{
  "abstract": "Centromeres are essential for accurate chromosome segregation during cell division, yet their highly repetitive sequence has historically hindered their complete assembly and characterization. Consequently, the full spectrum of centromere diversity across individuals, populations, and evolutionary contexts remains largely unexplored. Here, we address this gap in knowledge by assembling and characterizing 2,110 complete human centromeres from a diverse cohort of individuals representing 5 continental and 28 population groups. By developing a novel suite of bioinformatic tools tailored for centromeric regions, we uncover previously unknown variation within centromeres, including 226 novel centromere haplotypes and 1,870 new α-satellite higher-order repeat (HOR) variants. We find that mobile element insertions are present in 30% of centromeres, with chromosome 16 harboring Alu elements within the kinetochore site at an 11-fold higher frequency than expected. While most centromeres have a single kinetochore site, 6% of them have di-kinetochores, and <<1% have tri-kinetochores, which we confirm with long-read CENP-A CUT&RUN, DiMeLo-seq, and multi-generational inheritance. We further show that the position of the kinetochore is not random and is, instead, closely associated with the underlying sequence and structure of the centromere. To understand the nature of evolutionary change, we compared 2,110 complete human centromeres to 5,747 complete centromeres recently assembled from the Human Pangenome Reference Consortium. We show that centromeres have a >50-fold variation in mutation rate, with the most rapidly mutating centromeres on chromosome 1 and the slowest mutating centromeres on chromosome Y. Additionally, a subset of centromeres show evidence of introgression from archaic hominins, shaping their sequence, structure, and evolutionary history. We validate these centromere mutation rates in a four-generation family, spanning 28 family members and 483 accurately assembled centromeres, and show that the kinetochore site is the most rapidly mutating region in the centromere, with twofold more single-nucleotide variants than the rest of the centromeric α-satellite HOR array on average. We propose a model that reveals an ‘arms race’ between centromeric sequence and proteins, with frequent mutations within the site of the kinetochore that lead to changes in genetic and epigenetic landscapes and, ultimately, rapid evolution of these critically important regions.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Genetics, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA",
    "University of Pennsylvania",
    "Department of Genetics & Biochemistry, Clemson University, Clemson, SC, USA",
    "Institute for Human Genetics, Clemson University, Greenwood, SC, USA",
    "The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA",
    "The Jackson Laboratory for Genomic Medicine",
    "Stowers Institute for Medical Research, Kansas City, MO, USA",
    "University of Bari, Aldo Moro",
    "Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, Bari, Italy",
    "University of Minnesota",
    "Department of Genetics, Cell Biology, and Development, University of Minnesota, Twin Cities, MN, USA",
    "University of Arizona",
    "Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China",
    "Zhiyuan College, Shanghai Jiao Tong University, Shanghai, China",
    "Clemson University",
    "Center for Digital Medicine, Heinrich Heine University, Düsseldorf, Germany",
    "Institute for Medical Biometry and Bioinformatics, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany",
    "University of Bari Aldo Moro: Universita degli Studi di Bari Aldo Moro",
    "Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA",
    "European Molecular Biology Laboratory, Wellcome Genome Campus, European Bioinformatics Institute, Cambridge, UK",
    "New York Genome Center, New York, NY, USA",
    "The University of Connecticut Health Center, Farmington, CT, USA",
    "Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands",
    "Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany",
    "Oncode Institute, Utrecht, The Netherlands",
    "Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA",
    "Department of Biomedical Informatics and Data Science, Heersink School of Medicine, University of Alabama, Birmingham, AL, USA",
    "Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA",
    "Core Unit Bioinformatics, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany",
    "Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA",
    "European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cambridge, UK",
    "Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA",
    "Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA",
    "Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany",
    "Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada",
    "Department of Computer and Information Sciences, Temple University, Philadelphia, PA, USA",
    "Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, PA, USA",
    "Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA",
    "Cardiovascular Research Institute and Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA, USA",
    "Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 100,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Shenghan Gao",
      "orcid": "0000-0002-3810-6527"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Keisuke K. Oshima",
      "orcid": "0009-0002-2229-8998"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Shu-Cheng Chuang",
      "orcid": "0000-0002-3114-1880"
    },
    {
      "affs": [
        2,
        3,
        4,
        5
      ],
      "name": "Mark G. Loftus",
      "orcid": "0000-0002-6279-6855"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Tamara Potapova",
      "orcid": "0000-0003-2761-1795"
    },
    {
      "affs": [
        8,
        9
      ],
      "name": "Annalaura Montanari"
    },
    {
      "affs": [
        10,
        11
      ],
      "name": "David Gordon",
      "orcid": "0000-0001-6552-4022"
    },
    {
      "affs": [
        12,
        13,
        14
      ],
      "name": "Zikun Yang",
      "orcid": "0000-0002-8834-6377"
    },
    {
      "affs": [
        15,
        16,
        17
      ],
      "name": "Hufsah Ashraf",
      "orcid": "0000-0001-7760-0627"
    },
    {
      "affs": [
        4,
        1
      ],
      "name": "Peter A. Audano",
      "orcid": "0000-0002-5187-0415"
    },
    {
      "affs": [
        18
      ],
      "name": "Marcelo Ayllon",
      "orcid": "0000-0003-0360-5446"
    },
    {
      "affs": [
        19
      ],
      "name": "Andrey G Azov",
      "orcid": "0000-0002-3832-4604"
    },
    {
      "affs": [
        4
      ],
      "name": "Parithi Balachandran",
      "orcid": "0000-0003-3256-1403"
    },
    {
      "affs": [
        20
      ],
      "name": "Anna Okula Basile",
      "orcid": "0000-0001-5112-5880"
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    {
      "affs": [
        4,
        21
      ],
      "name": "Christine R. Beck",
      "orcid": "0000-0001-7821-8489"
    },
    {
      "affs": [
        22,
        23,
        24
      ],
      "name": "Marc Jan Bonder",
      "orcid": "0000-0002-8431-3180"
    },
    {
      "affs": [
        19
      ],
      "name": "Lucy Brooks",
      "orcid": "0000-0001-9778-4136"
    },
    {
      "affs": [
        20
      ],
      "name": "Marta S. Byrska‐Bishop",
      "orcid": "0000-0002-9118-1032"
    },
    {
      "affs": [
        25
      ],
      "name": "Mark Chaisson",
      "orcid": "0000-0001-5395-1457"
    },
    {
      "affs": [
        26
      ],
      "name": "Zechen Chong",
      "orcid": "0000-0001-5750-1808"
    },
    {
      "affs": [
        20
      ],
      "name": "André Corvelo",
      "orcid": "0000-0003-0989-7806"
    },
    {
      "affs": [
        27
      ],
      "name": "Jonathan Crabtree",
      "orcid": "0000-0002-7286-5690"
    },
    {
      "affs": [
        27
      ],
      "name": "Scott E. Devine",
      "orcid": "0000-0001-7629-8331"
    },
    {
      "affs": [
        15,
        28
      ],
      "name": "Peter Ebert",
      "orcid": "0000-0001-7441-532X"
    },
    {
      "affs": [
        15,
        16
      ],
      "name": "Jana Ebler",
      "orcid": "0000-0002-0382-3702"
    },
    {
      "affs": [
        18,
        29
      ],
      "name": "Evan E. Eichler",
      "orcid": "0000-0002-8246-4014"
    },
    {
      "affs": [
        19
      ],
      "name": "Aine Fairbrother-Browne",
      "orcid": "0000-0002-7196-1410"
    },
    {
      "affs": [
        26
      ],
      "name": "Chia-Hsuan Fan",
      "orcid": "0009-0000-9517-123X"
    },
    {
      "affs": [
        30,
        19
      ],
      "name": "Mallory Freeberg"
    },
    {
      "affs": [
        31,
        32
      ],
      "name": "Mark Gerstein",
      "orcid": "0000-0002-9746-3719"
    },
    {
      "affs": [
        25
      ],
      "name": "Bida Gu",
      "orcid": "0000-0001-8575-997X"
    },
    {
      "affs": [
        4
      ],
      "name": "Pille Hallast",
      "orcid": "0000-0002-0588-3987"
    },
    {
      "affs": [
        33
      ],
      "name": "Patrick Hasenfeld",
      "orcid": "0000-0003-2319-2482"
    },
    {
      "affs": [
        15,
        16
      ],
      "name": "Mir Henglin",
      "orcid": "0000-0003-3604-4868"
    },
    {
      "affs": [
        18
      ],
      "name": "Kendra Hoekzema",
      "orcid": "0000-0002-8058-0177"
    },
    {
      "affs": [
        26
      ],
      "name": "Kaili Hu"
    },
    {
      "affs": [
        30,
        19
      ],
      "name": "Sarah Hunt",
      "orcid": "0000-0002-8350-1235"
    },
    {
      "affs": [
        31,
        32
      ],
      "name": "Matthew Jensen",
      "orcid": "0000-0002-5153-8543"
    },
    {
      "affs": [
        31,
        32
      ],
      "name": "Yunzhe Jiang",
      "orcid": "0000-0001-8768-0050"
    },
    {
      "affs": [
        4
      ],
      "name": "Kwondo Kim",
      "orcid": "0000-0001-8254-528X"
    },
    {
      "affs": [
        33
      ],
      "name": "Jan O. Korbel",
      "orcid": "0000-0002-2798-3794"
    },
    {
      "affs": [
        18
      ],
      "name": "Youngjun Kwon",
      "orcid": "0000-0002-5024-2134"
    },
    {
      "affs": [
        34
      ],
      "name": "Peter M. Lansdorp",
      "orcid": "0000-0001-7435-1071"
    },
    {
      "affs": [
        4
      ],
      "name": "Charles Lee",
      "orcid": "0000-0001-7317-6662"
    },
    {
      "affs": [
        34
      ],
      "name": "Tiffany Y. Leung"
    },
    {
      "affs": [
        31,
        32
      ],
      "name": "Jiaqi Li",
      "orcid": "0000-0002-6796-335X"
    },
    {
      "affs": [
        35,
        36
      ],
      "name": "Chong Li"
    },
    {
      "affs": [
        18
      ],
      "name": "Jiadong Lin"
    },
    {
      "affs": [
        2,
        3,
        4
      ],
      "name": "Mark G. Loftus",
      "orcid": "0000-0002-6279-6855"
    },
    {
      "affs": [
        15,
        16
      ],
      "name": "Tobias Marschall",
      "orcid": "0000-0002-9376-1030"
    },
    {
      "affs": [
        2
      ],
      "name": "Gianni V. Martino",
      "orcid": "0009-0005-4143-7465"
    },
    {
      "affs": [
        37
      ],
      "name": "Ryan E. Mills"
    },
    {
      "affs": [
        38
      ],
      "name": "Yulia Mostovoy",
      "orcid": "0000-0002-9544-3538"
    },
    {
      "affs": [
        18
      ],
      "name": "Katherine M. Munson",
      "orcid": "0000-0001-8413-6498"
    },
    {
      "affs": [
        20
      ],
      "name": "Giuseppe Narzisi",
      "orcid": "0000-0003-1118-8849"
    },
    {
      "affs": [
        18
      ],
      "name": "Lingbin Ni",
      "orcid": "0000-0001-5046-934X"
    },
    {
      "affs": [
        4
      ],
      "name": "Carolyn A. Paisie",
      "orcid": "0000-0003-4306-4154"
    },
    {
      "affs": [
        15,
        16
      ],
      "name": "Samarendra Pani",
      "orcid": "0009-0002-2037-2533"
    },
    {
      "affs": [
        26
      ],
      "name": "Zishan Peng"
    },
    {
      "affs": [
        18,
        39
      ],
      "name": "David Porubskỳ",
      "orcid": "0000-0001-8414-8966"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7es0nd2myem4h.bib",
  "cited_by": 27,
  "doi": "10.1038/s41586-026-10841-9",
  "fulltext_url": null,
  "id": "7es0nd2myem4h",
  "issns": [
    "0028-0836",
    "1476-4687"
  ],
  "landing_url": "https://doi.org/10.1038/s41586-026-10841-9",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1110|Chromosomal and Genetic Variations"
    ],
    [
      "openalex",
      "1311|Chromosomal and Genetic Variations"
    ]
  ],
  "openalex": "W4417261234",
  "pdf_url": null,
  "pmcid": "PMC12822586",
  "pmid": "41573929",
  "published": "2026-07-29",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/7es0nd2myem4h.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:50Z",
      "native_id": "W4417261234",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41586-026-10841-9"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1311|Chromosomal and Genetic Variations",
      "subfield": "genetics-genomics"
    },
    {
      "field": "biology",
      "origin": "openalex:1110|Chromosomal and Genetic Variations",
      "subfield": "plant-biology"
    }
  ],
  "title": "A global view of human centromere variation and evolution",
  "title_text": "A global view of human centromere variation and evolution",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T13:20:41Z",
  "url": "https://research.draconitic.com/paper/7es0nd2myem4h",
  "venue": "Nature",
  "versions": []
}