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Nat Genet. 2016 Aug;48(8):935-9. doi: 10.1038/ng.3597. Epub 2016 Jun 20.

Parent-of-origin-specific signatures of de novo mutations.

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Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
Inova Translational Medicine Institute (ITMI), Inova Health Systems, Falls Church, Virginia, USA.
Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
Institute for Systems Biology, Seattle, Washington, USA.
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Department of Clinical Genetics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
Department of Pediatrics, Inova Children's Hospital, Inova Health System, Falls Church, Virginia, USA.
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.


De novo mutations (DNMs) originating in gametogenesis are an important source of genetic variation. We use a data set of 7,216 autosomal DNMs with resolved parent of origin from whole-genome sequencing of 816 parent-offspring trios to investigate differences between maternally and paternally derived DNMs and study the underlying mutational mechanisms. Our results show that the number of DNMs in offspring increases not only with paternal age, but also with maternal age, and that some genome regions show enrichment for maternally derived DNMs. We identify parent-of-origin-specific mutation signatures that become more pronounced with increased parental age, pointing to different mutational mechanisms in spermatogenesis and oogenesis. Moreover, we find DNMs that are spatially clustered to have a unique mutational signature with no significant differences between parental alleles, suggesting a different mutational mechanism. Our findings provide insights into the molecular mechanisms that underlie mutagenesis and are relevant to disease and evolution in humans.

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