Oocyte selection: a new model for the maternal-age dependence of Down syndrome

Abstract

Previously proposed mechanisms for Down syndrome (trisomy 21) have generally invoked a progressive increase in meiotic nondisjunction to explain maternal-age dependence, but models of this sort have failed to predict the observed patterns of marker segregation. Here we propose instead that age-dependent trisomy 21 results primarily from a mechanism that favors maturation and utilization of euploid oocytes in preference to the pre-existing aneuploid products of mitotic (premeiotic) nondisjunction. The increased utilization of aneuploid oocytes at later stages of maternal life would result from their increased proportion following many progressive cycles of selection against their maturation in earlier stages. Derivation of a quantitative model and evaluation of existing data indicate that the pattern of marker segregation associated with age-dependent trisomy 21 supports the proposed mechanism.

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.…”

Effect of maternal age on the frequency of cytogenetic abnormalities in human oocytes

“…A number of models exploring factors that could promote meiotic nondisjunction according to maternal age have been suggested. Since most of meiosis is completed in the ovary, models related to hormonal imbalances (Warburton, 1989), accelerated follicle maturation (Eichenlaub-Ritter and Boll, 1989), depletion of oocyte pools (Zheng and Byers, 1992), perifollicular microcirculation (Gaulden, 1992), reduced oxygen supply (Van Blerkom et al, 1997), chromosome coiling and decondensation (Hultén, 1990) or deficiency in the maintenance of sister chromatid cohesion (Wolstenholme and Angell, 2000) have been proposed in relation to ageing. In essence, all these models sustain the concept of an age-dependent deterioration of some cellular factors required for proper spindle function and chromosome progression through meiosis.…”

Causes and consequences of maternal age-related aneuploidy in oocytes: a review

“…The "limited oocyte pool" hypothesis suggests that the lower number of antral follicles in older women's ovaries causes the recruitment of suboptimal -premature or postmature -oocytes for ovulation (Warburton 1989). In addition, according to the oocyte selection model, cells of a higher quality are preferably selected for ovulation (Zheng and Byers 1992;Eichenlaub-Ritter 1998;Broekmans et al 2009). If the hypothesis is correct, a higher level of aneuploidy in women with a reduced oocyte pool should be expected regardless of their age.…”