Modeling the maternal-age dependency of reproductive failure and genetic fitness.

Abstract

The offspring of older parents are at a higher risk of suffering low birth weights and congenital birth defects that result from mutations and chromosomal anomalies. When the defect is paternal in origin, it often can be shown that the primary lesion arose during mitotic proliferation of the spermatogonial germ cell population. By contrast, germline mosaicism is seldom invoked to explain the age dependency of maternally derived aberrations because germline proliferation in the ovary is already completed during fetal development. Age-dependent defects of maternal origin might, however, be explained in part by the progressive loss of oocytes during the mother's reproductive life. A large number of oocytes undergo the initial stages of maturation each month, but typically only one completes maturation and is ovulated while the majority are discarded, probably by an apoptotic mechanism. Here we explore the possibility that the monthly choice of oocytes to undergo maturation is influenced by subtle phenotypic characters of those oocytes that may bear genetic defects such as trisomy 21. We have generated a mathematical model to describe the loss kinetics for such mutant oocytes relative to the overall pool of resting oocytes, and we assess evolutionary strategies that would favor their utilization faster than, at the same rate as, or slower than the normal oocytes. This formulation reveals that the slower-rate scheme would effectively diminish the utilization of mutant oocytes in young mothers but would increase the risk of related birth defects for older mothers. Accordingly, we propose that natural selection should have favored the delayed utilization of defective oocytes in a primitive high-mortality culture, but that this evolutionary strategy would be outmoded for modern society, because it would lead to an increased frequency of birth defects for older mothers.