{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:00:24Z","timestamp":1791892824016,"version":"4.3.4"},"reference-count":29,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5633","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[2003,8]]},"abstract":"<jats:p>\n                    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 (\n                    <jats:italic>FGFR2<\/jats:italic>\n                    ) 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.\n                  <\/jats:p>","DOI":"10.1126\/science.1085710","type":"journal-article","created":{"date-parts":[[2003,7,31]],"date-time":"2003-07-31T23:27:13Z","timestamp":1059694033000},"page":"643-646","source":"Crossref","is-referenced-by-count":245,"title":["Evidence for Selective Advantage of Pathogenic FGFR2 Mutations in the Male Germ Line"],"prefix":"10.1126","volume":"301","author":[{"given":"Anne","family":"Goriely","sequence":"first","affiliation":[{"name":"Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK."},{"name":"Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK."},{"name":"Department of Statistics, University of Oxford, South Parks Road, Oxford OX1 3TG, UK."},{"name":"Pyrosequencing AB, Vallongatan 1, SE-752 28 Uppsala, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilean A. T.","family":"McVean","sequence":"additional","affiliation":[{"name":"Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK."},{"name":"Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK."},{"name":"Department of Statistics, University of Oxford, South Parks Road, Oxford OX1 3TG, UK."},{"name":"Pyrosequencing AB, Vallongatan 1, SE-752 28 Uppsala, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Ro\u0308jmyr","sequence":"additional","affiliation":[{"name":"Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK."},{"name":"Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK."},{"name":"Department of Statistics, University of Oxford, South Parks Road, Oxford OX1 3TG, UK."},{"name":"Pyrosequencing AB, Vallongatan 1, SE-752 28 Uppsala, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bjo\u0308rn","family":"Ingemarsson","sequence":"additional","affiliation":[{"name":"Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK."},{"name":"Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK."},{"name":"Department of Statistics, University of Oxford, South Parks Road, Oxford OX1 3TG, UK."},{"name":"Pyrosequencing AB, Vallongatan 1, SE-752 28 Uppsala, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew O. M.","family":"Wilkie","sequence":"additional","affiliation":[{"name":"Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK."},{"name":"Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK."},{"name":"Department of Statistics, University of Oxford, South Parks Road, Oxford OX1 3TG, UK."},{"name":"Pyrosequencing AB, Vallongatan 1, SE-752 28 Uppsala, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/35049558"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-437X(02)00354-4"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1086\/338758"},{"key":"e_1_3_1_5_2","unstructured":"Mutation nomenclature follows the terminology proposed in ( 28 )."},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0295-165"},{"key":"e_1_3_1_7_2","first-page":"6117","year":"2001","unstructured":"M. Muenke, A. O. M. Wilkie, in The Metabolic and Molecular Bases of Inherited Disease, C. R. Scriver, A. L. Beaudet, W. S. Sly, D. Valle, Eds. (McGraw-Hill, New York, ed. 8, 2001), pp. 6117\u20136146.","journal-title":"The Metabolic and Molecular Bases of Inherited Disease"},{"key":"e_1_3_1_8_2","unstructured":"Apert Crouzon and Pfeiffer syndromes are characterized by a combination of craniosynostosis (premature fusion of the cranial sutures) with or without limb anomalies. These tend to be most severe in Apert syndrome and mildest in Crouzon syndrome ( 6 )."},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0596-48"},{"key":"e_1_3_1_10_2","first-page":"218","volume":"41","year":"1987","unstructured":"N. Risch, E. W. Reich, M. M. Wishnick, J. G. McCarthy, Am. J. Hum. Genet.41, 218 (1987).","journal-title":"Am. J. Hum. Genet."},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320420505"},{"key":"e_1_3_1_12_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_1_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/156.1.297"},{"key":"e_1_3_1_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10147"},{"key":"e_1_3_1_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/6.1.137"},{"key":"e_1_3_1_16_2","unstructured":"A. W. O'Rourke A. O. M. Wilkie unpublished observations."},{"key":"e_1_3_1_17_2","doi-asserted-by":"publisher","DOI":"10.3171\/jns.1999.90.3.0443"},{"key":"e_1_3_1_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.10775"},{"key":"e_1_3_1_19_2","unstructured":"Information on materials methods and statistical analysis is available on Science Online."},{"key":"e_1_3_1_20_2","unstructured":"The ability accurately to quantify 755C>G mutations at levels comparable to the observed birth rate of Apert syndrome was critical to the success of this work. By comparison an assay of mutations in FGFR3 causing achondroplasia was accurate only above 5 \u00d7 10 \u2013 5 ( 26 ) possibly leading to serious overestimates of sperm mutation prevalence in many younger individuals. Mutation levels <10 \u2013 7 were physically impossible to measure in our assay because 10 \u03bcg of DNA contains only \u223c2.8 \u00d7 10 6 haploid genome copies."},{"key":"e_1_3_1_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/7.9.1475"},{"key":"e_1_3_1_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.26.14536"},{"key":"e_1_3_1_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.121183798"},{"key":"e_1_3_1_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.287.5457.1489"},{"key":"e_1_3_1_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.25.14800"},{"key":"e_1_3_1_26_2","first-page":"3541","volume":"61","year":"2001","unstructured":"J.-H. Jang, K.-H. Shin, J.-G. Park, Cancer Res.61, 3541 (2001).","journal-title":"Cancer Res."},{"key":"e_1_3_1_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.232568699"},{"key":"e_1_3_1_28_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1017074823337"},{"key":"e_1_3_1_29_2","doi-asserted-by":"publisher","DOI":"10.1007\/s004390100505"},{"key":"e_1_3_1_30_2","unstructured":"We thank L. Maciocia Headlines Craniofacial Support the Oxford Craniofacial Unit fathers of Apert syndrome children and anonymous donors for help in obtaining semen samples; S. Smithson D. Moloney and K. Harper for earlier contributions; K. Walker R. Hansen and A. van Pelt for assistance; and B. Charlesworth J. Crow D. de Rooij D. Higgs and L. Hurst for comments. This work was supported by the Wellcome Trust (A.O.M.W.)."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.1085710","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T21:40:34Z","timestamp":1704836434000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.1085710"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,8]]},"references-count":29,"journal-issue":{"issue":"5633","published-print":{"date-parts":[[2003,8]]}},"alternative-id":["10.1126\/science.1085710"],"URL":"https:\/\/doi.org\/10.1126\/science.1085710","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1012352.194659","asserted-by":"object"}]},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2003,8]]}}}