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发挥着至关重要的作用，包括有机材料的回收、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。鉴于它们在医疗保健、农业、采矿、渔业和其他领域的核心作用，重要的是开发区分不同微生物组群的可靠方法。然而，大多数细菌群目前仅根据它们在16 S rRNA树中的分支来彼此区分。由于16 S序列信息本身并不提供大多数群体的表型性状的预测，因此不知道群体特异性的分子或生物化学特性。为了可靠和全面地了解不同微生物群体的生物学特性，鉴定特定目标群体唯一共有的进化保守性状是至关重要的，这些性状可以将它们与所有其他微生物区分开来。基因组序列提供了一个独特的和明确的资源，发现新的分子标记，是具体的每一组。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，保守特征插入缺失（CSI）和保守特征蛋白（CSP），它们在特定的生物群体中独特存在。由于基因型指定表型，这些分子标记物将提供重要的手段，用于发现新的生物化学/生物学特性，独特的每一组生物体和开发新的诊断和治疗针对这些生物体。在未来5年内，我们将利用基因组序列对三大类重要细菌，即假单胞菌目、乳杆菌目和芽孢杆菌目进行全面研究。这些细菌群中含有许多“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。我们将确定特定于不同致病细菌以及这些大群细菌中的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提供重要手段，并改进其鉴定方法。此外，该提案的一个重要目的是测试/建立蛋白质结构中的CSI可以靶向用于开发新型细胞生长抑制化合物的原理证明。这一概念的建立可以提供靶向含CSI生物体的新类别药物/抑制剂的巨大资源。总的来说，这里提出的工作应该大大促进我们对一些重要的微生物群体的理解，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着减少。

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.