Causal signals between codon bias, mRNA structure, and the efficiency of translation and elongation.

Cristina Pop,Jonathan S Weissman,Silvi Rouskin,Daphne Koller,Lu Han,Eric M Phizicky,Nicholas T Ingolia

doi:10.15252/msb.20145524

Abstract

Ribosome profiling data report on the distribution of translating ribosomes, at steady-state, with codon-level resolution. We present a robust method to extract codon translation rates and protein synthesis rates from these data, and identify causal features associated with elongation and translation efficiency in physiological conditions in yeast. We show that neither elongation rate nor translational efficiency is improved by experimental manipulation of the abundance or body sequence of the rare AGG tRNA. Deletion of three of the four copies of the heavily used ACA tRNA shows a modest efficiency decrease that could be explained by other rate-reducing signals at gene start. This suggests that correlation between codon bias and efficiency arises as selection for codons to utilize translation machinery efficiently in highly translated genes. We also show a correlation between efficiency and RNA structure calculated both computationally and from recent structure probing data, as well as the Kozak initiation motif, which may comprise a mechanism to regulate initiation.

Highlights

The translation of RNA into protein is the nexus of decoding genetic information into functional polypeptides and a central biosynthetic process consuming a substantial fraction of the cell’s resources
To extract high-quality estimates of protein synthesis rates and codon translation rates from the ribosome footprint data, we model the process of ribosome flow, using gene- and codon-dependent parameters, and the physical sampling that occurs in the experimental protocol from which these data are derived
Our work is consistent with an alternative model, aligned with previous results for Escherichia coli (Kudla et al, 2009), in which codon bias in highly translated genes results from selection to optimize utilization of the translational machinery, whose abundance and production represents a major limitation on cell growth (Andersson & Kurland, 1990; Bulmer, 1991; Kudla et al, 2009); this selection induces a correlation without implying that increasing codon bias optimizes efficiency on individual genes (Welch et al, 2009)

Summary

Introduction

The translation of RNA into protein is the nexus of decoding genetic information into functional polypeptides and a central biosynthetic process consuming a substantial fraction of the cell’s resources. A number of studies with different analysis approaches present varying hypotheses for the mechanisms underlying variation in elongation and translation efficiency in yeast and other organisms (Tuller et al, 2010a,b, 2011; Ingolia et al, 2011; Stadler & Fire, 2011; Qian et al, 2012; Charneski & Hurst, 2013; Shah et al, 2013; Woolstenhulme et al, 2013; Gardin et al, 2014; Lareau et al, 2014) These include codon effects mediated by tRNA abundance or wobble base pairing, as well as effects of mRNA structure and the nascent peptide on the ribosome

Methods

Results

Conclusion