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

基本信息

批准号：
9057068
负责人：
MATTHEW D DEAN
金额：
$ 30.25万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9057068
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 Regulation Generations Genes Genetic Genetic Polymorphism Genetic Transcription Genetic Variation Genetic study 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 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 laboratory experiment male next generation novel novel strategies phenome reproductive reproductive fitness reproductive success sample fixation sperm cell sperm morphology theories trait transcriptome transcriptome sequencing transcriptomics

项目摘要

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.

描述（由申请人提供）：该研究建议的总体目标是找到解释男性生育差异的遗传变异。人类中无法解释的男性不育症的发生率很高，这可能是在包括前列腺癌和睾丸癌在内的许多灾难性疾病之前的临床体征。在这个辅助生殖技术时代，导致男性不育症的突变以不断提高的步伐传递给下一代，这使得了解影响男性繁殖的基因至关重要。为了将遗传与表型差异联系起来，我们采用了一种新颖的方法，并将进化人群遗传分析与男性生殖性状的表型变异的实验室研究相结合。我们专注于在交配生态学上不同以剖析男性繁殖的遗传学的野生小鼠物种。从进化的角度来看，我们可以检测出对表型的微妙作用的突变，而不是仅在实验室中检测到的突变。我们有四个具体的目的：（1）基因组进化 - 从捕获从八种MUS中采样的个体，包括来自八种Mus和Spretus M. spretus的种群水平样品，两个物种，两个具有非常不同的MAS的种群样本，具有非常不同的MUS，捕获的人群水平样本，从而序列400个精确基因和400个精子发生基因。在进化人群遗传学框架中分析这些数据将导致我们获得经历适应性进化的基因。（2）转录组进化 - 在精子发生的三个不同的发育时间点上对基因表达进行基于序列的定量。这些数据将扩展我们对精子发生过程中基因调节的演变的理解，并允许我们识别表达自适应进化的表达模式。（3）蛋白质组进化 - 量化主要精液蛋白的相对丰度，以检验一种新的假设，即除了初级序列或基因表达的变化外，适应性通过蛋白质丰度的变化而发生。（4）现象进化 - 强烈表型是一组新建立的野生衍生的近交菌株，以研究三种具有独特交配生态的三种物种的男性生殖特征的差异。这四个特定的目的协同多个生物学信息，以获得男性繁殖遗传基础的基本见解。