Journal
GENES AND IMMUNITY
Volume 13, Issue 7, Pages 523-529Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gene.2012.28
Keywords
antibodies; human; binding sites; antibody; immunologic memory; antibody specificity
Categories
Funding
- NIH [U01 AI 78407, T32 HL069765, T32 AI060571]
- NIAID [HHSN272200900047C]
- Vanderbilt CTSA Grant from NCRR/NIH [UL1 RR024975-01]
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Following the initial diversity generated by V(D)J recombination, somatic hypermutation is the principal mechanism for producing further antibody repertoire diversity in antigen-experienced B cells. While somatic hypermutation typically results in single-nucleotide substitutions, the infrequent incorporation of genetic insertions and deletions has also been associated with the somatic hypermutation process. We used high-throughput antibody sequencing to determine the sequence of thousands of antibody genes containing somatic hypermutation-associated insertions and deletions (SHA indels), which revealed significant differences between the location of SHA indels and somatic mutations. Further, we identified a cluster of insertions and deletions in the antibody framework 3 region, which corresponds to the hypervariable region 4 (HV4) in T-cell receptors. We propose that this HV4-like region, identified by SHA indel analysis, represents a region of under-appreciated affinity maturation potential. Finally, through the analysis of both location and length distribution of SHA indels, we have determined regions of structural plasticity within the antibody protein.
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