Genetics and Genomics of the Ovarian Reserve and Female Fertility

项目总结/摘要 个性化生殖医学最终将通过患者定制的不孕症治疗来实现， 生育力保护规划。然而，妇女预测性基因检测的发展受到以下因素的阻碍： 重要生育因素的复杂病因，如卵巢储备。卵巢储备由 卵巢产生有活力的、可受精的卵母细胞的能力。卵巢储备功能受损可导致 不孕症，流产、出生缺陷和卵巢早衰的发生率增加。数千 哺乳动物的生殖过程中涉及的基因，不育可能是由于有害的组合， 多个等位基因，而不是单个基因缺陷，使得鉴定致病性多态性， 在大规模的人类基因研究中更具挑战性。因此，必须建立适当的遗传模型， 旨在识别反映生殖特征和固有风险的遗传因素及其特征 不同的人群。我们的总体假设是，多种遗传因素调节卵母细胞 发育决定了遗传多样性个体之间卵巢储备的差异， 确定的遗传图谱可用于预测卵巢储备功能缺陷的风险， 妇女的生育问题。我们提出了两项使用卵巢表型分析的补充研究 和数量性状基因座定位在遗传异质性小鼠从协作交叉（CC）和 Diversity Outbred（DO）计划。由不同自交系组成的CC是纵向研究的最佳选择 卵母细胞发育;而DO，由许多单一的遗传独特的个人，是理想的高 精确定位调节卵巢储备的遗传变异。目标1将确定遗传变异如何 影响小鼠早期卵母细胞发育并导致卵母细胞数量和质量差异 不同的基因背景。我们将CC小鼠的生殖性状，包括减数分裂， 重组，胎儿和围产期卵母细胞丢失，原始卵泡形成和卵巢储备的大小。 这些实验将确定与卵母细胞发育中的特定缺陷相关的遗传图谱， 生成一组表型模型，用于开发新的诊断工具和治疗方法 方法.我们将在Aim 2中完善与卵巢缺陷相关的潜在基因和基因网络列表， 我们将使用DO小鼠鉴定卵巢储备大小变异的遗传变异。我们 将进行数量性状基因座作图，并分析候选基因和非编码区的识别区域， 调控卵母细胞发育的因子。这一目标将提供一个潜在的基因，变异和途径的清单 潜在的卵巢储备功能低下是女性类似疾病的候选者。对于患有特发性 不孕症，推迟生育和接受卵巢毒性治疗的儿科癌症患者， 可以预测卵巢储备能力的基因检测可能为诊断和治疗提供新的途径。 治疗发现，以及前所未有的洞察力和控制他们的终身生育。

PROJECT SUMMARY/ABSTRACT Personalized reproductive medicine will ultimately be realized with patient-tailored infertility treatments and fertility preservation planning. However the development of predictive genetic tests for women is hampered by the complex etiology of important fertility factors, such as the ovarian reserve. The ovarian reserve constitutes the capacity of ovaries to produce viable, fertilizable oocytes. Deficiencies in the ovarian reserve can lead to infertility, and an increased incidence of miscarriages, birth defects and premature ovarian failure. Thousands of genes are involved in mammalian reproduction, and infertility likely arises from deleterious combinations of multiple alleles, rather than single gene defects, making the identification of causative polymorphisms that much more challenging in large-scale human genetic studies. Thus, appropriate genetic models must be developed to identify genetic factors and their profiles that reflect reproductive traits and risks inherent to diverse populations. Our overarching hypothesis is that multiple genetic factors regulating oocyte development determine differences in the ovarian reserve among genetically diverse individuals and that defined genetic profiles can be used to predict the risk of ovarian reserve deficiencies and subsequent fertility issues in women. We propose two complimentary studies using ovarian phenotyping and quantitative trait loci mapping in genetically heterogeneous mice from the Collaborative Cross (CC) and Diversity Outbred (DO) programs. The CC, comprised of diverse inbred lines, is optimal for longitudinal studies of oocyte development; while the DO, comprised of many single genetically unique individuals, is ideal for high precision mapping of genetic variants regulating ovarian reserve. Aim 1 will determine how genetic variation affects early oocyte development and contributes to differences in oocyte numbers and quality in mice with different genetic backgrounds. We will phenotype CC mice for reproductive traits including meiotic recombination, fetal and perinatal oocyte loss, primordial follicle formation and the size of the ovarian reserve. These experiments will define genetic profiles linked to specific deficiencies in oocyte development and generate a phenotyped collection of models for the development of new diagnostic tools and treatment methods. We will refine the list of potential genes and gene networks linked to ovarian deficiencies in Aim 2, where we will identify genetic variants underlying variation in ovarian reserve size using DO mice. We will perform quantitative trait loci mapping and analyze identified regions for candidate genes and non-coding elements regulating oocyte development. This aim will deliver a list of potential genes, variants and pathways underlying low ovarian reserve as candidates for similar conditions in women. For women with idiopathic infertility, those postponing child bearing and pediatric cancer patients undergoing ovario-toxic treatments, genetic tests that can predict the capacity of the ovarian reserve may provide avenues to diagnosis and novel treatment discovery, and unprecedented insight and control over their lifelong fertility.