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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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    as
    1. Yik Andy Yeung & Davide Foletti & Xiaodi Deng & Yasmina Abdiche & Pavel Strop & Jacob Glanville & Steven Pitts & Kevin Lindquist & Purnima D. Sundar & Marina Sirota & Adela Hasa-Moreno & Amber Pham & , 2016. "Germline-encoded neutralization of a Staphylococcus aureus virulence factor by the human antibody repertoire," Nature Communications, Nature, vol. 7(1), pages 1-14, December.
    2. Moriah Gidoni & Omri Snir & Ayelet Peres & Pazit Polak & Ida Lindeman & Ivana Mikocziova & Vikas Kumar Sarna & Knut E. A. Lundin & Christopher Clouser & Francois Vigneault & Andrew M. Collins & Ludvig, 2019. "Mosaic deletion patterns of the human antibody heavy chain gene locus shown by Bayesian haplotyping," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    3. Zhaoqing Ba & Jiangman Lou & Adam Yongxin Ye & Hai-Qiang Dai & Edward W. Dring & Sherry G. Lin & Suvi Jain & Nia Kyritsis & Kyong-Rim Kieffer-Kwon & Rafael Casellas & Frederick W. Alt, 2020. "CTCF orchestrates long-range cohesin-driven V(D)J recombinational scanning," Nature, Nature, vol. 586(7828), pages 305-310, October.
    4. Kyle Kai-How Farh & Alexander Marson & Jiang Zhu & Markus Kleinewietfeld & William J. Housley & Samantha Beik & Noam Shoresh & Holly Whitton & Russell J. H. Ryan & Alexander A. Shishkin & Meital Hatan, 2015. "Genetic and epigenetic fine mapping of causal autoimmune disease variants," Nature, Nature, vol. 518(7539), pages 337-343, February.
    5. Florian Rubelt & Christopher R. Bolen & Helen M. McGuire & Jason A. Vander Heiden & Daniel Gadala-Maria & Mikhail Levin & Ghia M. Euskirchen & Murad R. Mamedov & Gary E. Swan & Cornelia L. Dekker & Li, 2016. "Individual heritable differences result in unique cell lymphocyte receptor repertoires of naïve and antigen-experienced cells," Nature Communications, Nature, vol. 7(1), pages 1-12, June.
    6. Michal Levy-Sakin & Steven Pastor & Yulia Mostovoy & Le Li & Alden K. Y. Leung & Jennifer McCaffrey & Eleanor Young & Ernest T. Lam & Alex R. Hastie & Karen H. Y. Wong & Claire Y. L. Chung & Walfred M, 2019. "Genome maps across 26 human populations reveal population-specific patterns of structural variation," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    7. Benjamin B. Sun & Joseph C. Maranville & James E. Peters & David Stacey & James R. Staley & James Blackshaw & Stephen Burgess & Tao Jiang & Ellie Paige & Praveen Surendran & Clare Oliver-Williams & Mi, 2018. "Genomic atlas of the human plasma proteome," Nature, Nature, vol. 558(7708), pages 73-79, June.
    8. Khalid H. Bhat & Saurabh Priyadarshi & Sarah Naiyer & Xinyan Qu & Hammad Farooq & Eden Kleiman & Jeffery Xu & Xue Lei & Jose F. Cantillo & Robert Wuerffel & Nicole Baumgarth & Jie Liang & Ann J. Feene, 2023. "An Igh distal enhancer modulates antigen receptor diversity by determining locus conformation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    9. Quentin Marcou & Thierry Mora & Aleksandra M. Walczak, 2018. "High-throughput immune repertoire analysis with IGoR," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    10. Tom Parks & Mariana M. Mirabel & Joseph Kado & Kathryn Auckland & Jaroslaw Nowak & Anna Rautanen & Alexander J. Mentzer & Eloi Marijon & Xavier Jouven & Mai Ling Perman & Tuliana Cua & John K. Kauwe &, 2017. "Association between a common immunoglobulin heavy chain allele and rheumatic heart disease risk in Oceania," Nature Communications, Nature, vol. 8(1), pages 1-10, August.
    11. Daniel Felsky & Tina Roostaei & Kwangsik Nho & Shannon L. Risacher & Elizabeth M. Bradshaw & Vlad Petyuk & Julie A. Schneider & Andrew Saykin & David A. Bennett & Philip L. De Jager, 2019. "Neuropathological correlates and genetic architecture of microglial activation in elderly human brain," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    12. Louisa Hill & Anja Ebert & Markus Jaritz & Gordana Wutz & Kota Nagasaka & Hiromi Tagoh & Daniela Kostanova-Poliakova & Karina Schindler & Qiong Sun & Peter Bönelt & Maria Fischer & Jan-Michael Peters , 2020. "Wapl repression by Pax5 promotes V gene recombination by Igh loop extrusion," Nature, Nature, vol. 584(7819), pages 142-147, August.
    13. Carles A. Boix & Benjamin T. James & Yongjin P. Park & Wouter Meuleman & Manolis Kellis, 2021. "Regulatory genomic circuitry of human disease loci by integrative epigenomics," Nature, Nature, vol. 590(7845), pages 300-307, February.
    14. Bryan Briney & Anne Inderbitzin & Collin Joyce & Dennis R. Burton, 2019. "Commonality despite exceptional diversity in the baseline human antibody repertoire," Nature, Nature, vol. 566(7744), pages 393-397, February.
    15. Chunguang Guo & Hye Suk Yoon & Andrew Franklin & Suvi Jain & Anja Ebert & Hwei-Ling Cheng & Erica Hansen & Orion Despo & Claudia Bossen & Christian Vettermann & Jamie G. Bates & Nicholas Richards & Da, 2011. "CTCF-binding elements mediate control of V(D)J recombination," Nature, Nature, vol. 477(7365), pages 424-430, September.
    16. Cinque Soto & Robin G. Bombardi & Andre Branchizio & Nurgun Kose & Pranathi Matta & Alexander M. Sevy & Robert S. Sinkovits & Pavlo Gilchuk & Jessica A. Finn & James E. Crowe, 2019. "High frequency of shared clonotypes in human B cell receptor repertoires," Nature, Nature, vol. 566(7744), pages 398-402, February.
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