title: Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line.
abstract: Observed mutation rates in humans appear higher in male than female gametes and often increase with paternal age. This bias, usually attributed to the accumulation of replication errors or inefficient repair processes, has been difficult to study directly. Here, we describe a sensitive method to quantify substitutions at nucleotide 755 of the fibroblast growth factor receptor 2 (FGFR2) gene in sperm. Although substitution levels increase with age, we show that even high levels originate from infrequent mutational events. We propose that these FGFR2 mutations, although harmful to embryonic development, are paradoxically enriched because they confer a selective advantage to the spermatogonial cells in which they arise.
authors.affiliation: Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Goriely
authors.forename: Gilean A T
authors.initials: GA
authors.lastname: McVean
authors.forename: Maria
authors.initials: M
authors.lastname: Röjmyr
authors.forename: Björn
authors.initials: B
authors.lastname: Ingemarsson
authors.forename: Andrew O M
authors.initials: AO
authors.lastname: Wilkie
mesh_terms: D000168:Acrocephalosyndactylia / Q000235:genetics*; D000328:Adult; D000368:Aged; D000375:Aging; D019943:Amino Acid Substitution; D004252:DNA Mutational Analysis; D005260:Female; D006579:Heterozygote; D006801:Humans; D008024:Ligands; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D015233:Models, Statistical; D009154:Mutation; D010331:Paternal Age; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D012727:Sex Characteristics; D013091:Spermatogenesis; D013093:Spermatogonia / Q000502:physiology*; D013094:Spermatozoa / Q000502:physiology; D013234:Stem Cells / Q000502:physiology
chemical_list: D008024:Ligands; D017468:Receptors, Fibroblast Growth Factor; C496353:FGFR2 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2