Dataset Information

Correlations in Somatic Hypermutation Between Sites in IGHV Genes Can Be Explained by Interactions Between AID and/or Pol? Hotspots.

ABSTRACT: The somatic hypermutation (SHM) of Immunoglobulin (Ig) genes is a key process during antibody affinity maturation in B cells. The mutagenic enzyme activation induced deaminase (AID) is required for SHM and has a preference for WRC hotspots in DNA. Error-prone repair mechanisms acting downstream of AID introduce further mutations, including DNA polymerase eta (Pol?), part of the non-canonical mismatch repair pathway (ncMMR), which preferentially generates mutations at WA hotspots. Previously proposed mechanistic models lead to a variety of predictions concerning interactions between hotspots, for example, how mutations in one hotspot will affect another hotspot. Using a large, high-quality, Ig repertoire sequencing dataset, we evaluated pairwise correlations between mutations site-by-site using an unbiased measure similar to mutual information which we termed "mutational association" (MA). Interactions are dominated by relatively strong correlations between nearby sites (short-range MAs), which can be almost entirely explained by interactions between overlapping hotspots for AID and/or Pol?. We also found relatively weak dependencies between almost all sites throughout each gene (longer-range MAs), although these arise mostly as a statistical consequence of high pairwise mutation frequencies. The dominant short-range interactions are also highest within the most highly mutating IGHV sub-regions, such as the complementarity determining regions (CDRs), where there is a high hotspot density. Our results suggest that the hotspot preferences for AID and Pol? have themselves evolved to allow for greater interactions between AID and/or Pol? induced mutations.

SUBMITTER: Krantsevich A

PROVIDER: S-EPMC7884765 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Correlations in Somatic Hypermutation Between Sites in IGHV Genes Can Be Explained by Interactions Between AID and/or Polη Hotspots.

Krantsevich Artem A Tang Catherine C MacCarthy Thomas T

Frontiers in immunology 20210202

The somatic hypermutation (SHM) of Immunoglobulin (Ig) genes is a key process during antibody affinity maturation in B cells. The mutagenic enzyme activation induced deaminase (AID) is required for SHM and has a preference for WRC hotspots in DNA. Error-prone repair mechanisms acting downstream of AID introduce further mutations, including DNA polymerase eta (Polη), part of the non-canonical mismatch repair pathway (ncMMR), which preferentially generates mutations at WA hotspots. Previously prop ...[more]

PMID: 33603748

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Project description:Somatic hypermutation (SHM) of the immunoglobulin variable (IgV) loci is a key process in antibody affinity maturation. The enzyme activation-induced deaminase (AID), initiates SHM by creating C ? U mismatches on single-stranded DNA (ssDNA). AID has preferential hotspot motif targets in the context of WRC/GYW (W = A/T, R = A/G, Y = C/T) and particularly at WGCW overlapping hotspots where hotspots appear opposite each other on both strands. Subsequent recruitment of the low-fidelity DNA repair enzyme, Polymerase eta (Pol?), during mismatch repair, creates additional mutations at WA/TW sites. Although there are more than 50 functional immunoglobulin heavy chain variable (IGHV) segments in humans, the fundamental differences between these genes and their ability to respond to all possible foreign antigens is still poorly understood. To better understand this, we generated profiles of WGCW hotspots in each of the human IGHV genes and found the expected high frequency in complementarity determining regions (CDRs) that encode the antigen binding sites but also an unexpectedly high frequency of WGCW in certain framework (FW) sub-regions. Principal Components Analysis (PCA) of these overlapping AID hotspot profiles revealed that one major difference between IGHV families is the presence or absence of WGCW in a sub-region of FW3 sometimes referred to as "CDR4." Further differences between members of each family (e.g., IGHV1) are primarily determined by their WGCW densities in CDR1. We previously suggested that the co-localization of AID overlapping and Pol? hotspots was associated with high mutability of certain IGHV sub-regions, such as the CDRs. To evaluate the importance of this feature, we extended the WGCW profiles, combining them with local densities of Pol? (WA) hotspots, thus describing the co-localization of both types of hotspots across all IGHV genes. We also verified that co-localization is associated with higher mutability. PCA of the co-localization profiles showed CDR1 and CDR2 as being the main contributors to variance among IGHV genes, consistent with the importance of these sub-regions in antigen binding. Our results suggest that AID overlapping (WGCW) hotspots alone or in conjunction with Pol? (WA/TW) hotspots are key features of evolutionary variation between IGHV genes.

Dataset Information

Correlations in Somatic Hypermutation Between Sites in IGHV Genes Can Be Explained by Interactions Between AID and/or Pol? Hotspots.

Publications

Correlations in Somatic Hypermutation Between Sites in IGHV Genes Can Be Explained by Interactions Between AID and/or Polη Hotspots.

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