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)优化连锁不平衡定位人类疾病基因的关联研究策略，2)优化实验哺乳动物基因定位和克隆的实验策略，3)了解重组热点在进化过程中的作用，以及4)将基因重组理解为一个生物过程，具有相当重要的意义。 这项拟议的研究的目的是为小鼠基因组样本中热点的位置和属性提供分子描述。我们将映射到1.5KB的分辨率，900-1000个交叉的位置发生在小鼠基因组的五个5兆碱基区域，根据特定的特征进行选择。我们预计将描述近80个重组热点的交叉，将在(C57BL/6J x CAST/EIJ)F2后代的DNA中识别。我们的热点描述将提供所有热点的位置和重组频率，低至0.02厘米/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，这将是哺乳动物第一次进行如此大规模的努力。信息学研究将试图确定定义热点位置的关键热点序列和染色体特征。此外，对于其中一个染色体区域，我们将进行基因测试，以确定是否存在热点活动所需的反式作用基因。

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.