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Genetic variation in the immunoglobulin heavy chain locus shapes the human antibody repertoire

Author

Listed:
  • Oscar L. Rodriguez

    (University of Louisville School of Medicine)

  • Yana Safonova

    (Johns Hopkins University)

  • Catherine A. Silver

    (University of Louisville School of Medicine)

  • Kaitlyn Shields

    (University of Louisville School of Medicine)

  • William S. Gibson

    (University of Louisville School of Medicine)

  • Justin T. Kos

    (University of Louisville School of Medicine)

  • David Tieri

    (University of Louisville School of Medicine)

  • Hanzhong Ke

    (Harvard Medical School
    Department of Medicine, Harvard Medical School)

  • Katherine J. L. Jackson

    (The Garvan Institute of Medical Research)

  • Scott D. Boyd

    (Stanford University School of Medicine)

  • Melissa L. Smith

    (University of Louisville School of Medicine)

  • Wayne A. Marasco

    (Harvard Medical School
    Department of Medicine, Harvard Medical School)

  • Corey T. Watson

    (University of Louisville School of Medicine)

Abstract

Variation in the antibody response has been linked to differential outcomes in disease, and suboptimal vaccine and therapeutic responsiveness, the determinants of which have not been fully elucidated. Countering models that presume antibodies are generated largely by stochastic processes, we demonstrate that polymorphisms within the immunoglobulin heavy chain locus (IGH) impact the naive and antigen-experienced antibody repertoire, indicating that genetics predisposes individuals to mount qualitatively and quantitatively different antibody responses. We pair recently developed long-read genomic sequencing methods with antibody repertoire profiling to comprehensively resolve IGH genetic variation, including novel structural variants, single nucleotide variants, and genes and alleles. We show that IGH germline variants determine the presence and frequency of antibody genes in the expressed repertoire, including those enriched in functional elements linked to V(D)J recombination, and overlapping disease-associated variants. These results illuminate the power of leveraging IGH genetics to better understand the regulation, function, and dynamics of the antibody response in disease.

Suggested Citation

  • Oscar L. Rodriguez & Yana Safonova & Catherine A. Silver & Kaitlyn Shields & William S. Gibson & Justin T. Kos & David Tieri & Hanzhong Ke & Katherine J. L. Jackson & Scott D. Boyd & Melissa L. Smith , 2023. "Genetic variation in the immunoglobulin heavy chain locus shapes the human antibody repertoire," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40070-x
    DOI: 10.1038/s41467-023-40070-x
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