanism for heavy and light chain genes of mice and humans with
regional bias that is qualitatively, but not quantitatively, accounted
for by short nucleotide sequence composition.
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