The mechanism of somatic hypermutation studied with transgenic and transfected target genes

Author: Storb U.   Peters A.   Klotz E.   Rogerson B.   Hackett Jr J.  

Publisher: Academic Press

ISSN: 1044-5323

Source: Seminars in Immunology, Vol.8, Iss.3, 1996-03, pp. : 131-140

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Abstract

Somatic hypermutation of Ig genes is beginning to be understood in molecular terms. Ig transgenes have served as model test genes and been shown to mutate, just as endogenous genes, with a peak of mutation over the VJ region and a sparing of the C region. The levels of somatic mutation appear to be related to the expression of the transgenes. DNA hypermethylation of modified Ig transgenes interferes with both expression and somatic hypermutation. Test substrates consisting of bacterial lacZalpha or supF tRNA inserted within kappa transgenes were shown to be rescuable as expressible bacterial plasmids, but did not seem to be targeted. A synthetic sequence consisting of alternating restriction enzyme sites, that cannot be subject to methylation, was found to be a reliable transgenic substrate for easy assay of somatic mutation.The generation of a transgenic mouse with a kappa transgene in which the transcriptional promoter has been duplicated upstream of the C region has given new clues to the mutation mechanism. In this transgene, transcripts initiate from both the C region and the V region promoters, and both regions, but not the sequences between them, are hypermutated. These results suggest that somatic hypermutation is linked to the initiation of transcription. A model is proposed in which somatic mutation is dependent on transcription coupled DNA repair.