The biophysical basis of translational selection

翻译选择的生物物理学基础

• 批准号: 8073479
• 负责人: David Allan Drummond
• 金额: $ 24.6万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073479
• 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

DESCRIPTION (provided by applicant): 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? PUBLIC HEALTH RELEVANCE: All organisms have to translate proteins accurately and efficiently; mutations that interfere with efficient translation impair cellular function and cause disease states in humans. This project will identify the specific costs associated with mutations that affect translation, and will provide insight into which mutations are most likely to impose meaningful costs on cellular function. This research will impact several health-related areas, including the industrial production of drug compounds in genetically modified microbes and the cause and detection of certain kinds of genetic diseases in humans.

描述（由申请人提供）：进化过程中的全基因组序列分歧模式为了解细胞生命的基本代谢成本提供了一个独特的窗口。纯化选择消除了增加成本和/或促进遗传疾病的突变。这个过程可以辨别微小的成本差异，甚至是那些无法通过直接实验室实验轻易测量的差异。该项目将识别并解释通过一种特定成本（错误翻译蛋白质的成本）印入基因组的进化信号。错误翻译事件导致蛋白质错误折叠，错误折叠的蛋白质可能具有细胞毒性或需要昂贵的清理成本，并且选择在密码子和氨基酸水平上进行，以最大限度地减少细胞对错误折叠蛋白质的暴露。该项目的工作假设是，在与翻译相关的成本中，误译引起的错误折叠是主要成本，而其他成本，包括误译引起的功能丧失和翻译速度降低，则发挥次要作用。该假设将结合生物信息学、数学建模和计算机模拟进行测试，并且各种翻译相关成本的相对重要性将被量化。具体目标有三个。 1. 是什么使得翻译最优密码子变得最优？ 2. 针对蛋白质错误折叠的选择是否会影响同义密码子的使用？ 3.蛋白质生物物理学如何与翻译选择相互作用以限制序列进化？ 公共健康相关性：所有生物体都必须准确有效地翻译蛋白质；干扰有效翻译的突变会损害细胞功能并导致人类疾病状态。该项目将确定与影响翻译的突变相关的具体成本，并将深入了解哪些突变最有可能对细胞功能造成有意义的成本。这项研究将影响多个与健康相关的领域，包括转基因微生物药物化合物的工业生产以及人类某些遗传疾病的病因和检测。