Genetic Dissection of Quantitative Control of Recombination

描述（由申请人提供）：本提案解决的核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动的调控系统的性质，该系统的重要特征在很大程度上仍未得到解释。减数分裂是保证一个物种持续繁殖成功的关键。进一步了解这一调控背后的遗传系统对公共卫生具有重大意义。减数分裂不正确会导致非整倍体配子，导致大多数自然流产和人类不育。减数分裂负责遗传物质在世代之间的洗牌，减数分裂重组的位置决定了人类群体的遗传块。迄今为止，唯一已知的热点调节因子Prdm9通过指导沿染色体重组的位置来定性地起作用。相比之下，影响热点地区重组率的反式定量调控基因的身份仍然未知。本文概述的实验将通过将小鼠遗传学的力量与一种创新的方法相结合，利用高通量DNA测序来精确测量这些定量调控基因的重组产物，从而弥补这一缺陷。其他的遗传策略将应用于调查在小鼠中发现的Prdm9活性修饰因子的自然发生的等位基因多样性，并区分Prdm9依赖和独立途径。总之，这些实验的结果将进一步促进我们对控制哺乳动物重组热点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. PUBLIC HEALTH RELEVANCE: Meiosis is a specialized developmental process, required for sexual reproduction, giving rise to germ cells (sperm and egg). Aberrant meiosis results in the majority of spontaneous abortions in human pregnancies due to improper disjunction of chromosomes during a process called meiotic recombination. Research set out in this proposal seeks to identify the underlying genetic regulatory system controlling the position and rate of meiotic recombination.