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 VκOx1 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.
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1 June 1998
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June 01 1998
Increased Hypermutation at G and C Nucleotides in Immunoglobulin Variable Genes from Mice Deficient in the MSH2 Mismatch Repair Protein
Quy H. Phung,
Quy H. Phung
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
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David B. Winter,
David B. Winter
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
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Aaron Cranston,
Aaron Cranston
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
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Robert E. Tarone,
Robert E. Tarone
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
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Vilhelm A. Bohr,
Vilhelm A. Bohr
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
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Richard Fishel,
Richard Fishel
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
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Patricia J. Gearhart
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
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Quy H. Phung
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
David B. Winter
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
Aaron Cranston
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
Robert E. Tarone
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
Vilhelm A. Bohr
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
Richard Fishel
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
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
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: [email protected]
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; VκOx1, V gene for the κ chain that binds to oxazolone.
Received:
March 06 1998
Revision Received:
April 07 1998
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 187 (11): 1745–1751.
Article history
Received:
March 06 1998
Revision Received:
April 07 1998
Citation
Quy H. Phung, David B. Winter, Aaron Cranston, Robert E. Tarone, Vilhelm A. Bohr, Richard Fishel, Patricia J. Gearhart; Increased Hypermutation at G and C Nucleotides in Immunoglobulin Variable Genes from Mice Deficient in the MSH2 Mismatch Repair Protein . J Exp Med 1 June 1998; 187 (11): 1745–1751. doi: https://doi.org/10.1084/jem.187.11.1745
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