Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes
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Abstract
Mosaic mutations present in the germline have important implications for reproductive risk and disease transmission. We previously demonstrated a phenomenon occurring in the male germline, whereby specific mutations arising spontaneously in stem cells (spermatogonia) lead to clonal expansion, resulting in elevated mutation levels in sperm over time. This process, termed “selfish spermatogonial selection,” explains the high spontaneous birth prevalence and strong paternal age-effect of disorders such as achondroplasia and Apert, Noonan and Costello syndromes, with direct experimental evidence currently available for specific positions of six genes ( FGFR2 , FGFR3 , RET , PTPN11 , HRAS , and KRAS ). We present a discovery screen to identify novel mutations and genes showing evidence of positive selection in the male germline, by performing massively parallel simplex PCR using RainDance technology to interrogate mutational hotspots in 67 genes (51.5 kb in total) in 276 biopsies of testes from five men (median age, 83 yr). Following ultradeep sequencing (about 16,000×), development of a low-frequency variant prioritization strategy, and targeted validation, we identified 61 distinct variants present at frequencies as low as 0.06%, including 54 variants not previously directly associated with selfish selection. The majority (80%) of variants identified have previously been implicated in developmental disorders and/or oncogenesis and include mutations in six newly associated genes ( BRAF , CBL , MAP2K1 , MAP2K2 , RAF1 , and SOS1 ), all of which encode components of the RAS-MAPK pathway and activate signaling. Our findings extend the link between mutations dysregulating the RAS-MAPK pathway and selfish selection, and show that the aging male germline is a repository for such deleterious mutations.
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The 12 known germline selection genes all operate through activation of the RAS-MAPK signalling pathway.
“we initially focused on the 12 known germline selection genes, which all operate through activation of the RAS-MAPK signalling pathway25,26.”
From Evidence for 28 genetic disorders discovered by combining healthcare and research data (2020) · cites this paper as [26]
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Self-citation
- Authors
- Maher, G. J., Ralph, H. K., Ding, Z., Koelling, N., Mlcochova, H., Giannoulatou, E., Dhami, P., Paul, D. S., Stricker, S. H., Beck, S., McVean, G., Wilkie, A. O. M., & Goriely, A.
- Affiliations
- University of Oxford (GB)
- University College London (GB)
- Corresponding author
- Goriely, Anne
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2018-10-24
- Volume
- 28
- Issue
- 12
- Pages
- 1779-1790
- ISSN
- 1088-9051 (ISSN-L)
- 1549-5469
- PMC
- PMC6280762
- OpenAlex
- W2952956750
- Cited by
- 85
- References
- 70
- Citations by year
- 2026: 11 · 2025: 7 · 2024: 16 · 2023: 7 · 2022: 8 · 2021: 8 · 2020: 14 · 2019: 13 · 2018: 1
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Wellcome (99148, 090532)
- Wellcome Trust (091182, 102731, 105361)
- Simons Foundation (332759)
- National Institute for Health Research
- Medical Research Council
- WIMM Strategic Alliance (G0902418, MC_UU_12025)
- 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
- RAS/MAPK pathway, male germline, spermatogonia, clonal expansion, germline mosaicism, paternal age effect, mutational hotspots, low-frequency variants, BRAF, CBL, MEK1, MAP2K2, Raf-1, SOS1, developmental disorders, carcinogenesis
- MeSH terms
- Aged, Aged, 80 and over, Humans, Male, Middle Aged, Mutation, Testis, Genetic Variation, Signal Transduction, ras Proteins, Mitogen-Activated Protein Kinases
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