Genome-Wide and Experimental Resolution of Relative Translation Elongation Speed at Individual Gene Level in Human Cells

In the process of translation, ribosomes first assemble on mRNAs (translation initiation) and then translate along the mRNA (elongation) to synthesize proteins. Elongation pausing is deemed highly relevant to co-translational folding of nascent peptides and the functionality of protein products, which positioned the evaluation of elongation speed as one of the central questions in the field of translational control. By integrating three types of RNA-seq methods, we experimentally and computationally resolved elongation speed, with our proposed elongation velocity index (EVI), a relative measure at individual gene level and under physiological condition in human cells. We successfully distinguished slow-translating genes from the background translatome. We demonstrated that low-EVI genes encoded more stable proteins. We further identified cell-specific slow-translating codons, which might serve as a causal factor of elongation deceleration. As an example for the biological relevance, we showed that the relatively slow-translating genes tended to be associated with the maintenance of malignant phenotypes per pathway analyses. In conclusion, EVI opens a new view to understand why human cells tend to avoid simultaneously speeding up translation initiation and decelerating elongation, and the possible cancer relevance of translating low-EVI genes to gain better protein quality.

在蛋白质翻译过程中，核糖体首先在信使RNA（mRNA）上完成组装，即翻译起始（translation initiation），随后沿mRNA链进行翻译延伸（elongation）以合成蛋白质。翻译延伸暂停被认为与新生肽链的共翻译折叠及蛋白质产物的功能紧密相关，这使得对延伸速度的评估成为翻译调控领域的核心议题之一。本研究整合三类RNA测序（RNA-seq）方法，通过实验与计算手段解析了翻译延伸速度，并提出了延伸速度指数（EVI）——该指标是在人类细胞生理条件下、针对单个基因水平的相对量化参数。本研究成功从背景翻译组（translatome）中甄别出翻译速度较慢的基因；实验证实，低EVI基因所编码的蛋白质稳定性更强。本研究进一步鉴定出细胞特异性的慢速翻译密码子（codons），其可能是翻译延伸减速的潜在诱因。作为生物学相关性的例证，经通路富集分析，本研究发现相对慢速翻译的基因往往与恶性表型的维持密切相关。综上，延伸速度指数（EVI）为理解人类细胞为何倾向于避免同时加快翻译起始与减缓翻译延伸，以及翻译低EVI基因以获得更佳蛋白质质量与癌症发生的潜在关联提供了全新视角。