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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.

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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).
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f3: 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).

Mentions: An important question is whether different variations on the sequence motif in the vicinity of the translation start site are associated with, and perhaps even determining, difference in translation-initiation efficiency. It was previously shown that the 5′ untranslated sequence of yeast mRNAs is rich in A-residues, and that highly expressed genes commonly use the Serine UCU codon as second triplet in the open-reading frame (Hamilton et al, 1987). More recently, using data on genome-wide ribosome density (Ingolia et al, 2009), Robbins-Pianka et al (2010) reported on reduced predicted secondary structure in 5′ UTRs, especially in high ribosome-density genes in yeast. Genome-wide measurements of occupancy and density of ribosomes on mRNA enable us to systematically examine how sequence in the vicinity of the initiation site may affect initiation efficiency. Figure 3 shows a sequence motif logo of the sequence flanking the AUG start codon for two sets of S. cerevisiae genes—low ribosome-occupancy genes and high ribosome-occupancy genes, based on Arava's analysis of ribosome occupancy (Arava et al, 2003). Clearly, high ribosome-occupancy genes show a motif with moderate information content, whereas the low ribosome-occupancy motif shows little or no consensus. Specifically, the analysis shows the preferred usage of the A nucleotide along the 15 positions upstream to the start codon, and in particularly at positions −4 to −1, in high ribosome-occupancy genes. This analysis suggests a hierarchy between genes in the fit of their 5′ UTR sequences to a canonical-initiation motif, which may determine the relative initiation efficiency of each gene in the genome. In addition, for high-occupancy genes, the sequence logo shows a pointed elevated usage of nucleotides C and U, in the 5th and 6th positions in the open-reading frame. Interestingly, the second codon position shows elevated tAI values on average (Tuller et al, 2010a) suggesting a selection for high-translation efficiency for efficient release and recycling of the initiator methionine tRNA. Indeed, this signal is more pronounced in genes with high ribosome occupancy compared with genes with low occupancy (H Gingold and Y Pilpel, unpublished data, 2011).


Determinants of translation efficiency and accuracy.

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

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

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

f3: 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).
Mentions: An important question is whether different variations on the sequence motif in the vicinity of the translation start site are associated with, and perhaps even determining, difference in translation-initiation efficiency. It was previously shown that the 5′ untranslated sequence of yeast mRNAs is rich in A-residues, and that highly expressed genes commonly use the Serine UCU codon as second triplet in the open-reading frame (Hamilton et al, 1987). More recently, using data on genome-wide ribosome density (Ingolia et al, 2009), Robbins-Pianka et al (2010) reported on reduced predicted secondary structure in 5′ UTRs, especially in high ribosome-density genes in yeast. Genome-wide measurements of occupancy and density of ribosomes on mRNA enable us to systematically examine how sequence in the vicinity of the initiation site may affect initiation efficiency. Figure 3 shows a sequence motif logo of the sequence flanking the AUG start codon for two sets of S. cerevisiae genes—low ribosome-occupancy genes and high ribosome-occupancy genes, based on Arava's analysis of ribosome occupancy (Arava et al, 2003). Clearly, high ribosome-occupancy genes show a motif with moderate information content, whereas the low ribosome-occupancy motif shows little or no consensus. Specifically, the analysis shows the preferred usage of the A nucleotide along the 15 positions upstream to the start codon, and in particularly at positions −4 to −1, in high ribosome-occupancy genes. This analysis suggests a hierarchy between genes in the fit of their 5′ UTR sequences to a canonical-initiation motif, which may determine the relative initiation efficiency of each gene in the genome. In addition, for high-occupancy genes, the sequence logo shows a pointed elevated usage of nucleotides C and U, in the 5th and 6th positions in the open-reading frame. Interestingly, the second codon position shows elevated tAI values on average (Tuller et al, 2010a) suggesting a selection for high-translation efficiency for efficient release and recycling of the initiator methionine tRNA. Indeed, this signal is more pronounced in genes with high ribosome occupancy compared with genes with low occupancy (H Gingold and Y Pilpel, unpublished data, 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