Abstract

Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent–offspring trios at high coverage. We show that in our samples, with an average father’s age of 29.7, the average de novo mutation rate is 1.20 × 10−8 per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years. After accounting for random Poisson variation, father’s age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father’s age on the risk of diseases such as schizophrenia and autism.

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Acknowledgements

This research was partly funded by The National Institutes of Health grant MH071425 (K.S.); the European Community’s Seventh Framework Programme, PsychCNVs project, grant agreement HEALTH-F2-2009-223423, and NextGene project, grant agreement IAPP-MC-251592; The European Community IMI grant EU-AIMS, grant agreement 115300.

Author information

Affiliations

  1. deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland

    • Augustine Kong
    • , Michael L. Frigge
    • , Gisli Masson
    • , Soren Besenbacher
    • , Patrick Sulem
    • , Gisli Magnusson
    • , Sigurjon A. Gudjonsson
    • , Asgeir Sigurdsson
    • , Aslaug Jonasdottir
    • , Adalbjorg Jonasdottir
    • , Gunnar Sigurdsson
    • , G. Bragi Walters
    • , Stacy Steinberg
    • , Hannes Helgason
    • , Gudmar Thorleifsson
    • , Daniel F. Gudbjartsson
    • , Agnar Helgason
    • , Olafur Th. Magnusson
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  2. Bioinformatics Research Centre, Aarhus University, 8000 Aarhus, Denmark

    • Soren Besenbacher
  3. Illumina Cambridge Ltd, Chesterford Research Park, Little Chesterford, Essex CB10 1XL, UK

    • Wendy S. W. Wong
  4. University of Iceland, 101 Reykjavik, Iceland

    • Agnar Helgason
  5. Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland

    • Unnur Thorsteinsdottir
    •  & Kari Stefansson

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Contributions

A.K. and K.S. planned and directed the research. A.K. wrote the first draft and together with K.S., S.B., P.S., A.H. and U.T. wrote the final version. O.T.M. and U.T. oversaw the sequencing and laboratory work. G. Masson, G. Magnusson and G.S. processed the raw sequencing data. A.K. and M.L.F. analysed the data, with W.S.W.W., H.H., G.B.W., S.S., G.T. and D.F.G. providing assistance. P.S. and S.A.G. performed functional annotations. S.B. analysed the mutations with respect to sequence content. A.S., Aslaug J. and Adalbjorg J. did the Sanger sequencing. A.H. investigated the contribution of demographics.

Competing interests

The authors from deCODE Genetics are employees of or own stock options in deCODE Genetics. W.S.W.W. is an employee of Illumina Inc., a public company that develops and markets systems for genetic analysis; she receives stocks as part of her compensation.

Corresponding authors

Correspondence to Augustine Kong or Kari Stefansson.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Text, additional references, Supplementary Table 2 and Supplementary Figure 1.

Excel files

  1. 1.

    Supplementary Data

    This file contains Supplementary Table 1 which shows information for each of the 4,933 de novo mutations individually. They correspond to the summary in Supplementary Table 2. The positions are based on Human Assembly Build 36.

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DOI

https://doi.org/10.1038/nature11396

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