The characterization of mutational processes that generate sequence diversity in the human genome is of paramount importance both to medical genetics1,2 and to evolutionary studies3. To understand how the age and sex of transmitting parents affect de novo mutations, here we sequence 1,548 Icelanders, their parents, and, for a subset of 225, at least one child, to 35× genome-wide coverage. We find 108,778 de novo mutations, both single nucleotide polymorphisms and indels, and determine the parent of origin of 42,961. The number of de novo mutations from mothers increases by 0.37 per year of age (95% CI 0.32–0.43), a quarter of the 1.51 per year from fathers (95% CI 1.45–1.57). The number of clustered mutations increases faster with the mother’s age than with the father’s, and the genomic span of maternal de novo mutation clusters is greater than that of paternal ones. The types of de novo mutation from mothers change substantially with age, with a 0.26% (95% CI 0.19–0.33%) decrease in cytosine–phosphate–guanine to thymine–phosphate–guanine (CpG>TpG) de novo mutations and a 0.33% (95% CI 0.28–0.38%) increase in C>G de novo mutations per year, respectively. Remarkably, these age-related changes are not distributed uniformly across the genome. A striking example is a 20 megabase region on chromosome 8p, with a maternal C>G mutation rate that is up to 50-fold greater than the rest of the genome. The age-related accumulation of maternal non-crossover gene conversions also mostly occurs within these regions. Increased sequence diversity and linkage disequilibrium of C>G variants within regions affected by excess maternal mutations indicate that the underlying mutational process has persisted in humans for thousands of years. Moreover, the regional excess of C>G variation in humans is largely shared by chimpanzees, less by gorillas, and is almost absent from orangutans. This demonstrates that sequence diversity in humans results from evolving interactions between age, sex, mutation type, and genomic location.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    & De novo mutations in human genetic disease. Nat. Rev. Genet. 13, 565–575 (2012)

  2. 2.

    et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013)

  3. 3.

    & Revising the human mutation rate: implications for understanding human evolution. Nat. Rev. Genet. 13, 745–753 (2012)

  4. 4.

    et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature 488, 471–475 (2012)

  5. 5.

    et al. New observations on maternal age effect on germline de novo mutations. Nat. Commun. 7, 10486 (2016)

  6. 6.

    et al. Parent-of-origin-specific signatures of de novo mutations. Nat. Genet. 48, 935–939 (2016)

  7. 7.

    et al. Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA. Proc. Natl Acad. Sci. USA 111, 15474–15479 (2014)

  8. 8.

    et al. The molecular anatomy of spontaneous germline mutations in human testes. PLoS Biol. 5, 1912–1922 (2007)

  9. 9.

    & An expanded sequence context model broadly explains variability in polymorphism levels across the human genome. Nat. Genet. 48, 349–355 (2016)

  10. 10.

    et al. Differential relationship of DNA replication timing to different forms of human mutation and variation. Am. J. Hum. Genet. 91, 1033–1040 (2012)

  11. 11.

    et al. Large-scale whole-genome sequencing of the Icelandic population. Nat. Genet. 47, 435–444 (2015)

  12. 12.

    & Clusters of multiple mutations: incidence and molecular mechanisms. Annu. Rev. Genet. 49, 243–267 (2015)

  13. 13.

    et al. Cell-of-origin chromatin organization shapes the mutational landscape of cancer. Nature 518, 360–364 (2015)

  14. 14.

    et al. Timing, rates and spectra of human germline mutation. Nat. Genet. 48, 126–133 (2016)

  15. 15.

    et al. Genome-wide patterns and properties of de novo mutations in humans. Nat. Genet. 47, 822–826 (2015)

  16. 16.

    et al. Multi-nucleotide de novo mutations in humans. PLoS Genet. 12, e1006315 (2016)

  17. 17.

    et al. Genome-wide characteristics of de novo mutations in autism. npj Genomic Med. 1, 16027 (2016)

  18. 18.

    , & APOBEC3A/B-induced mutagenesis is responsible for 20% of heritable mutations in the TpCpW context. Genome Res. 27, 175–184 (2017)

  19. 19.

    et al. Whole genome characterization of sequence diversity of 15,220 Icelanders. Sci. Data 4, 170115 (2017)

  20. 20.

    & Hypermutation in human cancer genomes: footprints and mechanisms. Nat. Rev. Cancer 14, 786–800 (2014)

  21. 21.

    et al. The rate of meiotic gene conversion varies by sex and age. Nat. Genet. 48, 1377–1384 (2016)

  22. 22.

    , , , & Meiosis and maternal aging: insights from aneuploid oocytes and trisomy births. Cold Spring Harb. Perspect. Biol. 7, a017970 (2015)

  23. 23.

    , & Determinants of mutation rate variation in the human germline. Annu. Rev. Genomics Hum. Genet. 15, 47–70 (2014)

  24. 24.

    & Life history effects on the molecular clock of autosomes and sex chromosomes. Proc. Natl Acad. Sci. USA 113, 1588–1593 (2016)

  25. 25.

    , , & Interpreting the dependence of mutation rates on age and time. PLoS Biol. 14, e1002355 (2016)

  26. 26.

    , , & Variation in the molecular clock of primates. Proc. Natl Acad. Sci. USA 113, 10607–10612 (2016)

  27. 27.

    & Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009)

  28. 28.

    et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010)

  29. 29.

    et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009)

  30. 30.

    et al. Discovery and characterization of artifactual mutations in deep coverage targeted capture sequencing data due to oxidative DNA damage during sample preparation. Nucleic Acids Res. 41, e67 (2013)

  31. 31.

    et al. Parental origin of sequence variants associated with complex diseases. Nature 462, 868–874 (2009)

  32. 32.

    & BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010)

  33. 33.

    et al. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–49 (2014)

  34. 34.

    et al. Alignathon: a competitive assessment of whole-genome alignment methods. Genome Res. 24, 2077–2089 (2014)

Download references


We thank all the participants in this study. This study was performed in collaboration with Illumina.

Author information


  1. deCODE genetics/Amgen Inc., 101 Reykjavik, Iceland

    • Hákon Jónsson
    • , Patrick Sulem
    • , Birte Kehr
    • , Snaedis Kristmundsdottir
    • , Florian Zink
    • , Eirikur Hjartarson
    • , Marteinn T. Hardarson
    • , Kristjan E. Hjorleifsson
    • , Hannes P. Eggertsson
    • , Sigurjon Axel Gudjonsson
    • , Lucas D. Ward
    • , Gudny A. Arnadottir
    • , Einar A. Helgason
    • , Hannes Helgason
    • , Arnaldur Gylfason
    • , Adalbjorg Jonasdottir
    • , Aslaug Jonasdottir
    • , Thorunn Rafnar
    • , Mike Frigge
    • , Simon N. Stacey
    • , Olafur Th. Magnusson
    • , Unnur Thorsteinsdottir
    • , Gisli Masson
    • , Augustine Kong
    • , Bjarni V. Halldorsson
    • , Agnar Helgason
    • , Daniel F. Gudbjartsson
    •  & Kari Stefansson
  2. Faculty of Medicine, School of Health Sciences, University of Iceland, 101 Reykjavik, Iceland

    • Unnur Thorsteinsdottir
    •  & Kari Stefansson
  3. School of Engineering and Natural Sciences, University of Iceland, 101 Reykjavik, Iceland

    • Augustine Kong
    •  & Daniel F. Gudbjartsson
  4. School of Science and Engineering, Reykjavik University, 101 Reykjavik, Iceland

    • Bjarni V. Halldorsson
  5. Department of Anthropology, University of Iceland, 101 Reykjavik, Iceland

    • Agnar Helgason


  1. Search for Hákon Jónsson in:

  2. Search for Patrick Sulem in:

  3. Search for Birte Kehr in:

  4. Search for Snaedis Kristmundsdottir in:

  5. Search for Florian Zink in:

  6. Search for Eirikur Hjartarson in:

  7. Search for Marteinn T. Hardarson in:

  8. Search for Kristjan E. Hjorleifsson in:

  9. Search for Hannes P. Eggertsson in:

  10. Search for Sigurjon Axel Gudjonsson in:

  11. Search for Lucas D. Ward in:

  12. Search for Gudny A. Arnadottir in:

  13. Search for Einar A. Helgason in:

  14. Search for Hannes Helgason in:

  15. Search for Arnaldur Gylfason in:

  16. Search for Adalbjorg Jonasdottir in:

  17. Search for Aslaug Jonasdottir in:

  18. Search for Thorunn Rafnar in:

  19. Search for Mike Frigge in:

  20. Search for Simon N. Stacey in:

  21. Search for Olafur Th. Magnusson in:

  22. Search for Unnur Thorsteinsdottir in:

  23. Search for Gisli Masson in:

  24. Search for Augustine Kong in:

  25. Search for Bjarni V. Halldorsson in:

  26. Search for Agnar Helgason in:

  27. Search for Daniel F. Gudbjartsson in:

  28. Search for Kari Stefansson in:


H.J., F.Z., E.H., M.T.H., K.E.H., E.A.H., and D.F.G. analysed the data. H.J., B.K., S.K., F.Z., E.H., M.T.H., K.E.H., H.P.E., E.A.H., A.G., and D.F.G. created methods for analysing the data. Ad.J., As.J., and O.Th.M. performed the experiments. S.A.G., L.D.W., G.A.A., H.H., T.R., and M.F. collected the samples and information. H.J., P.S., U.T., G.M., A.K., B.V.H., A.H., D.F.G., and K.S. designed the study. H.J., P.S., B.V.H., A.H., D.F.G., and K.S. wrote the manuscript with input from S.N.S., U.T., G.M., and A.K.

Competing interests

All of the authors are employees of deCODE Genetics/Amgen, Inc.

Corresponding authors

Correspondence to Daniel F. Gudbjartsson or Kari Stefansson.

Reviewer Information Nature thanks S. Sunyaev and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Text and Data, Supplementary Tables 1-3, 5-11, 13-20 and Supplementary References.

Zip files

  1. 1.

    Supplementary Table 4

    This zipped file contains a gzipped tar archive of the DNMs with proband identifiers. The positions correspond to build hg38 of the human genome.

Text files

  1. 1.

    Supplementary Table 12

    This file contains the C>G enriched regions in 1Mb windows. The columns are the following: chromosome, the window number (1Mb) and region. One in the region column correspond to a C>G enriched region.

About this article

Publication history






Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.