The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/6/1745/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 11, June 1, 1998 1745-1751

Articles

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

Quy H. Phung*,{ddagger}, 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 {ddagger} 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. 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{kappa}Ox1 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.

Key Words: biological sciences • genetics • genes, immunoglobulin • mutation • DNA repair

Address correspondence to Dr. P.J. Gearhart, Laboratory of Molecular Genetics, National Institute of Aging, Gerontology Research Center, National Institutes of Health, 5600 Nathan Shock Dr., Baltimore, MD 21224. Phone: 410-558-8561; Fax: 410-558-8157; E-mail: gearharp{at}grc.nia.nih.gov

We gratefully thank Francis Chrest for assistance in flow cytometry, Michael Neuberger for antigen, Andrew Wakeham for advice in genotyping splenic DNA, Heinz Jacobs for sharing data before publication, and Richard Wood and Dennis Taub for many insightful comments on the manuscript.

1 Abbreviations used in this paper: MLH, Mut L homologue; MSH, Mut S homologue; Pfu, Pyrococcus furiosus; PMS, post-meiotic segregation; V{kappa}Ox1, V gene for the {kappa} chain that binds to oxazolone.


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