Population structure and transmission dynamics of Plasmodium vivax

描述（由申请人提供）：本研究的目的是表征人类疟疾寄生虫间日疟原虫的遗传结构和传播动力学，长期目标是了解该物种的进化生物学及其对疟疾治疗和控制的潜在影响。间日疟原虫与每年报告的7000万至8000万疟疾临床病例有关，全世界有26亿人面临感染风险。巴西和斯里兰卡这两个间日疟流行国家的机构正在与美国的主要研究小组合作，以解决以下具体研究目标：1)估计间日疟微卫星多样性水平、单核苷酸多态性（SNP）密度和重组率，并检查全球间日疟种群的地理结构；2)研究遗传上不同的间日疟原虫菌株在疟疾暴露人群中的传播动力学，确定新的单倍型在人群中引入或消失的速率；3)对4个间日疟原虫代表性菌株300 kb染色体片段进行SNP和微卫星发现，并对这些SNP在田间分离物中大规模分型的高通量策略进行标准化；4)将这些300 kb的间日疟原虫DNA序列与猴疟原虫诺氏疟原虫的相应序列进行比较，以获得间日疟原虫不同类型DNA序列（微卫星重复序列与复杂序列，编码DNA与非编码DNA）的单核苷酸突变率和SNP密度的估计，并允许在该染色体片段中鉴定正选择的基因。对这种人类疟疾寄生虫产生和维持遗传变异机制的深入分析将提供关键信息，以预测具有公共卫生重要性的新表型（如耐药性和新的抗原变异）在间日疟原虫自然种群中产生和传播的速度有多快。此外，通过对现场收集的分离物进行信息微卫星和SNP位点的全染色体分析，估计不同寄生虫种群的重组率，有助于设计全基因组关联作图研究，以确定在不同流行病学背景下负责重要寄生虫性状的基因。

DESCRIPTION (provided by applicant): The purpose of this research is to characterize the genetic structure and transmission dynamics of the human malaria parasite Plasmodium vivax, with the long-term goal of understanding the evolutionary biology of this species and its potential implications for malaria treatment and control. Plasmodium vivax is associated with 70-80 million clinical cases of malaria reported each year, with 2.6 billion people at risk of infection worldwide. Institutions based in two P. vivax-endemic countries, Brazil and Sri Lanka, are partnering with leading research groups in the USA to address the following specific research aims: 1) To estimate levels of microsatellite diversity, single-nucleotide polymorphism (SNP) density and recombination rates and to examine the geographic structure of worldwide populations of P. vivax; 2) To examine the transmission dynamics of genetically distinct P. vivax strains in a well-characterized cohort of malaria-exposed subjects and determine the rate at which new haplotypes are introduced or disappear in the population; 3) To carry out SNP and microsatellite discovery across a 300-kb chromosome segment of four representative strains of P. vivax and to standardize high-throughput strategies for large-scale typing of these SNPs in field isolates; 4) To compare these 300-kb of DNA sequence of P. vivax with the corresponding sequence in one of its closest relatives, the monkey malaria parasite P. knowlesi, to obtain estimates of single-nucleotide mutation rates and SNP density for various types of DNA sequence (microsatellite repeats vs. complex sequences, coding vs. noncoding DNA) of P. vivax and to allow the identification of genes under positive selection across this chromosome segment. This in-depth analysis of the mechanisms that create and maintain genetic variation in this human malaria parasite will provide crucial information to predict how fast novel phenotypes of public health importance, such as drug resistance and new antigenic variants, originate and spread in natural populations of P. vivax. In addition, the estimates of recombination rates in different parasite populations, to be generated by the chromosome-wide analysis of informative microsatellite and SNP loci in field-collected isolates, facilitate the design of genome-wide association mapping studies to identify genes that are responsible for important parasite traits in diverse epidemiological settings.