Human de novo mutation rates from a four-generation pedigree reference
Abstract
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 (~3.4 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.
Article Details
Authors (47)
David Porubsky
Harriet Dashnow
Thomas A. Sasani
Glennis A. Logsdon
Pille Hallast
Michelle D. Noyes
Zev N. Kronenberg
Tom Mokveld
Nidhi Koundinya
Cillian 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