Transacting Genes Regulating Recombination Hotspot Activities

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，这意味着疾病易感性等位基因在世代和种群之间的分配，对于所有生物体，产生进化变化的底物。虽然已经有相当大的进展，在了解重组过程中的分子细节，特别是在酵母物种中，在哺乳动物生物体中，我们仍然是相对无知的重组生物学的许多方面，包括决定的因素的位置和相对活性的个别重组热点，和选择之间的交叉和非交叉（基因转换）途径的重组过程的结果。 我们现在已经发现了一个交易监管系统的存在，它的产品控制着各个热点的行为。当剩余的基因组区域为纯合B6或杂合B6/CAST时，我们比较了Chr 1远侧半部分的杂合C57 BL/6 J和CAST/EiJ小鼠的热点重组图谱。在这个区域中的一些热点的活动是依赖于在遥远的基因和其他的CAST等位基因的存在被抑制这样的等位基因。CAST激活的热点以全有或全无的方式控制;我们不知道抑制的热点。 这一发现打开了新的方法来理解热点行为的可能性，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。这些发现最终将为识别参与重组过程的一类新分子和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，并且使用新的克隆测定来表征单个热点的重组事件，确定各种反式作用基因是否控制基因转换和交叉，或者特定于交叉。 公共卫生相关性：我们的基因遗传对我们对所有折磨我们的常见疾病的易感性有很大的影响。绘制这些易感性的基因图谱提供了一种手段，可以确定预防和治疗干预的目标，并开发适合我们个人体质的个性化药物。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，我们的项目与具有任何遗传成分的所有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育问题。

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.