Elucidating the Evolution of Bacterial Genes, Genomes and Communities

 描述(申请人提供)：基因组方法改变了细菌进化、适应和功能的研究，使几乎任何微生物和微生物群落的快速表征成为可能。然而，这样的分析并不是没有缺点：大型基因组数据集通常需要新的工具来揭示对进化有意义的模式；选择的签名几乎没有提供关于其生态原因的信息，而且大多数目前对微生物群的评估只能提供对群落内容和功能的有限了解。二十多年来，我的实验室的研究结合了信息学和实验的方法，为微生物基因、基因组和群落的进化提供了新的见解。这项提案涵盖了三个主要主题领域，在每个主题领域中，许多问题都源于最初通过比较基因组分析进行的观察。第一个主题领域询问新的基因和功能是如何在细菌基因组中产生的。大多数新基因进化的模型都是基于对现有遗传信息的复制和修改，而忽视了关于全新基因如何从头产生的问题。我们还问，那些已经存在于基因组中的基因如何才能承担全新的功能。第二个主题领域研究一种新发现的控制细菌基因组碱基组成的选择性试剂。长期以来的观点认为，基因组碱基组成的差异是由突变模式中的固有偏见造成的(一个严格的中性过程)。但最近的比较序列分析表明，细菌中的突变普遍偏向A-T，甚至在富含GC的基因组中也是如此，这表明选择在塑造碱基组成中发挥了作用。选择为什么以及如何作用于碱基组成是未知的，也没有已知的过程可以解释它的作用方式，所以我们正在调查这种新发现的选择压力的来源，它的作用机制，以及它的作用程度。第三个主题领域涉及微生物群落的问题，由于新的方法，这些问题最近得到了回答。我们研究了复杂群落中细菌之间的菌株水平差异，以回答有关特定宿主限制微生物如何与宿主共同进化的问题。在系统发育深度的另一个极端，我们将对目前无法分类的生物体进行分类，这些生物体通常代表微生物群落的很大一部分。我们的目标是在肠道微生物群中发现新的主要下降路线。最后，我们将在复杂微生物群落中单个细胞的水平上工作，以阐明功能相关的基因--全球重要的抗生素耐药性决定因素--是如何分布在群落的不同成员中的。

 DESCRIPTION (provided by applicant): Genomic methods have transformed the study of bacterial evolution, adaptation and function by enabling the rapid characterization of virtually any microorganism and microbial community. Such analyses, however, are not without shortcomings: large genomic datasets often require new tools to uncover evolutionarily meaningful patterns; signatures of selection impart little, if any, information about their ecological causes, and most current assessments of microbiomes offer only limited understanding of community contents and functions. For more than two decades, research from my laboratory has combined informatic and experimental approaches to provide new insights into the evolution of microbial genes, genomes and communities. This proposal covers three main Subject Areas, and in each, many of the questions addressed stem from observations first made by comparative genomic analysis. The first Subject Area asks how new genes and functions originate in bacterial genomes. Most models of new gene evolution are based on the duplication and modification of existing genetic information, and ignore questions about how completely new genes can arise de novo. We also ask how those genes that already exist in genomes can assume entirely new functions. The second Subject Area investigates a newly discovered selective agent that governs bacterial genomic base composition. The long-held view is that differences in genomic base composition were caused by inherent biases in the patterns of mutations (a strictly neutral process). But recent comparative sequence analyses demonstrate that mutation in bacteria is universally biased towards A+T, even in GC-rich genomes, indicating a role of selection in shaping base composition. Why and how selection operates on the base composition is not known, and no known processes can explain its mode of action, so we are investigating the source of this newly discovered selective pressure, the mechanism by which it operates, and the extent of its action. The third Subject Area addresses questions about microbial communities, newly answerable due to novel methodologies. We examine the strain-level variation among bacteria in complex communities to answer questions about how specific host-restricted microorganisms co-evolve with hosts. At the other extreme of phylogenetic depth, we will classify the currently unclassifiable organisms that often represent large fractions of microbial communities. Our aim here is to discover new major lines of descent within the gut microbiome. Finally, we will work at the level of individual cells in complex microbial communities to elucidate how functionally relevant genes-globally importantly antibiotic resistance determinants-are distributed across divergent members of a community.