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Epigenetic Patterns in a Complete Human Genome

View ORCID ProfileAriel Gershman, Michael E.G. Sauria, View ORCID ProfilePaul W. Hook, Savannah J. Hoyt, Roham Razaghi, Sergey Koren, View ORCID ProfileNicolas Altemose, Gina V. Caldas, Mitchell R. Vollger, Glennis A. Logsdon, View ORCID ProfileArang Rhie, Evan E. Eichler, Michael C. Schatz, Rachel J. O’Neill, Adam M. Phillippy, Karen H. Miga, View ORCID ProfileWinston Timp
doi: https://doi.org/10.1101/2021.05.26.443420
Ariel Gershman
1Department of Biomedical Engineering and Molecular Biology and Genetics, Johns Hopkins University, Baltimore, Maryland, USA
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  • ORCID record for Ariel Gershman
Michael E.G. Sauria
2Department of Biology and Computer Science, Johns Hopkins University, Baltimore, Maryland, USA
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Paul W. Hook
1Department of Biomedical Engineering and Molecular Biology and Genetics, Johns Hopkins University, Baltimore, Maryland, USA
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Savannah J. Hoyt
3Institute for Systems Genomics, University of Connecticut, Storrs, CT, USA
4Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, USA
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Roham Razaghi
1Department of Biomedical Engineering and Molecular Biology and Genetics, Johns Hopkins University, Baltimore, Maryland, USA
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Sergey Koren
5Genome Informatics Section, Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
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Nicolas Altemose
6Department of Bioengineering, University of California Berkeley, Berkeley, CA, USA
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Gina V. Caldas
7Department of Molecular and Cell Biology, University of California Berkeley, Berkeley CA, USA
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Mitchell R. Vollger
8Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
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Glennis A. Logsdon
8Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
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Arang Rhie
5Genome Informatics Section, Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
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Evan E. Eichler
8Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
9Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA
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Michael C. Schatz
2Department of Biology and Computer Science, Johns Hopkins University, Baltimore, Maryland, USA
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Rachel J. O’Neill
3Institute for Systems Genomics, University of Connecticut, Storrs, CT, USA
4Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, USA
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Adam M. Phillippy
5Genome Informatics Section, Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
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Karen H. Miga
10UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA, USA
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  • For correspondence: wtimp@jhu.edu
Winston Timp
1Department of Biomedical Engineering and Molecular Biology and Genetics, Johns Hopkins University, Baltimore, Maryland, USA
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  • For correspondence: wtimp@jhu.edu
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ABSTRACT

The completion of the first telomere-to-telomere human genome, T2T-CHM13, enables exploration of the full epigenome, removing limitations previously imposed by the missing reference sequence. Existing epigenetic studies omit unassembled and unmappable genomic regions (e.g. centromeres, pericentromeres, acrocentric chromosome arms, subtelomeres, segmental duplications, tandem repeats). Leveraging the new assembly, we were able to measure enrichment of epigenetic marks with short reads using k-mer assisted mapping methods. This granted array-level enrichment information to characterize the epigenetic regulation of these satellite repeats. Using nanopore sequencing data, we generated base level maps of the most complete human methylome ever produced. We examined methylation patterns in satellite DNA and revealed organized patterns of methylation along individual molecules. When exploring the centromeric epigenome, we discovered a distinctive dip in centromere methylation consistent with active sites of kinetochore assembly. Through long-read chromatin accessibility measurements (nanoNOMe) paired to CUT&RUN data, we found the hypomethylated region was extremely inaccessible and paired to CENP-A/B binding. With long-reads we interrogated allele-specific, longrange epigenetic patterns in complex macro-satellite arrays such as those involved in X chromosome inactivation. Using the single molecule measurements we can clustered reads based on methylation status alone distinguishing epigenetically heterogeneous and homogeneous areas. The analysis provides a framework to investigate the most elusive regions of the human genome, applying both long and short-read technology to grant new insights into epigenetic regulation.

Competing Interest Statement

W.T. has two patents (8,748,091 and 8,394,584) licensed to Oxford Nanopore Technologies.

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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Epigenetic Patterns in a Complete Human Genome
Ariel Gershman, Michael E.G. Sauria, Paul W. Hook, Savannah J. Hoyt, Roham Razaghi, Sergey Koren, Nicolas Altemose, Gina V. Caldas, Mitchell R. Vollger, Glennis A. Logsdon, Arang Rhie, Evan E. Eichler, Michael C. Schatz, Rachel J. O’Neill, Adam M. Phillippy, Karen H. Miga, Winston Timp
bioRxiv 2021.05.26.443420; doi: https://doi.org/10.1101/2021.05.26.443420
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Epigenetic Patterns in a Complete Human Genome
Ariel Gershman, Michael E.G. Sauria, Paul W. Hook, Savannah J. Hoyt, Roham Razaghi, Sergey Koren, Nicolas Altemose, Gina V. Caldas, Mitchell R. Vollger, Glennis A. Logsdon, Arang Rhie, Evan E. Eichler, Michael C. Schatz, Rachel J. O’Neill, Adam M. Phillippy, Karen H. Miga, Winston Timp
bioRxiv 2021.05.26.443420; doi: https://doi.org/10.1101/2021.05.26.443420

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