Elucidating a newly discovered selective agent operating in bacterial genomes

阐明一种新发现的在细菌基因组中起作用的选择剂

• 批准号: 8821634
• 负责人: Howard Ochman
• 金额: $ 27.46万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-15 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8821634
• 关键词: Accounting; Affect; Automobile Driving; Bacteria; Bacterial Genes; Bacterial Genome; Base Composition; Behavior monitoring; Biological Assay; Cell physiology; Codon Nucleotides; Equilibrium; Escherichia coli; Evolution; Fostering; Foundations; GC Rich Sequence; Gene Expression; Genes; Genetic Transcription; Genome; Genomics; Goals; Growth; Guanine + Cytosine Composition; Health; Link; Location; Mediating; Methods; Molecular; Mutation; Natural Selections; Open Reading Frames; Pattern; Phenotype; Point Mutation; Positioning Attribute; Process; Production; Property; Protein Engineering; Proteins; Research; Ribosomes; Role; Sequence Analysis; Shapes; Site; Source; Synthetic Genes; Taxon; Technology; Testing; Transcript; Translations; Variant; Work; base; cell growth; comparative; design; design and construction; fitness; genome-wide; improved; protein expression; research study

DESCRIPTION (provided by applicant): The wide variation in the genomic base compositions of bacteria, which ranges among species from 14% to 75% G+C, has led to much speculation as to its origin, its persistence and its implications for bacterial fitness. Several adaptive explanations have been proposed~ however, the most persuasive and widely held view, first posited over 50 years ago, is that this variation is neutral, caused by differences among taxa in the underlying pattern of mutations. This view was recently countered through comprehensive sequence comparisons, which determined that mutations are universally biased towards A+T, even in bacteria with high genomic G+C contents, indicating a role of natural selection in determining base composition. Moreover, preliminary experiments revealed that bacteria expressing GC-rich versions of genes display higher growth rates than those expressing the identical protein from AT-rich versions, again showing that selection favors higher genic G+C in a genome where mutations are biased towards A+T. Why and how selection operates on the base composition of genes is unknown~ and none of the processes known to exert constraints on synonymous sites, or on gene and protein expression, can explain the selective force favoring high G+C. The goals of the proposed work are to determine (i) the source of this newly discovered selective process, (ii) the universality of its action, and (iii) the mechanism by which it operates. These goals will be accomplished in four Aims, the first of which employs synthetic gene constructs that are designed to identify the key compositional features of genes that foster the selective differences. In the second Aim, these gene constructs will be tested for their selective effects in bacterial groups that differ with respect to their mutational patterns and overall genomic base compositions~ results will reveal if selection acts on a cellular process that is common to all bacteria. The third Aim will examine effects of base compositional variation in native genes to determine the extent to which the selective force on genic G+C is physiologically relevant and has affected genes that have resided in a genome for millions of years. Although sequence comparisons and fitness assays both offer robust methods for detecting the past action of selection, they provide little information about its actual causes. Therefore, the final Aim will apply a sensitive, genome-wide approach for studying the interactions between gene transcripts and ribosomes to elucidate the mechanistic basis of compositional selection. Together, these studies will resolve a longstanding question in bacterial evolution and increase our understanding of the molecular evolutionary processes that shape bacterial genomes.

描述（由申请人提供）：细菌基因组碱基组成的广泛变化，在物种之间的范围为14%至75% G+C，导致对其起源、持久性及其对细菌适应性的影响进行了许多推测。已经提出了几种适应性的解释，然而，最有说服力和广泛持有的观点，首先在50多年前提出，是这种变化是中性的，由潜在突变模式的分类群之间的差异引起。最近通过全面的序列比较反驳了这一观点，该比较确定突变普遍偏向A+T，即使在基因组G+C含量高的细菌中也是如此，这表明自然选择在确定碱基组成中的作用。此外，初步实验显示，表达富含GC的基因版本的细菌比表达来自富含AT的版本的相同蛋白质的细菌显示出更高的生长速率，再次表明选择有利于基因组中更高基因的G+C，其中突变偏向A+T。 选择为什么以及如何作用于基因的碱基组成尚不清楚，而且已知的对同义位点或基因和蛋白质表达施加限制的过程中，没有一个能够解释有利于高G+C的选择力。拟议工作的目标是确定（i）这个新发现的选择性过程的来源，（ii）其作用的普遍性，以及（iii） 它运作。这些目标将在四个目标中实现，其中第一个目标采用合成基因构建体，其设计用于识别促进选择性差异的基因的关键组成特征。在第二个目标中，将测试这些基因构建体在细菌组中的选择性作用，这些细菌组在突变模式和总体基因组碱基组成方面不同，结果将揭示选择是否作用于所有细菌共有的细胞过程。第三个目标将研究天然基因中碱基组成变异的影响，以确定基因G+C的选择力在多大程度上是生理相关的，并影响了数百万年来一直存在于基因组中的基因。虽然序列比较和适应性分析都提供了检测选择过去行为的可靠方法，但它们提供的关于其实际原因的信息很少。因此，最终的目标将应用一个敏感的，全基因组的方法来研究基因转录本和核糖体之间的相互作用，以阐明组成选择的机制基础。总之，这些研究将解决细菌进化中一个长期存在的问题，并增加我们对塑造细菌基因组的分子进化过程的理解。