Rate of de novo mutations and the importance of father’s age to disease risk

Journal name:
Nature
Volume:
488,
Pages:
471–475
Date published:
DOI:
doi:10.1038/nature11396
Received
Accepted
Published online

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 16.5years. 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.

At a glance

Figures

  1. A summary of the family types.
    Figure 1: A summary of the family types.

    a, Fifty-seven simple trios. b, Six sib-pairs accounting for 12 trios. c, Five three-generation families accounting for nine trios.

  2. Father/'s age and number of de novo mutations.
    Figure 2: Father’s age and number of de novo mutations.

    The number of de novo mutations called is plotted against father’s age at conception of child for the 78 trios. The solid black line denotes the linear fit. The dashed red curve is based on an exponential model fitted to the combined mutation counts. The dashed blue curve corresponds to a model in which maternal mutations are assumed to have a constant rate of 14.2 and paternal mutations are assumed to increase exponentially with father’s age.

  3. Effect of father/'s age by chromosome.
    Figure 3: Effect of father’s age by chromosome.

    By chromosome, the estimated increase in the number of de novo mutations per year of father’s age is plotted against the average number of mutations observed. The 95% confidence intervals are given. The solid straight line corresponds to the model in which the additive effect of father’s age on the number of de novo mutations is assumed to be proportional to the mean number of mutations on the chromosome. From left to right, the points correspond to chromosome 21, 22, 19, 20, 15, 17, 18, 14, 16, 13, 12, 9, 10, 11, 8, 7, 6, 3, 5, 4, 2 and 1.

  4. Demographics of Iceland and de novo mutations.
    Figure 4: Demographics of Iceland and de novo mutations.

    The deCODE Genetics genealogy database was used to assess fathers’ age at conception for all available 752,343 father–child pairs, in which the child’s birth year was≥1650. The mean age of fathers at conception (left vertical axis) is plotted by birth year of child, grouped into ten-year intervals. On the basis of the linear model fitted for the relationship between father’s age and the number of de novo mutations, the same plot, using the right vertical axis, shows the mean number of expected mutations for each ten-year interval.

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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

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 financial 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:

Author details

Supplementary information

PDF files

  1. Supplementary Information (937K)

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

Excel files

  1. Supplementary Data (523K)

    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.

Comments

  1. Report this comment #50001

    Daniel Helman said:

    Paternal Age and Technological Pollution

    Kong et al. (Nature, 23 August 2012) have done wonderfully in their work connecting a father's age to disease risk,1 and I am curious to know whether such a feature is endemic or caused by environmental factors particular to modernity. With the recent news that the common plasticizer and endocrine-disruptor Bisphenol A (BPA) can produce effects (in mice) for several generations, with an exposure level similar to what humans have, it begs the question of environmental influence, particularly since the effect of BPA described in this article look a lot like autism.2

    Though such studies are difficult to set up, I'd like to read a follow up on Kong et al.'s work. I don't think we've heard the last of this story.

    Daniel Helman
    MS Candidate in Geology
    California State University Long Beach
    danielhelmanteaching@yahoo.com

    1 Augustine Kong, et al. (2012) Rate of de novo mutations and the importance of father's age to disease risk. Nature 488: 471-475.
    http://www.nature.com/nature/journal/v488/n7412/full/nature11396.html

    2 Jennifer T. Wolstenholme, et al. (2012) Gestational Exposure to Bisphenol A Produces Transgenerational Changes in Behaviors and Gene Expression. Endocrinology 153: 3828.
    http://endo.endojournals.org/content/153/8/3828.abstract

  2. Report this comment #50369

    Bernard Crespi said:

    This is an outstanding paper that provides the first detailed quantification of how human de novo mutations in sperm and eggs vary with parental age. The paper and its aftermath provide a number of important lessons for researchers studying neurodevelopmental disorders and parental age:

    (1) The work demonstrates directly that CpG dinucleotides contribute the lion's share of new mutations. CpG sites are of particular interest to understanding effects of de novo mutations because they differentially create new transcription factor binding sites (Zemojtel et al. 2011), as well as mediating the effects of methylation and genomic imprinting. Such findings might help to focus efforts at interpreting the functional importance of the myriad de novo variants that pepper each genome.

    (2) The work generates an apparent paradox: if, as the authors claim, paternal age so strongly predominates over maternal age in its de novo mutational effects, why do so many parental-age studies of autism and schizophrenia show clear effects of maternal age as well (e. g., Lopez-Castroman et al. 2010; Parner et al. 2012; Rahbar et al. 2012; Sandon et al. 2012)? Might maternal-age effects be mediated by different processes?

    (3) The X chromosome was not included in the analysis, despite its expected contribution to de novo mutational effects being much stronger than for autosomes, due to its hemizygosity (as found, for example, in intellectual disability). A recent study also strikingly implicates the X in psychosis risk, perhaps involving epigenetic mechanisms (Goldstein et al. 2011).

    (4) It is important to avoid neurodevelopmental tunnel vision with regard to parental age effects. Advanced maternal age, for example, has been documented as a risk factor for a suite of other conditions, including hypertension, diabetes, cancer, and Alzheimer's (review in Myrskyla and Fenelon 2011), as expected if it exerts effects on all polygenic conditions.

    (5) As anyone following popular media accounts will have noticed, the paper has been fundamentally misinterpreted in translation from the scientific to popular literature. Contrary to almost all reports in the popular press (including, for example, the New York Times), the paper clearly does not show that higher paternal age is associated with mutations that increase the risk of autism or schizophrenia. To do so would require that the authors link paternal age with the number of new mutations that are actually known to contribute to autism or schizophrenia. This muddle should caution authors to be as clear in explaining what their findings do not show as they are in explaining what they actually demonstrate. If subsequent work shows that age-dependent point mutations themselves do not mediate increased autism or schizophrenia risk, scientific credibility will unjustifiably suffer.

    (6) Finally, the press has jumped on advanced parental age as an important possible factor in the increased diagnoses of autism over the past 30 or so years. But if increased mutation load has increased rates of autism, why haven't rates of schizophrenia increased in lockstep, albeit with a 20-year delay?

    Parental age has been suspected as an important factor in genetically-based, de novo conditions since Weinberg (of Hardy-Weinberg fame); noticed in 1912 that children with achondroplasia (a form of dwarfism); were later-born in sibships. One hundred years later, we are one large step closer to understanding why. Let us help to ensure that this step is free of de novo errors of interpretation and implication, and move forward with speed.

    References:

    Goldstein JM, Cherkerzian S, Seidman LJ, Petryshen TL, Fitzmaurice G, Tsuang MT, Buka SL. Sex-specific rates of transmission of psychosis in the New England high-risk family study. Schizophr Res. 2011 May;128(1-3):150-5.

    Lopez-Castroman J, Gómez DD, Belloso JJ, Fernandez-Navarro P, Perez-Rodriguez MM, Villamor IB, Navarrete FF, Ginestar CM, Currier D, Torres MR, Navio-Acosta M, Saiz-Ruiz J, Jimenez-Arriero MA, Baca-Garcia E. Differences in maternal and paternal age between schizophrenia and other psychiatric disorders. Schizophr Res. 2010 Feb;116(2-3):184-90.

    Myrskylä, M.; Fenelon, A. T.: Maternal age and offspring adult health: evidence from the Health and Retirement Study. MPIDR Working Paper WP-2011-009. www.demogr.mpg.de/en/institute/.../mikko_myrskylae_1747.htm

    Parner ET, Baron-Cohen S, Lauritsen MB, Jørgensen M, Schieve LA, Yeargin-Allsopp M, Obel C. Parental age and autism spectrum disorders. Ann Epidemiol. 2012 Mar;22(3):143-50.

    Rahbar MH, Samms-Vaughan M, Loveland KA, Pearson DA, Bressler J, Chen Z, Ardjomand-Hessabi M, Shakespeare-Pellington S, Grove ML, Beecher C, Bloom K, Boerwinkle E. Maternal and Paternal Age are Jointly Associated with Childhood Autism in Jamaica. J Autism Dev Disord. 2012 Sep;42(9):1928-38.

    Sandin S, Hultman CM, Kolevzon A, Gross R, MacCabe JH, Reichenberg A. Advancing maternal age is associated with increasing risk for autism: a review and meta-analysis. J Am Acad Child Adolesc Psychiatry. 2012 May;51(5):477-486.e1.

    Zemojtel T, Kielbasa SM, Arndt PF, Behrens S, Bourque G, Vingron M. CpG deamination creates transcription factor-binding sites with high efficiency. Genome Biol Evol. 2011;3:1304-11.

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