Complex genetic variation in nearly complete human genomes

作者：Glennis A. Logsdon, Peter Ebert, Peter A. Audano, Mark Loftus, David Porubskỳ, Jana Ebler, Feyza Yilmaz, Pille Hallast, Timofey Prodanov, DongAhn Yoo, Carolyn Paisie, William T. Harvey, Xuefang Zhao, Gianni V. Martino, Mir Henglin, Katherine M. Munson, K Siddique-e Rabbani, Chen-Shan Chin, Bida Gu, Hufsah Ashraf, 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 Hunt, Matthew Jensen, Yunzhe Jiang, Sergey Koren, Young-Jun 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, Stephan Scholz, 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, Mike E Talkowski, Mark Chaisson, Alexander Dilthey, Miriam K. Konkel, Jan O. Korbel, Charles Lee, Christine R. Beck, Evan E. Eichler, Tobias Marschall · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.09.24.614721 · 被引用次数：27 · 研究领域：Chromosomal and Genetic Variations、Genomics and Phylogenetic Studies、Genomic variations and chromosomal abnormalities

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 (130 Mbp median continuity), closing 92% of all previous assembly gaps and reaching telomere-to-telomere (T2T) 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 (SVs). In addition, we completely assemble and validate 1,246 human centromeres. We find up to 30-fold variation in α-satellite high-order repeat (HOR) array length and characterize the pattern of mobile element insertions into α-satellite HOR arrays. While 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 significantly enhances genotyping accuracy from short-read data, enabling whole-genome inference to a median quality value (QV) of 45. Using this approach, 26,115 SVs per sample are detected, substantially increasing the number of SVs now amenable to downstream disease association studies.