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Department of Immunology, National Jewish Medical and Research Center and University of Colorado School of Medicine, and
Division of Biostatistics, National Jewish Medical and Research Center, Denver, CO 80206
Ig variable (V) region genes are subjected to a somatic
hypermutation process as B lymphocytes participate in immune reactions
to protein Ags. Although little is known regarding the mechanism of
mutagenesis, a consistent hierarchy of trinucleotide target preferences
is evident. Analysis of trinucleotide regional distributions predicted
and we now empirically confirm the surprising finding that the
framework 2 region of 
V region genes is highly mutable despite its
importance to the structural integrity and function of the Ab molecule.
Interestingly, much of this mutability appears to be focused on the
third codon position where synonymous substitutions are most likely to
occur. We also observed a trend for high predicted mutability for codon
positions 1 and 2 in complementarity-determining regions. Consequently,
amino acid replacements should occur at a higher rate in
complementarity-determining regions than in framework regions due to
the distribution and subsequent targeting of microsequences by the
mutation mechanism. Our results reveal a subtle tier of V region gene
evolution in which DNA sequence has been molded to direct mutations to
specific base positions within codons in a manner that minimizes damage
and maximizes the benefits of the somatic hypermutation
process.
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