REGULATION OF GAMETE USE AND NEURAL PATHWAYS IN REPRODUCTION

生殖中配子使用和神经通路的调节

• 批准号: 10597149
• 负责人: ANDREW G CLARK
• 金额: $ 33.65万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-24 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597149
• 关键词: Affect; Alternative Splicing; Animals; Automobile Driving; Behavior; Behavioral; Biological Models; Brain; Collection; Complex; Copulation; Data; Differential Fertility; Disadvantaged; Discrimination; Drosophila genus; Ejaculation; Exons; Female; Fertility; Fertilization; Foundations; Funding; Furuncles; Future; Gene Expression Regulation; Genes; Genetic; Genetic Determinism; Genetic Variation; Genome; Genotype; Germ Cells; Human; Infertility; Internet; Link; Maps; Mediating; Methods; Modeling; Molecular; Nature; Neural Pathways; Neurons; Octopamine; Outcome; Partner in relationship; Pathway interactions; Perception; Phenotype; Pheromone; Play; Predictive Analytics; Process; Production; Regulation; Reproduction; Role; Seminal fluid; Series; Sexual Reproduction; Signal Transduction; Sorting; Sperm Count Procedure; Spliced Genes; Sports; Statistical Models; Surveys; Testing; Time; Transcript; Validation; Variant; Whole Organism; Work; experimental study; father role; fitness; follow-up; genome wide association study; male; model design; neural; novel; octopamine receptor; offspring; outcome prediction; programs; promoter; reproductive; reproductive fitness; reproductive outcome; reproductive success; reproductive tract; response; sex; sperm cell; success; transcriptome; zygote

PROJECT SUMMARY Sexual reproduction requires precise orchestration of expression of myriad genes in males and females. These genes mediate interactions between the sexes at molecular, cellular, neural and whole- organism levels, including the differential fertility success of sperm from two competing males that mate to a single female. In the current funding period, we used the tractable Drosophila model system to dissect the role of genes expressed in octopaminergic neurons in differential sperm use by a multiply-mated female. In this renewal application, we propose as Aim 1 a set of experiments that identify genes and quantify their effects on mating plug ejection, a proximal phenotype with a key role in sperm competition outcomes. Mating plug ejection timing allows females to exert control over paternity of their future offspring. Early ejection of a mating plug disadvantages the male by decreasing the number of his sperm that can be used; conversely longer retention of the plug gives the male a paternity advantage. Both males and females contribute to the mating plug and its ejection. After completing a GWAS for female and male determinants of mating plug ejection timing and validating the resulting genes, we will perform a grid cross to determine whether variation in mating plug timing is mostly determined by genetic variation in the male, or the female, or an interaction between the two. Follow-up perturbation of those genes will begin to unravel genetic pathways linking male quality or its perception with mating plug ejection. In Aim 2, we will pursue the implications of our recent discovery that mating induces differential exon or promoter use by a large suite of genes in the female brain. Intriguingly, two of these genes, desat1 and foraging, act in mating discrimination or other reproductive- relevant behaviors. Each strongly activates one of four alternative promoters in response to mating. We will survey the transcriptome to quantify how variation in male factors drive post-mating differential transcript use, how the latter varies across female genotypes, and how this regulation occurs. In Aim 3 we extend and generalize models designed to quantify and predict outcomes of pairwise interactions. The classical Bradley-Terry model, widely applied in predicting outcomes of sporting contests between teams that have not yet competed, has a direct analogy in sperm competition “contests.” Assessing fit to models of this class will test whether the males’ fitness can be rank-ordered, and whether those rank orders produce accurate outcome predictions. We will extend these models to the outcomes of the experiments in Aims 1 and 2, and those performed in this project over the years, using the results to assess the overall importance of male x female interactions in each case. Many of the processes that we will study show high levels of evolutionary conservation, implying that our results will expand our understanding of male x female interactions in reproduction that may have relevance to cases of idiopathic human infertility that may involve genetic incompatibility between the partners.

项目概要 有性生殖需要精确协调雄性和雌性体内无数基因的表达。 女性。这些基因在分子、细胞、神经和整体上介导两性之间的相互作用。 有机体水平，包括与一个交配的两个竞争雄性的精子的不同生育成功率 单身女性。在当前的资助期内，我们使用易处理的果蝇模型系统来剖析其作用 多交配雌性精子使用差异中八巴胺能神经元表达的基因。在这个 更新应用程序中，我们提出了一组实验来识别基因并量化它们 对交配栓弹出的影响，这是一种在精子竞争结果中发挥关键作用的近端表型。 交配插头弹出时间使雌性能够控制其未来后代的亲子关系。提前弹射 交配插头的失效会减少雄性可用的精子数量，从而对雄性不利；反过来 插头保留时间较长给雄性带来了亲子优势。男性和女性都对 配合插头及其弹出。完成 GWAS 后确定插配插头的雌雄决定因素 喷射时间并验证所得基因，我们将进行网格交叉以确定是否存在变异 交配插头时间主要由雄性或雌性的遗传变异或相互作用决定 两者之间。这些基因的后续扰动将开始解开连接男性的遗传途径 质量或其对配合插头弹出的感知。在目标 2 中，我们将探讨我们最近的研究的影响 发现交配诱导雌性体内大量基因使用差异外显子或启动子 脑。有趣的是，其中的两个基因，desat1 和觅食，在交配歧视或其他生殖方面发挥作用。 相关行为。每个启动子都会强烈激活四个替代启动子之一以响应交配。我们将 调查转录组以量化雄性因素的变化如何驱动交配后差异转录本的使用， 后者如何随着女性基因型的不同而变化，以及这种调节是如何发生的。在目标 3 中，我们扩展并 概括旨在量化和预测成对相互作用结果的模型。经典的 Bradley-Terry 模型，广泛应用于预测尚未参加比赛的球队之间的体育比赛结果 然而，竞争，与精子竞争“竞赛”有直接的类比。评估此类模型的适合度将 测试男性的健康状况是否可以排序，以及这些排序是否会产生准确的结果 预测。我们将把这些模型扩展到目标 1 和 2 中的实验结果，以及 多年来在该项目中进行，利用结果来评估男性 x 女性的总体重要性 每种情况下的相互作用。我们将研究的许多过程都显示出高水平的进化 保护，这意味着我们的结果将扩大我们对男性与女性相互作用的理解 可能与特发性人类不孕症病例有关的生殖，可能涉及遗传 合作伙伴之间的不兼容。