The biophysical basis of translational selection

项目摘要 随着进化时间的推移，全基因组范围的序列差异模式提供了一个独特的 了解强加于细胞生命的基本新陈代谢成本。净化所选内容 消除增加成本和/或促进遗传病的突变。这一过程可以 发现微小的成本差异，即使是那些可能不容易通过直接测量的差异 实验室实验。 这个项目将通过一个人识别和解释印记在基因组中的进化信号 比成本，错误翻译蛋白质的成本。误译事件导致蛋白质 错误折叠、错误折叠的蛋白质可能是细胞毒性的，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，最大限度地减少细胞对 错误折叠的蛋白质。该项目的工作假设是，在与以下各项相关的成本中 翻译，误译导致的错误折叠是主要的，而其他成本， 包括误译导致的功能丧失和翻译速度减慢，发挥作用 次要角色。这一假设将使用生物信息学、数学 建模和计算机模拟，以及各种翻译的相对重要性- 相关成本将被量化。 有三个具体目标。1.是什么让翻译上最优的密码子最优？2.是吗 针对蛋白质错误折叠的选择会影响同义密码子的使用吗？3.蛋白质是如何 生物物理学与翻译选择相互作用以限制序列进化？

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?