Germ line variable regions that match hypermutated sequences in genes encoding murine anti-hapten antibodies.
We asked whether there are germ line immunoglobulin variable (V) segments that match sites of hypermutation in V regions encoding murine antibodies. Murine germ line DNA was probed with a panel of short deoxyoligonucleotides identical in sequence to segments of hypermutated V regions from hybridomas generated in the BALB/c response to the hapten 2-phenyloxazolone (Ox). Germ line sequences that match mutations in both heavy and kappa light chain V regions were identified, and clones of some of these germ line V segments were obtained. Comparison of these clones with hypermutated V regions revealed regions of identity ranging in size from 7 to over 50 nucleotides. In an effort to separate the effects of antigen selection from the mutagenic process, we also searched for matches to a panel of silent mutations in VH regions from germinal center B cells. Fourteen silent mutations occur among a collection of 36 hypermutated VH regions from two separate germinal centers of C57BL/6 mice stimulated with the hapten 4-hydroxy-3-nitrophenyl. Matches to nine of these silent mutations can be found among published sequences of C57BL/6 VH regions of the J558 family. Taken together, these data are consistent with the possibility that a template-dependent mutational process, like gene conversion, may contribute to somatic hypermutation.
David
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Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06510.
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Maizels
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D000818:Animals; D001483:Base Sequence; D015342:DNA Probes; D005785:Gene Conversion; D015322:Gene Rearrangement, B-Lymphocyte; D005803:Genes, Immunoglobulin; D014644:Genetic Variation; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D051379:Mice / Q000235:genetics* / Q000276:immunology; D008807:Mice, Inbred BALB C / Q000235:genetics / Q000276:immunology; D008810:Mice, Inbred C57BL / Q000235:genetics / Q000276:immunology; D008969:Molecular Sequence Data; D009154:Mutation; D010081:Oxazolone / Q000031:analogs & derivatives / Q000276:immunology; D016415:Sequence Alignment
D015342:DNA Probes; D007135:Immunoglobulin Variable Region; C018361:2-phenyloxazolone; D010081:Oxazolone