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Location and length distribution of somatic hypermutation-associated DNA insertions and deletions reveals regions of antibody structural plasticity

Genes & Immunity volume 13, pages 523–529 (2012)Cite this article

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Abstract

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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Acknowledgements

This work was supported by NIH U01 AI 78407 and NIAID Contract HHSN272200900047C, and supported in part by the Vanderbilt CTSA Grant UL1 RR024975-01 from NCRR/NIH. BSB was supported by NIH T32 HL069765, and JRW by NIH T32 AI060571. We thank all patients for participating in the study. We also thank Chris L Wright and Alvaro G Hernandez at the WM Keck Center for Comparative and Functional Genomics at the University of Illinois at Urbana-Champaign for performing the 454 sequencing. We are grateful to the IMGT team for its helpful collaboration and the analysis of nucleotide sequences on the IMGT/HighV-QUEST web portal.

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Authors and Affiliations

  1. Departments of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

    B S Briney & J E Crowe Jr

  2. Department of Chemical and Physical Biology Program, Vanderbilt University Medical Center, Nashville, TN, USA

    J R Willis

  3. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA

    J E Crowe Jr

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  1. B S Briney
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  2. J R Willis
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  3. J E Crowe Jr
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Correspondence to J E Crowe Jr.

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Briney, B., Willis, J. & Crowe, J. Location and length distribution of somatic hypermutation-associated DNA insertions and deletions reveals regions of antibody structural plasticity. Genes Immun 13, 523–529 (2012). https://doi.org/10.1038/gene.2012.28

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