Association of the Maternal Exome with Risk of an Aneuploid Conception

项目总结/摘要 由于不孕不育是一个日益严重的公共卫生问题，我们必须了解 基本机制，并确定导致这种疾病的遗传风险因素。最 导致流产的常见遗传异常是非整倍体，即胚胎具有不适当的 染色体数目虽然非整倍体风险的增加与增加的 母亲年龄，在任何给定的年龄，非整倍体率存在显着差异，使年龄单独 这是一个不足以衡量非整倍体受孕风险的生物标志物。所以我们 假设生产高于平均水平的着床前阶段的妇女 在特定年龄的非整倍体具有基因中的因果变异， 产生非整倍体受孕的风险。为了验证这一假设，我们将对 胚胎植入前非整倍体表型的极端女性。这个项目需要一个 许多先前的成就，包括建立了一个妇女DNA库， 已接受体外受精（IVF）和全面的染色体筛查（CCS）， IVF衍生胚胎，以及CCS准确方法的开发和验证。两 这些障碍现已克服，使这一建议切实可行。达到统计学 为了准确识别致病基因，这项研究将完成外显子组测序， 利用试点项目资金开展的工作。以前确定的候选基因和那些 在本项目中通过测序鉴定的基因将在动物中评价功能意义 模型，因为涉及引入突变基因的研究在人类中是不可能的。这些 这些方法将揭示控制染色体分离的分子机制 在雌性配子中。最终，这项研究可能会导致母亲的遗传识别 产生非整倍体妊娠风险的标志物，并通过赋予 为妇女提供必要的个性化信息，以更好地保护其个人生育能力。

Project Summary/Abstract Because infertility is a growing public health problem, it is imperative that we understand the basic mechanisms and identify the genetic risk factors that give rise to this disease. The most common genetic abnormality that causes miscarriage is aneuploidy, an embryo with an improper number of chromosomes. While increased risk of aneuploidy is strongly correlated with increasing maternal age, significant variation exists in aneuploidy rates at any given age, making age alone an inadequate biomarker for the risk of producing an aneuploid conception. Therefore, we hypothesize that women who produce higher than average levels of preimplantation stage aneuploidy at a given age possess causal variants in genes which predispose them to an early risk of producing an aneuploid conception. To test this hypothesis, we will sequence the exomes of women at the extremes of the preimplantation aneuploidy phenotype. This project requires a significant number of prior achievements, including the creation of a DNA bank from women who have undergone in vitro fertilization (IVF) and comprehensive chromosome screening (CCS) of IVF-derived embryos, and the development and validation of an accurate method of CCS. Both of these hurdles have now been overcome making this proposal feasible. To achieve statistical power to accurately identify disease-causing genes, this study will complete exome-sequencing efforts that were initiated with pilot project funds. Previously identified candidate genes and those identified by sequencing in this project will be evaluated for functional significance in an animal model, because studies involving introduction of mutant genes are not possible in humans. These approaches will shed light on the molecular mechanisms that control chromosome segregation in female gametes. Ultimately, this study could lead to the identification of maternal genetic markers for risk of producing an aneuploid conception, and help prevent infertility by empowering women with necessary and personalized information to better preserve their individual fertility.