Genomic Organization of Recombination Hot Spots

描述（申请人提供）：了解哺乳动物重组的基因组分布对于1）优化通过连锁不平衡定位人类疾病基因的关联研究的策略，2）优化在实验哺乳动物中定位和克隆基因的实验策略，3）了解重组热点在进化过程中的作用，（4）理解基因重组是一个生物学过程。 这项研究的目的是提供一个分子描述的位置和性质的热点在一个样本的小鼠基因组。我们将以1.5 Kb的分辨率绘制小鼠基因组5个5兆碱基区域中发生的900-1000次交换的位置，这些区域是根据特定特征选择的。我们期望描述近80个重组热点的交叉将在来自（C57 BL/6 J X CAST/EiJ）F2后代的DNA中鉴定。我们的热点表征将提供所有热点的位置和重组频率低至0.02 cM/热点的水平，并将包括每个热点的单倍型和性别特异性。据我们所知，这将是第一次对哺乳动物进行如此大规模的研究。 信息学研究将试图确定关键的热点序列和确定热点位置的染色体特征。 此外，对于其中一个染色体区域，我们将进行基因检测，以确定热点活动所需的反式作用基因的存在。

DESCRIPTION (provided by applicant): Understanding the genomic distribution of mammalian recombination is a matter of considerable importance for 1) optimizing strategies for association studies mapping human disease genes by linkage disequilibrium, 2) optimizing experimental strategies for mapping and cloning genes in experimental mammals, 3) understanding the role of recombinational hotspots in evolutionary processes, and 4) understanding genetic recombination as a biological process. The purpose of the proposed research is to provide a molecular description of the locations and properties of hotspots in a sample of the mouse genome. We will map to a resolution of 1.5 Kb, the locations of 900-1000 crossovers occurring in five 5-megabase regions of the mouse genome, selected for specific characteristics. The crossovers, which we expect to describe nearly 80 recombinational hotspots, will be identified in DNAs from (C57BL/6J x CAST/EiJ) F2 progeny. Our hotspot characterizations will provide the locations and recombination frequencies of all hotspots down to a level of 0.02 cM/hotspot, and will include the haplotype and sex specificity of each hotspot. To our knowledge, this will be the first such large-scale effort for a mammal. Informatics studies will attempt to identify key hotspot sequences and chromosomal features that define hotspot locations. Additionally, for one of the chromosomal regions, we will carry out a genetic test for the existence of trans-acting genes required for hotspot activity.