Complex genetic variation in nearly complete human genomes

Glennis A. Logsdon, Peter Ebert, Peter A. Audano, Mark Loftus, David Porubsky, Jana Ebler, Feyza Yilmaz, Pille Hallast, Timofey Prodanov, DongAhn Yoo, Carolyn A. Paisie, William T. Harvey, Xuefang Zhao, Gianni V. Martino, Mir Henglin, Katherine M. Munson, Keon Rabbani, Chen-Shan Chin, Bida Gu, Hufsah Ashraf, Stephan Scholz, Olanrewaju Austine-Orimoloye, Parithi Balachandran, Marc Jan Bonder, Haoyu Cheng, Zechen Chong, Jonathan Crabtree, Mark Gerstein, Lisbeth A. Guethlein, Patrick Hasenfeld, Glenn Hickey, Kendra Hoekzema, Sarah E. Hunt, Matthew Jensen, Yunzhe Jiang, Sergey Koren, Youngjun Kwon, Chong Li, Heng Li, Jiaqi Li, Paul J. Norman, Keisuke K. Oshima, Benedict Paten, Adam M. Phillippy, Nicholas R. Pollock, Tobias Rausch, Mikko Rautiainen, Yuwei Song, Arda Söylev, Arvis Sulovari, Likhitha Surapaneni, Vasiliki Tsapalou, Weichen Zhou, Ying Zhou, Qihui Zhu, Michael C. Zody, Ryan E. Mills, Scott E. Devine, Xinghua Shi, Michael E. Talkowski, Mark J. P. Chaisson, Alexander T. Dilthey, Miriam K. Konkel (), Jan O. Korbel (), Charles Lee (), Christine R. Beck (), Evan E. Eichler () and Tobias Marschall ()
Additional contact information
Glennis A. Logsdon: University of Washington School of Medicine
Peter Ebert: Heinrich Heine University
Peter A. Audano: The Jackson Laboratory for Genomic Medicine
Mark Loftus: Clemson University
David Porubsky: University of Washington School of Medicine
Jana Ebler: Heinrich Heine University
Feyza Yilmaz: The Jackson Laboratory for Genomic Medicine
Pille Hallast: The Jackson Laboratory for Genomic Medicine
Timofey Prodanov: Heinrich Heine University
DongAhn Yoo: University of Washington School of Medicine
Carolyn A. Paisie: The Jackson Laboratory for Genomic Medicine
William T. Harvey: University of Washington School of Medicine
Xuefang Zhao: Broad Institute of MIT and Harvard
Gianni V. Martino: Clemson University
Mir Henglin: Heinrich Heine University
Katherine M. Munson: University of Washington School of Medicine
Keon Rabbani: University of Southern California
Chen-Shan Chin: Pathos AI Inc.
Bida Gu: University of Southern California
Hufsah Ashraf: Heinrich Heine University
Stephan Scholz: Heinrich Heine University
Olanrewaju Austine-Orimoloye: European Bioinformatics Institute
Parithi Balachandran: The Jackson Laboratory for Genomic Medicine
Marc Jan Bonder: University Medical Center Groningen
Haoyu Cheng: Yale School of Medicine
Zechen Chong: University of Alabama
Jonathan Crabtree: University of Maryland School of Medicine
Mark Gerstein: Yale University
Lisbeth A. Guethlein: Stanford University
Patrick Hasenfeld: European Molecular Biology Laboratory (EMBL)
Glenn Hickey: University of California
Kendra Hoekzema: University of Washington School of Medicine
Sarah E. Hunt: European Bioinformatics Institute
Matthew Jensen: Yale University
Yunzhe Jiang: Yale University
Sergey Koren: National Institutes of Health
Youngjun Kwon: University of Washington School of Medicine
Chong Li: Temple University
Heng Li: Dana-Farber Cancer Institute
Jiaqi Li: Yale University
Paul J. Norman: University of Colorado School of Medicine
Keisuke K. Oshima: University of Pennsylvania
Benedict Paten: University of California
Adam M. Phillippy: National Institutes of Health
Nicholas R. Pollock: University of Colorado School of Medicine
Tobias Rausch: European Molecular Biology Laboratory (EMBL)
Mikko Rautiainen: University of Helsinki
Yuwei Song: University of Alabama
Arda Söylev: Heinrich Heine University
Arvis Sulovari: University of Washington School of Medicine
Likhitha Surapaneni: European Bioinformatics Institute
Vasiliki Tsapalou: European Molecular Biology Laboratory (EMBL)
Weichen Zhou: University of Michigan
Ying Zhou: Dana-Farber Cancer Institute
Qihui Zhu: The Jackson Laboratory for Genomic Medicine
Michael C. Zody: New York Genome Center
Ryan E. Mills: University of Michigan
Scott E. Devine: University of Maryland School of Medicine
Xinghua Shi: Temple University
Michael E. Talkowski: Broad Institute of MIT and Harvard
Mark J. P. Chaisson: University of Southern California
Alexander T. Dilthey: Heinrich Heine University
Miriam K. Konkel: Clemson University
Jan O. Korbel: European Molecular Biology Laboratory (EMBL)
Charles Lee: The Jackson Laboratory for Genomic Medicine
Christine R. Beck: The Jackson Laboratory for Genomic Medicine
Evan E. Eichler: University of Washington School of Medicine
Tobias Marschall: Heinrich Heine University

Nature, 2025, vol. 644, issue 8076, 430-441

Abstract: Abstract Diverse sets of complete human genomes are required to construct a pangenome reference and to understand the extent of complex structural variation. Here we sequence 65 diverse human genomes and build 130 haplotype-resolved assemblies (median continuity of 130 Mb), closing 92% of all previous assembly gaps1,2 and reaching telomere-to-telomere status for 39% of the chromosomes. We highlight complete sequence continuity of complex loci, including the major histocompatibility complex (MHC), SMN1/SMN2, NBPF8 and AMY1/AMY2, and fully resolve 1,852 complex structural variants. In addition, we completely assemble and validate 1,246 human centromeres. We find up to 30-fold variation in α-satellite higher-order repeat array length and characterize the pattern of mobile element insertions into α-satellite higher-order repeat arrays. Although most centromeres predict a single site of kinetochore attachment, epigenetic analysis suggests the presence of two hypomethylated regions for 7% of centromeres. Combining our data with the draft pangenome reference1 significantly enhances genotyping accuracy from short-read data, enabling whole-genome inference3 to a median quality value of 45. Using this approach, 26,115 structural variants per individual are detected, substantially increasing the number of structural variants now amenable to downstream disease association studies.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-025-09140-6 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:644:y:2025:i:8076:d:10.1038_s41586-025-09140-6

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-025-09140-6

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().