{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T08:51:21Z","timestamp":1791190281428,"version":"4.1.0"},"reference-count":44,"publisher":"National Academy of Sciences","issue":"29","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,7,22]]},"abstract":"<jats:p>\n                    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\u20131,000 times more common than genomic mutation frequency data predict. Here, we report on the C758G\n                    <jats:italic>de novo<\/jats:italic>\n                    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\u20134 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\u2013Delbruck \u201cmutation jackpots.\u201d 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0801267105","type":"journal-article","created":{"date-parts":[[2008,7,16]],"date-time":"2008-07-16T21:39:53Z","timestamp":1216244393000},"page":"10143-10148","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":83,"title":["A germ-line-selective advantage rather than an increased mutation rate can explain some unexpectedly common human disease mutations"],"prefix":"10.1073","volume":"105","author":[{"given":"Soo-Kyung","family":"Choi","sequence":"first","affiliation":[{"name":"Molecular and Computational Biology Program, University of Southern California, 1050 Childs Way, Los Angeles, CA 90089-2910"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song-Ro","family":"Yoon","sequence":"additional","affiliation":[{"name":"Molecular and Computational Biology Program, University of Southern California, 1050 Childs Way, Los Angeles, CA 90089-2910"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Calabrese","sequence":"additional","affiliation":[{"name":"Molecular and Computational Biology Program, University of Southern California, 1050 Childs Way, Los Angeles, CA 90089-2910"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norman","family":"Arnheim","sequence":"additional","affiliation":[{"name":"Molecular and Computational Biology Program, University of Southern California, 1050 Childs Way, Los Angeles, CA 90089-2910"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2008,7,22]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-662-03356-2"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02982403"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/378419"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1085710"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.232568699"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0050224"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19971112)72:4<394::AID-AJMG4>3.0.CO;2-R"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320420505"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/156.1.297"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10147"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1269\/jrr.47.B75"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0500267102"},{"key":"e_1_3_3_13_2","first-page":"218","article-title":"Spontaneous mutation and parental age in humans","volume":"41","author":"Risch N","year":"1987","unstructured":"N Risch, EW Reich, MM Wishnick, JG McCarthy, Spontaneous mutation and parental age in humans. Am J Hum Genet 41, 218\u2013248 (1987).","journal-title":"Am J Hum Genet"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/sageke.2004.3.re1"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/35049558"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmh030"},{"key":"e_1_3_3_17_2","author":"Muenke M","year":"2007","unstructured":"M Muenke, AO Wilkie Craniosynostosis Syndromes: The Online Metabolic and Molecular Bases of Inherited Disease, www.ommbid.com\/OMMBID\/the_online_metabolic_bases_of_inherited_disease\/b\/fulltext\/part30\/ch245\/9. 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