Genome Surveillance for drug resistant malaria

恶性疟原虫，人类疟疾的主要病原体，一直是一种 主要的健康威胁在一定程度上是通过耐药生物的进化，例如 最便宜的抗疟疾药物不再有效，对 较新的药物。寄生虫的遗传多样性很可能是导致 寄生虫种群的许多适应性变化。了解频率和 在现存寄生虫种群中的多态分布对于 开发基因作图工具，提供一种强大的方法来识别 遗传基因座负责重要的表型，如抗药性。人类 单倍型图谱(HapMap)项目开创了系统化、全基因组的研究道路 扫描以检测与几乎任何类型的 复杂的性状，包括识别可能在正向或正向下进化的基因 平衡选择。当人类的HapMap处于最后阶段时，我们开始工作 与布罗德研究所的合作者一起确定SNPs(单核苷酸 多态)跨越恶性疟原虫基因组，使用类似的密集努力来 监控和建立高质量的数据，就像人类HapMap中使用的数据一样。这个 基本原理是生产可用于遗传的社区资源 恶性疟原虫的关联性研究，受到较小规模的巨大效用的鼓舞 其他人的研究确定了氯喹和 对乙胺嘧啶耐药。SNP发现阶段最近已经完成， 一种强大的基因分型工具已经开发出来。我们在这里请求支持，以使用 SNP数据库用于对世界各地的恶性疟原虫分离株进行基因分型，以便进行 确定遗传决定因素的关联研究的原则验证验证 抗药性。这种方法代表了P的可用性的汇合。 恶性疟原虫基因组序列，常见SNPs数据库(博德研究所) 世界范围内83株恶性疟原虫分离株的可用性 人口，体外测试技术，以确定准确的药物敏感性 表型，以及开发廉价、准确的高通量技术 SNP基因分型。

Plasmodium falciparum, the major causative agent of human malaria, has remained a major health threat in part through the evolution of drug resistant organisms, such that the cheapest antimalarial drugs are no longer effective and resistance is emerging to newer drugs. Genetic diversity in the parasite is likely to be a major determinant for many of the adaptive changes in parasite populations. Understanding the frequency and distribution of polymorphisms in the extant parasite population is essential for the development of genetic mapping tools that can provide a powerful approach to identify genetic loci responsible for important phenotypes such as drug resistance. The human haplotype map (HapMap) project has pioneered the way for systematic, genome-wide scans for the detection of chromosomal regions associated with virtually any kind of complex trait, including the identification of genes likely evolving under positive or balancing selection. As the human HapMap was in its final stages, we began working with collaborators at the Broad Institute to ascertain SNPs (single-nucleotide polymorphisms) across the genome of P. falciparum, using similar intense efforts to monitor and establish high quality data as those employed in the human HapMap. The rationale was to produce community resources that could be used for genetic association studies in P. falciparum, encouraged by the great utility of smaller scale studies by others that identified the genes responsible for chloroquine and pyrimethamine resistance. The SNP discovery phase has recently been completed and a robust genotyping tool has been developed. We are here requesting support to use the SNP database to genotype world-wide isolates of P. falciparum in order to perform a proof-of-principle validation of association studies to identify genetic determinants of drug resistance. This approach represents a confluence of the availability of the P. falciparum genomic sequence, a database of common SNPs (Broad Institute), the availability of 83 isolates of Plasmodium falciparum derived from the world-wide population, the technology for in vitro testing to determine accurate drug sensitivity phenotypes, and the development of inexpensive, accurate technologies for highthroughput SNP genotyping.