Complex genetic variation in nearly complete human genomes.

Nature
Authors
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 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 significantly enhances genotyping accuracy from short-read data, enabling whole-genome inference 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.

Year of Publication
2025
Journal
Nature
Volume
644
Issue
8076
Pages
430-441
Date Published
08/2025
ISSN
1476-4687
DOI
10.1038/s41586-025-09140-6
PubMed ID
40702183
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