The biophysical basis of translational selection

描述（由申请人提供）：进化时间序列分化的全基因组模式为研究细胞生命的基本代谢成本提供了一个独特的窗口。净化选择消除了增加成本和/或促进遗传疾病的突变。这个过程可以辨别微小的成本差异，甚至是那些可能无法通过直接实验室实验测量的差异。这个项目将通过一种特定的代价，即错误翻译蛋白质的代价，来识别和解释烙印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理，选择在密码子和氨基酸水平上进行，以尽量减少细胞对错误折叠蛋白质的暴露。本项目的工作假设是，在与翻译相关的成本中，误译导致的错误折叠是占主导地位的成本，而其他成本，包括误译导致的功能丧失和翻译速度降低，只占次要地位。这一假设将采用生物信息学、数学建模和计算机模拟相结合的方法进行检验，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. 翻译最佳密码子为什么是最佳的？2. 对蛋白质错误折叠的选择是否决定了同义密码子的使用？3. 蛋白质生物物理学如何与翻译选择相互作用以约束序列进化？

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.