title: The observed human sperm mutation frequency cannot explain the achondroplasia paternal age effect.
abstract: 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 de novo 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 (FGFR3) 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.
authors.affiliation: Molecular and Computational Biology Program, University of Southern California, Los Angeles 90089-1340, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Tiemann-Boege
authors.forename: William
authors.initials: W
authors.lastname: Navidi
authors.forename: Raji
authors.initials: R
authors.lastname: Grewal
authors.forename: Dan
authors.initials: D
authors.lastname: Cohn
authors.forename: Brenda
authors.initials: B
authors.lastname: Eskenazi
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wyrobek
authors.forename: Norman
authors.initials: N
authors.lastname: Arnheim
mesh_terms: D000130:Achondroplasia / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D004247:DNA / Q000032:analysis / Q000235:genetics; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010331:Paternal Age; D016133:Polymerase Chain Reaction; D015203:Reproducibility of Results; D013094:Spermatozoa / Q000473:pathology*
chemical_list: D004247:DNA