Assembly of 43 human Y chromosomes reveals extensive complexity and variation.

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JGM, Humans, Male, Chromosomes, Human, Y, Genome, Human, Genomics, Mutation Rate, Phenotype, Evolution, Molecular, Euchromatin, Pseudogenes, Genetic Variation, Chromosomes, Human, X, Pseudoautosomal Regions

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Nature. 2023;621(7978):355-64.








Funding was provided by National Institutes of Health (NIH) grants U24HG007497 (to C. Lee, E.E.E., J.O.K. and T.M.), U01HG010973 (to T.M., E.E.E. and J.O.K.), R01HG002385 and R01HG010169 (to E.E.E.), and GM123312 (to S.J.H. and R.J.O.); the German Federal Ministry for Research and Education (BMBF 031L0184 to J.O.K. and T.M.); the German Research Foundation (DFG 391137747 to T.M.); the German Human Genome-Phenome Archive (DFG (NFDI 1/1) to J.O.K.); the European Research Council (ERC Consolidator grant 773026 to J.O.K.); the EMBL (to J.O.K. and P. Hasenfeld); the EMBL International PhD Programme (to W.H.); the Jackson Laboratory Postdoctoral Scholar Award (to K.K.); NIH National Institute of General Medical Sciences (NIGMS R35GM133600 to C.R.B.; 1P20GM139769 to M.K.K. and M.L.) and the National Cancer Institute (NCI) (P30CA034196 to C.R.B. and P.A.A.); U24HG007497 (P. Hallast, F.Y., Q.Z., F.T. and J.Y.K.); NIGMS K99GM147352 (to G.A.L.); and Wellcome grant 098051 (to C.T.-S.). This work was also supported, in part, by the P30 CA034196 grant from the NCI. E.E.E. is an investigator of the Howard Hughes Medical Institute. We thank A. Rhie and A. Phillippy for coordination and discussions; Y. Xue for discussions and advice throughout the project; J. Wood and the members of the Genome Reference Informatics Team at the Wellcome Sanger Institute for suggestions and feedback on assembly evaluation; L. Skov for advice and sharing his scripts for gene conversion detection; the members of the HPRC (https://humanpangenome.org) for making their data publicly available; the staff at Clemson University for their allotment of compute time on the Palmetto Cluster; staff at the Center for Information and Media Technology at Heinrich Heine University Düsseldorf and the Scientific Services at the Jackson Laboratory, including the Genome Technologies Service for their assistance with the work described herein and Research IT for providing computational infrastructure and support and the members of the Phillippy laboratory (NIH/NHGRI) for their Verkko support; and the people who contributed samples as part of the 1000 Genomes Project.


The prevalence of highly repetitive sequences within the human Y chromosome has prevented its complete assembly to date1 and led to its systematic omission from genomic analyses. Here we present de novo assemblies of 43 Y chromosomes spanning 182,900 years of human evolution and report considerable diversity in size and structure. Half of the male-specific euchromatic region is subject to large inversions with a greater than twofold higher recurrence rate compared with all other chromosomes2. Ampliconic sequences associated with these inversions show differing mutation rates that are sequence context dependent, and some ampliconic genes exhibit evidence for concerted evolution with the acquisition and purging of lineage-specific pseudogenes. The largest heterochromatic region in the human genome, Yq12, is composed of alternating repeat arrays that show extensive variation in the number, size and distribution, but retain a 1:1 copy-number ratio. Finally, our data suggest that the boundary between the recombining pseudoautosomal region 1 and the non-recombining portions of the X and Y chromosomes lies 500 kb away from the currently established1 boundary. The availability of fully sequence-resolved Y chromosomes from multiple individuals provides a unique opportunity for identifying new associations of traits with specific Y-chromosomal variants and garnering insights into the evolution and function of complex regions of the human genome.