Genome Surveillance for drug resistant malaria

耐药性疟疾的基因组监测

• 批准号: 7463500
• 负责人: Dyann F Wirth
• 金额: $ 55.03万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-21 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7463500
• 关键词: Africa; African; Antimalarials; Area; Attention; Biological; Biological Assay; Candidate Disease Gene; Chloroquine; Chloroquine resistance; Chromosome Mapping; Chromosomes, Human, Pair 4; Chromosomes, Human, Pair 7; Classification; Communities; Complex; Data; Data Quality; Databases; Detection; Development; Disease; Drug resistance; Equilibrium; Evolution; Fostering; Frequencies; Genes; Genetic; Genetic Crosses; Genetic Determinism; Genetic Polymorphism; Genetic Variation; Genome; Genomics; Genotype; Goals; Haplotypes; Health; Human; Human Genome; Immune response; In Vitro; Inhibitory Concentration 50; Institutes; Intervention; Laboratories; Lead; Linkage Disequilibrium; Longevity; Malaria; Maps; Measures; Methods; Monitor; Mutation; Natural Selections; Organism; Papua New Guinea; Parasites; Patients; Pharmaceutical Preparations; Phase; Phenotype; Plasmodium falciparum; Population; Public Health; Publishing; Pyrimethamine; Research; Research Design; Research Personnel; Resistance; Resources; Role; Scanning; Single Nucleotide Polymorphism; Snow; South America; Southeastern Asia; Staging; Technology; Testing; Therapeutic; Time; Validation; Work; clinical phenotype; cost; drug sensitivity; epidemiological model; gene discovery; genetic association; genome wide association study; genome-wide; genome-wide analysis; high throughput technology; in vitro testing; migration; mortality; parasite genome; pressure; prevent; research study; success; tool; trait; transmission process; vector mosquito

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.

恶性疟原虫是人类疟疾的主要病原体，一直是 主要的健康威胁部分是由于耐药生物体的进化造成的，例如 最便宜的抗疟药物不再有效，并且耐药性正在出现 较新的药物。寄生虫的遗传多样性可能是寄生虫的主要决定因素 寄生虫种群的许多适应性变化。了解频率和 现有寄生虫种群中多态性的分布对于 开发遗传图谱工具，可以提供强大的方法来识别 负责重要表型（例如耐药性）的遗传位点。人类 单倍型图谱 (HapMap) 项目开创了系统性、全基因组 扫描检测与几乎任何类型的染色体相关的区域 复杂的性状，包括识别可能在积极或积极的情况下进化的基因 平衡选择。当人类 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 SNP（单核苷酸 多态性）跨越恶性疟原虫的基因组，使用类似的大力努力 监测并建立人类 HapMap 中使用的高质量数据。这 理由是产生可用于遗传的社区资源 恶性疟原虫的关联研究，受到小规模的巨大效用的鼓励 其他人的研究确定了负责氯喹和 乙胺嘧啶耐药。 SNP 发现阶段最近已完成 已经开发出强大的基因分型工具。我们在此请求支持以使用 SNP 数据库对全球恶性疟原虫分离株进行基因分型，以便进行 关联研究的原理验证验证，以确定遗传决定因素 耐药性。这种方法代表了 P 可用性的融合。 恶性疟原虫基因组序列，常见 SNP 数据库（博德研究所）， 可获得来自世界各地的 83 株恶性疟原虫分离株 人群，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。