MAPPING DRUG RESISTANCE GENES IN PLASMODIUM FALCIPARUM

疟疾寄生虫恶性疟原虫对目前使用的大多数主要类别的抗疟疾药物产生了抗药性，这严重阻碍了我们控制这种疾病的能力。了解耐药性的遗传基础将有助于深入了解抗疟疾药物的作用方式，并为开发新化合物和重新设计现有药物提供基础。我们建议利用恶性疟原虫致密的微卫星图谱和新兴的基因组序列数据，结合统计遗传学的最新进展来定位耐药基因。我们的方法将包括野外采集的寄生虫的表型和基因特征。我们将测试4种重要的抗疟疾化合物-甲氟喹、奎宁、青蒿素和氯喹的体外敏感性，这些化合物来自泰国-缅甸边境的一个地点。然后，我们将对这些寄生虫的200个微卫星标记进行基因分型，这些标记以5-10 cM的间隔分布在寄生虫基因组上。为了定位含有抗药性数量性状基因座的基因组区域，我们将使用两阶段策略。首先，我们将使用方差分量连锁方法，其中我们使用遗传标记数据来推断寄生虫之间的亲缘关系。然后，我们将通过检查标记基因和耐药基因之间的连锁不平衡，精细绘制包含抗药性数量性状基因座的基因组区域。候选基因将使用疟疾基因组计划产生的序列数据来确定。

The malaria parasite, Plasmodium falciparum, has developed resistance to most of the major classes of antimalarial drugs currently in use, which severly hampers our ability to control this disease. Knowledge of the genetic basis of resistance would provide insights into mode of action of antimalarial drugs, as well as providing a basis for development of novel compounds and redesign of existing drugs. We propose to exploit the dense microsatellite map and the emerging genome sequence data frm P. falciparum together with recent advances in statistical genetics to locate genes underlying drug resistance. Our approach will involve both phenotypic and genotypic characterization of field collected parasites. We will measure in vitro susceptibility to 4 important antimalarial compounds-mefloquine, quinine, artemisinin and chloroquine in malaria parasites obtained from a site on the Thai-Burmese border. We will then genotype these parasites for 200 microsatellite markers distributed at 5-10 cM intervals across the parasite genome. To locate genomic regions containing quantitative trait loci for drug resistance we will use two-stage strategy. First we will use variance component linkage methods in which we use genetic marker data to infer kinship relationships between parasites. We will then fine-scale map regions of the genome containing quantitative trait loci for drug resistance, by inspecting linkage disequilibrium between marker loci and genes underlying resistance. Candidate genes will be identified using sequence data emerging from the malaria genome project.