Genetic Dissection of Quantitative Control of Recombination

描述（由申请人提供）：本提案中解决的中心问题是确定哺乳动物减数分裂期间控制重组热点定量活性的调节系统的性质，该系统的显著特征在很大程度上仍无法解释。减数分裂是必不可少的，确保一个物种的持续繁殖成功。进一步了解这一规定背后的遗传系统对公共卫生具有重大意义。不能正确地进行减数分裂可导致非整倍体配子，从而导致大多数人类自然流产和不育。减数分裂负责遗传物质在世代之间的改组，减数分裂重组的位置决定了人类群体中的遗传区块。迄今为止，唯一已知的热点调节因子Prdm9通过引导重组沿着染色体的位置来定性地发挥作用。相反，反式作用的定量调控基因的身份影响重组率在热点仍然未知。这里概述的实验将通过将小鼠遗传学的力量与一种创新方法相结合来弥补这一缺陷，该方法通过利用高通量DNA测序来精确测量重组产物，以绘制这些定量调控基因。其他遗传策略将被应用于调查自然发生的等位基因多样性在小鼠中发现的Prdm9活动的修饰剂和区分Prdm9依赖性和独立的途径。总之，这些实验的结果将进一步推进我们对控制哺乳动物重组热点的位置和相对激活的系统的理解。

DESCRIPTION (provided by applicant): The central question addressed in this proposal is to identify the nature of a regulatory system controlling the quantitative activity of recombination hotspots during mammalian meiosis, a system of whose significant features remain largely unexplained. Meiosis is essential, assuring continued reproductive success of a species. Gaining a further understanding of the genetic system behind this regulation has substantial implications on public health. Failure to properly execute meiosis can result in aneuploid gametes causing the majority of spontaneously aborted pregnancies and sterility in humans. Meiosis is responsible for the shuffling of genetic material between generations and the positions of meiotic recombination determine the blocks of inheritance in human populations. To date the only known regulator of hotspots, Prdm9, functions qualitatively by directing the position of recombination along chromosomes. In contrast, the identity of the trans-acting quantitative regulatory genes influencing the rate of recombination at hotspots remains unknown. Experiments outlined here will remedy this deficit by combining the power of mouse genetics with an innovative method to accurately measure the products of recombination by leveraging high-throughput DNA sequencing to map these quantitative regulatory genes. Additional genetic strategies will be applied to survey the naturally occurring allelic diversity found in mice for modifiers of Prdm9 activities and differentiate between Prdm9- dependent and independent pathways. Together, results from these experiments will further advance our understanding of the system controlling the position and relative activates of mammalian recombination hotspots.