Examining Variation in Recombination Levels in the Human Female: A Test of the Production-Line Hypothesis

Abstract

The most important risk factor for human aneuploidy is increasing maternal age, but the basis of this association remains unknown. Indeed, one of the earliest models of the maternal-age effect--the "production-line model" proposed by Henderson and Edwards in 1968--remains one of the most-cited explanations. The model has two key components: (1) that the first oocytes to enter meiosis are the first ovulated and (2) that the first to enter meiosis have more recombination events (crossovers) than those that enter meiosis later in fetal life. Studies in rodents have demonstrated that the first oocytes to enter meiosis are indeed the first to be ovulated, but the association between the timing of meiotic entry and recombination levels has not been tested. We recently initiated molecular cytogenetic studies of second-trimester human fetal ovaries, allowing us to directly examine the number and distribution of crossover-associated proteins in prophase-stage oocytes. Our observations on over 8,000 oocytes from 191 ovarian samples demonstrate extraordinary variation in recombination within and among individuals but provide no evidence of a difference in recombination levels between oocytes entering meiosis early in fetal life and those entering late in fetal life. Thus, our data provide a direct test of the second tenet of the production-line model and suggest that it does not provide a plausible explanation for the human maternal-age effect, meaning that-45 years after its introduction-we can finally conclude that the production-line model is not the basis for the maternal-age effect on trisomy.

Escape from crossover interference increases with maternal age

“…Finally, a third possibility is related to the so-called ‘production line’ hypothesis, in which oocytes are selected for maturation sequentially in the same order as their generation, and later oocytes have therefore potentially undergone additional mitotic divisions prior to entering meiosis 17 . However, the existence of a production line has been debated for many years 17 18 19 , and so the likelihood of this explanation is unclear.…”

Interpreting the Dependence of Mutation Rates on Age and Time

“…In any case, our model predicts that a maternal age effect should be detectable with sufficient data and reliable identification of parental origin of mutations (e.g., by sequencing of a third generation). Conversely, the detection of a maternal age effect on mutation rate would provide prima facie evidence for the existence of non-replicative mutations that are not efficiently repaired (assuming no relationship between the age at which an oocyte is ovulated and the number of cell divisions experienced during oocytogenesis [ 35 ]).…”

Meiosis and Maternal Aging: Insights from Aneuploid Oocytes and Trisomy Births

“…For example, according to the "production line hypothesis," oocytes formed later in gestation have fewer crossovers and are the last to be ovulated (Edwards 1970). How-ever, a recent analysis of human fetal ovaries indicates that there is no such gradient in the number of crossovers formed during human development (Rowsey et al 2014). Therefore, the more plausible explanation is that the shift in susceptibility of specific chiasmate configurations is a consequence of defects in chromosome structure acquired during an extended period of prophase arrest.…”