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Complex genetic variation in nearly complete human genomes

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  • Additional Information
    • Publication Date:
      2025
    • Collection:
      University of Groningen research database
    • 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.
    • File Description:
      application/pdf
    • ISSN:
      0028-0836
      1476-4687
    • Relation:
      info:eu-repo/semantics/altIdentifier/pmid/40702183; info:eu-repo/semantics/altIdentifier/hdl/https://hdl.handle.net/11370/806fe6f7-2184-4a8c-80a6-66329689dde0; info:eu-repo/semantics/altIdentifier/pissn/0028-0836; info:eu-repo/semantics/altIdentifier/eissn/1476-4687
    • Accession Number:
      10.1038/s41586-025-09140-6
    • Online Access:
      https://hdl.handle.net/11370/806fe6f7-2184-4a8c-80a6-66329689dde0
      https://research.rug.nl/en/publications/806fe6f7-2184-4a8c-80a6-66329689dde0
      https://doi.org/10.1038/s41586-025-09140-6
      https://pure.rug.nl/ws/files/1475222592/s41586-025-09140-6.pdf
      https://www.scopus.com/pages/publications/105011342429
    • Rights:
      info:eu-repo/semantics/openAccess ; http://creativecommons.org/licenses/by/4.0/
    • Accession Number:
      edsbas.13B82FAA