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Nat Genet. 2015 Jul;47(7):822-826. doi: 10.1038/ng.3292. Epub 2015 May 18.

Genome-wide patterns and properties of de novo mutations in humans.

Author information

1
Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
2
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
3
Department of Genetics, Harvard Medical School, Boston, MA, USA.
4
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
5
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
6
University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, The Netherlands.
7
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
8
Section of Molecular Epidemiology, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
9
Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.
10
The Genome Institute, Washington University, St. Louis, MO, USA.
11
European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
12
Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.
13
Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
#
Contributed equally

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.

PMID:
25985141
PMCID:
PMC4485564
DOI:
10.1038/ng.3292
[Indexed for MEDLINE]
Free PMC Article

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