A germ-line-selective advantage rather than an increased mutation rate can explain some unexpectedly common human disease mutations.

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: 9.81). 07/2008; 105(29):10143-8. DOI: 10.1073/pnas.0801267105
Source: PubMed

ABSTRACT 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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    ABSTRACT: Apert syndrome is a rare congenital type I acrocephalosyndanctyly syndrome, characterized by craniosynostosis, severe syndactyly of the hands and feet, symphalangism and dysmorphic facial features. Here we reported one case of Apert syndrome and reviewed the literature. This patient presented with the clinical triad that characterized Apert syndrome: brachycephalic skull, midface hypoplasia and syndactyly of feet. Bayley infantile development scale manifested low intellectual score in this case. Rehabilitation therapies such as physical therapy, occupational therapy and speech therapy were introduced to promote the development of motor and intelligence. One and half years follow-up showed that the patient could walk independently without abnormal gait, and the intellectual condition was improved. The aim is to alert pediatricians and surgeons about the early diagnosis and appropriate treatment may improve the quality of life and the prognosis of Apert syndrome.
    Human Health and Biomedical Engineering (HHBE), 2011 International Conference on; 01/2011
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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.
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    ABSTRACT: Spermatogenesis is a long and complex process that, despite the shared overall goal of producing the male gamete, displays striking amounts of interspecific diversity. In this review, we argue that sperm competition has been an important selection pressure acting on multiple aspects of spermatogenesis, causing variation in the number and morphology of sperm produced, and in the molecular and cellular processes by which this happens. We begin by reviewing the basic biology of spermatogenesis in some of the main animal model systems to illustrate this diversity, and then ask to what extent this variation arises from the evolutionary forces acting on spermatogenesis, most notably sperm competition. We explore five specific aspects of spermatogenesis from an evolutionary perspective, namely: (i) interspecific diversity in the number and morphology of sperm produced; (ii) the testicular organizations and stem cell systems used to produce them; (iii) the large number and high evolutionary rate of genes underpinning spermatogenesis; (iv) the repression of transcription during spermiogenesis and its link to the potential for haploid selection; and (v) the phenomenon of selection acting at the level of the germline. Overall we conclude that adopting an evolutionary perspective can shed light on many otherwise opaque features of spermatogenesis, and help to explain the diversity of ways in which males of different species perform this fundamentally important process.
    Molecular Human Reproduction 10/2014; · 3.48 Impact Factor

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