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.

Adaptive-filtering of trisomy 21: risk of Down syndrome depends on family size and age of previous child

“…Recent data on large numbers of human oocytes at metaphase II suggest that aneuploidies might actually exhibit an accelerating trend with maternal age (Pellestor et al 2005). While it might be argued that this finding terminates the relevance of aberrant embryo filtering for our understanding of DS incidence dynamics, Zheng et al (2000) argue that the accelerating increase of aberrant ova is consistent with the view of optimal selection from the pool of developing ova, i.e., adaptive RFS.…”

On the origin of trisomy 21 Down syndrome

“…It seems reasonable to conclude that T21 foetal oocytes may lag behind the normal during foetal development, when there is a dramatic reduction in numbers by apoptosis from age 20 weeks until birth and then postnatally until puberty (Figure 5 ). It is also possible that there is a further selection against T21 oocytes leading up to the total 300–400 maturing to ovulation between puberty and menopause as discussed with respect to the oocyte selection model proposed by Zeng and co-workers [ 18 , 19 ]. The net effect of this situation is that any T21 oocytes in the original pool will comprise a larger proportion of the ovarian reserve at later maternal ages.…”

On the origin of the maternal age effect in trisomy 21 Down syndrome: the Oocyte Mosaicism Selection model

“…As regards the origin of T21 emphasis has previously been placed on maternal T21 oocyte selection taking place postnatally during oocyte development from puberty until menopause (Vig 1984, Zheng & Byers 1992, Sensi & Ricci 1993, Zheng & Byers 1996a, 1996b) and a mathematical model to this effect has been produced by Zheng et al (2000). The implication of our version of this model, which we have here termed OMS for Oocyte Mosaicism Selection, is twofold.…”

“…Most authors assume that the main problem concerns meiotic segregation errors of a normal disomic oocyte, as reiterated by for example Hunt & Hassold (2008), Jones (2008), Mailhes (2008), Martin (2008), Oliver et al (2008), Vogt et al (2008), Allen et al (2009), Coppedè (2009, Driscoll & Gross (2009), Garcia-Cruz et al (2009) and Ghosh et al (2009). We have recently performed a study (Hultén et al 2008) relevant to the possibility that the maternal age effect is instead due to the accumulation of pre-existing T21 cells in ovaries of human females during their development from foetal life to adulthood, a hypothesis akin to the oocyte selection model by Vig (1984), Zheng & Byers (1992), Sensi & Ricci (1993), Zheng & Byers (1996a, 1996b, Zheng et al (2000) and Zheng (2004). We found that in fact all eight normal foetuses analysed in this respect were T21 ovarian mosaics (average 0.54%, range 0.20-0.88; S.D.…”