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

微生物在生命的各个方面发挥着至关重要的作用，包括有机物质的回收、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，必须发展可靠的方法来区分不同的微生物群。然而，目前大多数细菌群之间的区别仅仅是基于它们在16S rRNA树中的分支。由于16S序列信息本身不能为大多数群体提供表型性状的预测，因此没有已知群体特异性的分子或生化特性。为了可靠和全面地了解不同微生物群体的生物学特性，确定特定群体所独有的进化保守特征是至关重要的，这些特征可以将它们与所有其他群体区分开来。基因组序列提供了一个独特的和明确的资源，为发现新的分子标记是特定于每个群体。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，保守特征索引（CSIs）和保守特征蛋白（CSPs），这两种标记在特定的生物群体中是唯一发现的。由于基因型指定表型，这些分子标记将为发现每组生物独特共享的新生化/生物学特性以及针对这些生物的新诊断和治疗方法的开发提供重要手段。在接下来的5年里，我们将利用基因组序列对假单胞菌、乳酸杆菌和芽胞杆菌这三种重要的细菌群进行全面的研究。这些群体窝藏着许多“优先的人类病原体”，几种主要的植物病原体，以及在乳制品和农业工业中起关键作用的其他细菌。我们将确定这些大群体中不同致病细菌和有益细菌的多种可靠特征，从而为发现这些细菌的新生化特征和改进鉴定手段提供重要手段。此外，本提案的一个重要目标是测试/建立原理证明，即蛋白质结构中的csi可以作为开发新型细胞生长抑制化合物的靶点。这一概念的建立可以为针对含csi生物的新型药物/抑制剂提供大量资源。总的来说，这里提出的工作应该大大促进我们对一些重要微生物群体的理解，这些发现的应用应该导致这些细菌造成的健康，农业和经济负担的显著减少。

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.