Complex genetic variation in nearly complete human genomes
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 gaps 1,2 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 reference 1 significantly enhances genotyping accuracy from short-read data, enabling whole-genome inference 3 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.
Article Details
Authors (68)
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
Tobias Marschall