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Complete sequences of six Major Histocompatibility Complex haplotypes, including all the major MHC class II structures

View ORCID ProfileTorsten Houwaart, Stephan Scholz, Nicholas R Pollock, William H. Palmer, Katherine M. Kichula, Daniel Strelow, Duyen B Le, Dana Belick, Tobias Lautwein, Thorsten Wachtmeister, Birgit Henrich, Karl Köhrer, Peter Parham, Lisbeth A Guethlein, View ORCID ProfilePaul J Norman, View ORCID ProfileAlexander T Dilthey
doi: https://doi.org/10.1101/2022.04.28.489875
Torsten Houwaart
1Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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  • ORCID record for Torsten Houwaart
Stephan Scholz
1Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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Nicholas R Pollock
2Division of Biomedical Informatics and Personalized Medicine, and Department of Immunology and Microbiology, Anschutz Medical Campus, University of Colorado, Aurora, USA
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William H. Palmer
2Division of Biomedical Informatics and Personalized Medicine, and Department of Immunology and Microbiology, Anschutz Medical Campus, University of Colorado, Aurora, USA
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Katherine M. Kichula
2Division of Biomedical Informatics and Personalized Medicine, and Department of Immunology and Microbiology, Anschutz Medical Campus, University of Colorado, Aurora, USA
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Daniel Strelow
1Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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Duyen B Le
1Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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Dana Belick
1Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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Tobias Lautwein
3Biologisch-Medizinisches-Forschungszentrum (BMFZ), Genomics & Transcriptomics Laboratory, Heinrich Heine University Düsseldorf, Germany
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Thorsten Wachtmeister
3Biologisch-Medizinisches-Forschungszentrum (BMFZ), Genomics & Transcriptomics Laboratory, Heinrich Heine University Düsseldorf, Germany
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Birgit Henrich
1Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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Karl Köhrer
3Biologisch-Medizinisches-Forschungszentrum (BMFZ), Genomics & Transcriptomics Laboratory, Heinrich Heine University Düsseldorf, Germany
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Peter Parham
4Department of Structural Biology, and Department of Microbiology and Immunology Stanford University, Stanford, USA
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Lisbeth A Guethlein
4Department of Structural Biology, and Department of Microbiology and Immunology Stanford University, Stanford, USA
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Paul J Norman
2Division of Biomedical Informatics and Personalized Medicine, and Department of Immunology and Microbiology, Anschutz Medical Campus, University of Colorado, Aurora, USA
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  • For correspondence: paul.norman@cuanschutz.edu dilthey@hhu.de
Alexander T Dilthey
1Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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  • ORCID record for Alexander T Dilthey
  • For correspondence: paul.norman@cuanschutz.edu dilthey@hhu.de
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Abstract

Accurate and comprehensive immunogenetic reference panels are key to the successful implementation of population-scale immunogenomics. The 5Mbp Major Histocompatibility Complex (MHC) is the most polymorphic region of the human genome and associated with multiple immune-mediated diseases, transplant matching and therapy responses. Analysis of MHC genetic variation is severely complicated by complex patterns of sequence variation, linkage disequilibrium and a lack of fully resolved MHC reference haplotypes, increasing the risk of spurious findings on analyzing this medically important region. Integrating Illumina and ultra-long Nanopore sequencing as well as bespoke bioinformatics, we completed five of the alternative MHC reference haplotypes of the current (B38) build of the human reference genome and added one other. The six assembled MHC haplotypes encompass the DR1 and DR4 haplotype structures in addition to the previously completed DR2 and DR3, as well as six distinct classes of the structurally variable C4 region. Analysis of the assembled haplotypes showed that MHC class II sequence structures, including repeat element positions, are generally conserved within the DR haplotype supergroups, and that sequence diversity peaks in three regions around HLA-A, HLA-B+C, and the HLA class II genes. Demonstrating the potential for improved short-read analysis, the number of proper read pairs recruited to the MHC was found to be increased by 0.32% – 0.69% in a 1000 Genomes Project read re-mapping experiment with seven diverse samples. Furthermore, the assembled haplotypes can serve as references for the community and provide the basis of a structurally accurate genotyping graph of the complete MHC region.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Better formatting for tables and figures.

  • https://pypi.org/project/MHC-Annotation/

  • https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA764575

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 4.0 International license.
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Posted May 06, 2022.
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Complete sequences of six Major Histocompatibility Complex haplotypes, including all the major MHC class II structures
Torsten Houwaart, Stephan Scholz, Nicholas R Pollock, William H. Palmer, Katherine M. Kichula, Daniel Strelow, Duyen B Le, Dana Belick, Tobias Lautwein, Thorsten Wachtmeister, Birgit Henrich, Karl Köhrer, Peter Parham, Lisbeth A Guethlein, Paul J Norman, Alexander T Dilthey
bioRxiv 2022.04.28.489875; doi: https://doi.org/10.1101/2022.04.28.489875
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Complete sequences of six Major Histocompatibility Complex haplotypes, including all the major MHC class II structures
Torsten Houwaart, Stephan Scholz, Nicholas R Pollock, William H. Palmer, Katherine M. Kichula, Daniel Strelow, Duyen B Le, Dana Belick, Tobias Lautwein, Thorsten Wachtmeister, Birgit Henrich, Karl Köhrer, Peter Parham, Lisbeth A Guethlein, Paul J Norman, Alexander T Dilthey
bioRxiv 2022.04.28.489875; doi: https://doi.org/10.1101/2022.04.28.489875

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