Comparative Evolutionary Genomics and Infectious Disease

描述(申请人提供)：为了发展传染病的预测科学，需要了解形成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，以及核外DNA，如质粒、线粒体和叶绿体基因组，都受到不同的进化压力。进化过程一般可以看作是三种主要力量的组合：突变、选择和遗传漂移。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，从而提供新的基因和基因产物库，从而产生新的表型，如增加毒力、抗药性或过渡到新的地理生态位，这是产生传染病预测指标的绝对要求。我们建议使用包括进化生物学、比较基因组学、生物信息学和群体遗传学理论和方法在内的多个学科的组合来识别和表征形成传染病基因组的进化力量。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之间的选择限制模式；(3)研究最流行的人类疟疾物种的遗传变异和种群结构。我们的研究结合了理论、定量和实验的方法来实现这些目标。通过提供对几种主要致病病原体的分析框架，识别和表征形成其他传染病病原体基因组的进化力量，从而形成传染病表型，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 3 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 8 species of Plasmodium parasite are being sequenced to varying degrees of completion, which represents the largest body of multi-species data available from 1 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 1 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.