Mutation frequency declines during spermatogenesis in young mice but increases in old mice.
Five percent of live-born human offspring will have a genetic disorder. Of these, 20% are because of germ-line de novo mutations. Several genetic diseases, such as neurofibromatosis and Duchenne muscular dystrophy, are associated with a high percentage of de novo germ-line mutations. Until recently, a direct analysis of spontaneous mutation frequencies in mammalian germ cells has been prevented by technical limitations. We have measured spontaneous mutation frequencies in a lacI transgene by using enriched populations of specific spermatogenic cell types. Similar to previously published results, we observed a lower mutation frequency for seminiferous tubule cell preparations, which contain all stages of spermatogenesis, relative to somatic tissues. We made the unexpected observation of a decline in mutation frequency during spermatogenesis, such that the mutation frequencies of type B spermatogonia and all subsequent stages of spermatogenesis are lower than the frequency for primitive type A spermatogonia. In addition, spermatogenic cells from old mice have significantly increased mutation frequencies compared with spermatogenic cells from young or middle-aged mice. Finally, the mutation frequency was observed to increase during spermiogenesis in postreplicative cell types when spermatogenic cells were obtained from old mice.
Walter
C A
CA
Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284-7762, USA. walter@uthscsa.edu
Intano
G W
GW
McCarrey
J R
JR
McMahan
C A
CA
Walter
R B
RB
D000375:Aging / Q000235:genetics*; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D029968:Escherichia coli Proteins; D005798:Genes, Bacterial; D018095:Germ-Line Mutation; D006801:Humans; D056968:Lac Repressors; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012097:Repressor Proteins / Q000235:genetics; D012671:Seminiferous Tubules / Q000166:cytology; D013087:Spermatids / Q000166:cytology; D013090:Spermatocytes / Q000166:cytology; D013091:Spermatogenesis / Q000235:genetics*; D013094:Spermatozoa / Q000166:cytology
D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D056968:Lac Repressors; D012097:Repressor Proteins