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Determinants of translation efficiency and accuracy.

Gingold H, Pilpel Y - Mol. Syst. Biol. (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.

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.

Show MeSH
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.
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f1: 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.

Mentions: But should we expect tAI and CAI values of genes to correlate with the corresponding mRNA or protein abundances? To begin with, mRNA and protein abundances are often correlated between themselves (de Sousa Abreu et al, 2009; Vogel et al, 2010) so that any measure that correlates with one of them might show above-random levels of correlation with the other. Ideally, a measure of translation efficiency should correlate with the ratio of protein to mRNA level, and indeed the tAI has been shown to correlate with measures of this sort. In S. cerevisiae, the simple correlation between tAI and protein-to-mRNA ratio is very weak compared with the correspondence between tAI and mRNA levels, and yet it is still statistically significant (Pearson's correlation=0.123, P-value=1.47 × 10−9). The correlation between protein abundance and tAI, given the genes' mRNA levels, however, is higher (Pearson's partial correlation=0.38, P-value=8.54 × 10−81; Tuller et al, 2010b). Similarly, significant positive correlations were detected between tAI and protein levels for sets of yeast proteins having the same mRNA levels (Man and Pilpel, 2007). Furthermore, in S. cerevisiae, the contribution of codon choice to the variations in the mRNA–protein correlation remains of prime importance even where RNA decay and protein half-life are taken in consideration (Wu et al, 2008). Interestingly though, measures such as CAI and tAI have been shown (especially in unicellulars) to correlate with both mRNA and protein levels, yet probably due to completely different reasons (Figure 1). More intuitive is the correlation with protein levels—high CAI or tAI values for genes should increase translation efficiency and thus increase protein levels at a given mRNA level. Less intuitive is the correlation between mRNA levels and CAI or tAI. Non-optimal codon usage of genes can be detrimental to the cell as it will increase the sequestration of ribosomes during translation, while usage of preferred codons might optimize the allocation of ribosomes to certain genes (Andersson and Kurland, 1990; Kudla et al, 2009). The interesting point is that the weight of such effects depends on mRNA levels, so that wasteful sequestration of ribosomes on a low copy mRNA will have a minor effect on the cellular ribosomal pool. Thus, the evolutionary pressure to optimize the codons of genes should increase with their mRNA levels, thereby presumably creating the correlation between mRNA levels and measures such as CAI and tAI.


Determinants of translation efficiency and accuracy.

Gingold H, Pilpel Y - Mol. Syst. Biol. (2011)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3101949&req=5

f1: 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.
Mentions: But should we expect tAI and CAI values of genes to correlate with the corresponding mRNA or protein abundances? To begin with, mRNA and protein abundances are often correlated between themselves (de Sousa Abreu et al, 2009; Vogel et al, 2010) so that any measure that correlates with one of them might show above-random levels of correlation with the other. Ideally, a measure of translation efficiency should correlate with the ratio of protein to mRNA level, and indeed the tAI has been shown to correlate with measures of this sort. In S. cerevisiae, the simple correlation between tAI and protein-to-mRNA ratio is very weak compared with the correspondence between tAI and mRNA levels, and yet it is still statistically significant (Pearson's correlation=0.123, P-value=1.47 × 10−9). The correlation between protein abundance and tAI, given the genes' mRNA levels, however, is higher (Pearson's partial correlation=0.38, P-value=8.54 × 10−81; Tuller et al, 2010b). Similarly, significant positive correlations were detected between tAI and protein levels for sets of yeast proteins having the same mRNA levels (Man and Pilpel, 2007). Furthermore, in S. cerevisiae, the contribution of codon choice to the variations in the mRNA–protein correlation remains of prime importance even where RNA decay and protein half-life are taken in consideration (Wu et al, 2008). Interestingly though, measures such as CAI and tAI have been shown (especially in unicellulars) to correlate with both mRNA and protein levels, yet probably due to completely different reasons (Figure 1). More intuitive is the correlation with protein levels—high CAI or tAI values for genes should increase translation efficiency and thus increase protein levels at a given mRNA level. Less intuitive is the correlation between mRNA levels and CAI or tAI. Non-optimal codon usage of genes can be detrimental to the cell as it will increase the sequestration of ribosomes during translation, while usage of preferred codons might optimize the allocation of ribosomes to certain genes (Andersson and Kurland, 1990; Kudla et al, 2009). The interesting point is that the weight of such effects depends on mRNA levels, so that wasteful sequestration of ribosomes on a low copy mRNA will have a minor effect on the cellular ribosomal pool. Thus, the evolutionary pressure to optimize the codons of genes should increase with their mRNA levels, thereby presumably creating the correlation between mRNA levels and measures such as CAI and tAI.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.

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.

Show MeSH