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Peer-reviewedCC BYNature

A global view of human centromere variation and evolution

  • Shenghan Gao1,2
  • Keisuke K. Oshima1,2
  • Shu-Cheng Chuang1,2
  • Mark G. Loftus3,4,5,6
  • Tamara Potapova7,8
  • Annalaura Montanari9,10
  • David Gordon11,12
  • Zikun Yang13,14,15
  • Hufsah Ashraf16,17,18
  • Peter A. Audano5,2
  • Marcelo Ayllon19
  • Andrey G Azov20
88 more authors
  • Parithi Balachandran5
  • Anna Okula Basile21
  • Christine R. Beck5,22
  • Marc Jan Bonder23,24,25
  • Lucy Brooks20
  • Marta S. Byrska‐Bishop21
  • Mark Chaisson26
  • Zechen Chong27
  • André Corvelo21
  • Jonathan Crabtree28
  • Scott E. Devine28
  • Peter Ebert16,29
  • Jana Ebler16,17
  • Evan E. Eichler19,30
  • Aine Fairbrother-Browne20
  • Chia-Hsuan Fan27
  • Mallory Freeberg31,20
  • Mark Gerstein32,33
  • Bida Gu26
  • Pille Hallast5
  • Patrick Hasenfeld34
  • Mir Henglin16,17
  • Kendra Hoekzema19
  • Kaili Hu27
  • Sarah Hunt31,20
  • Matthew Jensen32,33
  • Yunzhe Jiang32,33
  • Kwondo Kim5
  • Jan O. Korbel34
  • Youngjun Kwon19
  • Peter M. Lansdorp35
  • Charles Lee5
  • Tiffany Y. Leung35
  • Jiaqi Li32,33
  • Chong Li36,37
  • Jiadong Lin19
  • Mark G. Loftus3,4,5
  • Tobias Marschall16,17
  • Gianni V. Martino3
  • Ryan E. Mills38
  • Yulia Mostovoy39
  • Katherine M. Munson19
  • Giuseppe Narzisi21
  • Lingbin Ni19
  • Carolyn A. Paisie5
  • Samarendra Pani16,17
  • Zishan Peng27
  • David Porubskỳ19,40

60 listed; 100 in total.

40 affiliations
  1. 1Department of Genetics, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  2. 2University of Pennsylvania
  3. 3Department of Genetics & Biochemistry, Clemson University, Clemson, SC, USA
  4. 4Institute for Human Genetics, Clemson University, Greenwood, SC, USA
  5. 5The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
  6. 6The Jackson Laboratory for Genomic Medicine
  7. 7Stowers Institute for Medical Research, Kansas City, MO, USA
  8. 8University of Bari, Aldo Moro
  9. 9Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, Bari, Italy
  10. 10University of Minnesota
  11. 11Department of Genetics, Cell Biology, and Development, University of Minnesota, Twin Cities, MN, USA
  12. 12University of Arizona
  13. 13Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
  14. 14Zhiyuan College, Shanghai Jiao Tong University, Shanghai, China
  15. 15Clemson University
  16. 16Center for Digital Medicine, Heinrich Heine University, Düsseldorf, Germany
  17. 17Institute for Medical Biometry and Bioinformatics, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
  18. 18University of Bari Aldo Moro: Universita degli Studi di Bari Aldo Moro
  19. 19Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
  20. 20European Molecular Biology Laboratory, Wellcome Genome Campus, European Bioinformatics Institute, Cambridge, UK
  21. 21New York Genome Center, New York, NY, USA
  22. 22The University of Connecticut Health Center, Farmington, CT, USA
  23. 23Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  24. 24Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
  25. 25Oncode Institute, Utrecht, The Netherlands
  26. 26Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
  27. 27Department of Biomedical Informatics and Data Science, Heersink School of Medicine, University of Alabama, Birmingham, AL, USA
  28. 28Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
  29. 29Core Unit Bioinformatics, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
  30. 30Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA
  31. 31European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cambridge, UK
  32. 32Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
  33. 33Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
  34. 34Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
  35. 35Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada
  36. 36Department of Computer and Information Sciences, Temple University, Philadelphia, PA, USA
  37. 37Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, PA, USA
  38. 38Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA
  39. 39Cardiovascular Research Institute and Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA, USA
  40. 40Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
Open at sourceDOICite

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.

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Cite

BibTeXRIS
BibTeX
@article{gao2026global,
  title = {{A global view of human centromere variation and evolution}},
  author = {Shenghan Gao and Keisuke K. Oshima and Shu-Cheng Chuang and Mark G. Loftus and Tamara Potapova and Annalaura Montanari and David Gordon and Zikun Yang and Hufsah Ashraf and Peter A. Audano and Marcelo Ayllon and Andrey G Azov and Parithi Balachandran and Anna Okula Basile and Christine R. Beck and Marc Jan Bonder and Lucy Brooks and Marta S. Byrska‐Bishop and Mark Chaisson and Zechen Chong and André Corvelo and Jonathan Crabtree and Scott E. Devine and Peter Ebert and Jana Ebler and Evan E. Eichler and Aine Fairbrother-Browne and Chia-Hsuan Fan and Mallory Freeberg and Mark Gerstein and Bida Gu and Pille Hallast and Patrick Hasenfeld and Mir Henglin and Kendra Hoekzema and Kaili Hu and Sarah Hunt and Matthew Jensen and Yunzhe Jiang and Kwondo Kim and Jan O. Korbel and Youngjun Kwon and Peter M. Lansdorp and Charles Lee and Tiffany Y. Leung and Jiaqi Li and Chong Li and Jiadong Lin and Mark G. Loftus and Tobias Marschall and Gianni V. Martino and Ryan E. Mills and Yulia Mostovoy and Katherine M. Munson and Giuseppe Narzisi and Lingbin Ni and Carolyn A. Paisie and Samarendra Pani and Zishan Peng and David Porubskỳ},
  journal = {Nature},
  year = {2026},
  month = jul,
  doi = {10.1038/s41586-026-10841-9},
  url = {https://doi.org/10.1038/s41586-026-10841-9},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - A global view of human centromere variation and evolution
AU  - Shenghan Gao
AU  - Keisuke K. Oshima
AU  - Shu-Cheng Chuang
AU  - Mark G. Loftus
AU  - Tamara Potapova
AU  - Annalaura Montanari
AU  - David Gordon
AU  - Zikun Yang
AU  - Hufsah Ashraf
AU  - Peter A. Audano
AU  - Marcelo Ayllon
AU  - Andrey G Azov
AU  - Parithi Balachandran
AU  - Anna Okula Basile
AU  - Christine R. Beck
AU  - Marc Jan Bonder
AU  - Lucy Brooks
AU  - Marta S. Byrska‐Bishop
AU  - Mark Chaisson
AU  - Zechen Chong
AU  - André Corvelo
AU  - Jonathan Crabtree
AU  - Scott E. Devine
AU  - Peter Ebert
AU  - Jana Ebler
AU  - Evan E. Eichler
AU  - Aine Fairbrother-Browne
AU  - Chia-Hsuan Fan
AU  - Mallory Freeberg
AU  - Mark Gerstein
AU  - Bida Gu
AU  - Pille Hallast
AU  - Patrick Hasenfeld
AU  - Mir Henglin
AU  - Kendra Hoekzema
AU  - Kaili Hu
AU  - Sarah Hunt
AU  - Matthew Jensen
AU  - Yunzhe Jiang
AU  - Kwondo Kim
AU  - Jan O. Korbel
AU  - Youngjun Kwon
AU  - Peter M. Lansdorp
AU  - Charles Lee
AU  - Tiffany Y. Leung
AU  - Jiaqi Li
AU  - Chong Li
AU  - Jiadong Lin
AU  - Mark G. Loftus
AU  - Tobias Marschall
AU  - Gianni V. Martino
AU  - Ryan E. Mills
AU  - Yulia Mostovoy
AU  - Katherine M. Munson
AU  - Giuseppe Narzisi
AU  - Lingbin Ni
AU  - Carolyn A. Paisie
AU  - Samarendra Pani
AU  - Zishan Peng
AU  - David Porubskỳ
PY  - 2026
DA  - 2026/07/29
JO  - Nature
DO  - 10.1038/s41586-026-10841-9
UR  - https://doi.org/10.1038/s41586-026-10841-9
AB  - 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.
SN  - 0028-0836
SN  - 1476-4687
ER  -