ArticleScience (New York, N.Y.)2021
Population sequencing data reveal a compendium of mutational processes in the human germ line.
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Article in Science (New York, N.Y.), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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46citing papers in PubMed
4.9field-weighted citation impact, top 3% of its field
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46 citing papers in PubMed, 72 citations in OpenAlex.
- Maternal age as a driver of genome instability: mechanisms linking aneuploidy, mutagenesis and mitochondrial dysfunction.Archives of toxicology · 2026Review
- Article
- Effect of methylation on genome mutability in cattle.Genetics, selection, evolution : GSE · 2026Article
- Inference of elevated mutation rates and variant effects using 700k exomes.bioRxiv : the preprint server for biology · 2026Article
- Topographical archetypes of somatic mutagenesis in cancer.bioRxiv : the preprint server for biology · 2026Article
- Transcription start sites experience a high influx of heritable variants fueled by early development.Nature communications · 2025Article
- Cell line-matched reference enables high-precision functional genomics.Nature communications · 2025Article
- Advances in single-cell DNA sequencing enable insights into human somatic mosaicism.Nature reviews. Genetics · 2025Review
- Identifying Single-Origin Rare Variants in Population Genomic Data.Molecular biology and evolution · 2025Article
- Sex differences in transcription-associated mutagenesis in the human germline.bioRxiv : the preprint server for biology · 2025Article
- NoncodingiScience · 2025Article
- Estimation of demography and mutation rates from one million haploid genomes.American journal of human genetics · 2025Article
- Mechanisms underlying low mutation rates in mammalian oocytes and preimplantation embryos.Nucleic acids research · 2025Review
- Estimating mutation rate and characterising single nucleotide de novo mutations in pigs.Genetics, selection, evolution : GSE · 2025Article
- Computational studies on the functional and structural impact of pathogenic mutations in enzymes.Protein science : a publication of the Protein Society · 2025Review
- Human-Specific Organization of Proliferation and Stemness in Squamous Epithelia: A Comparative Study to Elucidate Differences in Stem Cell Organization.International journal of molecular sciences · 2025Article
- MutSeqR: an open source R package for standardized analysis of error-corrected next-generation sequencing data in genetic toxicology.Bioinformatics advances · 2025Article
- Transcription and DNA replication collisions lead to large tandem duplications and expose targetable therapeutic vulnerabilities in cancer.Nature cancer · 2024Article
- Mutational signature analyses in multi-child families reveal sources of age-related increases in human germline mutations.Communications biology · 2024Article
- Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes.Science (New York, N.Y.) · 2024Article
Corrections and comments
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Authors and funding
44 authors at 20 institutions in 5 countries.
Vladimir B Seplyarskiy *Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.ORCID 0000-0003-3161-8770
Ruslan A Soldatov *Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-5670-5881
Evan KochDivision of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-1124-4559
Ryan J McGintyDivision of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.ORCID 0000-0003-3439-7301
Jakob M GoldmannDepartment of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.ORCID 0000-0002-8514-573X
Ryan D HernandezQuantitative Life Sciences, McGill University, Montreal, QC, Canada.ORCID 0000-0001-5249-504X
Kathleen BarnesDepartment of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
Adolfo CorreaDepartment of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.ORCID 0000-0002-9501-600X
Esteban G BurchardDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.ORCID 0000-0001-7475-2035
Patrick T EllinorProgram in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0002-2067-0533
Stephen T McGarveyInternational Health Institute, Brown University, Providence, RI, USA.ORCID 0000-0003-1233-6970
Braxton D MitchellDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.ORCID 0000-0003-4920-4744
Ramachandran S VasanDepartment of Medicine, Boston University School of Medicine, Boston, MA, USA.ORCID 0000-0001-7357-5970
Susan RedlineDepartment of Medicine, Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-6585-1610
Edwin SilvermanChanning Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.ORCID 0000-0002-3641-3822
Scott T WeissDepartment of Medicine, Harvard Medical School, Boston, MA, USA.ORCID 0000-0001-7196-303X
Donna K ArnettDepartment of Epidemiology, University of Kentucky, Lexington, KY, USA.ORCID 0000-0003-2219-657X
John BlangeroDepartment of Human Genetics, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
Eric BoerwinkleUniversity of Texas Health Science Center at Houston, Houston, TX, USA.
Jiang HeDepartment of Epidemiology, Tulane University, New Orleans, LA, USA.ORCID 0000-0002-8286-9652
Courtney MontgomeryDivision of Genomics and Data Science, Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.ORCID 0000-0002-9606-3772
D C RaoDivision of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
Jerome I RotterThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.ORCID 0000-0001-7191-1723
Kent D TaylorThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.ORCID 0000-0002-2756-4370
Jennifer A BrodyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.ORCID 0000-0001-8509-148X
Yii-Der Ida ChenDepartment of Pediatrics, The Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
Lisa de las FuentesDivision of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.ORCID 0000-0002-4689-325X
Chii-Min HwuNational Yang-Ming University School of Medicine, Taipei, Taiwan.ORCID 0000-0002-8209-9627
Stephen S RichCenter for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.ORCID 0000-0003-3872-7793
Ani W ManichaikulCenter for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.ORCID 0000-0002-5998-795X
Josyf C MychaleckyjCenter for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.ORCID 0000-0003-2595-0005
Nicholette D PalmerDepartment of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.ORCID 0000-0001-8883-2511
Jennifer A SmithDepartment of Epidemiology, School of Public Health, University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109-2029, USA.ORCID 0000-0002-3575-5468
Sharon L R KardiaSurvey Research Center, Institute for Social Research, University of Michigan 426 Thompson St, Room Ann Arbor, MI 48104, USA.
Patricia A PeyserSurvey Research Center, Institute for Social Research, University of Michigan 426 Thompson St, Room Ann Arbor, MI 48104, USA.ORCID 0000-0002-9717-8459
Lawrence F BielakSurvey Research Center, Institute for Social Research, University of Michigan 426 Thompson St, Room Ann Arbor, MI 48104, USA.
Timothy D O'ConnorProgram for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Leslie S EmeryUniversity of Washington Department of Biostatistics, Seattle, WA 98195, USA.ORCID 0000-0002-9070-9886
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
TOPMed Population Genetics Working Group
Christian GilissenDepartment of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.ORCID 0000-0003-1693-9699
Wendy S W WongInova Translational Medicine Institute (ITMI), Inova Health Systems, Falls Church, VA, USA.ORCID 0000-0001-9850-3797
Peter V KharchenkoDepartment of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-6036-5875
Shamil SunyaevDivision of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ssunyaev@rics.bwh.harvard.edu.ORCID 0000-0001-5715-5677
Brigham and Women's Hospital · USInstitute for Social Research · NOUniversity of Virginia · USInova Health System · USRadboud University Nijmegen · NLUCLA Medical Center · USUniversity of California, San Francisco · USUniversity of Maryland, Baltimore · USUniversity of Washington · USWashington University in St. Louis · USBaylor College of Medicine · USBoston University · USBroad Institute · USBrown University · USHarvard University · USJackson Memorial Hospital · USNational Yang Ming Chiao Tung University · TWOklahoma Medical Research Foundation · USThe Lundquist Institute · USThe University of Texas Rio Grande Valley · US
Funding
Systems Biology of Airway DiseaseP01HL132825 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI WEISS, SCOTT T · 2016 to 2020
$12.6MUtilizing the Phenomics of IBD to Enhance Gene DiscoveryU01DK062413 · NIDDK · CEDARS-SINAI MEDICAL CENTER · PI Dermot Patrick McGovern · 2002 to 2026
$12.2MStudies of Rare Genetic Variation in the Isolated Population of SardiniaR01HL117626 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ABECASIS, GONCALO · 2013 to 2016
$10.5MStatistical methods for studies of rare variantsR01MH101244 · NIMH · HARVARD MEDICAL SCHOOL · PI Benjamin Michael Neale, ALKES L PRICE · 2013 to 2026
$9.4MRare variants and NHLBI traits in deeply phenotyped cohortsR01HL120393 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M, RICE, KENNETH M. · 2014 to 2016
$8.9MThe origin, the function and the phenotypic impact of human allelesR35GM127131 · NIGMS · HARVARD MEDICAL SCHOOL · PI SHAMIL SUNYAEV · 2018 to 2026
$8.1MPhenotypic and Molecular Signatures for Sleep Apnea and Related MorbiditiesR35HL135818 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI REDLINE, SUSAN S. · 2017 to 2023
$7.2MPowering whole genome sequence-based genetic discovery for common human diseases- Extended 2021-2022.U01HG009088 · NHGRI · HARVARD SCHOOL OF PUBLIC HEALTH · PI LIN, XIHONG, NEALE, BENJAMIN MICHAEL · 2016 to 2021
$5.1MIntegrated pathogenicity assessment of clinically actionable genetic variantsR01HG010372 · NHGRI · BRIGHAM AND WOMEN'S HOSPITAL · PI CASSA, CHRISTOPHER · 2018 to 2022
$3.5MStatistical methods for analysis of single-cell variabilityR01HL131768 · NHLBI · HARVARD MEDICAL SCHOOL · PI KHARCHENKO, PETER V · 2015 to 2019
$2.4MNHGRI NIH HHS R01 HG010372NHGRI NIH HHS U01 HG009088NHLBI NIH HHS HHSN268201800001CNHLBI NIH HHS P01 HL132825NHLBI NIH HHS R01 HL117626NHLBI NIH HHS R01 HL120393NHLBI NIH HHS R01 HL131768NHLBI NIH HHS R35 HL135818NIDDK NIH HHS U01 DK062413NIGMS NIH HHS R35 GM127131NIMH NIH HHS R01 MH101244
Abstract
Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.
Indexed as
Genome, HumanGerm-Line MutationAlgorithmsCpG IslandsDNA DamageDNA DemethylationDNA Mutational AnalysisDNA ReplicationGenetic VariationGerm CellsHumansLong Interspersed Nucleotide ElementsMutagenesisOocytesTranscription, Genetic
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