Promoter-associated displacement of hypermutations

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.