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<p>Centromeres are essential chromosomal regions that ensure accurate chromosome segregation during cell division, yet their highly repetitive sequence has historically hindered their complete assembly and characterization<sup><CitationRef CitationID="CR1">1</CitationRef></sup>. 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 centromeres from diverse individuals representing 5 continental and&#xa0;28 population groups. Using bioinformatic tools tailored for centromeres, we identify variation, including 226 centromere haplotypes and 1,870 α-satellite higher-order repeat variants. While most centromeres have a single kinetochore site, we find that&#xa0;around 6% have di-kinetochores, and less than 1% have tri-kinetochores, which we confirm using long-read chromatin profiling and multigenerational inheritance. We also show that kinetochore position is closely associated with the&#xa0;underlying sequence and structure of the centromere. To understand the nature of evolutionary change, we compared these centromeres to 5,747 centromeres assembled by the Human Pangenome Reference Consortium. We show that centromeres have a 20-fold variation in mutation rate, and a subset of centromeres has evidence of archaic hominin introgression. We validate these mutation rates in a 4-generation, 28-member family and show that the kinetochore site is the most rapidly mutating region in the centromere. We propose a model that reveals an ‘arms race’ between centromeric sequence and proteins, with frequent mutations within the kinetochore&#xa0;site that lead to changes in genetic and epigenetic landscapes and, ultimately, rapid evolution of these critically important regions.</p>

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A global view of human centromere variation and evolution

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Shenghan Gao,
  • Keisuke K. Oshima,
  • Shu-Cheng Chuang,
  • Mark Loftus,
  • Tamara A. Potapova,
  • Annalaura Montanari,
  • David S. Gordon,
  • Zikun Yang,
  • Hufsah Ashraf,
  • Peter A. Audano,
  • Marcelo Ayllon,
  • Andrey Azov,
  • Parithi Balachandran,
  • Anna O. Basile,
  • Christine R. Beck,
  • Marc Jan Bonder,
  • Lucy Brooks,
  • Marta Byrska-Bishop,
  • Mark J. P. Chaisson,
  • Zechen Chong,
  • André Corvelo,
  • Jonathan Crabtree,
  • Scott E. Devine,
  • Peter Ebert,
  • Jana Ebler,
  • Evan E. Eichler,
  • Aine Fairbrother-Browne,
  • Chia-Hsuan Fan,
  • Mallory Freeberg,
  • Mark B. Gerstein,
  • Bida Gu,
  • Pille Hallast,
  • Patrick Hasenfeld,
  • Mir Henglin,
  • Kendra Hoekzema,
  • Kaili Hu,
  • Sarah Hunt,
  • Matthew Jensen,
  • Yunzhe Jiang,
  • Kwondo Kim,
  • Jan O. Korbel,
  • Youngjun Kwon,
  • Peter M. Lansdorp,
  • Charles Lee,
  • Tiffany Leung,
  • Jiaqi Li,
  • Chong Li,
  • Jiadong Lin,
  • Mark Loftus,
  • Tobias Marschall,
  • Gianni V. Martino,
  • Ryan E. Mills,
  • Yulia Mostovoy,
  • Katherine M. Munson,
  • Giuseppe Narzisi,
  • Lingbin Ni,
  • Carolyn Paisie,
  • Samarendra Pani,
  • Zishan Peng,
  • David Porubsky,
  • Timofey Prodanov,
  • Keon Rabbani,
  • Tobias Rausch,
  • Xinghua Shi,
  • Yuwei Song,
  • Kaitlyn Sun,
  • Likhitha Surapaneni,
  • Michael E. Talkowski,
  • Vasiliki Tsapalou,
  • Andres Veidenberg,
  • Feyza Yilmaz,
  • DongAhn Yoo,
  • Xuefang Zhao,
  • Weichen Zhou,
  • Qihui Zhu,
  • Michael C. Zody,
  • Derek Albracht,
  • Ivan A. Alexandrov,
  • Jamie Allen,
  • Alawi A. Alsheikh-Ali,
  • Nicolas Altemose,
  • Casey Andrews,
  • Dmitry Antipov,
  • Lucinda Antonacci-Fulton,
  • Mobin Asri,
  • Jennifer R. Balacco,
  • Floris P. Barthel,
  • Edward A. Belter Jr,
  • Halle D. Bender,
  • Andrew P. Blair,
  • Davide Bolognini,
  • Katherine E. Bonini,
  • Christina Boucher,
  • Guillaume Bourque,
  • Silvia Buonaiuto,
  • Shuo Cao,
  • Andrew Carroll,
  • Ann M. Mc Cartney,
  • Monika Cechova,
  • Pi-Chuan Chang,
  • Xian Chang,
  • Jitender Cheema,
  • Haoyu Cheng,
  • Claudio Ciofi,
  • Hiram Clawson,
  • Sarah Cody,
  • Vincenza Colonna,
  • Holland C. Conwell,
  • Robert Cook-Deegan,
  • Mark Diekhans,
  • Maria Angela Diroma,
  • Daniel Doerr,
  • Zheng Dong,
  • Danilo Dubocanin,
  • Richard Durbin,
  • Jordan M. Eizenga,
  • Parsa Eskandar,
  • Eddie Ferro,
  • Anna-Sophie Fiston-Lavier,
  • Sarah M. Ford,
  • Willard W. Ford,
  • Giulio Formenti,
  • Adam Frankish,
  • Mallory A. Freeberg,
  • Qichen Fu,
  • Stephanie M. Fullerton,
  • Robert S. Fulton,
  • Yan Gao,
  • Gage H. Garcia,
  • Obed A. Garcia,
  • Joshua M. V. Gardner,
  • Shilpa Garg,
  • Erik Garrison,
  • Nanibaa’ A. Garrison,
  • John E. Garza,
  • Margarita Geleta,
  • Mohammadmersad Ghorbani,
  • Tina A. Graves-Lindsay,
  • Richard E. Green,
  • Cristian Groza,
  • Andrea Guarracino,
  • Melissa Gymrek,
  • Maximilian Haeussler,
  • Leanne Haggerty,
  • Ira M. Hall,
  • Nancy F. Hansen,
  • Yue Hao,
  • Mohammad Amiruddin Hashmi,
  • David Haussler,
  • Prajna Hebbar,
  • Peter Heringer,
  • Glenn Hickey,
  • Todd L. Hillaker,
  • S. Nakib Hossain,
  • Neng Huang,
  • Sarah E. Hunt,
  • Toby Hunt,
  • Alexander G. Ioannidis,
  • Nafiseh Jafarzadeh,
  • Nivesh Jain,
  • Erich D. Jarvis,
  • Maryam Jehangir,
  • Juan Jiang,
  • Eimear E. Kenny,
  • Juhyun Kim,
  • Bonhwang Koo,
  • Sergey Koren,
  • Milinn Kremitzki,
  • Charles H. Langley,
  • Ben Langmead,
  • Heather A. Lawson,
  • Daofeng Li,
  • Heng Li,
  • Wen-Wei Liao,
  • Tianjie Liu,
  • Ryan Lorig-Roach,
  • Jonathan LoTempio Jr,
  • Hailey Loucks,
  • Jane E. Loveland,
  • Jianguo Lu,
  • Shuangjia Lu,
  • Julian K. Lucas,
  • Walfred Ma,
  • Juan F. Macias-Velasco,
  • Kateryna D. Makova,
  • Maximillian G. Marin,
  • Christopher Markovic,
  • Franco L. Marsico,
  • Fergal J. Martin,
  • Mira Mastoras,
  • Capucine Mayoud,
  • Brandy McNulty,
  • Jack A. Medico,
  • Julian M. Menendez,
  • Karen H. Miga,
  • Anna Minkina,
  • Matthew W. Mitchell,
  • Saswat K. Mohanty,
  • Younes Mokrab,
  • Jean Monlong,
  • Shabir Moosa,
  • Avelina Moreno-Ochando,
  • Shinichi Morishita,
  • Jonathan M. Mudge,
  • Njagi Mwaniki,
  • Nasna Nassir,
  • Chiara Natali,
  • Shloka Negi,
  • Adam M. Novak,
  • Faith Okamoto,
  • Pilar N. Ossorio,
  • Chie Owa,
  • Sadye Paez,
  • Benedict Paten,
  • Clelia Peano,
  • Adam M. Phillippy,
  • Brandon D. Pickett,
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  • Nadia Pisanti,
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  • Pjotr Prins,
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  • T. Rhyker Ranallo-Benavidez,
  • Brian J. Raney,
  • Mikko Rautiainen,
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  • Luyao Ren,
  • Arang Rhie,
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  • Samuel Sacco,
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  • Michael C. Schatz,
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  • William E. Seligmann,
  • Mahsa Shabani,
  • Kishwar Shafin,
  • Shadi Shahatit,
  • Ruhollah Shemirani,
  • Vikram S. Shivakumar,
  • Swati Sinha,
  • Jouni Sirén,
  • Linnéa Smeds,
  • Steven J. Solar,
  • Marco Sollitto,
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  • Andrew B. Stergachis,
  • Marie-Marthe Suner,
  • Yoshihiko Suzuki,
  • Arda Söylev,
  • Ahmad Abou Tayoun,
  • Jack A. S. Tierney,
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  • Mohammed Uddin,
  • Matteo Tommaso Ungaro,
  • Rahul Varki,
  • Flavia Villani,
  • Ivo Violich,
  • Mitchell R. Vollger,
  • Brian P. Walenz,
  • Charles Wang,
  • Lisa E. Wang,
  • Ting Wang,
  • Aaron M. Wenger,
  • Conor V. Whelan,
  • Zilan Xin,
  • Zheng Xu,
  • Kai Ye,
  • Wenjin Zhang,
  • Ying Zhou,
  • Xiaoyu Zhuo,
  • Giulia Zunino,
  • Yafei Mao,
  • PingHsun Hsieh,
  • Jennifer L. Gerton,
  • Miriam K. Konkel,
  • Mario Ventura,
  • Glennis A. Logsdon

摘要

Centromeres are essential chromosomal regions that ensure accurate chromosome segregation during cell division, yet their highly repetitive sequence has historically hindered their complete assembly and characterization1. 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 centromeres from diverse individuals representing 5 continental and 28 population groups. Using bioinformatic tools tailored for centromeres, we identify variation, including 226 centromere haplotypes and 1,870 α-satellite higher-order repeat variants. While most centromeres have a single kinetochore site, we find that around 6% have di-kinetochores, and less than 1% have tri-kinetochores, which we confirm using long-read chromatin profiling and multigenerational inheritance. We also show that kinetochore position is closely associated with the underlying sequence and structure of the centromere. To understand the nature of evolutionary change, we compared these centromeres to 5,747 centromeres assembled by the Human Pangenome Reference Consortium. We show that centromeres have a 20-fold variation in mutation rate, and a subset of centromeres has evidence of archaic hominin introgression. We validate these mutation rates in a 4-generation, 28-member family and show that the kinetochore site is the most rapidly mutating region in the centromere. We propose a model that reveals an ‘arms race’ between centromeric sequence and proteins, with frequent mutations within the kinetochore site that lead to changes in genetic and epigenetic landscapes and, ultimately, rapid evolution of these critically important regions.