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 MarkovicValerie 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, Adam M. Phillippy

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

128 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)79-84
Number of pages6
JournalNature
Volume585
Issue number7823
DOIs
Publication statusPublished - 3 Sep 2020
Externally publishedYes

Bibliographical note

Funding Information:
Acknowledgements We acknowledge conversations with I. Lee on methylation analysis and a review of the manuscript by H. F. Willard. Funding support: NIH/NHGRI R21 1R21HG010548-01 and NIH/NHGRI U01 1U01HG010971 (K.H.M.); Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (S.K., A.R., V.M., A.D., G.G.B., A.M.C., N.F.H., A.Y., J.C.M. and A.M.P.); Korea Health Technology R&D Project through the Korea Health Industry Development Institute HI17C2098 (A.R.); Intramural Research Program of the National Library of Medicine, National Institutes of Health (V.A.S. and F.T.-N.); Common Fund, Office of the Director, NIH (V.M.); Stowers Institute for Medical Research (E.H., T.P. and J.L.G.); NIH R01 GM124041 (B.A.S.); NIH HG002385 and HG010169 (E.E.E.); E.E.E. is an investigator of the Howard Hughes Medical Institute; National Library of Medicine Big Data Training Grant for Genomics and Neuroscience 5T32LM012419-04 (M.R.V.); NIH 1F32GM134558-01 (G.A.L.); NIH/NHGRI U54 1U54HG007990, W. M. Keck Foundation DT06172015, NIH/NHLBI U01 1U01HL137183 and NIH/NHGRI/EMBL 2U41HG007234 (B.P.); NIH/NHGRI R01 HG009190 and NIGMS T32 GM007445 (W.T. and A.G.); NIH R01CA181308 (R.R.); NIH/NHGRI 2R44HG008118 (A.D.S. and S.S.); Wellcome Trust (212965/Z/18/Z) (N.H., N.J.L. and M.L.); and National Institute for Health Research (NIHR) Surgical Reconstruction and Microbiology Research Centre (SRMRC) (J.Q.). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This work used the computational resources of the NIH HPC Biowulf cluster (https://hpc.nih.gov).

Publisher Copyright:
© 2020, The Author(s).

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