The biophysical basis of translational selection

描述（由申请人提供）：全基因组序列差异模式随进化时间的推移提供了一个独特的窗口，对细胞生命的基本代谢成本。纯化选择消除了增加成本和/或促进遗传疾病的突变。这一过程可以识别微小的成本差异，即使是那些不容易通过直接实验室实验测量的差异。该项目将通过一个特定的成本，即错误翻译蛋白质的成本，来识别和解释印记在基因组中的进化信号。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除，并且选择在密码子和氨基酸水平上操作以最小化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，误译导致的错误折叠是主要的成本，而其他成本，包括误译导致的功能丧失和翻译速度降低，起着次要的作用。这一假设将使用生物信息学、数学建模和计算机模拟相结合的方法进行测试，各种翻译相关成本的相对重要性将被量化。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.针对蛋白质错误折叠的选择是否形成同义密码子使用？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？ 公共卫生相关性：所有生物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。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产生有意义的成本。这项研究将影响几个与健康相关的领域，包括转基因微生物中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。

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.