Abstract

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.

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Acknowledgements

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

Author information

Affiliations

  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

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Contributions

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

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    Supplementary Information

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

Zip files

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    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.

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https://doi.org/10.1038/nature24018

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