小柯机器人

美国华盛顿大学医学院Evan E. Eichler小组取得一项新突破。他们的最新研究揭示了人完整8号染色体的结构、功能和进化关系。该项研究成果在线发表在2021年4月7日的《自然》上。

使用互补长读测序技术，研究人员完成了人8号染色体的线性组装。该组装克服了以前长期存在的五个缺口序列，包括一个2.08Mb着丝粒α-卫星阵列、在644kb拷贝数多态性β-防御素基因簇中这种蛋白质对疾病发生很重要，并且在8q21.2号染色体上有一个863kb可变数目的串联重复序列，其可以充当新着丝粒。研究表明除了73 kb的低甲基化区域，着丝粒α卫星序列通常被甲基化，其中富含高浓度CENP-A的核小体各种高阶α卫星与动粒的位置一致。

此外，研究人员还揭示了人二倍体基因组中着丝粒的整体组织和甲基化模式。使用双重长读测序方法，研究人员完成了黑猩猩、猩猩和猕猴中第8号染色体直系着丝粒的高质量装配草图，以重建其进化史。比较和系统发育分析表明，高阶α-卫星结构在层状对称祖先中演化，其中更古老的高阶重复序列位于单体α-卫星的外围。研究人员估计，与基因组的独特序列相比，着丝粒卫星DNA的突变率增加了2.2倍以上，并且这种加速可扩展到侧翼序列中。

据悉，人单个染色体的完整组装对于理解人类生物学和进化是必不可少的。

附：英文原文

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

Author: 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. de 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, Evan E. Eichler

Issue&Volume: 2021-04-07

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.

DOI: 10.1038/s41586-021-03420-7

Source: https://www.nature.com/articles/s41586-021-03420-7

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