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Critical Reviews™ in Immunology
IF: 1.352 5-Year IF: 3.347 SJR: 1.022 SNIP: 0.55 CiteScore™: 2.19

ISSN Print: 1040-8401
ISSN Online: 2162-6472

Critical Reviews™ in Immunology

DOI: 10.1615/CritRevImmunol.v22.i3.20
18 pages

DNA Target Motifs of Somatic Mutagenesis in Antibody Genes

Gary S. Shapiro
Department of Immunology, National Jewish Medical and Research Center and University of Colorado School of Medicine, Denver, CO 80206
Lawrence J. Wysocki
Department of Immunology, National Jewish Medical and Research Center and University of Colorado School of Medicine, Denver, CO 80206

ABSTRACT

During humoral immunity to T-cell-dependent antigens, responding В lymphocytes selectively mutate their antibody variable region genes at a high rate. This, together with the process of clonal selection, ultimately enhances the affinity and specificity of the antibody molecule and memory В cells that express it as a receptor. Despite several decades of investigation, the mutation mechanism has remained unresolved, largely due to the convoluted nature of experimental systems used to approach it. Somatic mutations preferentially occur within specific oligonucleotide motifs, and this targeting is consistent in all immunoglobulin genes of humans and mice that we have examined, suggesting that a conserved mechanism operates in both species. Our mutation targeting analyses implicate evolution of germline variable gene sequences to direct somatic mutations to specific codon positions in a manner that regulates the frequency of amino acid replacements to the benefit of the antibody product. Finally, our recent strand bias analyses support the idea that somatic mutation occurs preferentially, perhaps exclusively, at two bases on both strands of DNA. These and related observations from other laboratories support a mutation model that invokes at least two error-prone polymerases that have distinct template biases and requirements for elements of postreplicative mismatch repair.


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