{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T09:24:14Z","timestamp":1781429054614,"version":"3.54.1"},"reference-count":42,"publisher":"National Academy of Sciences","issue":"23","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2002,11,12]]},"abstract":"<jats:p>\n                    The lifelong spermatogonial stem cell divisions unique to male germ cell production are thought to contribute to a higher mutation frequency in males. The fact that certain\n                    <jats:italic>de novo<\/jats:italic>\n                    human genetic conditions (e.g., achondroplasia) increase in incidence with the age of the father is consistent with this idea. Although it is assumed that the paternal age effect is the result of an increasing frequency of mutant sperm as a man grows older, no direct molecular measurement of the germ-line mutation frequency has been made to confirm this hypothesis. Using sperm DNA from donors of different ages, we determined the frequency of the nucleotide substitution in the fibroblast growth factor receptor 3 (\n                    <jats:italic>FGFR3<\/jats:italic>\n                    ) gene that causes achondroplasia. Surprisingly, the magnitude of the increase in mutation frequency with age appears insufficient to explain why older fathers have a greater chance of having a child with this condition. A number of alternatives may explain this discrepancy, including selection for sperm that carry the mutation or an age-dependent increase in premutagenic lesions that remain unrepaired in sperm and are inefficiently detected by the PCR assay.\n                  <\/jats:p>","DOI":"10.1073\/pnas.232568699","type":"journal-article","created":{"date-parts":[[2002,11,12]],"date-time":"2002-11-12T13:44:20Z","timestamp":1037108660000},"page":"14952-14957","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":136,"title":["The observed human sperm mutation frequency cannot explain the achondroplasia paternal age effect"],"prefix":"10.1073","volume":"99","author":[{"given":"Irene","family":"Tiemann-Boege","sequence":"first","affiliation":[{"name":"Molecular and Computational Biology Program, University of Southern California, Los Angeles, CA 90089-1340; Department of Mathematical and Computer Sciences, Colorado School of Mines, Golden, CO 80401; New Jersey Neuroscience Institute, 65 James Street, Edison, NJ 08820; Burns and Allen Cedars-Sinai Research Institute\/Ahmanson Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048; School of Public Health, University of California, Berkeley, CA 94720; and Biology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Navidi","sequence":"additional","affiliation":[{"name":"Molecular and Computational Biology Program, University of Southern California, Los Angeles, CA 90089-1340; Department of Mathematical and Computer Sciences, Colorado School of Mines, Golden, CO 80401; New Jersey Neuroscience Institute, 65 James Street, Edison, NJ 08820; Burns and Allen Cedars-Sinai Research Institute\/Ahmanson Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048; School of Public Health, University of California, Berkeley, CA 94720; and Biology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raji","family":"Grewal","sequence":"additional","affiliation":[{"name":"Molecular and Computational Biology Program, University of Southern California, Los Angeles, CA 90089-1340; Department of Mathematical and Computer Sciences, Colorado School of Mines, Golden, CO 80401; New Jersey Neuroscience Institute, 65 James Street, Edison, NJ 08820; Burns and Allen Cedars-Sinai Research Institute\/Ahmanson Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048; School of Public Health, University of California, Berkeley, CA 94720; and Biology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Cohn","sequence":"additional","affiliation":[{"name":"Molecular and Computational Biology Program, University of Southern California, Los Angeles, CA 90089-1340; Department of Mathematical and Computer Sciences, Colorado School of Mines, Golden, CO 80401; New Jersey Neuroscience Institute, 65 James Street, Edison, NJ 08820; Burns and Allen Cedars-Sinai Research Institute\/Ahmanson Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048; School of Public Health, University of California, Berkeley, CA 94720; and Biology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda","family":"Eskenazi","sequence":"additional","affiliation":[{"name":"Molecular and Computational Biology Program, University of Southern California, Los Angeles, CA 90089-1340; Department of Mathematical and Computer Sciences, Colorado School of Mines, Golden, CO 80401; New Jersey Neuroscience Institute, 65 James Street, Edison, NJ 08820; Burns and Allen Cedars-Sinai Research Institute\/Ahmanson Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048; School of Public Health, University of California, Berkeley, CA 94720; and Biology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Wyrobek","sequence":"additional","affiliation":[{"name":"Molecular and Computational Biology Program, University of Southern California, Los Angeles, CA 90089-1340; Department of Mathematical and Computer Sciences, Colorado School of Mines, Golden, CO 80401; New Jersey Neuroscience Institute, 65 James Street, Edison, NJ 08820; Burns and Allen Cedars-Sinai Research Institute\/Ahmanson Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048; School of Public Health, University of California, Berkeley, CA 94720; and Biology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norman","family":"Arnheim","sequence":"additional","affiliation":[{"name":"Molecular and Computational Biology Program, University of Southern California, Los Angeles, CA 90089-1340; Department of Mathematical and Computer Sciences, Colorado School of Mines, Golden, CO 80401; New Jersey Neuroscience Institute, 65 James Street, Edison, NJ 08820; Burns and Allen Cedars-Sinai Research Institute\/Ahmanson Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048; School of Public Health, University of California, Berkeley, CA 94720; and Biology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2002,10,23]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4615-9068-2_4"},{"key":"e_1_3_3_2_2","doi-asserted-by":"crossref","unstructured":"Vogel F. & Motulsky A. 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