Increased hypermutation at G and C nucleotides in immunoglobulin variable genes from mice deficient in the MSH2 mismatch repair protein

Rearranged immunoglobulin variable genes are extensively mutated after stimulation of B lymphocytes by antigen. Mutations are likely generated by an error-prone DNA polymerase, and the mismatch repair pathway may process the mispairs. To examine the role of the MSH2 mismatch repair protein in hypermutation, Msh2(-/-) mice were immunized with oxazolone, and B cells were analyzed for mutation in their V(k)Oxl light chain genes. The frequency of mutation in the repair-deficient mice was similar to that in Msh2(+/+) mice, showing that MSH2-dependent mismatch repair does not cause hypermutation. However, there was a striking bias for mutations to occur at germline G and C nucleotides. The results suggest that the hypermutation pathway frequently mutates G C pairs, and a MSH2-dependent pathway preferentially corrects mismatches at G and C.