Clustered Mutations at the Murine and Human IgH Locus Exhibit Significant Linkage Consistent with Templated Mutagenesis

Somatic hypermutation generates a myriad of Ab mutants in Ag-specific B cells, from which high-affinity mutants are selected. Chickens, sheep, and rabbits use nontemplated point mutations and templated mutations via gene conversion to diversify their expressed Ig loci, whereas mice and humans rely s...

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Published in:The Journal of immunology (1950) 2019-09, Vol.203 (5), p.1252-1264
Main Authors: Dale, Gordon A, Wilkins, Daniel J, Bohannon, Caitlin D, Dilernia, Dario, Hunter, Eric, Bedford, Trevor, Antia, Rustom, Sanz, Ignacio, Jacob, Joshy
Format: Article
Language:English
Subjects:
Animals
DNA Helicases - physiology
DNA-Binding Proteins - physiology
Genetic Linkage
Genetic Loci
Germinal Center - immunology
Humans
Immunoglobulin Heavy Chains - genetics
Immunoglobulin Variable Region - genetics
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mutagenesis
Mutation
Plasma Cells - immunology
Somatic Hypermutation, Immunoglobulin
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Summary:Somatic hypermutation generates a myriad of Ab mutants in Ag-specific B cells, from which high-affinity mutants are selected. Chickens, sheep, and rabbits use nontemplated point mutations and templated mutations via gene conversion to diversify their expressed Ig loci, whereas mice and humans rely solely on untemplated somatic point mutations. In this study, we demonstrate that, in addition to untemplated point mutations, templated mutagenesis readily occurs at the murine and human Ig loci. We provide two distinct lines of evidence that are not explained by the Neuberger model of somatic hypermutation: 1) across multiple data sets there is significant linkage disequilibrium between individual mutations, especially among close mutations, and 2) among those mutations, those
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1801615