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

Understanding the human de novo mutation (DNM) rate requires complete sequence information<sup>1</sup>. 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.

Authors

Institutions

Publication Details

Journal
Nature
Published
2025-04-23
DOI
https://doi.org/10.1038/s41586-025-08922-2
Citations
59
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
105.40
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Sean McGee, Cairbre Fanslow, Christine Lambert, Kirill Grigorev et al.
59 citations
Nature
Genomics and Rare Diseases
105.40
article

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

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

Abstract

Understanding the human de novo mutation (DNM) rate requires complete sequence information<sup>1</sup>. 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.

NatureVol. 643(8071)
Ames Research Center (US), BC Cancer Agency (CA), Howard Hughes Medical Institute (US), University of British Columbia (CA), University of Kentucky (US), University of Tennessee Health Science Center (US), University of Washington (US), Cornell University (US), University of Utah (US), Düsseldorf University Hospital (DE), Jackson Laboratory (US), Blue Marble Space (US), Blue Marble Space Institute of Science (US), Weill Cornell Medicine (US), Altos Labs, Elements Biosciences (United States), Heinrich Heine University Düsseldorf (DE), University of Colorado Anschutz Medical Campus (US), Pacific Biosciences (United States) (US), University of Pennsylvania (US)
Openalex Percentile: Top 0%
Genomics and Rare Diseases
105.40
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.