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. 2014 Jul 3;95(1):108-12.
doi: 10.1016/j.ajhg.2014.06.008.

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

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

Ross Rowsey et al. Am J Hum Genet. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Recombination in Human Oocytes (A) Representative image from a pachytene-stage human fetal oocyte. Antibodies against SYCP3 (representing the axial-lateral elements of the SC) are visualized in red, those against the crossover-associated DNA-mismatch-repair protein MLH1 are in green, and those against CREST antiserum-positive signals (recognizing centromeric regions) are in blue. (B) Distribution of mean MLH1 values per cell in 191 fetal ovarian samples. (C) Estimates of female genetic map lengths from genetic linkage studies (left, in blue) and cytological studies of pachytene oocytes (right, in red). References are indicated beneath each estimate.
Figure 2
Figure 2
Influence of Gestational Age on Genome-wide Recombination Levels For each of the 191 cases, the mean number of MLH1 foci per case is represented by red diamonds, and the values for individual cells are represented by blue diamonds. No obvious effect of gestational age on recombination levels was observed.
Figure 3
Figure 3
Influence of Gestational Age on the Number of Crossovers on Individual Chromosomes For a subset of cases, we analyzed the number of MLH1 foci on individual chromosomes, i.e., (A) nine cases for chromosome 16, (B) seven cases for chromosome 18, (C) 11 cases for chromosome 21, and (D) 11 cases for chromosome 22. There was no obvious effect of gestational age on the number of MLH1 foci per chromosome; in particular, the number of chromosomes lacking an MLH1 focus was not affected by gestational age.
Figure 4
Figure 4
Influence of Maternal Age on Genome-wide Recombination Levels For each of the 119 cases, the mean number of MLH1 foci per case is represented by red diamonds, and the values for individual cells are represented by blue diamonds. No obvious effect of maternal age on recombination levels was observed.

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