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A novel framework for characterizing genomic haplotype diversity in the human immunoglobulin heavy chain locus

View ORCID ProfileO. L. Rodriguez, W. S. Gibson, View ORCID ProfileT. Parks, M. Emery, J. Powell, M. Strahl, G. Deikus, K. Auckland, View ORCID ProfileE. E. Eichler, W. A. Marasco, View ORCID ProfileR. Sebra, A. J. Sharp, View ORCID ProfileM. L. Smith, A. Bashir, View ORCID ProfileC. T. Watson
doi: https://doi.org/10.1101/2020.04.19.049270
O. L. Rodriguez
1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York USA
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  • ORCID record for O. L. Rodriguez
W. S. Gibson
2Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, Kentucky USA
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T. Parks
3The Wellcome Centre for Human Genetics, University of Oxford, Oxford, Oxfordshire, UK
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M. Emery
1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York USA
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J. Powell
1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York USA
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M. Strahl
1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York USA
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G. Deikus
1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York USA
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K. Auckland
3The Wellcome Centre for Human Genetics, University of Oxford, Oxford, Oxfordshire, UK
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E. E. Eichler
4Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA
5Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA
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W. A. Marasco
6Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
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R. Sebra
1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York USA
7Icahn Institute of Data Science and Genomic Technology, New York, New York USA
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A. J. Sharp
1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York USA
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M. L. Smith
1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York USA
7Icahn Institute of Data Science and Genomic Technology, New York, New York USA
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  • For correspondence: corey.watson@louisville.edu ali.bashir@gmail.com melissa.smith@mssm.edu
A. Bashir
1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York USA
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  • For correspondence: corey.watson@louisville.edu ali.bashir@gmail.com melissa.smith@mssm.edu
C. T. Watson
2Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, Kentucky USA
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  • For correspondence: corey.watson@louisville.edu ali.bashir@gmail.com melissa.smith@mssm.edu
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Abstract

An incomplete ascertainment of genetic variation within the highly polymorphic immunoglobulin heavy chain locus (IGH) has hindered our ability to define genetic factors that influence antibody and B cell mediated processes. To date, methods for locus-wide genotyping of all IGH variant types do not exist. Here, we combine targeted long-read sequencing with a novel bioinformatics tool, IGenotyper, to fully characterize genetic variation within IGH in a haplotype-specific manner. We apply this approach to eight human samples, including a haploid cell line and two mother-father-child trios, and demonstrate the ability to generate high-quality assemblies (>98% complete and >99% accurate), genotypes, and gene annotations, including 2 novel structural variants and 16 novel gene alleles. We show that multiplexing allows for scaling of the approach without impacting data quality, and that our genotype call sets are more accurate than short-read (>35% increase in true positives and >97% decrease in false-positives) and array/imputation-based datasets. This framework establishes a foundation for leveraging IG genomic data to study population-level variation in the antibody response.

Competing Interest Statement

E.E.E. is on the scientific advisory board (SAB) of DNAnexus, Inc.

Footnotes

  • Error in figures/tables.

Copyright 
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-NC-ND 4.0 International license.
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A novel framework for characterizing genomic haplotype diversity in the human immunoglobulin heavy chain locus
O. L. Rodriguez, W. S. Gibson, T. Parks, M. Emery, J. Powell, M. Strahl, G. Deikus, K. Auckland, E. E. Eichler, W. A. Marasco, R. Sebra, A. J. Sharp, M. L. Smith, A. Bashir, C. T. Watson
bioRxiv 2020.04.19.049270; doi: https://doi.org/10.1101/2020.04.19.049270
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A novel framework for characterizing genomic haplotype diversity in the human immunoglobulin heavy chain locus
O. L. Rodriguez, W. S. Gibson, T. Parks, M. Emery, J. Powell, M. Strahl, G. Deikus, K. Auckland, E. E. Eichler, W. A. Marasco, R. Sebra, A. J. Sharp, M. L. Smith, A. Bashir, C. T. Watson
bioRxiv 2020.04.19.049270; doi: https://doi.org/10.1101/2020.04.19.049270

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