TY - JOUR T1 - Clustered Mutations at the Murine and Human IgH Locus Exhibit Significant Linkage Consistent with Templated Mutagenesis JF - The Journal of Immunology JO - J. Immunol. DO - 10.4049/jimmunol.1801615 SP - ji1801615 AU - Dale, Gordon A. AU - Wilkins, Daniel J. AU - Bohannon, Caitlin D. AU - Dilernia, Dario AU - Hunter, Eric AU - Bedford, Trevor AU - Antia, Rustom AU - Sanz, Ignacio AU - Jacob, Joshy Y1 - 2019/08/02 UR - http://www.jimmunol.org/content/early/2019/08/01/jimmunol.1801615.abstract N2 - Somatic mutations in close proximity exhibit high linkage disequilibrium.Pairs of somatic mutations within 8 bp are templated from IgHV gene segments.Pairs of somatic mutations in non-Ig genes at the IgH locus are similarly templated.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 &lt;8 bp apart are significantly more likely to match microhomologous regions in the IgHV repertoire than predicted by the mutation profiles of somatic hypermutation. Together, this supports the role of templated mutagenesis during somatic diversification of Ag-activated B cells. ER -