Genome Surveillance for drug resistant malaria

恶性疟原虫是人类疟疾的主要病原体， 主要的健康威胁部分是通过抗药性生物体的进化， 最便宜的抗疟药物不再有效， 新药寄生虫的遗传多样性可能是寄生虫的主要决定因素 许多寄生虫种群的适应性变化。了解频率和 在现存的寄生虫种群中多态性的分布对于 开发基因图谱工具，可以提供一种强有力的方法来识别 负责重要表型如耐药性的遗传基因座。人类 单倍型图（HapMap）项目开创了系统的，全基因组的 扫描检测与几乎任何类型的染色体相关的染色体区域 复杂性状，包括鉴定可能在阳性或阴性条件下进化的基因， 平衡选择当人类HapMap处于最后阶段时， 与布罗德研究所的合作者一起确定SNPs（单核苷酸 多态性）在恶性疟原虫的基因组中，使用类似的密集努力， 监测和建立高质量的数据，如在人类HapMap中使用的数据。的 其基本原理是生产可用于遗传学的社区资源， 在恶性疟原虫的关联研究，鼓励小规模的巨大效用， 其他人的研究确定了负责氯喹的基因， 乙胺嘧啶抗性。SNP发现阶段最近已经完成， 已经开发了一种强有力的基因分型工具。我们在这里请求支持使用 SNP数据库对全球恶性疟原虫分离株进行基因分型， 关联研究的原理验证，以确定 耐药性这种方法代表了P. 恶性疟原虫基因组序列，常见SNP数据库（布罗德研究所）， 来自世界各地的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，并开发廉价，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.