Parent-of-origin-specific signatures of de novo mutations.
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.
Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
Jakob M
0000-0002-8514-573X
JM
Goldmann
Inova Translational Medicine Institute (ITMI), Inova Health Systems, Falls Church, Virginia, USA.
Wendy S W
WS
Wong
Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
Michele
0000-0002-5927-1185
M
Pinelli
Institute for Systems Biology, Seattle, Washington, USA.
Terry
T
Farrah
Inova Translational Medicine Institute (ITMI), Inova Health Systems, Falls Church, Virginia, USA.
Dale
D
Bodian
Institute for Systems Biology, Seattle, Washington, USA.
Anna B
AB
Stittrich
Institute for Systems Biology, Seattle, Washington, USA.
Gustavo
G
Glusman
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
Lisenka E L M
LE
Vissers
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
Alexander
A
Hoischen
Institute for Systems Biology, Seattle, Washington, USA.
Jared C
JC
Roach
Inova Translational Medicine Institute (ITMI), Inova Health Systems, Falls Church, Virginia, USA.|Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Joseph G
JG
Vockley
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Clinical Genetics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
Joris A
JA
Veltman
Inova Translational Medicine Institute (ITMI), Inova Health Systems, Falls Church, Virginia, USA.|Department of Pediatrics, Inova Children's Hospital, Inova Health System, Falls Church, Virginia, USA.|Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Benjamin D
BD
Solomon
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
Christian
0000-0003-1693-9699
C
Gilissen
Inova Translational Medicine Institute (ITMI), Inova Health Systems, Falls Church, Virginia, USA.|Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
John E
JE
Niederhuber
D005260:Female; D005786:Gene Expression Regulation; D015894:Genome, Human; D018095:Germ-Line Mutation / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008423:Maternal Age; D016296:Mutagenesis / Q000235:genetics*; D010331:Paternal Age