The biophysical basis of translational selection

翻译选择的生物物理学基础

• 批准号: 8269780
• 负责人: David Allan Drummond
• 金额: $ 24.63万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269780
• 关键词: Affect; Amino Acids; Area; Arts; Bioinformatics; Biophysics; Cell physiology; Codon Nucleotides; Computer Simulation; Cues; Detection; Disease; Drug Compounding; Event; Evolution; Exposure to; Genome; Health; Hereditary Disease; Human; Laboratories; Lead; Life; Link; Measurable; Metabolic; Microbe; Minor; Mutation; Organism; Pattern; Play; Process; Production; Proteins; Rattus; Relative (related person); Research; Role; Shapes; Signal Transduction; Speed; Testing; Time; Translating; Translations; Work; base; cost; cytotoxic; genome-wide; imprint; insight; loss of function; mathematical model; protein misfolding; public health relevance; research study

Project Summary Genome-wide patterns of sequence divergence over evolutionary time provide a unique window into the fundamental metabolic costs imposed on cellular life. Purifying selection eliminates mutations that increase costs and/or promote genetic disease. This process can discern minor cost differences, even ones that may not be readily measurable by direct laboratory experiments. This project will identify and interpret the evolutionary signals imprinted into genomes by one specific cost, the cost of erroneously translating proteins. Mistranslation events lead to protein misfolding, misfolded proteins can be cytotoxic or require costly cleanup, and selection operates both on the codon and on the amino-acid level to minimize cellular exposure to misfolded proteins. The working hypothesis for this project is that among the costs linked to translation, mistranslation-induced misfolding is the dominant one, whereas other costs, including mistranslation-induced loss of function and translation at reduced speed, play a minor role. This hypothesis will be tested using a combination of bioinformatics, mathematical modeling, and computer simulation, and the relative importance of the various translation- linked costs will be quantified. There are three specific aims. 1. What makes translationally optimal codons optimal? 2. Does selection against protein misfolding shapes synonymous codon usage? 3. How does protein biophysics interact with translational selection to constrain sequence evolution?

项目摘要 全基因组范围内的序列差异模式在进化过程中提供了一个独特的 一扇窗户，让我们了解细胞生命的基本代谢成本。净化选择 消除了增加成本和/或促进遗传疾病的突变。这个过程可以 识别微小的成本差异，即使是那些可能无法直接测量的差异， 实验室实验 该项目将识别和解释由一个人印记到基因组中的进化信号。 具体成本，错误翻译蛋白质的成本。误译事件导致蛋白质 错误折叠的蛋白质可能具有细胞毒性，或者需要昂贵的清理和选择 在密码子和氨基酸水平上都起作用，以使细胞暴露于 错误折叠的蛋白质该项目的工作假设是，在与 翻译，误译导致的错误折叠是占主导地位的，而其他成本， 包括误译导致的功能丧失和翻译速度降低， 次要角色这一假设将使用生物信息学、数学和生物技术相结合的方法进行测试。 建模和计算机模拟，以及各种翻译的相对重要性- 将量化相关成本。 有三个具体目标。1.是什么让进化上最优的密码子成为最优的？2.并 对蛋白质错误折叠的选择形成同义密码子使用？3.蛋白质如何 生物物理学与翻译选择相互作用来限制序列进化？