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 humans1.
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We thank all the clinical, laboratory, information technology, and informatics staff for their support on this research project, especially R. Haridas and R. Smith for Sanger sequencing. We would like to thank D. Aguiar and S. Istrail for helpful discussions on their HapCompass software. We would also like to express our gratitude to the participating individuals and their families. The ITMI was supported by the Inova Health System, a nonprofit healthcare system in Northern Virginia. This work was partly financially supported by grants from the Netherlands Organization for Scientific Research (918-15-667 to J.A.V., 916-14-043 to C.G., and SH-271-13 to C.G. and J.A.V.), the European Research Council (ERC Starting grant DENOVO 281964 to J.A.V.), the German Academic Exchange Service DAAD (postdoctoral grant to A.B.S.), and the German Research Foundation DFG (Postdoc grant to A.B.S.).
Number of phased and unphased mutations per trio. First column lists the trio identifiers, second column the number of DNMs per trio; third and fourth columns give the number of paternal and maternal mutations, respectively. Fifth and sixth columns indicate the age category of father and mother for the analysis in Figure 2a. Seventh and eighth columns give the age category of the paternal and maternal mutations in the clustering analysis in Figure 3c. See Supplementary Table 26 for the ranges of the age categories.
List of identified SNV DNMs and their phase.
The genomic coordinates and the phmm states of the 2,659 nonoverlapping 1-Mb windows. The phmm assigned mutation rate states and the genomic coordinates of the 2,659 nonoverlapping 1-Mb windows with callable bases >50%.
The genomic features and de novo mutation rates in each category for each of the 2,634 nonoverlapping 1-Mb windows with callable bases >50% and no missing values are denoted in the supplementary file.
Nucleotide substitutions and contexts by gender. List of all 96 mutation categories as defined by their nucleotide substitutions and surrounding nucleotides. Second and third columns indicate the fractions of paternal and maternal DNMs that falls into that category, respectively. Fourth column indicates the difference between paternal and maternal fractions (visualized in Fig. 3b). Fifth column indicates the log2 of the paternal/maternal ratio. Sixth column gives multiple-testing corrected P-value of true difference between maternal and paternal fraction.