Understanding genetic risk for 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 染色体数目尽管非整倍体风险的增加与 随着母亲年龄的增加，在任何给定的年龄，非整倍体率都存在显着变化， 年龄本身不足以作为产生非整倍体妊娠风险的生物标志物。因此，我们认为， 我们假设，那些产生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，我们将开发一些方法， 使用从胚泡获得的低覆盖度全基因组序列鉴定致病基因 接受了植入前非整倍体基因检测（PGT-A）。PGT-A测序是 通常用于临床护理以指导单个整倍体胚胎移植，因此， 大量的序列要分析方法开发的成功可能会产生深远影响 使诊所能够进行自己的基于遗传学的评估。候选基因 通过本项目中的PGT-A分析和先前分析的数据集识别， 通过使用蠕虫和苍蝇模式生物测试和验证因果关系。高级 候选生物和没有模式生物同源物的候选生物将进行一次最终确认 在建立含有遗传基因的小鼠模型之前， 在人体内无法进行的体内研究的目标变体。这些 这些方法将揭示控制减数分裂染色体的分子机制 雌性配子的分离。最终，这项研究可能会导致识别产妇 遗传标记的风险产生一个非整倍体的概念，并帮助避免不孕不育， 为妇女提供必要的个性化信息， 个体生育力

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. Although 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 develop methods to identify causal genes using low-coverage whole genome sequences obtained from blastocysts that underwent preimplantation genetic testing for aneuploidy (PGT-A). PGT-A sequencing is common for clinical care to guide single euploid embryo transfer, and therefore there is an abundance of sequences to analyze. Success in method development will likely have far reaching utility in enabling clinics to conduct their own genetics-based evaluations. Candidate genes identified by PGT-A analysis in this project and from previously analyzed datasets will be rapidly tested and validated for causation by using worm and fly model organisms. High-ranking candidates, and candidates without model organism homologs, will undergo one final validation pass in a mouse oocyte in vitro system, before creating mouse models that harbor the genetic variant of interest for in vivo studies that are not possible to conduct in humans. These approaches will shed light on the molecular mechanisms that control meiotic 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 avoid infertility by empowering women with necessary and personalized information to better preserve their individual fertility.