Choi, S. K., Yoon, S. R., Calabrese, P. & Arnheim, N. A germ-line-selective advantage rather than an increased mutation rate can explain some unexpectedly common human disease mutations. Proc. Natl Acad. Sci. USA 105, 10143-10148

Molecular and Computational Biology Program, University of Southern California, 1050 Childs Way, Los Angeles, CA 90089-2910, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2008; 105(29):10143-8. DOI: 10.1073/pnas.0801267105
Source: PubMed


Two nucleotide substitutions in the human FGFR2 gene (C755G or C758G) are responsible for virtually all sporadic cases of Apert syndrome. This condition is 100-1,000 times more common than genomic mutation frequency data predict. Here, we report on the C758G de novo Apert syndrome mutation. Using data on older donors, we show that spontaneous mutations are not uniformly distributed throughout normal testes. Instead, we find foci where C758G mutation frequencies are 3-4 orders of magnitude greater than the remaining tissue. We conclude this nucleotide site is not a mutation hot spot even after accounting for possible Luria-Delbruck "mutation jackpots." An alternative explanation for such foci involving positive selection acting on adult self-renewing Ap spermatogonia experiencing the rare mutation could not be rejected. Further, the two youngest individuals studied (19 and 23 years old) had lower mutation frequencies and smaller foci at both mutation sites compared with the older individuals. This implies that the mutation frequency of foci increases as adults age, and thus selection could explain the paternal age effect for Apert syndrome and other genetic conditions. Our results, now including the analysis of two mutations in the same set of testes, suggest that positive selection can increase the relative frequency of premeiotic germ cells carrying such mutations, although individuals who inherit them have reduced fitness. In addition, we compared the anatomical distribution of C758G mutation foci with both new and old data on the C755G mutation in the same testis and found their positions were not correlated with one another.

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Available from: Song-ro Yoon
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    • "Moreover, excessive selfrenewal signals induce oncogenic transformation and impair SSC maintenance (Goertz et al., 2011; Lee et al., 2009). In contrast, gain-of-function (GOF) mutations in fibroblast growth factor receptor 2 (FGFR2), associated with enhanced FGF signaling, are the basis for Apert syndrome , in which the PAE is particularly robust (Choi et al., 2008). Furthermore, other disorders that exhibit a strong PAE (e.g., achondroplasia and MEN2B) are due to mutant alleles that also increase growth factor signaling in affected organs and tissues (Goriely and Wilkie, 2012). "
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    ABSTRACT: Pathogenic de novo mutations increase with fathers' age and could be amplified through competition between genetically distinct subpopulations of spermatogonial stem cells (SSCs). Here, we tested the fitness of SSCs bearing wild-type human FGFR2 or an Apert syndrome mutant, FGFR2 (S252W), to provide experimental evidence for SSC competition. The S252W allele conferred enhanced FGFR2-mediated signaling, particularly at very low concentrations of ligand, and also subtle changes in gene expression. Mutant SSCs exhibited improved competitiveness in vitro and increased stem cell activity in vivo upon transplantation. The fitness advantage in vitro only occurred in low concentrations of fibroblast growth factor (FGF), was independent of FGF-driven proliferation, and was accompanied by increased response to glial cell line-derived neurotrophic factor (GDNF). Our studies provide experimental evidence of enhanced stem cell fitness in SSCs bearing a paternal age-associated mutation. Our model will be useful for interrogating other candidate mutations in the future to reveal mechanisms of disease risk.
    Full-text · Article · Aug 2014 · Stem Cell Reports
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    • "With today's understanding of selfish spermatogonial selection, we propose that these spermatogonial clusters represent the clonal expansion of mutant selfish cells, based on their morphology, expression of relevant markers, and their size and distribution. As younger men also produce spermatozoa with PAE mutations (Goriely et al., 2003, 2009; Yoon et al., 2009; Giannoulatou et al., 2013) and have foci of mutations in their testes (Qin et al., 2007; Choi et al., 2008, 2012; Yoon et al., 2013), immunopositive tubules should also be apparent in younger men. The lack of reporting of such clusters of spermatogonia may be attributed to a number of reasons: (i) the limited studies of 'normal' (i.e. "
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    ABSTRACT: Owing to a recent trend for delayed paternity, the genomic integrity of spermatozoa of older men has become a focus of increased interest. Older fathers are at higher risk for their children to be born with several monogenic conditions collectively termed paternal age effect (PAE) disorders, which include achondroplasia, Apert syndrome and Costello syndrome. These disorders are caused by specific mutations originating almost exclusively from the male germline, in genes encoding components of the tyrosine kinase receptor/RAS/MAPK signalling pathway. These particular mutations, occurring randomly during mitotic divisions of spermatogonial stem cells (SSCs), are predicted to confer a selective/growth advantage on the mutant SSC. This selective advantage leads to a clonal expansion of the mutant cells over time, which generates mutant spermatozoa at levels significantly above the background mutation rate. This phenomenon, termed selfish spermatogonial selection, is likely to occur in all men. In rare cases, probably because of additional mutational events, selfish spermatogonial selection may lead to spermatocytic seminoma. The studies that initially predicted the clonal nature of selfish spermatogonial selection were based on DNA analysis, rather than the visualization of mutant clones in intact testes. In a recent study that aimed to identify these clones directly, we stained serial sections of fixed testes for expression of melanoma antigen family A4 (MAGEA4), a marker of spermatogonia. A subset of seminiferous tubules with an appearance and distribution compatible with the predicted mutant clones were identified. In these tubules, termed 'immunopositive tubules', there is an increased density of spermatogonia positive for markers related to selfish selection (FGFR3) and SSC self-renewal (phosphorylated AKT). Here we detail the properties of the immunopositive tubules and how they relate to the predicted mutant clones, as well as discussing the utility of identifying the potential cellular source of PAE mutations.
    Preview · Article · Dec 2013 · Andrology
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    • "All that is required is a slight chance of undergoing a symmetric division (selection model parameter = 0.0059, selection model with cell death value = 0.011). Similar clustering patterns in the testes of middle-aged and older men were also observed for Apert syndrome and MEN2B, but not in young (<21 years) testes, indicating that the clonal expansion occurs in the adult phase of spermatogenesis (19,20), and this is also likely true for the ACH mutation. "
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    ABSTRACT: There are certain de novo germline mutations associated with genetic disorders whose mutation rates per generation are orders of magnitude higher than the genome average. Moreover, these mutations occur exclusively in the male germ line and older men have a higher probability of having an affected child than younger ones, known as the paternal age-effect. The classic example of a genetic disorder exhibiting a PAE is achondroplasia, caused predominantly by a single nucleotide substitution (c.1138G>A) in FGFR3. To elucidate what mechanisms might be driving the high frequency of this mutation in the male germline, we examined the spatial distribution of the c.1138G>A substitution in a testis from an 80-year old unaffected man. Using a technology based on bead-emulsion amplification, we were able to measure mutation frequencies in 192 individual pieces of the dissected testis with a false positive rate lower than 2.7x10(-6). We observed that most mutations are clustered in a few pieces with 95% of all mutations occurring in 27% of the total testis. Using computational simulations, we rejected the model proposing an elevated mutation rate per cell division at this nucleotide site. Instead we determined that the observed mutation distribution fits a germline selection model, where mutant spermatogonial stem cells have a proliferative advantage over unmutated cells. Combined with data on several other PAE mutations, our results support the idea that the PAE, associated with a number of Mendelian disorders, may be explained primarily by a selective mechanism.
    Full-text · Article · Jun 2013 · Human Molecular Genetics
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