Sharma Ajeet K, Ahmed Nabeel, O'Brien Edward P
Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Bioinformatics and Genomics Graduate Program, The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Phys Rev E. 2018 Feb;97(2-1):022409. doi: 10.1103/PhysRevE.97.022409.
Ribosome profiling experiments have found greater than 100-fold variation in ribosome density along mRNA transcripts, indicating that individual codon elongation rates can vary to a similar degree. This wide range of elongation times, coupled with differences in codon usage between transcripts, suggests that the average codon translation-rate per gene can vary widely. Yet, ribosome run-off experiments have found that the average codon translation rate for different groups of transcripts in mouse stem cells is constant at 5.6 AA/s. How these seemingly contradictory results can be reconciled is the focus of this study. Here, we combine knowledge of the molecular factors shown to influence translation speed with genomic information from Escherichia coli, Saccharomyces cerevisiae and Homo sapiens to simulate the synthesis of cytosolic proteins in these organisms. The model recapitulates a near constant average translation rate, which we demonstrate arises because the molecular determinants of translation speed are distributed nearly randomly amongst most of the transcripts. Consequently, codon translation rates are also randomly distributed and fast-translating segments of a transcript are likely to be offset by equally probable slow-translating segments, resulting in similar average elongation rates for most transcripts. We also show that the codon usage bias does not significantly affect the near random distribution of codon translation rates because only about 10% of the total transcripts in an organism have high codon usage bias while the rest have little to no bias. Analysis of Ribo-Seq data and an in vivo fluorescent assay supports these conclusions.
核糖体谱分析实验发现，沿mRNA转录本的核糖体密度变化超过100倍，这表明单个密码子的延伸速率也能在相似程度上发生变化。这种广泛的延伸时间范围，再加上不同转录本之间密码子使用的差异，表明每个基因的平均密码子翻译速率可能有很大差异。然而，核糖体释放实验发现，小鼠干细胞中不同转录本组的平均密码子翻译速率恒定为5.6个氨基酸/秒。如何调和这些看似矛盾的结果是本研究的重点。在这里，我们将已证明会影响翻译速度的分子因素的知识与来自大肠杆菌、酿酒酵母和智人的基因组信息相结合，以模拟这些生物体中胞质蛋白的合成。该模型再现了近乎恒定的平均翻译速率，我们证明这是由于翻译速度的分子决定因素几乎随机分布在大多数转录本中。因此，密码子翻译速率也是随机分布的，转录本的快速翻译片段可能会被同样可能的慢速翻译片段抵消，导致大多数转录本的平均延伸速率相似。我们还表明，密码子使用偏好不会显著影响密码子翻译速率的近乎随机分布，因为生物体中只有约10%的转录本具有高密码子使用偏好，而其余的偏好很小或没有偏好。对核糖体测序数据的分析和一项体内荧光测定支持了这些结论。
