Comparative Evolutionary Genomics and Infectious Disease

描述（由申请人提供）：为了发展传染病的预测科学，需要了解塑造基因组的进化力量的范围和强度。生物体的基因组，即编码区和非编码区，以及细胞核DNA，如质粒、线粒体和质体基因组，都受到不同的进化压力。进化过程通常可以被视为三种主要力量的结合：突变，选择和遗传漂变。这些进化压力的程度和力量仍有待充分描述。彻底了解基因组随时间变化的方式，从而提供一个新的基因和基因产物库，产生新的表型，如增加的毒力，耐药性或过渡到一个新的地理生态位，是产生传染病预测措施的绝对要求。 我们建议使用学科的组合，包括进化生物学，比较基因组学，生物信息学和人口遗传学的理论和方法，以确定和表征的进化力量，塑造传染病基因组。我们将使用疟疾寄生虫物种作为我们分析的模型系统。8种疟原虫的基因组正在不同程度地完成测序，这是从一个真核生物属获得的最大的多物种数据。我们建议：（1）记录疟原虫染色体组织的进化;（2）确定编码和非编码序列的选择性约束模式;（3）研究最流行的人类疟疾物种的遗传变异和种群结构。我们的研究结合联合收割机理论，定量和实验方法来实现这些目标。通过提供一个框架的几个物种的一个主要的致病病原体的分析，识别和表征的进化力量，塑造其他基因组的传染病病原体，因此传染病的表型，应该是可能的。

DESCRIPTION (provided by applicant): In order to develop a predictive science of infectious disease, an understanding of the range and intensity of evolutionary forces that shape genomes is required. The genome of an organism, i.e. the coding and non-coding regions, as well as extranuclear DNA such as plasmids, mitochondrial and plastid genomes, are all subject to different evolutionary pressures. The evolutionary process can generally be regarded as a combination of three major forces: mutation, selection and genetic drift. The extent and force of these evolutionary pressures remain to be fully characterized. A thorough understanding of the means by which genomes change overtime, and hence provide a new repertoire of genes and gene products which generate novel phenotypes such as increased virulence, resistance to drugs or transition into a new geographical niche, is an absolute requirement for the generation of predictive measures of infectious disease. We propose to use a combination of disciplines including evolutionary biology, comparative genomics, bioinformatics, and population genetic theories and methodologies to identify and characterize the evolutionary forces that shape infectious disease genomes. We will use the malaria parasite species as a model system for our analysis. The genomes of eight species of Plasmodium parasite are being sequenced to varying degrees of completion, which represents the largest body of multi-species data available from one eukaryotic genus. We propose to (1) chronicle the evolution of Plasmodium chromosome organization; (2) determine the patterns of selective constraints across coding and non-coding sequences; (3) study the genetic variation and population structure of the most prevalent human malaria species. Our studies combine theoretical, quantitative and experimental approaches to achieve these aims. By providing a framework of analysis of several species of one major disease-causing pathogen, identification and characterization of the evolutionary forces that shape other genomes of infectious disease agents, and hence infectious disease phenotypes, should be possible.