Determinants of translation efficiency and accuracy

Abstract

Proper functioning of biological cells requires that the process of protein expression be carried out with high efficiency and fidelity. Given an amino-acid sequence of a protein, multiple degrees of freedom still remain that may allow evolution to tune efficiency and fidelity for each gene under various conditions and cell types. Particularly, the redundancy of the genetic code allows the choice between alternative codons for the same amino acid, which, although 'synonymous,' may exert dramatic effects on the process of translation. Here we review modern developments in genomics and systems biology that have revolutionized our understanding of the multiple means by which translation is regulated. We suggest new means to model the process of translation in a richer framework that will incorporate information about gene sequences, the tRNA pool of the organism and the thermodynamic stability of the mRNA transcripts. A practical demonstration of a better understanding of the process would be a more accurate prediction of the proteome, given the transcriptome at a diversity of biological conditions.

Figure 1

mRNA levels have an evolutionary effect on translation efficiency, which in turn affects protein levels on a physiological timescale. The positive correlation between mRNAs level to measures of translation efficiency, such as CAI or tAI, might reflect an evolutionary pressure to optimize the codon usage of highly expressed mRNAs so as not to sequester too many ribosomes—the faster the elongation rate is, the shorter the time in which a ribosome is bound to any particular mRNA. The extent of evolutionary pressure to optimize a gene should thus positively correlate with its mRNA level. On the other hand, the positive correlation between translation efficiency measures and protein abundance probably acts on a much faster timescale, of mechanistic physiological processes, and it is also governed by evolutionary forces. The codon usage of proteins that are needed at high expression levels is adjusted to achieve high-translation efficiency at a given mRNA level. The significant correlation between the tAI and protein-to-mRNA ratio suggests the causal effect on protein levels.

Figure 2

Advanced challenges in assessing translation efficiency. New evidences challenge the common simplified assumptions in assessing translation efficiency. Shown in all sub-figures are two codon types, which may differ in their translation elongation efficiency, a ‘blue' and a ‘orange', served respectively by a ‘blue' and a ‘orange' types of tRNA. Some of the amino acids on the polypeptides are also colored blue or orange, reflecting the different efficiency of the codons that code for them. The following lines of further research into the mechanisms of translation are suggested: (A) The order of high- and low-efficiency codons (the later are colored in orange) is meaningful and can be utilized by evolution to design an optimal schedule for ribosomal flow on transcripts. In particular, the slow ‘ramp' observed in the 5′ end, especially of highly expressed genes, may avoid jamming of ribosomes once they passed it. (B) A local concentration of a tRNA molecule that was just released from the ribosome is high in the vicinity of the subsequent codons. Thus, although some tRNAs might be at low concentration over the entire cell volume, they might be present at relatively higher level in proximity of the codons they just finished translating. According to this possibility, the efficiency of translation of a codon depends also on whether that codon was used a few codons upstream on the same mRNA molecule. An indication for the mechanism might be that similar codons tend to cluster together on mRNA sequences. (C) Regulation of expression of the tRNAs could lead to dynamic changes in their availability in time or space dimensions, e.g., under various conditions, differential developmental stages, or at different tissues. (D) The efficiency of translation is a function of the ratio between the supply and the demand for each tRNA. The demand for different tRNAs, namely—the actual representation of the 61 codons at the transcriptome, might vary between different cell types, different environmental conditions and different time points along organism's life. Here, during the transition from condition I to II, the transcriptome changes from mainly consisting of genes that are rich in the blue codon to genes that more heavily biased towards the orange one; as a result the demand for the corresponding orange tRNA increases in the second condition.

Figure 3

Sequence motifs in the vicinity of the initiation site and ribosome occupancy. The figure displays sequence motif logos of the sequence spanning between positions −15 and +18 relative to the initiating AUG for two yeast genes sets—high ribosome-occupancy genes and low ribosome-occupancy genes (Arava et al, 2003). The sequence logos show an interesting signature of enrichment in Adenine nucleotides upstream to the initiating AUG codon in genes with high ribosome occupancy (A), accompanied with particular nucleotide preference at positions +5 and +6 (B). The 5′ UTR sequence of low ribosome-occupancy genes is also enriched with Adenine nucleotides (C), yet to a much lower extent. Genes with low ribosome occupancy show no nucleotide preference downstream to the initiating AUG codons (D). For this display, high ribosome-occupancy and low ribosome-occupancy genes (204 and 206 genes, respectively) were defined as genes at the top and at the bottom of the ribosome-occupancy distribution (occupancy>0.85, or occupancy<0.6 correspondingly). The 5′ UTR sequences of the investigated genes were derived from the study by Nagalakshmi et al (2008); the coding regions were downloaded from SGD web site. Sequence logos were created using WebLogo (Crooks et al, 2004).

Figure 4

The predominant effect of selection on synonymous site on gene expression. Synonymous codons correspond to the same amino acid and yet might differ from each other by their adaptation to the cellular tRNA pool and also by their contribution to the secondary structure and the stability of the transcript. The effect of each attribute on translation properties and the further consequences on gene expression is marked with pale blue (for codon–anticodon adaptation) or yellow (for mRNA folding).