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

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 and Evan E. Eichler ()
Additional contact information
David Porubsky: University of Washington School of Medicine
Harriet Dashnow: University of Utah
Thomas A. Sasani: University of Utah
Glennis A. Logsdon: University of Washington School of Medicine
Pille Hallast: The Jackson Laboratory for Genomic Medicine
Michelle D. Noyes: University of Washington School of Medicine
Zev N. Kronenberg: PacBio
Tom Mokveld: PacBio
Nidhi Koundinya: University of Washington School of Medicine
Cillian Nolan: PacBio
Cody J. Steely: University of Utah
Andrea Guarracino: University of Tennessee Health Science Center
Egor Dolzhenko: PacBio
William T. Harvey: University of Washington School of Medicine
William J. Rowell: PacBio
Kirill Grigorev: NASA Ames Research Center
Thomas J. Nicholas: University of Utah
Michael E. Goldberg: University of Utah
Keisuke K. Oshima: University of Pennsylvania
Jiadong Lin: University of Washington School of Medicine
Peter Ebert: Heinrich Heine University
W. Scott Watkins: University of Utah
Tiffany Y. Leung: BC Cancer Agency
Vincent C. T. Hanlon: BC Cancer Agency
Sean McGee: University of Washington School of Medicine
Brent S. Pedersen: University of Utah
Hannah C. Happ: University of Utah
Hyeonsoo Jeong: University of Washington School of Medicine
Katherine M. Munson: University of Washington School of Medicine
Kendra Hoekzema: University of Washington School of Medicine
Daniel D. Chan: BC Cancer Agency
Yanni Wang: BC Cancer Agency
Jordan Knuth: University of Washington School of Medicine
Gage H. Garcia: University of Washington School of Medicine
Cairbre Fanslow: PacBio
Christine Lambert: PacBio
Charles Lee: The Jackson Laboratory for Genomic Medicine
Joshua D. Smith: University of Washington School of Medicine
Shawn Levy: Element Biosciences
Christopher E. Mason: Weill Cornell Medicine
Erik Garrison: University of Tennessee Health Science Center
Peter M. Lansdorp: BC Cancer Agency
Deborah W. Neklason: University of Utah
Lynn B. Jorde: University of Utah
Aaron R. Quinlan: University of Utah
Michael A. Eberle: PacBio
Evan E. Eichler: University of Washington School of Medicine

Nature, 2025, vol. 643, issue 8071, 427-436

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.

Date: 2025
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DOI: 10.1038/s41586-025-08922-2

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