Cited by 365Sperm and Testicular FunctionGenomics and Rare DiseasesCancer Genomics and Diagnostics

Paternal Age Effect Mutations and Selfish Spermatogonial Selection: Causes and Consequences for Human Disease

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Goriely, Anne, Wilkie, Andrew O.M.·2012·The American Journal of Human Genetics

Abstract

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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Crossref · 10.1016/j.ajhg.2011.12.017

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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).”

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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)
OpenAlex
W2010786205
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
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

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