The variation and evolution of complete human centromeres

作者：Glennis A. Logsdon, Allison N. Rozanski, Fedor Ryabov, Tamara Potapova, В. А. Шепелев, Claudia Rita Catacchio, David Porubskỳ, Yafei Mao, DongAhn Yoo, Mikko Rautiainen, Sergey Koren, Sergey Nurk, Julian Lucas, Kendra Hoekzema, Katherine M. Munson, Jennifer L. Gerton, Adam M. Phillippy, Mario Ventura, Ivan A. Alexandrov, Evan E. Eichler · 发表于：Nature · 年份：2024 · 被引用次数：207 · 研究领域：Chromosomal and Genetic Variations、Genomics and Phylogenetic Studies、Plant Virus Research Studies

Abstract 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 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 nove...