Document Type
Article
Publication Date
8-1-2025
Original Citation
Logsdon G,
Ebert P,
Audano P,
Loftus M,
Porubsky D,
Ebler J,
Yilmaz F,
Hallast P,
Prodanov T,
Yoo D,
Paisie C,
Harvey W,
Zhao X,
Martino G,
Henglin M,
Munson K,
Rabbani K,
Chin C,
Gu B,
Ashraf H,
Scholz S,
Austine-Orimoloye O,
Balachandran P,
Bonder M,
Cheng H,
Chong Z,
Crabtree J,
Gerstein M,
Guethlein L,
Hasenfeld P,
Hickey G,
Hoekzema K,
Hunt S,
Jensen M,
Jiang Y,
Koren S,
Kwon Y,
Li C,
Li H,
Li J,
Norman P,
Oshima K,
Paten B,
Phillippy A,
Pollock N,
Rausch T,
Rautiainen M,
Song Y,
Söylev A,
Sulovari A,
Surapaneni L,
Tsapalou V,
Zhou W,
Zhou Y,
Zhu Q,
Zody M,
Mills R,
Devine S,
Shi X,
Talkowski M,
Chaisson M,
Dilthey A,
Konkel M,
Korbel J,
Lee C,
Beck C,
Eichler E,
Marschall T.
Complex genetic variation in nearly complete human genomes. Nature. 2025;644(8076):430-41
Keywords
JGM, Humans, Genome, Human, Centromere, Haplotypes, Genetic Variation, Telomere, Major Histocompatibility Complex, Epigenesis, Genetic, Kinetochores, Genomics, Genotype
JAX Source
Nature. 2025;644(8076):430-41
ISSN
1476-4687
PMID
40702183
DOI
https://doi.org/10.1038/s41586-025-09140-6
Grant
U24HG007497 (to S.E.H., O.A.-O., L.S., E.E.E., S.E.D., B.G., T.M. and C. Lee); R35GM133600 (to P.A.A., P.B. and C.R.B.); P30CA034196 (to P.A.A. and C.R.B.)
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.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.