Human de novo mutation rates from a four-generation pedigree reference.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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
Аннотация
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 (~3.4 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.