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

The offspring of older parents are at a higher risk of suffering low birth weights and congenital birth defects that result from mutations and chromos omal anomalies. When the defect is paternal in origin, it often can be show n that the primary lesion arose during mitotic proliferation of the spermat ogonial germ cell population. By contrast, germline mosaicism is seldom inv oked to explain the age dependency of maternally derived aberrations becaus e germline proliferation in the ovary is already completed during fetal dev elopment. Age-dependent defects of maternal origin might, however, be expla ined in part by the progressive loss of oocytes during the mother's reprodu ctive life. A large number of oocytes undergo the initial stages of maturat ion 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 m aturation is influenced by subtle phenotypic characters of those oocytes th at may bear genetic defects such as trisomy 21. We have generated a mathema tical model to describe the loss kinetics for such mutant oocytes relative to the overall pool of resting oocytes, and we assess evolutionary strategi es that would favor their utilization faster than, at the same rate as, or slower than the normal oocytes. This formulation reveals that the slower-ra te scheme would effectively diminish the utilization of mutant oocytes in y oung mothers but would increase the risk of related birth defects for older mothers. Accordingly, we propose that natural selection should have favore d the delayed utilization of defective oocytes in a primitive high-mortalit y 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.