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.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Veltman, J.A. & Brunner, H.G. De novo mutations in human genetic disease. Nat. Rev. Genet. 13, 565–575 (2012).
Kong, A. et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488, 471–475 (2012).
Michaelson, J.J. et al. Whole-genome sequencing in autism identifies hot spots for de novo germline mutation. Cell 151, 1431–1442 (2012).
Campbell, C.D. & Eichler, E.E. Properties and rates of germline mutations in humans. Trends Genet. 29, 575–584 (2013).
Roach, J.C. et al. Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science 328, 636–639 (2010).
Makova, K.D. & Hardison, R.C. The effects of chromatin organization on variation in mutation rates in the genome. Nat. Rev. Genet. 16, 213–223 (2015).
Crow, J.F. The origins, patterns and implications of human spontaneous mutation. Nat. Rev. Genet. 1, 40–47 (2000).
Drmanac, R. et al. Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays. Science 327, 78–81 (2010).
Wong, W.S. et al. New observations on maternal age effect on germline de novo mutations. Nat. Commun. 7, 10486 (2016).
Forster, P. et al. Elevated germline mutation rate in teenage fathers. Proc. R. Soc. Lond. B 282, 20142898 (2015).
Ségurel, L., Wyman, M.J. & Przeworski, M. Determinants of mutation rate variation in the human germline. Annu. Rev. Genomics Hum. Genet. 15, 47–70 (2014).
Schuster-Böckler, B. & Lehner, B. Chromatin organization is a major influence on regional mutation rates in human cancer cells. Nature 488, 504–507 (2012).
Smith, D.I., Zhu, Y., McAvoy, S. & Kuhn, R. Common fragile sites, extremely large genes, neural development and cancer. Cancer Lett. 232, 48–57 (2006).
White, S. et al. A multi-exon deletion within WWOX is associated with a 46,XY disorder of sex development. Eur. J. Hum. Genet. 20, 348–351 (2012).
Francioli, L.C. et al. Genome-wide patterns and properties of de novo mutations in humans. Nat. Genet. 47, 822–826 (2015).
Alexandrov, L.B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
Rahbari, R. et al. Timing, rates and spectra of human germline mutation. Nat. Genet. 48, 126–133 (2016).
Titus, S. et al. Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans. Sci. Transl. Med. 5, 172ra21 (2013).
Chan, K. & Gordenin, D.A. Clusters of multiple mutations: incidence and molecular mechanisms. Annu. Rev. Genet. 49, 243–267 (2015).
Bodian, D.L. et al. Utility of whole-genome sequencing for detection of newborn screening disorders in a population cohort of 1,696 neonates. Genet. Med. 221–230 (2016).
Bodian, D.L. et al. Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. PLoS One 9, e94554 (2014).
Carnevali, P. et al. Computational techniques for human genome resequencing using mated gapped reads. J. Comput. Biol. 19, 279–292 (2012).
1000 Genomes Project Consortium. et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).
Gilissen, C. et al. Genome sequencing identifies major causes of severe intellectual disability. Nature 511, 344–347 (2014).
Glusman, G., Caballero, J., Mauldin, D.E., Hood, L. & Roach, J.C. Kaviar: an accessible system for testing SNV novelty. Bioinformatics 27, 3216–3217 (2011).
ENCODE Project Consortium. A user's guide to the encyclopedia of DNA elements (ENCODE). PLoS Biol. 9, e1001046 (2011).
Acuna-Hidalgo, R. et al. Post-zygotic point mutations are an underrecognized source of de novo genomic variation. Am. J. Hum. Genet. 97, 67–74 (2015).
Peters, B.A. et al. Accurate whole-genome sequencing and haplotyping from 10 to 20 human cells. Nature 487, 190–195 (2012).
Cingolani, P. et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 6, 80–92 (2012).
Paila, U., Chapman, B.A., Kirchner, R. & Quinlan, A.R. GEMINI: integrative exploration of genetic variation and genome annotations. PLoS Comput. Biol. 9, e1003153 (2013).
R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, 2008).
pvclust: Hierarchical Clustering with P-Values via Multiscale Bootstrap Resampling (2015).
Hellmann, I. et al. Why do human diversity levels vary at a megabase scale? Genome Res. 15, 1222–1231 (2005).
Quinlan, A.R. & Hall, I.M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010).
Rosenbloom, K.R. et al. The UCSC Genome Browser database: 2015 update. Nucleic Acids Res. 43, D670–D681 (2015).
Koren, A. et al. Differential relationship of DNA replication timing to different forms of human mutation and variation. Am. J. Hum. Genet. 91, 1033–1040 (2012).
Kundaje, A. et al. Integrative analysis of 111 reference human epigenomes. Nature 518, 317–330 (2015).
Visser, I.S.M. depmixS4: an R package for hidden Markov models. J. Stat. Softw. 36, 1–21 (2010).
Roberts, S.A. et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat. Genet. 45, 970–976 (2013).
Pettersen, H.S. et al. AID expression in B-cell lymphomas causes accumulation of genomic uracil and a distinct AID mutational signature. DNA Repair (Amst.) 25, 60–71 (2015).
Qian, J. et al. B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity. Cell 159, 1524–1537 (2014).
Conrad, D.F. et al. Variation in genome-wide mutation rates within and between human families. Nat. Genet. 43, 712–714 (2011).
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.).
The authors declare no competing financial interests.
Supplementary Tables 1–13,16–20, 23, 24, 26–35, Supplementary Figures 1–11, and Supplementary Note (PDF 3467 kb)
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)
List of identified SNV DNMs and their phase. (XLSX 1251 kb)
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)
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)
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)
About this article
Cite this article
Goldmann, J., Wong, W., Pinelli, M. et al. Parent-of-origin-specific signatures of de novo mutations. Nat Genet 48, 935–939 (2016). https://doi.org/10.1038/ng.3597
Scientific Reports (2022)
Parental folate deficiency induces birth defects in mice accompanied with increased de novo mutations
Cell Discovery (2022)
Familial Cancer (2022)
Nature Communications (2022)