Evolutionary and Functional Genetics of Male Reproduction using Wild Mice as a Mo

描述(由申请人提供)：这项研究提案的总体目标是找到解释男性生育能力差异的基因变异。原因不明的男性不育症在人类中的发病率很高，这可能是许多更具破坏性的疾病之前的临床征兆，包括前列腺癌和睾丸癌。在这个辅助生殖技术的时代，导致男性不育的突变正在以越来越快的速度传递给下一代，这使得了解影响男性生殖的基因变得至关重要。为了将遗传与表型差异联系起来，我们采取了一种新的方法，将进化群体遗传分析与男性生殖性状表型变异的实验室研究相结合。我们聚焦于交配生态不同的野生小鼠物种，剖析雄性繁殖的遗传学。从进化的角度来看，我们可以检测到对表型有更微妙影响的突变，而不是仅仅在实验室中检测到。我们有四个具体的目标：(1)基因组进化-从八种小鼠的野生捕获个体中对400个精液基因和400个精子发生基因进行测序，其中包括家蝇和小鼠的种群水平样本，这两个物种具有非常不同的交配生态和可能的选择机制。在进化的种群遗传学框架中分析这些数据将把我们引向经历了适应性进化的基因。(2)转录组进化-对精子发生的三个不同发育时间点的基因表达进行基于序列的量化。这些数据将扩大我们对精子发生过程中基因调控进化的理解，并使我们能够识别指示适应性进化的表达模式。(3)蛋白质组进化--量化主要精液蛋白的相对丰度，检验一种新的假设，即除了初级序列或基因表达的变化外，适应还通过蛋白质丰度的变化来发生。(4)物候组进化--对一组新建立的野生近交系进行密集表型，以研究三个交配生态不同的物种之间雄性生殖特征的差异。这四个特定的目标协同多层次的生物信息，以获得对男性生殖的遗传基础的基本见解。

DESCRIPTION (provided by applicant): The overall goal of this research proposal is to find genetic variation that explains differences in male fertility. There is a high incidence of unexplained male infertility in humans, which can be a clinical sign that precedes many more devastating diseases, including prostate cancer and testicular cancer. In this era of assisted reproductive technologies, mutations that lead to male infertility are being passed to the next generation at an ever increasing pace, making it critically important to understand the genes that affect male reproduction. To link genetic with phenotypic divergence, we take a novel approach and combine evolutionary population genetic analyses with laboratory investigations of phenotypic variation in male reproductive traits. We focus on wild mice species that differ in their mating ecology to dissect the genetics of male reproduction. With an evolutionary perspective, we can detect mutations with much subtler effects on phenotype than can be detected solely in the laboratory. We have four specific aims: (1) Genome Evolution - to sequence 400 seminal fluid genes and 400 spermatogenesis genes from wild caught individuals sampled from eight species of Mus, including population level samples from M. domesticus and M. spretus, two species with very different mating ecologies and presumably selective regimes. Analyzing these data in an evolutionary population genetics framework will lead us to genes that have undergone adaptive evolution. (2) Transcriptome Evolution - to perform sequence-based quantification of gene expression across three distinct developmental timepoints of spermatogenesis. These data will extend our understanding of the evolution of gene regulation during spermatogenesis and allow us to identify patterns of expression indicative of adaptive evolution. (3) Proteome Evolution - to quantify the relative abundance of the major seminal fluid proteins, to test a novel hypothesis that adaptation occurs via shifts in protein abundance in addition to changes in primary sequence or gene expression. (4) Phenome Evolution - to intensively phenotype a newly established set of wild derived inbred strains to investigate the divergence of male reproductive traits across three species with distinct mating ecologies. These four specific aims synergize multiple levels of biological information to gain fundamental insights into the genetic basis of male reproduction.