Paternal Age Effect Mutations and Selfish Spermatogonial Selection: Causes and Consequences for Human Disease
Open accessAbstract
Advanced paternal age has been associated with an increased risk for spontaneous congenital disorders and common complex diseases (such as some cancers, schizophrenia, and autism), but the mechanisms that mediate this effect have been poorly understood. A small group of disorders, including Apert syndrome (caused by FGFR2 mutations), achondroplasia, and thanatophoric dysplasia (FGFR3), and Costello syndrome (HRAS), which we collectively term "paternal age effect" (PAE) disorders, provides a good model to study the biological and molecular basis of this phenomenon. Recent evidence from direct quantification of PAE mutations in sperm and testes suggests that the common factor in the paternal age effect lies in the dysregulation of spermatogonial cell behavior, an effect mediated molecularly through the growth factor receptor-RAS signal transduction pathway. The data show that PAE mutations, although arising rarely, are positively selected and expand clonally in normal testes through a process akin to oncogenesis. This clonal expansion, which is likely to take place in the testes of all men, leads to the relative enrichment of mutant sperm over time-explaining the observed paternal age effect associated with these disorders-and in rare cases to the formation of testicular tumors. As regulation of RAS and other mediators of cellular proliferation and survival is important in many different biological contexts, for example during tumorigenesis, organ homeostasis and neurogenesis, the consequences of selfish mutations that hijack this process within the testis are likely to extend far beyond congenital skeletal disorders to include complex diseases, such as neurocognitive disorders and cancer predisposition.
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Positive germline selection can increase the apparent mutation rate more strongly than clinical ascertainment or hypermutability.
“Positive germline selection can increase the apparent mutation rate more strongly23 than either clinical ascertainment (10-100X in our dataset) or hypermutability (~10X for CpGs).”
From Evidence for 28 genetic disorders discovered by combining healthcare and research data (2020) · cites this paper as [23]
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- Authors
- Goriely, A., & Wilkie, A. O. M.
- Affiliations
- University of Oxford (GB)
- Corresponding author
- Goriely, Anne
- Wilkie, Andrew O.M.
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 90
- Issue
- 2
- Pages
- 175-200
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC3276674
- OpenAlex
- W2010786205
- Semantic Scholar
- 80b5a9c79ff84a1b264ec636f644f1869491b444
- Cited by
- 365
- References
- 197
- Citations by year
- 2026: 18 · 2025: 25 · 2024: 26 · 2023: 25 · 2022: 31 · 2021: 21 · 2020: 25 · 2019: 37 · 2018: 25 · 2017: 17 · 2016: 27 · 2015: 23 · 2014: 24 · 2013: 30 · 2012: 10
- FWCI
- 3.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (091182)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- paternal age effect, FGFR2 mutations, FGFR3 mutation, HRAS mutation, Costello syndrome, Apert syndrome, achondroplasia, thanatophoric dysplasia, clonal expansion, Ras signaling, testicular tumors, spontaneous mutation, testis, congenital skeletal disorders, complex diseases, cancer susceptibility, neurocognitive disorders
- MeSH terms
- Animals, Humans, Male, Mutation, Paternal Age, Spermatogonia, Spermatozoa, Testis, Genetic Predisposition to Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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