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Cited by 146Sperm and Testicular FunctionGenomics and Rare DiseasesEvolution and Genetic Dynamics

Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia

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Goriely, Anne, McVean, Gilean A. T., van Pelt, Ans M. M., O'Rourke, Anthony W., Wall, Steven A., de Rooij, Dirk G., Wilkie, Andrew O. M.·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0500267102
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Abstract

Despite the importance of mutation in genetics, there are virtually no experimental data on the occurrence of specific nucleotide substitutions in human gametes. C>G transversions at position 755 of FGF receptor 2 ( FGFR2 ) cause Apert syndrome; this mutation, encoding the gain-of-function substitution Ser252Trp, occurs with a birth rate elevated 200- to 800-fold above background and originates exclusively from the unaffected father. We previously demonstrated high levels of both 755C>G and 755C>T FGFR2 mutations in human sperm and proposed that these particular mutations are enriched because the encoded proteins confer a selective advantage to spermatogonial cells. Here, we examine three corollaries of this hypothesis. First, we show that mutation levels at the adjacent FGFR2 nucleotides 752-754 are low, excluding any general increase in local mutation rate. Second, we present three instances of double-nucleotide changes involving 755C, expected to be extremely rare as chance events. Two of these double-nucleotide substitutions are shown, either by assessment of the pedigree or by direct analysis of sperm, to have arisen in sequential steps; the third (encoding Ser252Tyr) was predicted from structural considerations. Finally, we demonstrate that both major alternative spliceforms of FGFR2 ( Fgfr2b and Fgfr2c ) are expressed in rat spermatogonial stem cell lines. Taken together, these observations show that specific FGFR2 mutations attain high levels in sperm because they encode proteins with gain-of-function properties, favoring clonal expansion of mutant spermatogonial cells. Among FGFR2 mutations, those causing Apert syndrome may be especially prevalent because they enhance signaling by FGF ligands specific for each of the major expressed isoforms.

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  • Nearly all Apert syndrome mutations arise de novo and originate exclusively from the father.

    “Nearly all Apert syndrome mutations arise de novo, and have been shown to originate exclusively from the father.”

    From Craniosynostosis (2011) · cites this paper as [15]

    The Abstract (page unavailable) says the Apert-causing FGFR2 755C>G mutation originates exclusively from an unaffected father, while describing FGFR2 mutations more broadly as having a nearly exclusive paternal origin. The Discussion (page unavailable) refers to a high rate of de novo Apert syndrome mutations. These passages support the general pattern but do not establish that nearly all Apert syndrome mutations are de novo or that every type originates exclusively from the father. (LLM, conf=0.85)

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  • Most FGF receptor mutation cases originate from mutations in adult spermatogonia; despite strong positive selection, these mutations never make up large fractions of sperm.

    “This is because the vast majority of cases arise from mutations occurring in adult spermatogonia, which although subject to strong positive selection never populate large proportions of the sperm.15,16”

    From Craniosynostosis (2011) · cites this paper as [15]

    The Discussion supports positive selection of FGFR2 mutations in spermatogonial cells, and the reported sperm frequencies are small even at the highest measured levels. But the paper does not establish that the vast majority of cases originate from mutations occurring in adult spermatogonia, or that such mutations never occupy large fractions of sperm; those claims are broader than its findings. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • These mutations provide a paradigm for paternal age effect mutations that are enriched in sperm owing to a selective advantage to mutant spermatogonial cells in the testis.

    “These mutations provide a paradigm for paternal age effect mutations that are enriched in sperm owing to a paradoxical selective advantage to mutant spermatogonial cells in the testis.15,16”

    From Craniosynostosis (2011) · cites this paper as [15]

  • For FGF receptor mutations, when both parents' blood tests are negative, recurrence risk is very low (well under 1%).

    “In the case of FGF receptor mutations, provided that the blood of both parents is negative for the mutation, the recurrence risk is very low (well under 1%).”

    From Craniosynostosis (2011) · cites this paper as [15]

    The Analysis of Mutations at FGFR2 Nucleotides 752–755 section compares mutation levels in sperm and blood, but does not estimate recurrence risk after negative parental blood tests. The Double Mutations section describes one family in which the mother had a normal FGFR2 sequence and the father carried a mutation; it does not address the claim’s condition or its well-under-1% figure. Searches for recurrence risk, negative parental blood tests, and the stated percentage found no supporting passage. (LLM, conf=0.73)

    Experimental — accuracy not yet measured

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Cites

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Research works printed but not linked: 7

  1. Cooper, D. N. (Nature Publishing Group, London), Vol. 4, pp. 218-222.
  2. Yu, K., Herr, A. B., Waksman, G. & Ornitz, D. M. (2000) Proc. Natl. Acad. Sci. USA 97, 14536-14541.
  3. Yu, K. & Ornitz, D. M. (2001) Proc. Natl. Acad. Sci. USA 98, 3641-3643.
  4. Ibrahimi, O. A., Eliseenkova, A. V., Plotnikov, A. N., Ornitz, D. M. & Mohammadi, M. (2001) Proc. Natl. Acad. Sci. USA 98, 7182-7187.
  5. Kubota, H., Avarbock, M. R. & Brinster, R. L. (2004) Proc. Natl. Acad. Sci. USA 101, 16489-16494.
  6. Robertson, S. C., Meyer, A. N., Hart, K. C., Galvin, B. D., Webster, M. K. & Donoghue, D. J. (1998) Proc. Natl. Acad. Sci. USA 95, 4567-4572.
  7. Tiemann-Boege, I., Navidi, W., Grewal, R., Cohn, D., Eskenazi, B., Wyrobek, A. J. & Arnheim, N. (2002) Proc. Natl. Acad. Sci. USA 99, 14952-14957.

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Authors
Goriely, A., McVean, G. A. T., van Pelt, A. M. M., O'Rourke, A. W., Wall, S. A., de Rooij, D. G., & Wilkie, A. O. M.
Affiliations
  • Utrecht University (NL)
  • Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom; Department of Statistics, University of Oxford, South Parks Road, Oxford OX1 3TG, United Kingdom; Department of Endocrinology, Utrecht University, 3584 CH, Utrecht, The Netherlands; Oxford Regional Genetics Laboratories, Churchill Hospital, Oxford OX3 7LJ, United Kingdom; Department of Plastic Surgery, Craniofacial Unit, Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom; and...
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2005-04-19
Volume
102
Issue
17
Pages
6051-6056
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0500267102
OpenAlex
W1975823415
Cited by
146
References
45
Citations by year
2026: 3 · 2025: 2 · 2024: 1 · 2022: 16 · 2021: 4 · 2020: 2 · 2019: 7 · 2018: 7 · 2017: 2 · 2016: 8 · 2015: 3 · 2014: 7 · 2013: 11 · 2012: 15
FWCI
11.92
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed (publishedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
Funders
Wellcome Trust
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 › Genetics › Evolution and Genetic Dynamics
Keywords
FGFR2, Apert syndrome, gain-of-function mutations, spermatogonia, clonal expansion, FGFR2b, FGF signaling, positive selection, spermatogonial stem cells
MeSH terms
Acrocephalosyndactylia, Base Sequence, Genetic Carrier Screening, Humans, Male, Spermatogonia, Polymerase Chain Reaction, Mutagenesis, Site-Directed, Receptors, Fibroblast Growth Factor, DNA Primers, Amino Acid Substitution, Polymorphism, Single Nucleotide, Receptor Protein-Tyrosine Kinases, Receptor, Fibroblast Growth Factor, Type 2

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