Genetic Dissection of Quantitative Control of Recombination

重组定量控制的基因剖析

• 批准号: 8448923
• 负责人: Christopher Lee Baker
• 金额: $ 1.93万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448923
• 关键词: Address; Alleles; Aneuploidy; CAST/EiJ Mouse; Chromosome Mapping; Chromosomes; DNA Sequence; Developmental Process; Dissection; Evolution; Failure; Fertility; Generations; Genes; Genetic; Genetic Materials; Genetic Recombination; Genetic Variation; Genome; Germ Cells; Health; Human; Inbred Strains Mice; Individual; Left; Location; Mammalian Chromosomes; Maps; Measures; Mediating; Meiosis; Meiotic Recombination; Methods; Mouse Strains; Mus; Nature; Organism; Pathway interactions; Phenotype; Population; Positioning Attribute; Pregnancy; Process; Public Health; Regulation; Regulator Genes; Relative (related person); Reproduction; Research; Resolution; Rest; Single Nucleotide Polymorphism; Site; Specificity; Spontaneous abortion; Sterility; Surveys; System; Trans-Activators; Zinc Fingers; egg; genome sequencing; innovation; insight; male; reproductive success; research study; sperm cell

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.

描述（由申请人提供）：本提案解决的核心问题是确定控制哺乳动物减数分裂期间重组热点定量活动的调节系统的性质，该系统的显着特征在很大程度上仍无法解释。减数分裂至关重要，可确保物种的持续繁殖成功。进一步了解这一监管背后的遗传系统对公共健康具有重大影响。未能正确执行减数分裂可能会导致非整倍体配子，从而导致人类大多数自然流产和不育。减数分裂负责世代间遗传物质的改组，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 通过指导染色体上的重组位置来定性地发挥作用。相比之下，影响热点重组率的反式作用定量调控基因的身份仍然未知。这里概述的实验将通过将小鼠遗传学的力量与创新方法相结合来弥补这一缺陷，通过利用高通量 DNA 测序来绘制这些定量调控基因，从而准确测量重组产物。将应用额外的遗传策略来调查小鼠中发现的自然发生的等位基因多样性，以调节 Prdm9 活性，并区分 Prdm9 依赖性和独立途径。总之，这些实验的结果将进一步加深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。