华盛顿大学医学院Evan E. Eichler研究团队取得一项新突破。他们报道了来自四代谱系参考的人类新生突变率。这一研究成果于2025年4月23日发表在国际顶尖学术期刊《自然》上。

在这里，该课题组研究人员将五种互补的短读和长读测序技术作为主题，在一个有28个成员的家族中（CEPH 1463），分阶段组装了超过95%的二倍体人类基因组。小组估计每次传递98-206个DNMs，包括74.5个新产生的单核苷酸变异，7.4个非串联重复序列序列，65.3个新产生的序列或源于串联重复序列的结构变异，以及4.4个着丝粒DNMs。在雄性个体中，研究组发现每代12.4个Y染色体新生事件。短串联重复序列和可变数串联重复序列是最易变的，有32个位点在世代中表现出反复突变。研究组准确地组装了288个着丝粒和6条Y染色体，并证明DNM率根据重复内容，长度和序列身份而变化。课题组研究人员发现所有形式的种系DNM都存在强烈的父系偏倚（75-81%），但课题组研究人员估计16%的新生单核苷酸变异是在合子后起源的，没有父系偏倚，包括早期种系马赛克突变。研究组将所有这些变化放在高分辨率重组图的背景下(~3.4KB断点分辨率)，并发现减数分裂交叉和从头结构变异之间没有相关性。这些近端粒到端粒的家族基因组为理解人类遗传变异的最基本过程提供了一个真理集。

据了解，了解人类从头突变（DNM）率需要完整的序列信息。

附：英文原文

Title: Human de novo mutation rates from a four-generation pedigree reference

Author: Porubsky, David, Dashnow, Harriet, Sasani, Thomas A., Logsdon, Glennis A., Hallast, Pille, Noyes, Michelle D., Kronenberg, Zev N., Mokveld, Tom, Koundinya, Nidhi, Nolan, Cillian, Steely, Cody J., Guarracino, Andrea, Dolzhenko, Egor, Harvey, William T., Rowell, William J., Grigorev, Kirill, Nicholas, Thomas J., Goldberg, Michael E., Oshima, Keisuke K., Lin, Jiadong, Ebert, Peter, Watkins, W. Scott, Leung, Tiffany Y., Hanlon, Vincent C. T., McGee, Sean, Pedersen, Brent S., Happ, Hannah C., Jeong, Hyeonsoo, Munson, Katherine M., Hoekzema, Kendra, Chan, Daniel D., Wang, Yanni, Knuth, Jordan, Garcia, Gage H., Fanslow, Cairbre, Lambert, Christine, Lee, Charles, Smith, Joshua D., Levy, Shawn, Mason, Christopher E., Garrison, Erik, Lansdorp, Peter M., Neklason, Deborah W., Jorde, Lynn B., Quinlan, Aaron R., Eberle, Michael A., Eichler, Evan E.

Issue&Volume: 2025-04-23

Abstract: Understanding the human de novo mutation (DNM) rate requires complete sequence information1. Here using five complementary short-read and long-read sequencing technologies, we phased and assembled more than 95% of each diploid human genome in a four-generation, twenty-eight-member family (CEPH 1463). We estimate 98–206 DNMs per transmission, including 74.5 de novo single-nucleotide variants, 7.4 non-tandem repeat indels, 65.3 de novo indels or structural variants originating from tandem repeats, and 4.4 centromeric DNMs. Among male individuals, we find 12.4 de novo Y chromosome events per generation. Short tandem repeats and variable-number tandem repeats are the most mutable, with 32 loci exhibiting recurrent mutation through the generations. We accurately assemble 288 centromeres and six Y chromosomes across the generations and demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length and sequence identity. We show a strong paternal bias (75–81%) for all forms of germline DNM, yet we estimate that 16% of de novo single-nucleotide variants are postzygotic in origin with no paternal bias, including early germline mosaic mutations. We place all this variation in the context of a high-resolution recombination map (~3.4kb breakpoint resolution) and find no correlation between meiotic crossover and de novo structural variants. These near-telomere-to-telomere familial genomes provide a truth set to understand the most fundamental processes underlying human genetic variation.

DOI: 10.1038/s41586-025-08922-2

Source: https://www.nature.com/articles/s41586-025-08922-2