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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.

Original publication

DOI

10.1038/ng.3292

Type

Journal article

Journal

Nature genetics

Publication Date

07/2015

Volume

47

Pages

822 - 826

Addresses

Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

Keywords

Genome of the Netherlands Consortium, Animals, Humans, Pan troglodytes, Evolution, Molecular, Paternal Age, Germ-Line Mutation, Genome, Human, Models, Genetic, Female, Male, Mutation Rate