title: Genome-wide patterns and properties of de novo mutations in humans.
abstract: Mutations create variation in the population, fuel evolution and cause genetic diseases. Current knowledge about de novo mutations is incomplete and mostly indirect. Here we analyze 11,020 de novo mutations from the whole genomes of 250 families. We show that de novo mutations in the offspring of older fathers are not only more numerous but also occur more frequently in early-replicating, genic regions. Functional regions exhibit higher mutation rates due to CpG dinucleotides and show signatures of transcription-coupled repair, whereas mutation clusters with a unique signature point to a new mutational mechanism. Mutation and recombination rates independently associate with nucleotide diversity, and regional variation in human-chimpanzee divergence is only partly explained by heterogeneity in mutation rate. Finally, we provide a genome-wide mutation rate map for medical and population genetics applications. Our results provide new insights and refine long-standing hypotheses about human mutagenesis.
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Laurent C
authors.initials: LC
authors.lastname: Francioli
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Paz P
authors.initials: PP
authors.lastname: Polak
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA, USA.
authors.forename: Amnon
authors.initials: A
authors.lastname: Koren
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Androniki
authors.initials: A
authors.lastname: Menelaou
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Sung
authors.initials: S
authors.lastname: Chun
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ivo
authors.initials: I
authors.lastname: Renkens
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, The Netherlands.
authors.forename: Morris
authors.initials: M
authors.lastname: Swertz
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, The Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Gertjan
authors.initials: G
authors.lastname: van Ommen
authors.affiliation: Section of Molecular Epidemiology, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.affiliation: Section of Molecular Epidemiology, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.|The Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Ye
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Victor
authors.initials: V
authors.lastname: Guryev
authors.affiliation: Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Arndt
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Wigard P
authors.initials: WP
authors.lastname: Kloosterman
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Paul I W
authors.initials: PIW
authors.lastname: de Bakker
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Shamil R
authors.initials: SR
authors.lastname: Sunyaev
mesh_terms: D000818:Animals; D019143:Evolution, Molecular; D005260:Female; D015894:Genome, Human; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008957:Models, Genetic; D059645:Mutation Rate; D002679:Pan troglodytes / Q000235:genetics; D010331:Paternal Age