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