Association of the Maternal Exome with Risk of an Aneuploid Conception

项目摘要/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 并确定导致这种疾病的遗传风险因素。最多的 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 染色体的数目。而非整倍体风险的增加与 母亲的年龄，在任何给定的年龄，非整倍体率都存在显著的差异，这使得单独使用年龄 不足以预测产生非整倍体受孕风险的生物标志物。因此，我们 假设那些生产高于平均水平的植入前阶段的女性 特定年龄的非整倍体在基因上具有因果变异，这些变异使他们容易患上早产儿 产生非整倍体受孕的风险。为了验证这一假设，我们将对外显子进行测序 处于植入前非整倍体表型极端的女性。这个项目需要一个 取得了许多以前的成就，包括创建了一个DNA库 接受了体外受精(IVF)和全面的染色体筛查(CCS) 体外受精衍生胚胎，以及CCS准确方法的开发和验证。两个都是 这些障碍现在已经被克服，使这项提议变得可行。要实现统计 为了准确识别致病基因，这项研究将完成外显子组测序 用试点项目资金发起的努力。以前确定的候选基因和那些 在这个项目中通过测序确定的将被评估对动物的功能意义 模型，因为涉及在人类中引入突变基因的研究是不可能的。这些 这些方法将阐明控制染色体分离的分子机制。 在雌配子中。最终，这项研究可能导致对母体基因的识别 非整倍体受孕风险的标记，并通过赋权帮助预防不孕症 为妇女提供必要和个性化的信息，以更好地保护她们的个人生育能力。

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.