The variation and evolution of complete human centromeres

Glennis A. Logsdon, Allison N. Rozanski, Fedor Ryabov, Tamara Potapova, Valery A. Shepelev, Claudia R. Catacchio, David Porubsky, Yafei Mao, DongAhn Yoo, Mikko Rautiainen, Sergey Koren, Sergey Nurk, Julian K. Lucas, Kendra Hoekzema, Katherine M. Munson, Jennifer L. Gerton, Adam M. Phillippy, Mario Ventura, Ivan A. Alexandrov and Evan E. Eichler ()
Additional contact information
Glennis A. Logsdon: University of Washington School of Medicine
Allison N. Rozanski: University of Washington School of Medicine
Fedor Ryabov: Masters Program in National Research University Higher School of Economics
Tamara Potapova: Stowers Institute for Medical Research
Valery A. Shepelev: Institute of Molecular Genetics
Claudia R. Catacchio: University of Bari Aldo Moro
David Porubsky: University of Washington School of Medicine
Yafei Mao: Shanghai Jiao Tong University
DongAhn Yoo: University of Washington School of Medicine
Mikko Rautiainen: National Institutes of Health
Sergey Koren: National Institutes of Health
Sergey Nurk: National Institutes of Health
Julian K. Lucas: University of California, Santa Cruz
Kendra Hoekzema: University of Washington School of Medicine
Katherine M. Munson: University of Washington School of Medicine
Jennifer L. Gerton: Stowers Institute for Medical Research
Adam M. Phillippy: National Institutes of Health
Mario Ventura: University of Bari Aldo Moro
Ivan A. Alexandrov: Tel Aviv University
Evan E. Eichler: University of Washington School of Medicine

Nature, 2024, vol. 629, issue 8010, 136-145

Abstract: Abstract Human centromeres have been traditionally very difficult to sequence and assemble owing to their repetitive nature and large size1. As a result, patterns of human centromeric variation and models for their evolution and function remain incomplete, despite centromeres being among the most rapidly mutating regions2,3. Here, using long-read sequencing, we completely sequenced and assembled all centromeres from a second human genome and compared it to the finished reference genome4,5. We find that the two sets of centromeres show at least a 4.1-fold increase in single-nucleotide variation when compared with their unique flanks and vary up to 3-fold in size. Moreover, we find that 45.8% of centromeric sequence cannot be reliably aligned using standard methods owing to the emergence of new α-satellite higher-order repeats (HORs). DNA methylation and CENP-A chromatin immunoprecipitation experiments show that 26% of the centromeres differ in their kinetochore position by >500 kb. To understand evolutionary change, we selected six chromosomes and sequenced and assembled 31 orthologous centromeres from the common chimpanzee, orangutan and macaque genomes. Comparative analyses reveal a nearly complete turnover of α-satellite HORs, with characteristic idiosyncratic changes in α-satellite HORs for each species. Phylogenetic reconstruction of human haplotypes supports limited to no recombination between the short (p) and long (q) arms across centromeres and reveals that novel α-satellite HORs share a monophyletic origin, providing a strategy to estimate the rate of saltatory amplification and mutation of human centromeric DNA.

Date: 2024
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DOI: 10.1038/s41586-024-07278-3

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