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
2025-07-23
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.