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

使用野生小鼠作为雄性生殖的进化和功能遗传学

• 批准号: 8246193
• 负责人: MATTHEW D DEAN
• 金额: $ 30.97万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246193
• 关键词: Accounting; Affect; Alleles; Assisted Reproductive Technology; Base Sequence; Biological; Biological Models; Categories; Cell Separation; Characteristics; Clinical; Code; Complement; DNA Resequencing; Data; Data Analyses; Development; Disease; Ecology; Evolution; Exons; Female; Fertility; Fertilization; Frequencies; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genome; Genomics; Genotype; Goals; Health; Hepatocyte; Human; Immune response; Inbred Strain; Incidence; Individual; Investigation; Laboratories; Laboratory Study; Lead; Link; Male Infertility; Malignant neoplasm of prostate; Malignant neoplasm of testis; Measures; Meiosis; Mind; Mitotic; Molecular; Mus; Mus musculus domesticus; Mutation; Nature; Noise; Partner in relationship; Pattern; Phenotype; Plant Roots; Population; Population Genetics; Population Sizes; Probability; Process; Proteins; Proteome; Proteomics; RNA; Relative (related person); Reproduction; Research; Research Proposals; Resources; Sampling; Seminal fluid; Shapes; Source; Sperm Motility; Spermatids; Spermatocytes; Spermatogenesis; Spermatogonia; Staging; Technology; Testing; Time; Tissues; Variant; X Inactivation; base; expectation; experience; fitness; genetic analysis; insight; male; next generation; novel; novel strategies; phenome; reproductive; reproductive success; research study; sample fixation; sperm cell; sperm morphology; theories; trait; transcriptomics

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. PUBLIC HEALTH RELEVANCE: We propose to find the genetic basis of male reproductive variance, using a novel combination of evolutionary and laboratory studies. Our specific aims are to study adaptive evolution at the genomic, transcriptomic, and proteomic levels, and then to make the critical next step of linking molecular variation at these three levels to variation at a large set of male reproductive traits. We focus on wild mice species that differ in mating ecology, providing a powerful complement to classical inbred strains and other existing resources.

描述（由申请人提供）：本研究提案的总体目标是找到解释男性生育力差异的遗传变异。在人类中，不明原因的男性不育症的发病率很高，这可能是许多更具破坏性的疾病（包括前列腺癌和睾丸癌）之前的临床迹象。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，因此了解影响男性生殖的基因至关重要。为了将遗传与表型差异联系起来，我们采用了一种新的方法，将联合收割机进化群体遗传分析与雄性生殖性状表型变异的实验室调查相结合。我们专注于野生小鼠物种，不同的交配生态解剖雄性生殖的遗传学。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，而不仅仅是在实验室中检测到的。我们有四个具体目标：（1）基因组进化-对从八种小鼠中采集的野生捕获个体的400个精液基因和400个精子发生基因进行测序，包括从小鼠中采集的种群水平样本。Acetylticus和M. spretus，两个物种有非常不同的交配生态和可能的选择制度。在进化群体遗传学框架中分析这些数据将使我们找到经历了适应性进化的基因。(2)转录组进化-在精子发生的三个不同发育时间点进行基于序列的基因表达定量。这些数据将扩展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-量化主要精液蛋白质的相对丰度，以测试一种新的假设，即除了一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发生。(4)表型进化-集中表型一组新建立的野生衍生的近交系，以调查男性生殖性状的分歧，在三个物种与不同的交配生态。这四个具体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。 公共卫生关系：我们建议使用一种新的进化和实验室研究相结合的方法来寻找雄性生殖变异的遗传基础。我们的具体目标是在基因组、转录组和蛋白质组水平上研究适应性进化，然后迈出关键的下一步，将这三个水平上的分子变异与大量雄性生殖性状的变异联系起来。我们专注于交配生态不同的野生小鼠物种，为经典的近交系和其他现有资源提供了有力的补充。