Inferring efficiency of translation initiation and elongation from ribosome profiling

Abstract

Ribosome profiles are often interpreted with underlying naive models that are unable to grasp the complexity of the biological process. We develop a Non-Equilibrium Analysis of Ribo-seq (NEAR), and provide unprecedented estimates of translation initiation and elongation efficiencies, emphasising the importance of rating these two stages of translation separately. When examining ribosome profiling in yeast, we observe that translation initiation and elongation are close to their optima, and traffic is minimised at the beginning of the transcript to favour ribosome recruitment. However, we find many sites of congestion along the mRNAs where the probability of ribosome interference can reach 50%. Our analysis excludes unreliable datapoints and discusses biases of the experimental technique; as a result, we conclude that current analyses and definitions of translation efficiency are not adapt to quantitatively asses ribosome interference. *

Inferring translational heterogeneity from ribosome profiling data

“…A main limiting factor in current Ribo-seq studies may simply be too shallow sequencing depth. While it has been suggested that inference from individual experiments may be limited (87), our work of deriving and analyzing a consensus signal demonstrates that a comparative meta-analysis of several datasets can yield important additional insights. Many details of programmed translational heterogeneity result from the complex interplay of many different contributions and await to be characterized at much higher resolution.…”

The fitness landscapes of translation

“…The key feature of the translation process that enables sign epistasis is the fact that, somewhat counter-intuitively, the introduction of slow codons can decrease the ribosome travel time by reducing the amount of ribosome queuing [36,37,38]. To the extent that ribosome queuing is a generic feature of translation [15,16], sign-epistatic interactions in the ribosome speed are therefore likely to arise. The model of discrete, well-separated bottlenecks predicts a specific fitness landscape structure where the hypercube of genotypes decomposes into lower-dimensional subcubes of constant fitness (Fig.…”

“…In line with the experimental observations [7], we assume that the effect of the synonymous mutations on organismal fitness is mediated by the efficiency of protein translation. The process of translation can be described by stochastic particle models of exclusion type, which have been used in the field for more than 50 years [10,11,12,13,14,15]. These models treat ribosomes as particles moving unidirectionally along a one-dimensional lattice of sites representing the codons.…”

“…These models treat ribosomes as particles moving unidirectionally along a one-dimensional lattice of sites representing the codons. The exclusion interaction ensuring that two particles cannot occupy the same site accounts for ribosome queuing [15,16].…”

What determines eukaryotic translation elongation: recent molecular and quantitative analyses of protein synthesis

“…The steady states of such models are typically not known analytically and they are obtained via approximations or Monte Carlo simulations. Such models have been extensively used in the interpretation and analysis of ribo-seq data, especially to infer initiation and elongation rates [7,11,56,[119][120][121][122][123] and to quantify ribosome queueing [68]. In addition, the study of these theoretical models has shed light on the main features of the codon sequence determining protein synthesis rate [10].…”