Analysis of strand biased 'G'•C hypermutation in human immunoglobulin Vλ gene segments suggests that both DNA strands are targets for deamination by activation-induced cytidine deaminase

Somatic hypermutation, which diversifies the immunoglobulin repertoire by introducing mutations into rearranged IgV genes, is dependent on the expression of activation-induced cytidine deaminase (AID). It has been proposed that AID deaminates DNA directly, generating mutations at C bases. Mutations from C and G are linked, and it has been suggested that mutations from G arise either during repair of DNA following deamination of C or by deamination of C on both DNA strands. Studies demonstrating that AID deaminates ssDNA on the non-transcribed strand support the former hypothesis. However, analyses of microsequences surrounding mutations suggest that the G.C mutator acts on both DNA strands equivalently. Unusually, in human IgV(lambda) genes, there is G.C strand bias favoring mutation from G. In IgV(lambda), 92% of mutations from G occur in GNW motifs. Hotspots for mutation from G IgV(lambda) are often independent of C nucleotides in the context of local microsequence. This independence of G and C mutation, yet retained dependence on local microsequence suggests that mutations from G arise independent of C on the non-transcribed strand. We suggest that both DNA strands are deaminated and that the transcribed strand is preferentially deaminated in human IgV(lambda) resulting in bias towards mutations from G. (C) 2003 Elsevier Ltd. All rights reserved.