BIAS IN SOMATIC HYPERMUTATION OF HUMAN V-H GENES

Translationally silent mutations, which are not antigen selected, of h uman V-H6 Ig gene rearrangements isolated from human spleen were analy zed for bias to gain insight into intrinsic features of the mutation p rocess. Sixty-three clones representing 38 V-H6 DJ rearrangements had an overall mutation frequency of 4.5%, a replacement/silent (R/S) muta tion ratio of 2.1 and 167 unique silent mutations. The silent mutation s showed bias in: (i) targeting to CDR1 and CDR2, (ii) an increased fr equency of mutations of A compared to T nucleotide bases on the coding strand, and (iii) an increased frequency of transitions versus transv ersions. Bias of C --> G over C --> A, of G --> C over G --> T and of A --> C over A --> T transversions was also present. Hot spots of muta tion were observed, some which corresponded to potential sites of stem - loop formation. The results suggest that the somatic mutation proce ss in man may be targeted to the complementarity determining region fo r some V genes, exhibits specific base substitutions favoring transiti ons and specific types of transversions, and may be occurring on only one DNA strand.