SOMATIC HYPERMUTATION OF IMMUNOGLOBULIN GENES IS LINKED TO TRANSCRIPTION INITIATION

To identify DNA sequences that target the somatic hypermutation proces s, the immunoglobulin gene promoter located upstream of the variable ( V region was duplicated upstream of the constant (C) region of a kappa transgene. Normally, kappa genes are somatically mutated only in the VJ region, but not in the C region. In B cell hybridomas from mice wit h this kappa transgene (P5'C), both the VJ region and the C region, bu t not the region between them, were mutated at similar frequencies, su ggesting that the mutation mechanism is related to transcription. The downstream promoter was not occluded by transcripts from the upstream promoter. In fact, the levels of transcripts originating from the two promoters were similar, supporting a mutation model based on initiatio n of transcripts. Several ''hotspots'' of somatic mutation were noted, further demonstrating that this transgene has the hallmarks of somati c mutation of endogenous immunoglobulin genes. A model linking somatic mutation to transcription-coupled DNA repair is proposed.