title: A germ-line-selective advantage rather than an increased mutation rate can explain some unexpectedly common human disease mutations.
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.
authors.affiliation: Molecular and Computational Biology Program, University of Southern California, 1050 Childs Way, Los Angeles, CA 90089-2910, USA.
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Choi
authors.forename: Song-Ro
authors.initials: SR
authors.lastname: Yoon
authors.forename: Peter
authors.initials: P
authors.lastname: Calabrese
authors.forename: Norman
authors.initials: N
authors.lastname: Arnheim
mesh_terms: D000168:Acrocephalosyndactylia / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000367:Age Factors; D001483:Base Sequence; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D010331:Paternal Age; D017354:Point Mutation; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D012641:Selection, Genetic; D013093:Spermatogonia / Q000378:metabolism / Q000473:pathology; D013737:Testis / Q000378:metabolism / Q000473:pathology
chemical_list: D017931:DNA Primers; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2