The variation and evolution of complete human centromeres

• 成果类型: Article
• 署名作者: Logsdon, Glennis A.; Rozanski, Allison N.; Ryabov, Fedor; Potapova, Tamara; Shepelev, Valery A.; Catacchio, Claudia R.; Porubsky, David; Mao, Yafei; Yoo, Dongahn; Rautiainen, Mikko; Koren, Sergey; Nurk, Sergey; Lucas, Julian K.; Hoekzema, Kendra; Munson, Katherine M.; Gerton, Jennifer L.; Phillippy, Adam M.; Ventura, Mario; Alexandrov, Ivan A.; Eichler, Evan E.
• 署名单位: University of Washington; University of Washington Seattle; HSE University (National Research University Higher School of Economics); Stowers Institute for Medical Research; Universita degli Studi di Bari Aldo Moro; Shanghai Jiao Tong University; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI); University of California System; University of California Santa Cruz; University of California System; University of California Santa Cruz; Tel Aviv University; Tel Aviv University; Sackler Faculty of Medicine; Tel Aviv University; University of Washington; University of Washington Seattle; Howard Hughes Medical Institute; University of Pennsylvania; University of Helsinki; Oxford Nanopore Technologies
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4049
• DOI: 10.1038/s41586-024-07278-3
• 发表日期: 2024-05-02
• 关键词: human genome; great ape; sequence; chromosomes; dna; ORGANIZATION; alignment; platform; region; mafft

摘要

Human centromeres have been traditionally very difficult to sequence and assemble owing to their repetitive nature and large size(1). 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 regions(2,3). Here, using long-read sequencing, we completely sequenced and assembled all centromeres from a second human genome and compared it to the finished reference genome(4,5). 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 alpha-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 alpha-satellite HORs, with characteristic idiosyncratic changes in alpha-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 alpha-satellite HORs share a monophyletic origin, providing a strategy to estimate the rate of saltatory amplification and mutation of human centromeric DNA.