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

• 成果类型: Article
• 署名作者: 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.
• 署名单位: University of Washington; University of Washington Seattle; Utah System of Higher Education; University of Utah; University of Colorado System; University of Colorado Anschutz Medical Campus; Jackson Laboratory; University of Kentucky; University of Tennessee System; University of Tennessee Health Science Center; National Aeronautics & Space Administration (NASA); NASA Ames Research Center; University of Pennsylvania; Heinrich Heine University Dusseldorf; Heinrich Heine University Dusseldorf; Heinrich Heine University Dusseldorf Hospital; Heinrich Heine University Dusseldorf; British Columbia Cancer Agency; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; University of British Columbia; Howard Hughes Medical Institute; University of Washington; University of Washington Seattle
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2544
• DOI: 10.1038/s41586-025-08922-2
• 发表日期: 2025-07-10
• 关键词: multiple sequence alignment; structural variation; recombination rate; gene conversion; genome; patterns; repeat; map; performance; accurate

摘要

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 (similar to 3.4 kb 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.