The structure, function and evolution of a complete human chromosome 8

Glennis A. Logsdon, Mitchell R. Vollger, PingHsun Hsieh, Yafei Mao, Mikhail A. Liskovykh, Sergey Koren, Sergey Nurk, Ludovica Mercuri, Philip C. Dishuck, Arang Rhie, Leonardo G. Lima, Tatiana Dvorkina, David Porubsky, William T. Harvey, Alla Mikheenko, Andrey V. Bzikadze, Milinn Kremitzki, Tina A. Graves-Lindsay, Chirag Jain, Kendra Hoekzema, Shwetha C. Murali, Katherine M. Munson, Carl Baker, Melanie Sorensen, Alexandra M. Lewis, Urvashi Surti, Jennifer L. Gerton, Vladimir Larionov, Mario Ventura, Karen H. Miga, Adam M. Phillippy and Evan E. Eichler ()
Additional contact information
Glennis A. Logsdon: University of Washington School of Medicine
Mitchell R. Vollger: University of Washington School of Medicine
PingHsun Hsieh: University of Washington School of Medicine
Yafei Mao: University of Washington School of Medicine
Mikhail A. Liskovykh: National Cancer Institute
Sergey Koren: National Institutes of Health
Sergey Nurk: National Institutes of Health
Ludovica Mercuri: University of Bari, Aldo Moro
Philip C. Dishuck: University of Washington School of Medicine
Arang Rhie: National Institutes of Health
Leonardo G. Lima: Stowers Institute for Medical Research
Tatiana Dvorkina: Saint Petersburg State University
David Porubsky: University of Washington School of Medicine
William T. Harvey: University of Washington School of Medicine
Alla Mikheenko: Saint Petersburg State University
Andrey V. Bzikadze: University of California, San Diego
Milinn Kremitzki: Washington University School of Medicine
Tina A. Graves-Lindsay: Washington University School of Medicine
Chirag Jain: National Institutes of Health
Kendra Hoekzema: University of Washington School of Medicine
Shwetha C. Murali: University of Washington School of Medicine
Katherine M. Munson: University of Washington School of Medicine
Carl Baker: University of Washington School of Medicine
Melanie Sorensen: University of Washington School of Medicine
Alexandra M. Lewis: University of Washington School of Medicine
Urvashi Surti: University of Pittsburgh
Jennifer L. Gerton: Stowers Institute for Medical Research
Vladimir Larionov: National Cancer Institute
Mario Ventura: University of Bari, Aldo Moro
Karen H. Miga: University of California, Santa Cruz
Adam M. Phillippy: National Institutes of Health
Evan E. Eichler: University of Washington School of Medicine

Nature, 2021, vol. 593, issue 7857, 101-107

Abstract: Abstract The complete assembly of each human chromosome is essential for understanding human biology and evolution1,2. Here we use complementary long-read sequencing technologies to complete the linear assembly of human chromosome 8. Our assembly resolves the sequence of five previously long-standing gaps, including a 2.08-Mb centromeric α-satellite array, a 644-kb copy number polymorphism in the β-defensin gene cluster that is important for disease risk, and an 863-kb variable number tandem repeat at chromosome 8q21.2 that can function as a neocentromere. We show that the centromeric α-satellite array is generally methylated except for a 73-kb hypomethylated region of diverse higher-order α-satellites enriched with CENP-A nucleosomes, consistent with the location of the kinetochore. In addition, we confirm the overall organization and methylation pattern of the centromere in a diploid human genome. Using a dual long-read sequencing approach, we complete high-quality draft assemblies of the orthologous centromere from chromosome 8 in chimpanzee, orangutan and macaque to reconstruct its evolutionary history. Comparative and phylogenetic analyses show that the higher-order α-satellite structure evolved in the great ape ancestor with a layered symmetry, in which more ancient higher-order repeats locate peripherally to monomeric α-satellites. We estimate that the mutation rate of centromeric satellite DNA is accelerated by more than 2.2-fold compared to the unique portions of the genome, and this acceleration extends into the flanking sequence.

Date: 2021
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DOI: 10.1038/s41586-021-03420-7

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