Targeted and complete genomic sequencing of the major histocompatibility complex in haplotypic form of individual heterozygous samples
- Taishan Hu1,5,6,7,
- Timothy L. Mosbruger1,5,
- Nikolaos G. Tairis1,
- Amalia Dinou1,
- Pushkala Jayaraman2,8,
- Mahdi Sarmady2,9,
- Kingham Brewster3,
- Yang Li1,
- Tristan J. Hayeck1,4,
- Jamie L. Duke1 and
- Dimitri S. Monos1,4
- 1Immunogenetics Laboratory, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;
- 2Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;
- 3Sequencing and Genotyping Center, Delaware Biotechnology Institute, University of Delaware, Newark, Delaware 19713, USA;
- 4Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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↵5 These authors contributed equally to this work.
Abstract
The human major histocompatibility complex (MHC) is a ∼4 Mb genomic segment on Chromosome 6 that plays a pivotal role in the immune response. Despite its importance in various traits and diseases, its complex nature makes it challenging to accurately characterize on a routine basis. We present a novel approach allowing targeted sequencing and de novo haplotypic assembly of the MHC region in heterozygous samples, using long-read sequencing technologies. Our approach is validated using two reference samples, two family trios, and an African-American sample. We achieved excellent coverage (96.6%–99.9% with at least 30× depth) and high accuracy (99.89%–99.99%) for the different haplotypes. This methodology offers a reliable and cost-effective method for sequencing and fully characterizing the MHC without the need for whole-genome sequencing, facilitating broader studies on this important genomic segment and having significant implications in immunology, genetics, and medicine.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.278588.123.
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Freely available online through the Genome Research Open Access option.
- Received October 26, 2023.
- Accepted September 19, 2024.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
