School of Molecular Biosciences and Center for Reproductive Biology, Washington State University, Pullman, WA 99164, USA.
Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53706, USA.
Am J Hum Genet. 2014 Jul 3;95(1):108-12. doi: 10.1016/j.ajhg.2014.06.008.
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.
人类非整倍体的最重要的风险因素是母亲年龄的增长，但这种关联的基础尚不清楚。事实上，最早的母体年龄效应模型之一——亨德森和爱德华兹（Henderson and Edwards）在 1968 年提出的“生产线模型”（production-line model）仍然是被引用最多的解释之一。该模型有两个关键组成部分：（1）进入减数分裂的第一批卵母细胞是最早排卵的；（2）最早进入减数分裂的卵母细胞比在胎儿期后期进入减数分裂的卵母细胞有更多的重组事件（交叉）。在啮齿动物中的研究表明，确实是最早进入减数分裂的卵母细胞最早被排出，但减数分裂进入的时间与重组水平之间的联系尚未得到测试。我们最近开始对人类胎儿卵巢的中期进行分子细胞遗传学研究，使我们能够直接检查减数分裂前期卵母细胞中交叉相关蛋白的数量和分布。我们对来自 191 个卵巢样本的 8000 多个卵母细胞的观察结果表明，个体内和个体间的重组存在显著差异，但没有证据表明在胎儿生命早期进入减数分裂的卵母细胞和在胎儿生命晚期进入减数分裂的卵母细胞之间存在重组水平的差异。因此，我们的数据直接检验了生产线模型的第二个原则，并表明它不能为人类母体年龄效应提供合理的解释，这意味着——在其提出 45 年后，我们终于可以得出结论，生产线模型不是母体年龄对三体的影响的基础。
