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）：遗传重组负责每一代等位基因的重新分配；对于我们自己的物种而言，这意味着各个世代和人群以及所有生物体的疾病易感性等位基因产生了进化变化的底物。尽管在理解重新组合过程的分子细节方面取得了很大进展，尤其是在酵母菌中，在哺乳动物的生物中，我们仍然对重组生物学的许多方面相对不了解，包括确定单个重组热点的位置和相对活性的因素，以及跨界和非交叉（Gene Conversion Conversion）的选择（Gene Conversion）的选择（Gene Conversion）的路径（Gene Converconion）的启动过程。 现在，我们发现了一个跨作用调节系统的存在，其产品控制了单个热点的行为。我们比较了小鼠的杂合C57BL/6J的热点重组图和CHR 1的远端cons/eij的热点图，其余的基因组区域是纯合B6或杂合B6/cast。该区域中某些热点的活性取决于远处基因的铸造等位基因的存在，而其他等位基因则抑制了这些等位基因。铸造激活的热点以全或任何方式控制；我们不知道被抑制的热点。 这一发现为理解热点行为的新方法开辟了可能性，通过表征控制系统的遗传结构，以及它是否调节双链DNA断裂的形成，从而启动重组或调节交叉和非交叉途径之间的选择。这些发现最终将为识别参与重组过程的新分子和阐明重组控制机制开辟道路。 我们将确定跨作用基因的数量和位置及其相互作用的相互作用。热点活性对跨作用基因等位基因剂量的依赖性，以及使用新的克隆测定法来表征各个热点处的重组事件，确定各种跨作用基因是否控制基因转化和交叉，还是特定于交叉。 公共卫生相关性：我们的遗传遗产对我们对困扰我们的所有常见疾病的敏感性有很大的影响。映射负责这些敏感性的基因提供了一种识别预防和治疗性干预目标的方法，并开发了适合我们个人宪法的个性化医学。提出的实验将帮助我们了解基因组合如何从一代传播到第二代，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任何遗传成分的健康和疾病问题有关，特别是涉及DNA重排和修复的肿瘤发生和不育问题。