Significance of the perigametic interval as a major source of spontaneous mutations that result in mosaics.

An earlier analysis showed that a significant percentage of spontaneous specific-locus mutations in mice are recovered as mosaics and that the spontaneous mutation rate per cell cycle is probably higher for those mutations that produce mosaics than for those that produce whole-body mutants. The finding that the average germline composition of the mosaics was approximately 50% supported the suggestion that single-strand DNA alterations during the perigametic interval constitute the major source of spontaneous mosaics. Here, alternative origins of 50% germline mosaicism are examined. Supporting the earlier hypothesis is the finding that spontaneous mutations that are recovered as clusters constitute a different array of types from those giving rise to singletons, and the evidence from interspecies comparisons that a unique component of the life cycle, probably meiosis, makes a major contribution to spontaneous mutations. Biological factors associated with the perigametic interval were examined in an effort to suggest explanations for the observations that 1) the spontaneous mutation rate in that interval is high relative to that characterizing any mitotic cell cycle, 2) the types of mutations appear to be different from those arising during mitotic divisions, and 3) the spontaneous mutation rate for males is higher than that for females. It is concluded that the higher yield from the perigametic interval is consistent with what is known about methylation status in development of both sexes and with repair capacity in the male germline. For both parameters, differences between the sexes during their respective perigametic intervals may be at least partly responsible for the fact that the spontaneous mutation rate of mammalian females is lower than that of males. Copyright 1999 Wiley-Liss, Inc.