International Immunology, Vol 10, 1131-1138, Copyright © 1998 by Oxford University Press
P Wu and L Claflin
The distribution of somatic hypermutations around the rearranged V(D)J in
antigen-selected B cells is asymmetrical. At the 5' end of the gene a high
frequency of mutations does not occur until approximately 200 bp downstream
of the V gene promoter in the leader intron. This finding seems
inconsistent with recently proposed, transcription-coupled models of
hypermutation. Here we describe studies on extensively mutated copies of a
kappa light chain transgene which appear to exist as passenger genes for a
significant portion of their mutational history. These transgenes contain
between one and four in-frame stop codons, and have a ratio of replacement
to silent mutations in framework regions that is near random; the ratio in
their functional counterparts is clearly non-random. When non-functional
passenger and functional transgenes are compared, the patterns of mutation
in the leader intron are not significantly different; the frequency 3' is
greater in the passenger transgenes. This result indicates that the low
level mutational activity immediately 3' of the promoter followed by rapid
rise in activity is an intrinsic feature of the mutational process. One
inference from this finding is that there is a structural feature in V
region DNA or one induced during transcription which is critical to a
functioning mutator.
ARTICLES
Promoter-associated displacement of hypermutations
Department of Microbiology and Immunology, The University of Michigan Medical School, Ann Arbor 48109-0620, USA.
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