The boundaries of the distribution of somatic hypermutation of rearranged immunoglobulin variable genes

Available evidence about the mechanisms and distribution of somatic hypermutation (SHM) of rearranged immunoglobulin (IgV) genes is reviewed with particular emphasis on the 5′ boundary. In heavy (H) chain genes, the 5′ boundary of SHM is the transcription start site; in contrast to κ light (L) chain genes, it is located in the leader (L) intron. DNA-based models of SHM cannot account for this difference. However, an updated reverse transcriptase (RT)-based model invoking error-prone RT activity of DNA polymerase η copying IgV pre-mRNA templates to produce cDNA of the transcribed strand (TS) of IgV DNA, which then replaces the corresponding section of the original TS, can explain the difference. This explanation incorporates recent knowledge of pre-mRNA processing, in particular, binding of the splicing-associated protein termed U2AF to a pyrimidine-rich tract in the L intron of pre-mRNA of κ L chains that may block RT progression further upstream to the end of the pre-mRNA template (transcription start site). Reasons why this block may not occur in H chains and other aspects of the updated RT-model are discussed.