Telomere-to-telomere assembly of a complete human X chromosome

Karen H. Miga (), Sergey Koren, Arang Rhie, Mitchell R. Vollger, Ariel Gershman, Andrey Bzikadze, Shelise Brooks, Edmund Howe, David Porubsky, Glennis A. Logsdon, Valerie A. Schneider, Tamara Potapova, Jonathan Wood, William Chow, Joel Armstrong, Jeanne Fredrickson, Evgenia Pak, Kristof Tigyi, Milinn Kremitzki, Christopher Markovic, Valerie Maduro, Amalia Dutra, Gerard G. Bouffard, Alexander M. Chang, Nancy F. Hansen, Amy B. Wilfert, Françoise Thibaud-Nissen, Anthony D. Schmitt, Jon-Matthew Belton, Siddarth Selvaraj, Megan Y. Dennis, Daniela C. Soto, Ruta Sahasrabudhe, Gulhan Kaya, Josh Quick, Nicholas J. Loman, Nadine Holmes, Matthew Loose, Urvashi Surti, Rosa ana Risques, Tina A. Graves Lindsay, Robert Fulton, Ira Hall, Benedict Paten, Kerstin Howe, Winston Timp, Alice Young, James C. Mullikin, Pavel A. Pevzner, Jennifer L. Gerton, Beth A. Sullivan, Evan E. Eichler and Adam M. Phillippy ()
Additional contact information
Karen H. Miga: University of California Santa Cruz
Sergey Koren: Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health
Arang Rhie: Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health
Mitchell R. Vollger: University of Washington School of Medicine
Ariel Gershman: Johns Hopkins University
Andrey Bzikadze: University of California San Diego
Shelise Brooks: National Institutes of Health
Edmund Howe: Stowers Institute for Medical Research
David Porubsky: University of Washington School of Medicine
Glennis A. Logsdon: University of Washington School of Medicine
Valerie A. Schneider: National Institutes of Health
Tamara Potapova: Stowers Institute for Medical Research
Jonathan Wood: Wellcome Sanger Institute
William Chow: Wellcome Sanger Institute
Joel Armstrong: University of California Santa Cruz
Jeanne Fredrickson: University of Washington
Evgenia Pak: National Institutes of Health
Kristof Tigyi: University of California Santa Cruz
Milinn Kremitzki: McDonnell Genome Institute at Washington University
Christopher Markovic: McDonnell Genome Institute at Washington University
Valerie Maduro: National Institutes of Health
Amalia Dutra: National Institutes of Health
Gerard G. Bouffard: National Institutes of Health
Alexander M. Chang: Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health
Nancy F. Hansen: National Human Genome Research Institute, National Institutes of Health
Amy B. Wilfert: University of Washington School of Medicine
Françoise Thibaud-Nissen: National Institutes of Health
Anthony D. Schmitt: Arima Genomics
Jon-Matthew Belton: Arima Genomics
Siddarth Selvaraj: Arima Genomics
Megan Y. Dennis: University of California Davis
Daniela C. Soto: University of California Davis
Ruta Sahasrabudhe: University of California Davis
Gulhan Kaya: University of California Davis
Josh Quick: University of Birmingham
Nicholas J. Loman: University of Birmingham
Nadine Holmes: University of Nottingham
Matthew Loose: University of Nottingham
Urvashi Surti: University of Pittsburgh
Rosa ana Risques: University of Washington
Tina A. Graves Lindsay: McDonnell Genome Institute at Washington University
Robert Fulton: McDonnell Genome Institute at Washington University
Ira Hall: McDonnell Genome Institute at Washington University
Benedict Paten: University of California Santa Cruz
Kerstin Howe: Wellcome Sanger Institute
Winston Timp: Johns Hopkins University
Alice Young: National Institutes of Health
James C. Mullikin: National Institutes of Health
Pavel A. Pevzner: University of California San Diego
Jennifer L. Gerton: Stowers Institute for Medical Research
Beth A. Sullivan: Duke University Medical Center
Evan E. Eichler: University of Washington School of Medicine
Adam M. Phillippy: Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health

Nature, 2020, vol. 585, issue 7823, 79-84

Abstract: Abstract After two decades of improvements, the current human reference genome (GRCh38) is the most accurate and complete vertebrate genome ever produced. However, no single chromosome has been finished end to end, and hundreds of unresolved gaps persist1,2. Here we present a human genome assembly that surpasses the continuity of GRCh382, along with a gapless, telomere-to-telomere assembly of a human chromosome. This was enabled by high-coverage, ultra-long-read nanopore sequencing of the complete hydatidiform mole CHM13 genome, combined with complementary technologies for quality improvement and validation. Focusing our efforts on the human X chromosome3, we reconstructed the centromeric satellite DNA array (approximately 3.1 Mb) and closed the 29 remaining gaps in the current reference, including new sequences from the human pseudoautosomal regions and from cancer-testis ampliconic gene families (CT-X and GAGE). These sequences will be integrated into future human reference genome releases. In addition, the complete chromosome X, combined with the ultra-long nanopore data, allowed us to map methylation patterns across complex tandem repeats and satellite arrays. Our results demonstrate that finishing the entire human genome is now within reach, and the data presented here will facilitate ongoing efforts to complete the other human chromosomes.

Date: 2020
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DOI: 10.1038/s41586-020-2547-7

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