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

An Author Correction to this article was published on 05 October 2018

This article has been updated


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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Figure 1: Correlation of paternal and maternal age with the number of DNMs with resolved parent of origin.
Figure 2: Regions enriched for maternally and paternally derived DNMs.
Figure 3: Differences in paternal and maternal mutation profiles and correlation with parental age at conception.
Figure 4: Mutation profiles of clustered DNMs.

Change history

  • 05 October 2018

    In the version of this article published, the P values for the enrichment of single mutation categories were inadvertently not corrected for multiple testing. After multiple-testing correction, only two of the six mutation categories mentioned are still statistically significant. To reflect this, the text "More specifically, paternally derived DNMs are enriched in transitions in A[.]G contexts, especially ACG>ATG and ATG>ACG (Bonferroni-corrected P = 1.3 × 10−2 and P = 1 × 10−3, respectively). Additionally, we observed overrepresentation of ATA>ACA mutations (Bonferroni-corrected P = 4.28 × 10−2) for DNMs of paternal origin. Among maternally derived DNMs, CCA>CTA, GCA>GTA and TCT>TGT mutations were significantly overrepresented (Bonferroni-corrected P = 4 × 10−4, P = 5 × 10−4, P = 1 × 10−3, respectively)" should read "More specifically, CCA>CTA and GCA>GTA mutations were significantly overenriched on the maternal allele (Bonferroni-corrected P = 0.0192 and P = 0.048, respectively)." Additionally, the last sentence to the legend for Fig. 3b should read "Green boxes highlight the mutation categories that differ significantly” instead of “Green boxes highlight the mutation categories that differ more than 1% of mutation load with a bootstrapping P value <0.05." Corrected versions of Fig. 3b and Supplementary Table 25 appear with the Author Correction.


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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.).

Author information

Authors and Affiliations



J.A.V., C.G., and J.E.N. designed the study. J.M.G., W.S.W.W., and M.P. performed the data analyses. M.P., L.E.L.M.V., and A.H. provided and analyzed preliminary data and assisted in writing the final manuscript. J.G.V., B.D.S., and J.E.N. supervised the data collection, sequencing and writing of the manuscript. D.B., A.B.S., G.G., and J.C.R. assisted in data analyses and interpretation. T.F. assisted in data processing. J.M.G., W.S.W.W., and C.G. drafted the manuscript. All authors contributed to the final version of the paper.

Corresponding authors

Correspondence to Christian Gilissen or John E Niederhuber.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–13,16–20, 23, 24, 26–35, Supplementary Figures 1–11, and Supplementary Note (PDF 3467 kb)

Supplementary Table 14

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. (XLSX 32 kb)

Supplementary Table 15

List of identified SNV DNMs and their phase. (XLSX 1251 kb)

Supplementary Table 21

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%. (XLSX 129 kb)

Supplementary Table 22

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. (XLSX 629 kb)

Supplementary Table 25

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. (XLSX 15 kb)

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Goldmann, J., Wong, W., Pinelli, M. et al. Parent-of-origin-specific signatures of de novo mutations. Nat Genet 48, 935–939 (2016).

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