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Antibody repertoire gene usage is explained by common genetic variants in the immunoglobulin heavy chain locus

Oscar L. Rodriguez, Yana Safonova, Catherine A. Silver, Kaitlyn Shields, William S. Gibson, Justin T. Kos, David Tieri, Hanzhong Ke, Katherine J. L. Jackson, View ORCID ProfileScott Boyd, Melissa L. Smith, Wayne A. Marasco, Corey T. Watson
doi: https://doi.org/10.1101/2022.07.04.498729
Oscar L. Rodriguez
1Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, USA
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Yana Safonova
2Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA
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Catherine A. Silver
1Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, USA
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Kaitlyn Shields
1Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, USA
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William S. Gibson
1Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, USA
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Justin T. Kos
1Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, USA
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David Tieri
1Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, USA
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Hanzhong Ke
3Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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Katherine J. L. Jackson
4The Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
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Scott Boyd
5Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
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Melissa L. Smith
1Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, USA
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  • For correspondence: corey.watson@louisville.edu Wayne_Marasco@dfci.harvard.edu ml.smith@louisville.edu
Wayne A. Marasco
3Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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  • For correspondence: corey.watson@louisville.edu Wayne_Marasco@dfci.harvard.edu ml.smith@louisville.edu
Corey T. Watson
1Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, USA
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  • For correspondence: corey.watson@louisville.edu Wayne_Marasco@dfci.harvard.edu ml.smith@louisville.edu
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Abstract

The contribution of heritable factors to antibody function and diversity is not fully understood, but has profound implications for delineating variation in the antibody response observed at the population-level. We performed matched long-read-based characterization of the immunoglobulin heavy chain (IGH) locus and expressed antibody repertoire profiling at population-scale to examine, for the first time, the impact of IGH genomic variation on the antibody repertoire. We characterized extensive IGH polymorphism, including novel structural variants (SVs), small insertion/deletions (indels), single nucleotide variants (SNVs), and IG genes and alleles. Countering models that antibody repertoire diversity is driven largely by stochastic processes, we demonstrate that IGH genetic factors make significant contributions to gene usage in both the naive and antigen-experienced repertoire. Specifically, the usage of 73% of IGH genes was associated with common polymorphisms, including those capable of explaining >70% of variance in gene usage. These variants were enriched in transcription factor binding sites and other functional elements associated with V(D)J recombination, and overlapped polymorphisms from genome-wide association studies. Furthermore, we found evidence for the coordinated regulation of IGH genes across the repertoire, demonstrating complex interactions between IGH variants and gene usage. These results refine our understanding of variation observed in the antibody repertoire, and will advance the study of antibody function in disease.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted July 04, 2022.
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Antibody repertoire gene usage is explained by common genetic variants in the immunoglobulin heavy chain locus
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 Boyd, Melissa L. Smith, Wayne A. Marasco, Corey T. Watson
bioRxiv 2022.07.04.498729; doi: https://doi.org/10.1101/2022.07.04.498729
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Antibody repertoire gene usage is explained by common genetic variants in the immunoglobulin heavy chain locus
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 Boyd, Melissa L. Smith, Wayne A. Marasco, Corey T. Watson
bioRxiv 2022.07.04.498729; doi: https://doi.org/10.1101/2022.07.04.498729

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