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Inversion polymorphism in a complete human genome assembly

View ORCID ProfileDavid Porubsky, View ORCID ProfileWilliam T. Harvey, View ORCID ProfileAllison N. Rozanski, View ORCID ProfileJana Ebler, View ORCID ProfileWolfram Höps, View ORCID ProfileHufsah Ashraf, View ORCID ProfilePatrick Hasenfeld, Human Pangenome Reference Consortium (HPRC), Human Genome Structural Variation Consortium (HGSVC), View ORCID ProfileBenedict Paten, View ORCID ProfileAshley D. Sanders, View ORCID ProfileTobias Marschall, View ORCID ProfileJan O. Korbel, View ORCID ProfileEvan E. Eichler
doi: https://doi.org/10.1101/2022.10.06.511148
David Porubsky
1Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
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William T. Harvey
1Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
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Allison N. Rozanski
1Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
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Jana Ebler
2Heinrich Heine University, Medical Faculty, Institute for Medical Biometry and Bioinformatics, Moorenstraße 5, 40225 Düsseldorf, Germany
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Wolfram Höps
3European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany
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Hufsah Ashraf
2Heinrich Heine University, Medical Faculty, Institute for Medical Biometry and Bioinformatics, Moorenstraße 5, 40225 Düsseldorf, Germany
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Patrick Hasenfeld
3European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany
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Benedict Paten
4UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA, USA
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Ashley D. Sanders
5Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
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Tobias Marschall
2Heinrich Heine University, Medical Faculty, Institute for Medical Biometry and Bioinformatics, Moorenstraße 5, 40225 Düsseldorf, Germany
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Jan O. Korbel
3European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany
6European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom
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Evan E. Eichler
1Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
7Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA
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Abstract

The completion of the human genome significantly improved our ability to discover and interpret genome copy number variation. In order to understand its impact on the characterization of inversion polymorphisms, we remapped data from 41 human genomes and 10 new samples against the telomere-to-telomere (T2T) reference genome as compared to the standard GRCh38 reference. Our analysis shows a ~21% increase in sensitivity identifying and improving mapping of 63 inversions. We further identify 26 misorientations within GRCh38, and show that the T2T reference is three times more likely to represent the correct orientation of the major human allele. As a result, we report a significant bias for inversions accumulating within the pericentromeric regions of specific chromosomes and show that functional annotations around inverted regions, such as topological-associated domains, can be better interpreted.

Competing Interest Statement

E.E.E. is a scientific advisory board (SAB) member of Variant Bio, Inc. The following authors have previously disclosed a patent application (no. EP19169090) relevant to Strand-seq: J.O.K., T.M., and D.P. The other authors declare no competing interests.

Footnotes

  • ↵* For a complete list of HPRC and HGSVC members, see Supplemental Material.

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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Posted October 06, 2022.
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Inversion polymorphism in a complete human genome assembly
David Porubsky, William T. Harvey, Allison N. Rozanski, Jana Ebler, Wolfram Höps, Hufsah Ashraf, Patrick Hasenfeld, Human Pangenome Reference Consortium (HPRC), Human Genome Structural Variation Consortium (HGSVC), Benedict Paten, Ashley D. Sanders, Tobias Marschall, Jan O. Korbel, Evan E. Eichler
bioRxiv 2022.10.06.511148; doi: https://doi.org/10.1101/2022.10.06.511148
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Inversion polymorphism in a complete human genome assembly
David Porubsky, William T. Harvey, Allison N. Rozanski, Jana Ebler, Wolfram Höps, Hufsah Ashraf, Patrick Hasenfeld, Human Pangenome Reference Consortium (HPRC), Human Genome Structural Variation Consortium (HGSVC), Benedict Paten, Ashley D. Sanders, Tobias Marschall, Jan O. Korbel, Evan E. Eichler
bioRxiv 2022.10.06.511148; doi: https://doi.org/10.1101/2022.10.06.511148

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