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

描述（由申请人提供）： 精子发生过程中性染色体的适当遗传和表观遗传调控对正常男性生育力的发育至关重要。性染色体在物种间杂种雄性不育的进化中也起着核心作用，但这些早期生殖障碍的发育原因仍不清楚。这项拟议中的研究将使用家鼠的定量遗传和基因组实验来弥合我们对雄性不育发育基础的理解中的重大差距。小鼠是人类生殖生物学的主要遗传模型，因此在小鼠中可以比在大多数其他系统中更详细地研究雄性不育。在这里，我们专注于两个密切相关的小鼠物种，部分分离的杂交雄性不育，提供了一个理想的模型系统，研究自然遗传分歧的后果，精子发生的进展。我们的中心目标之一是测试长期存在的假说，即精子发生过程中X失活的调控破坏在杂种不育的进化中起着核心作用。为此，我们提出了四个协同研究项目。首先，我们将使用最先进的测序方法为我们的研究生物体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不育杂交雄性小鼠精子发生关键阶段的基因表达。这些数据将用于确定在精子发生的后期阶段X连锁基因调控的破坏是否是小鼠杂种雄性不育的主要发育原因。我们还将利用这些数据来确定参与破坏精子发生的潜在遗传相互作用的候选基因。第三，我们将使用额外的遗传实验来直接测试候选的不相容性是否确实与X染色体相互作用而导致不育。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，其中一个或多个相互作用的基因，导致杂种雄性不育保持多态性的物种之一。这最后一组实验将利用小鼠系统的广泛遗传资源，在它们在物种之间固定之前的最早可能阶段研究杂交不相容性的进化。总的来说，这些实验将为男性不育的发育原因提供重要的见解。

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.