The variation and evolution of complete human centromeres.
The variation and evolution of complete human centromeres.
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完整人类着丝粒的变异和进化。
DOI：
10.1101/2023.05.30.542849
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Phillipp
中科院分区：
文献类型：
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作者：
Logsdon,GlennisA;Rozanski,AllisonN;Ryabov,Fedor;Potapova,Tamara;Shepelev,ValeryA;Mao,Yafei;Rautiainen,Mikko;Koren,Sergey;Nurk,Sergey;Porubsky,David;Lucas,JulianK;Hoekzema,Kendra;Munson,KatherineM;Gerton,JenniferL;Phillipp
由于人类着丝粒的重复性和大尺寸，传统上很难测序和组装。因此，人类着丝粒变异的模式及其进化和功能的模型仍然不完整，尽管着丝粒是突变最快的区域之一。在这里，使用长读序测序，我们完全测序并组装了来自第二个人类基因组的所有着丝粒，并将其与完成的参考基因组进行比较。我们发现，这两套着丝粒显示出至少4.1倍的增加，单核苷酸的变化相比，其独特的侧翼和变化高达3倍的大小。此外，我们发现，45.8%的着丝粒序列不能可靠地使用标准的方法进行比对，由于新的α-卫星高阶重复序列（HORs）的出现。DNA甲基化和CENP-A染色质免疫沉淀实验表明，26%的着丝粒在它们的动粒位置上相差>500 kb。为了理解进化的变化，我们选择了6条染色体，并从黑猩猩、猩猩和猕猴的基因组中测序和组装了31个正着丝粒。比较分析显示，几乎完全的周转α-卫星HORs，与每个物种的α-卫星HORs的特征特异质的变化。人类单倍型的系统发育重建支持跨着丝粒的短臂（p）和长臂（q）之间有限或无重组，并揭示新型α-卫星HOR具有单系起源，提供了估计跳跃扩增速率的策略和突变人类着丝粒DNA。
Human centromeres have been traditionally very difficult to sequence and assemble owing to their repetitive nature and large size. 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,. 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,. 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.