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.
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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.
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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.
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This file contains Supplementary Text, additional references, Supplementary Table 2 and Supplementary Figure 1. (PDF 937 kb)
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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. (XLS 523 kb)
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Kong, A., Frigge, M., Masson, G. et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature 488, 471–475 (2012). https://doi.org/10.1038/nature11396
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DOI: https://doi.org/10.1038/nature11396
Daniel Helman
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,<sup class="footnote">1</sup> 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.<sup class="footnote">2</sup>
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
[email protected]
<sup class="footnote">1</sup> 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/natur...
<sup class="footnote">2</sup> 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.or...
Bernard Crespi
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.
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