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 gen e a high frequency of mutations does not occur until similar to 200 bp downstream of the V gene promoter in the leader intron. This finding seems inconsistent with recently proposed, transcription-coupled model s of hypermutation. Here we describe studies on extensively mutated co pies of a Ic light chain transgene which appear to exist as passenger genes for a significant portion of their mutational history. These tra nsgenes 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 c ompared, the patterns of mutation in the reader intron are not signifi cantly different; the frequency 3' is greater in the passenger transge nes. This result indicates that the low level mutational activity imme diately 3' of the promoter followed by rapid rise in activity is an in trinsic feature of the mutational process. One inference from this fin ding is that there is a structural feature in V region DNA or one indu ced during transcription which is critical to a functioning mutator.