Mathematical modeling of human oocyte aneuploidy.
Mathematical modeling of human oocyte aneuploidy.
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人类卵母细胞非整倍性的数学模型。
DOI：
10.1073/pnas.1912853117
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发表时间：
2020
影响因子：
11.1
通讯作者：
Xing,Jinchuan
中科院分区：
文献类型：
--
作者：
Tyc,KatarzynaM;McCoy,RajivC;Schindler,Karen;Xing,Jinchuan
非整倍体是人类妊娠流产、先天性异常和体外受精（IVF）失败的主要原因。尽管大多数非整倍体概念被认为起源于雌性生殖系的减数分裂错误，但缺乏将观察到的表型与潜在错误机制联系起来的定量研究。在这项研究中，我们开发了一个数学模型框架来量化错误染色体分离的不同机制对非整倍体卵子产生的贡献。我们的模型考虑了由减数分裂错误引起的所有可能的染色体获得/失去结果的概率，例如减数分裂I和减数分裂II中的不分离（NDJ），以及减数分裂I中姐妹染色单体的过早分离（PSSC）和反向分离（RS）。为了了解不同减数分裂错误的贡献，我们将我们的模型拟合到来自11,157个囊胚期胚胎的非整倍体数据。我们的最佳拟合模型捕获了女性减数分裂的几个已知特征，例如，母亲年龄对PSSC的影响。更重要的是，我们的模型揭示了先前描述的模式，包括受减数分裂i错误影响的卵中减数分裂II错误的频率增加。这一观察结果表明，减数分裂II中NDJ的发生与卵的倍性状态有关。我们进一步证明，该模型可用于识别产生极端数量的非整倍体胚胎的体外受精患者。我们的数学模型的动态性使其成为理解人类女性减数分裂中染色体错分离机制的相对贡献和预测辅助生殖结果的有力工具。
Aneuploidy is the leading contributor to pregnancy loss, congenital anomalies, and in vitro fertilization (IVF) failure in humans. Although most aneuploid conceptions are thought to originate from meiotic division errors in the female germline, quantitative studies that link the observed phenotypes to underlying error mechanisms are lacking. In this study, we developed a mathematical modeling framework to quantify the contribution of different mechanisms of erroneous chromosome segregation to the production of aneuploid eggs. Our model considers the probabilities of all possible chromosome gain/loss outcomes that arise from meiotic errors, such as nondisjunction (NDJ) in meiosis I and meiosis II, and premature separation of sister chromatids (PSSC) and reverse segregation (RS) in meiosis I. To understand the contributions of different meiotic errors, we fit our model to aneuploidy data from 11,157 blastocyst-stage embryos. Our best-fitting model captures several known features of female meiosis, for instance, the maternal age effect on PSSC. More importantly, our model reveals previously undescribed patterns, including an increased frequency of meiosis II errors among eggs affected by errors in meiosis I. This observation suggests that the occurrence of NDJ in meiosis II is associated with the ploidy status of an egg. We further demonstrate that the model can be used to identify IVF patients who produce an extreme number of aneuploid embryos. The dynamic nature of our mathematical model makes it a powerful tool both for understanding the relative contributions of mechanisms of chromosome missegregation in human female meiosis and for predicting the outcomes of assisted reproduction.