Increased Hypermutation at G and C Nucleotides in Immunoglobulin Variable Genes from Mice Deficient in the MSH2 Mismatch Repair Protein

doi:10.1084/jem.187.11.1745

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J. Exp. Med., Volume 187, Number 11, June 1, 1998 1745-1751

Increased Hypermutation at G and C Nucleotides in Immunoglobulin Variable Genes from Mice Deficient in the MSH2 Mismatch Repair Protein

By Quy H. Phung,^* David B. Winter,^* Aaron Cranston,^§ Robert E. Tarone, Vilhelm A. Bohr,^* Richard Fishel,^§ and Patricia J. Gearhart^*

From the ^* Laboratory of Molecular Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224; the Graduate Program in Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; the ^§ Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; and the Biostatistics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

Rearranged immunoglobulin variable genes are extensively mutated after stimulation of B lymphocytes by antigen. Mutationsare likely generated by an error-prone DNA polymerase, and themismatch repair pathway may process the mispairs. To examine therole of the MSH2 mismatch repair protein in hypermutation, Msh2^/ mice were immunized with oxazolone, and B cells were analyzedfor mutation in their VOx1 light chain genes. The frequencyof mutation in the repair-deficient mice was similar to that inMsh2^+/+ mice, showing that MSH2-dependent mismatch repair does not causehypermutation. However, there was a striking bias for mutationsto occur at germline G and C nucleotides. The results suggestthat the hypermutation pathway frequently mutates G·C pairs, anda MSH2-dependent pathway preferentially corrects mismatches atG and C.

Key words: biological sciences; genetics; genes, immunoglobulin; mutation; DNA repair

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