Abstract
Perturbations play an important role both in engineered systems and cellular processes. Thus, understanding their effect on protein synthesis should contribute to all biomedical disciplines. Here we describe the first genome-scale analysis of perturbations in translation-related factors in S. cerevisiae. To this end, we used simulations based on a computational model that takes into consideration the fundamental stochastic and bio-physical nature of translation. We found that the initiation rate has a key role in determining the sensitivity to perturbations. For low initiation rates, the first codons of the coding region dominate the sensitivity, which is highly correlated with the ratio between initiation rate and mean elongation rate (r = −0.95), with the open reading frame (ORF) length (r = 0.6) and with protein abundance (r = 0.45). For high initiation rates (that may rise, for example, due to cellular growth), the sensitivity of a gene is dominated by all internal codons and is correlated with the decoding rate. We found that various central intracellular functions are associated with the sensitivity: for example, both genes that are sensitive and genes that are robust to perturbations are over-represented in the group of genes related to translation regulation; this may suggest that robustness to perturbations is a trait that undergoes evolutionary selection in relation to the function of the encoded protein. We believe that the reported results, due to their quantitative value and genome-wide perspective, should contribute to disciplines such as synthetic biology, functional genomics, comparative genomics and molecular evolution.
Highlights
Codon decoding rates and initiation rates are key factors in understanding and modelling the effect of cellular perturbations on mRNA translation
The sensitivity profiles were characterized by three regimes of the relation between sensitivity and ξ, the ratio between initiation rate and mean elongation rate (Fig. 4)
Analysis was performed both for the baseline initiation rates (α = 1) and for the 10-fold increased ones (α = 10), revealing the full space of possible regimes in real genes
Summary
Codon decoding rates and initiation rates are key factors in understanding and modelling the effect of cellular perturbations on mRNA translation. Currently there are no practical experimental tools that can be used to perform an accurate, high resolution analysis of perturbations in translation-related factors for the entire S. cerevisiae genome: it is extremely difficult to design and perform a reliable experiment that properly isolates the discussed effect for each codon in each gene at a single-cell level. To bridge these gaps, our study aims at creating a genome-scale framework for quantifying the effect of perturbations. Our study is an important step towards understanding and accurate modelling of translation perturbations at a genomic level
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