Meiotic sex chromosome inactivation and the developmental basis of hybrid male st

减数分裂性染色体失活及杂交雄性的发育基础

基本信息

批准号：
9081238
负责人：
Jeffrey Good
金额：
$ 29.9万
依托单位：
UNIVERSITY OF MONTANA
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：
2012-07-26 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9081238
关键词：
Address Animal Model Animals Base Sequence Biological Models Biology Candidate Disease Gene Communities Data Development Developmental Process Disease Evolution Fertility Fluorescence-Activated Cell Sorting Gene Expression Gene Expression Regulation Genes Genetic Genetic Drift Genetic Models Genetic Polymorphism Genomic Segment Genomics Goals Health House mice Human Hybrids Inbred Strain Knowledge Link Male Infertility Male Sterility Maps Meiosis Methods Modeling Mouse Strains Mus Mus musculus domesticus Mutation Nature Organism Pattern Play Population Quantitative Genetics Reproduction Reproductive Biology Research Research Project Grants Resources Role Series Sex Chromosomes Spermatogenesis Staging Sterility System Taxon Testing Testis Time X Chromosome X Inactivation Y Chromosome base cell type cellular targeting design developmental genetics epigenetic regulation genetic resource genome sequencing innovation insight male next generation sequencing novel programs reproductive reproductive fitness research study sample fixation sex tool transcriptomics whole genome

项目摘要

DESCRIPTION (provided by applicant): Proper genetic and epigenetic regulation of the sex chromosomes during spermatogenesis is crucial for the development of normal male fertility. The sex chromosomes also play a central role in the evolution of hybrid male sterility between species, but the developmental causes of these incipient reproductive barriers remain unclear. The proposed research will use quantitative genetic and genomic experiments in house mice to bridge significant gaps in our understanding of the developmental underpinnings of male sterility. Mice are the predominant genetic models for human reproductive biology, thus male sterility can be studied in greater detail in mice than in most other systems. Here we focus on two closely related mouse species that are partially isolated by hybrid male sterility, providing an ideal model system for studying the consequences of natural genetic divergence on the progression of spermatogenesis. One of our central goals is to test the long- standing hypothesis that regulatory disruption of X-inactivation during spermatogenesis plays a central role in the evolution of hybrid sterility. Towards this end, we are proposing four synergistic research projects. First, we will use cutting-edge sequencing approaches to generate complete genomic sequences for our study organisms. Second, we will use powerful methods of targeted cellular enrichment to study gene expression across key stages of spermatogenesis in two species of mice and their sterile hybrid males. These data will be used to determine if the disruption of X-linked gene regulation during the later stages of spermatogenesis is a primary developmental cause of hybrid male sterility in mice. We will also use these data to identify candidate genes involved in the underlying genetic interactions that disrupt spermatogenesis. Third, we will use additional genetic experiments to directly test if candidate incompatibilities do indeed interact with the X chromosome to cause sterility. Fourth, we will use quantitative genetic methods to further dissect one set of incompatibilities where one or more of the interacting genes that cause hybrid male sterility remain polymorphic within one of the species. This final set of experiments will utilize the extensive genetic resources of the mouse system to study the evolution of hybrid incompatibilities at their earliest possible stage - prior to their fixation between species. Collectively, these experiments will provide important insights into the developmental causes of male sterility.

描述（由申请人提供）：精子发生过程中性别染色体的适当遗传和表观遗传调节对于正常男性生育能力的发展至关重要。性染色体在物种之间杂交男性不育的演变中也起着核心作用，但是这些初期的生殖屏障的发育原因尚不清楚。拟议的研究将在房屋小鼠中使用定量遗传和基因组实验，以弥合我们对男性不育的发育基础的理解。小鼠是人类生殖生物学的主要遗传模型，因此，在小鼠中，男性不育率比大多数其他系统更详细地研究。在这里，我们关注两种密切相关的小鼠物种，这些小鼠物种通过混合男性不育部分分离，为研究自然遗传差异对精子发生进展的后果提供了理想的模型系统。我们的核心目标之一是检验长期的假设，即精子发生过程中X灭活的调节中断在杂交不育的演变中起着核心作用。为此，我们提出了四个协同的研究项目。首先，我们将使用尖端的测序方法为我们的研究生物生成完整的基因组序列。其次，我们将使用强大的靶向细胞富集方法来研究两种小鼠及其无菌杂交雄性的精子发生关键阶段的基因表达。这些数据将用于确定精子发生后期X连锁基因调节的破坏是小鼠混合雄性无菌性的主要发育原因。我们还将使用这些数据来识别涉及破坏精子发生的潜在遗传相互作用的候选基因。第三，我们将使用其他基因实验直接测试候选不兼容是否确实与X染色体相互作用以引起不育。第四，我们将使用定量遗传学方法进一步剖析一组不相容性，其中一种或多种相互作用的基因引起混合雄性无菌性，在其中一种物种中仍然是多态性的。这组最终的实验将利用小鼠系统的广泛遗传资源来研究杂种不相容性在最早的阶段的演变 - 在物种之间固定之前。总的来说，这些实验将为男性不育的发展原因提供重要的见解。