Genetic Dissection of Quantitative Control of Recombination

描述(由申请人提供)：本提案的中心问题是确定在哺乳动物减数分裂过程中控制重组热点数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。减数分裂是确保物种持续繁殖成功的关键。进一步了解这一规定背后的遗传系统对公众健康具有重大影响。如果减数分裂执行不当，可能会导致非整倍体配子，导致人类大多数自然流产的妊娠和不孕。减数分裂负责遗传物质在世代之间的转移，减数分裂重组的位置决定了人类群体中的遗传障碍。到目前为止，唯一已知的热点调节因子Prdm9通过指导重组在染色体上的位置而定性地发挥作用。相比之下，影响热点重组率的反式作用数量调控基因的特性尚不清楚。这里概述的实验将通过结合小鼠遗传学的力量和一种创新的方法来弥补这一缺陷，通过利用高通量DNA测序来定位这些定量调控基因，从而准确地测量重组的产物。将应用其他遗传策略来调查在小鼠中发现的Prdm9活性修饰物的自然发生的等位基因多样性，并区分Prdm9依赖和独立的途径。综上所述，这些实验结果将进一步加深我们对哺乳动物重组热点位置和相对激活的控制系统的理解。 与公共卫生相关：减数分裂是一个专门的发育过程，需要有性繁殖，产生生殖细胞(精子和卵子)。减数分裂的异常导致人类妊娠中的大多数自然流产，这是由于在一个称为减数分裂重组的过程中染色体不正确地分离所致。这项提案中提出的研究试图确定控制减数分裂重组位置和速度的潜在基因调控系统。

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.