Applications of Genomics Derived Characteristics for Evolutionary and Functional studies and for Development of Novel Diagnostics and Therapeutics

微生物在生活的各个方面都起着至关重要的作用，包括有机物质的循环利用、固氮、光合作用、废物分解、生物修复、抗生素和其他重要化合物的生产，以及人类健康和疾病的主要决定因素。鉴于它们在保健、农业、采矿、渔业和其他领域的核心作用，重要的是开发可靠的手段来区分不同的微生物群。然而，目前大多数细菌群只是根据它们在16S rRNA树上的分枝来区分的。由于16S序列信息本身不能预测大多数群体的表型性状(S)，因此尚不清楚群体特有的分子或生化性质。为了可靠和全面地了解不同微生物组的生物学特性，至关重要的是确定特定兴趣组唯一共有的、能够将它们与所有其他组区分开来的进化保守特征。基因组序列为发现每个群体特有的新的分子标记提供了唯一和明确的资源。利用基因组序列，我的团队率先发现了两种类型的分子标记，保守签名INDELs(CSIS)和保守签名蛋白(CSPs)，这是在特定生物体群体中唯一发现的。由于基因的表型不同，这些分子标记将为发现每一组生物体独有的新的生化/生物学特性以及开发针对这些生物体的新的诊断和治疗方法提供重要手段。在接下来的5年里，我们在这一领域的工作将利用基因组序列来全面研究三个重要的细菌群体，即细菌。假单胞菌、乳杆菌和芽孢杆菌。这些群体拥有许多“优先人类病原体”，几种主要的植物病原体，以及在乳制品和农业中发挥关键作用的其他细菌。我们将为这些大类群中不同的致病细菌和有益细菌鉴定出多种可靠的特性，从而为发现这些细菌的新生化特性和改进它们的鉴定手段提供重要手段。此外，这项建议的一个重要目标是测试/建立蛋白质结构中的CSIS可以作为开发新的细胞生长抑制化合物的靶点的原则证明。这一概念的建立可以提供大量针对含CSI生物体的新型药物/抑制剂的资源。总体而言，这里提出的工作应该会极大地促进我们对一些重要微生物群体的了解，这些发现的应用应该会大大减少这些细菌造成的健康、农业和经济负担。

Microorganisms play vital roles in all aspects of life including recycling of organic materials, nitrogen fixation, photosynthesis, waste decomposition, bioremediation, production of antibiotics and other important compounds, as well as major determinants of human health and diseases. In view of their central roles in health care, agriculture, mining, fishing and other areas, it is important to develop reliable means for distinguishing different groups of microorganisms. However, most of the bacterial groups are currently distinguished from each other only on the basis of their branching in the 16S rRNA trees. As 16S sequence information does not, in itself, provide prediction of phenotypic trait(s) for most groups, no group-specific molecular or biochemical properties are known. For a reliable and comprehensive understanding of the biological properties of diverse groups of microorganisms, it is critically important to identify evolutionarily conserved traits that are uniquely shared by specific groups of interest and which can distinguish them from all others. Genome sequences provide a unique and definitive resource for discovering novel molecular markers that are specific for each group. Using genome sequences, my group has pioneered the discovery of two types of molecular markers, Conserved Signature Indels (CSIs) and Conserved Signature Proteins (CSPs), which are uniquely found in specific groups of organisms. As the genotype specifies phenotype, these molecular markers will provide important means for discovering novel biochemical/biological properties uniquely shared by each group of organisms and for development of novel diagnostics and therapeutics aimed at these organisms. During the next 5 years, our work in this area will use genome sequences to comprehensively investigate three important groups of bacteria viz. Pseudomonadales, Lactobacillales and Bacillales. These groups harbor many “priority human pathogens,” several major plant pathogens, as well as other bacteria playing key roles in the dairy and agriculture industries. We will identify multiple reliable characteristics specific for different disease-causing as well as beneficial bacteria that are part of these large groups, thereby providing important means for discovering novel biochemical traits of these bacteria and improving the means for their identification. Additionally, an important objective of this proposal is to test/establish the proof of principle that the CSIs in protein structures can be targeted for development of novel cell-growth inhibitory compounds. The establishment of this concept can provide a vast resource of new classes of drugs/inhibitors targeting the CSI-containing organisms. Overall, the work proposed here should greatly advance our understanding of a number of important groups of microorganisms and the applications of these findings should lead to a significant reduction in the health, agricultural and economic burden caused by these bacteria.