Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania, United States of America.
Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
PLoS Comput Biol. 2019 May 23;15(5):e1007070. doi: 10.1371/journal.pcbi.1007070. eCollection 2019 May.
Analysis methods based on simulations and optimization have been previously developed to estimate relative translation rates from next-generation sequencing data. Translation involves molecules and chemical reactions, hence bioinformatics methods consistent with the laws of chemistry and physics are more likely to produce accurate results. Here, we derive simple equations based on chemical kinetic principles to measure the translation-initiation rate, transcriptome-wide elongation rate, and individual codon translation rates from ribosome profiling experiments. Our methods reproduce the known rates from ribosome profiles generated from detailed simulations of translation. By applying our methods to data from S. cerevisiae and mouse embryonic stem cells, we find that the extracted rates reproduce expected correlations with various molecular properties, and we also find that mouse embryonic stem cells have a global translation speed of 5.2 AA/s, in agreement with previous reports that used other approaches. Our analysis further reveals that a codon can exhibit up to 26-fold variability in its translation rate depending upon its context within a transcript. This broad distribution means that the average translation rate of a codon is not representative of the rate at which most instances of that codon are translated, and it suggests that translational regulation might be used by cells to a greater degree than previously thought.
先前已经开发出基于模拟和优化的分析方法，以从下一代测序数据中估计相对翻译速率。翻译涉及分子和化学反应，因此与化学和物理定律一致的生物信息学方法更有可能产生准确的结果。在这里，我们根据化学动力学原理推导出简单的方程，以从核糖体分析实验中测量翻译起始速率、转录本全长延伸速率和单个密码子翻译速率。我们的方法再现了从翻译详细模拟生成的核糖体图谱中已知的速率。通过将我们的方法应用于来自酿酒酵母和小鼠胚胎干细胞的数据，我们发现提取的速率与各种分子特性的预期相关性重现，并且我们还发现小鼠胚胎干细胞的整体翻译速度为 5.2 AA/s，与之前使用其他方法的报告一致。我们的分析进一步表明，一个密码子的翻译速率在转录本内的上下文可以有多达 26 倍的变化。这种广泛的分布意味着密码子的平均翻译速率不能代表该密码子的大多数实例的翻译速率，并且这表明细胞可能以前所未有的程度使用翻译调节。
