title: Germline Stem Cell Competition, Mutation Hot Spots, Genetic Disorders, and Older Fathers.
abstract: Some de novo human mutations arise at frequencies far exceeding the genome average mutation rate. Examples include the common mutations at one or a few sites in the genes that cause achondroplasia, Apert syndrome, multiple endocrine neoplasia type 2B, and Noonan syndrome. These mutations are recurrent, provide a gain of function, are paternally derived, and are more likely to be transmitted as the father ages. Recent experiments have tested whether the high mutation frequencies are due to an elevated mutation rate per cell division, as expected, or to an advantage of the mutant spermatogonial stem cells over wild-type stem cells. The evidence, which includes the surprising discovery of testis mutation clusters, rules out the former model but not the latter. We propose how the mutations might alter spermatogonial stem cell function and discuss how germline selection contributes to the paternal age effect, the human mutational load, and adaptive evolution.
authors.affiliation: Molecular and Computational Biology Program, University of Southern California, Los Angeles, California 90089-2910; email: arnheim@usc.edu , petercal@usc.edu.
authors.forename: Norman
authors.initials: N
authors.lastname: Arnheim
authors.affiliation: Molecular and Computational Biology Program, University of Southern California, Los Angeles, California 90089-2910; email: arnheim@usc.edu , petercal@usc.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Calabrese
mesh_terms: D000072956:Adult Germline Stem Cells / Q000378:metabolism*; D002455:Cell Division / Q000235:genetics*; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D012641:Selection, Genetic; D013737:Testis / Q000254:growth & development
keywords: asymmetric and symmetric cell divisions; computational analysis; mutation frequency; mutational load; selective advantage