Transacting Genes Regulating Recombination Hotspot Activities

调节重组热点活动的基因交易

• 批准号: 7894602
• 负责人: KENNETH PAIGEN
• 金额: $ 34.45万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7894602
• 关键词: Affect; Alleles; Animals; Architecture; Backcrossings; Behavior; Behavior Control; Biological; Biological Assay; Biological Process; Biology; Chromatids; Chromosomal Rearrangement; Chromosome Mapping; Cloning; Complement; Constitution; DNA Double Strand Break; Data; Dependence; Disease; Disease susceptibility; Distal; Distant; Double Strand Break Repair; Elements; Escherichia coli; Event; Frequencies; Gene Combinations; Gene Conversion; Gene Proteins; Gene Rearrangement; Generations; Genes; Genetic; Genetic Crossing Over; Genetic Recombination; Genome; Genomics; Goals; Health; Human; Individual; Infertility; Intervention; Linkage Disequilibrium; Literature; Location; Mammals; Maps; Medicine; Meiotic Recombination; Molecular; Molecular Models; Mus; Organism; Outcome; Pathway interactions; Pattern; Phenotype; Population; Predisposition; Preventive; Process; Property; Proteins; Quantitative Trait Loci; Relative (related person); Research; Resolution; Rest; Role; Sex Behavior; Site; Synaptonemal Complex; System; Techniques; Testing; Therapeutic; Time; Trans-Activators; Transact; Variant; Vascular Plant; Yeasts; dosage; gene cloning; genome wide association study; human disease; improved; insight; interest; male; molecular modeling; novel; novel strategies; public health relevance; repaired; research study; segregation; sperm cell; trait; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Genetic recombination is responsible for the re-assortment of alleles at each generation; for our own species, this means the assortment of disease susceptibility alleles across generations and populations, and for all organisms, generating the substrates of evolutionary change. While there has been considerable progress in understanding the molecular details underlying recombination processes, especially in yeast species, among mammalian organisms we are still relatively ignorant of many aspects of recombination biology, including the factors determining the location and relative activity of individual recombination hotspots, and the choice between the crossover and non-crossover (gene conversion) pathways as outcomes of the recombination process. We have now discovered the existence of a trans-acting regulatory system whose products control the behavior of individual hotspots. We compared the hotspot recombination maps of mice heterozygous C57BL/6J and CAST/EiJ for the distal half of Chr 1 when the remaining genomic regions were either homozygous B6 or heterozygous B6/CAST. The activities of some hotspots in this region are dependent on the presence of CAST alleles at distant genes and others are suppressed by such alleles. CAST activated hotspots are controlled in an all-or-none fashion; we do not know about suppressed hotspots. This discovery opens the possibility of new approaches to understanding hotspot behavior by characterizing the genetic architecture of the control system and whether it regulates the formation of the double strand DNA breaks that initiate recombination or regulates the choice between crossover and noncrossover pathways. These findings will eventually open the way to identifying a new class of molecules involved in recombination processes and elucidating recombination control mechanisms. We will determine the number and the location of the trans-acting genes and how they interact; the dependence of hotspot activity on the dosage of trans-acting gene alleles, and, using a new cloning assay for characterizing recombination events at individual hotspots, determine whether the various trans-acting genes control both gene conversion and crossing over, or are specific to crossing over. PUBLIC HEALTH RELEVANCE: Our genetic heritage has a strong influence on our susceptibility to all of the common diseases that afflict us. Mapping the genes responsible for these susceptibilities provides a means of identifying targets for intervention, both preventive and therapeutic, and for developing a personalized medicine adapted to our individual constitutions. The proposed experiments will help us understand how combinations of genes are transmitted from one generation to the next and how we can improve our ability to identify the genes underlying disease susceptibility. Our project thus has relevance to all issues of health and disease that have any genetic component, and specifically to problems of tumorigenesis and infertility that involve DNA rearrangements and repair.

描述（由申请人提供）：基因重组负责每一代等位基因的重新分类；对于我们自己的物种来说，这意味着跨世代和群体的疾病易感性等位基因的分类，对于所有生物体来说，这意味着产生进化变化的基础。虽然在理解重组过程的分子细节方面已经取得了相当大的进展，特别是在酵母物种中，但在哺乳动物生物体中，我们对重组生物学的许多方面仍然相对无知，包括决定个体重组热点的位置和相对活性的因素，以及作为重组过程结果的交叉和非交叉（基因转换）途径之间的选择。 我们现在发现了一个交易监管系统的存在，其产品控制着单个热点的行为。我们比较了当其余基因组区域是纯合子 B6 或杂合子 B6/CAST 时，小鼠杂合子 C57BL/6J 和 CAST/EiJ 对于 Chr 1 远端一半的热点重组图。该区域中一些热点的活动取决于远处基因上 CAST 等位基因的存在，而其他热点则受到此类等位基因的抑制。 CAST 激活的热点以全有或全无的方式进行控制；我们不知道受压制的热点。 这一发现通过表征控制系统的遗传结构以及它是否调节启动重组的双链DNA断裂的形成或调节交叉和非交叉途径之间的选择，开启了理解热点行为的新方法的可能性。这些发现最终将为识别参与重组过程的一类新分子并阐明重组控制机制开辟道路。 我们将确定反式作用基因的数量和位置以及它们如何相互作用；热点活性对反式作用基因等位基因剂量的依赖性，并使用新的克隆测定来表征各个热点的重组事件，确定各种反式作用基因是否控制基因转换和交换，或者是特定于穿越。 公共卫生相关性：我们的遗传基因对我们对所有困扰我们的常见疾病的易感性有很大影响。绘制导致这些易感性的基因图谱提供了一种确定预防性和治疗性干预目标的方法，以及开发适合我们个人体质的个性化药物的方法。拟议的实验将帮助我们了解基因组合如何从一代传递到下一代，以及我们如何提高识别疾病易感性基因的能力。因此，我们的项目与所有具有遗传成分的健康和疾病问题相关，特别是涉及 DNA 重排和修复的肿瘤发生和不孕症问题。