ImmunoTyper-SR: A computational approach for genotyping immunoglobulin heavy chain variable genes using short-read data

Michael K B Ford; Ananth Hari; Oscar Rodriguez; Junyan Xu; Justin Lack; Cihan Oguz; Yu Zhang; Sarah Weber; Mary Magliocco; Jason Barnett; Sandhya Xirasagar; Smilee Samuel; Luisa Imberti; Paolo Bonfanti; Andrea Biondi; Clifton L Dalgard; Stephen Chanock; Lindsey Rosen; Steven Holland; Helen Su; Luigi Notarangelo; NIAID COVID Consortium; Uzi Vishkin; Corey T Watson; S Cenk Sahinalp

doi:10.1016/j.cels.2022.08.008

ImmunoTyper-SR: A computational approach for genotyping immunoglobulin heavy chain variable genes using short-read data

Cell Syst. 2022 Oct 19;13(10):808-816.e5. doi: 10.1016/j.cels.2022.08.008.

Authors

Michael K B Ford¹, Ananth Hari², Oscar Rodriguez³, Junyan Xu⁴, Justin Lack⁵, Cihan Oguz⁵, Yu Zhang⁵, Sarah Weber⁵, Mary Magliocco⁵, Jason Barnett⁵, Sandhya Xirasagar⁵, Smilee Samuel⁵, Luisa Imberti⁶, Paolo Bonfanti⁷, Andrea Biondi⁷, Clifton L Dalgard⁸, Stephen Chanock⁴, Lindsey Rosen⁵, Steven Holland⁵, Helen Su⁵, Luigi Notarangelo⁵; NIAID COVID Consortium; Uzi Vishkin⁹, Corey T Watson³, S Cenk Sahinalp¹⁰

Affiliations

¹ National Cancer Institute, NIH, Bethesda, MD, USA. Electronic address: mike.ford@nih.gov.
² National Cancer Institute, NIH, Bethesda, MD, USA; Department of Electrical Engineering, University of Maryland, College Park, MD, USA.
³ Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, USA.
⁴ National Cancer Institute, NIH, Bethesda, MD, USA.
⁵ National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
⁶ Diagnostic Department, ASST Spedali Civili di Brescia, Brescia, Italy.
⁷ University of Milano-Bicocca, Fondazione MBBM, Monza, Italy.
⁸ Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁹ Department of Electrical Engineering, University of Maryland, College Park, MD, USA.
¹⁰ National Cancer Institute, NIH, Bethesda, MD, USA. Electronic address: cenk.sahinalp@nih.gov.

Abstract

Human immunoglobulin heavy chain (IGH) locus on chromosome 14 includes more than 40 functional copies of the variable gene (IGHV), which are critical for the structure of antibodies that identify and neutralize pathogenic invaders as a part of the adaptive immune system. Because of its highly repetitive sequence composition, the IGH locus has been particularly difficult to assemble or genotype when using standard short-read sequencing technologies. Here, we introduce ImmunoTyper-SR, an algorithmic tool for the genotyping and CNV analysis of the germline IGHV genes on Illumina whole-genome sequencing (WGS) data using a combinatorial optimization formulation that resolves ambiguous read mappings. We have validated ImmunoTyper-SR on 12 individuals, whose IGHV allele composition had been independently validated, as well as concordance between WGS replicates from nine individuals. We then applied ImmunoTyper-SR on 585 COVID patients to investigate the associations between IGHV alleles and anti-type I IFN autoantibodies, which were previously associated with COVID-19 severity.

Keywords: ILP; WGS; algorithms; computational biology; genomics; genotyping; immunogenomics; immunoglobulin; next generation sequencing; optimization.

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Autoantibodies / genetics
COVID-19* / genetics
Genotype
High-Throughput Nucleotide Sequencing
Humans
Immunoglobulin Heavy Chains / genetics
Immunoglobulin Variable Region* / genetics

Substances

Immunoglobulin Variable Region
Immunoglobulin Heavy Chains
Autoantibodies

Grants and funding

ZIA BC011987/ImNIH/Intramural NIH HHS/United States