Journal Article

DKFZ-2025-01506

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Complex genetic variation in nearly complete human genomes.

Logsdon, G. A. ; Ebert, P. ; Audano, P. A. ; Loftus, M. ; Porubsky, D. ; Ebler, J. ; Yilmaz, F. ; Hallast, P. ; Prodanov, T. ; Yoo, D. ; Paisie, C. A. ; Harvey, W. T. ; Zhao, X. ; Martino, G. V. ; Henglin, M. ; Munson, K. M. ; Rabbani, K. ; Chin, C.-S. ; Gu, B. ; Ashraf, H. ; Scholz, S. ; Austine-Orimoloye, O. ; Balachandran, P. ; Bonder, M. J.DKFZ* ; Cheng, H. ; Chong, Z. ; Crabtree, J. ; Gerstein, M. ; Guethlein, L. A. ; Hasenfeld, P. ; Hickey, G. ; Hoekzema, K. ; Hunt, S. E. ; Jensen, M. ; Jiang, Y. ; Koren, S. ; Kwon, Y. ; Li, C. ; Li, H. ; Li, J. ; Norman, P. J. ; Oshima, K. K. ; Paten, B. ; Phillippy, A. M. ; Pollock, N. R. ; Rausch, T. ; Rautiainen, M. ; Song, Y. ; Söylev, A. ; Sulovari, A. ; Surapaneni, L. ; Tsapalou, V. ; Zhou, W. ; Zhou, Y. ; Zhu, Q. ; Zody, M. C. ; Mills, R. E. ; Devine, S. E. ; Shi, X. ; Talkowski, M. E. ; Chaisson, M. J. P. ; Dilthey, A. T. ; Konkel, M. K. ; Korbel, J. O. ; Lee, C. ; Beck, C. R. ; Eichler, E. E. ; Marschall, T.

2025
Nature Publ. Group London [u.a.]

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Please use a persistent id in citations: doi:10.1038/s41586-025-09140-6

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.

Note: Division of Computational Genomics and Systems Genetics, German Cancer Research Center, Heidelberg, Germany. / 2025 Aug;644(8076):430-441

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Contributing Institute(s):

1. B260 Bioinformatik der Genomik und Systemgenetik (B260)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2025

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