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.