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Missing heritability: paternal age effect mutations and selfish spermatogonia

Nature Reviews Genetics volume 11, page 589 (2010)Cite this article

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In a recent Viewpoint on missing heritability (Missing heritability and strategies for finding the underlying causes of complex disease. Nature Rev. Genet. 11, 446–450 (2010))1, several commentators mentioned the expected importance of rare variants. Except for copy number polymorphisms (CNPs), contemporary technologies do not enable the systematic identification of rare variants that, given moderate effect size, could contribute significantly to missing heritability2. However strategies to identify such sequence changes will soon become available3.

In this context we wish to highlight an emerging mechanism contributing to the introduction of new disease alleles into the population, which we term paternal age effect (PAE) mutation. The best-characterized PAE mutations encode mutant proteins with gain-of-function properties and share other distinctive features: near-exclusive paternal origin, high apparent germline mutation rate (up to 1,000-fold above background), and elevated paternal age (by 2–5 years, compared to the population average). Well-documented examples are in the fibroblast growth factor receptor 2 (FGFR2), FGFR3, RET, protein tyrosine phosphatase, non-receptor type 11 (PTPN11) and HRAS genes, heterozygous substitutions of which cause congenital skeletal disorders, sometimes with additional predisposition to cancer4.

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Figure 1: Illustrative depiction of how enrichment of functionally significant paternal age effect mutations could occur.

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  1. Anne Goriely and Andrew O.M. Wilkie are at the Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.,

    Anne Goriely & Andrew O. M. Wilkie

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  1. Anne Goriely
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Correspondence to Anne Goriely.

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Goriely, A., Wilkie, A. Missing heritability: paternal age effect mutations and selfish spermatogonia. Nat Rev Genet 11, 589 (2010). https://doi.org/10.1038/nrg2809-c1

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