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.