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Clustering of codons with rare cognate tRNAs in human genes suggests an extra level of expression regulation.

Parmley JL, Huynen MA - PLoS Genet. (2009)

Bottom Line: In species with large effective population sizes, highly expressed genes tend to be encoded by codons with highly abundant cognate tRNAs to maximize translation rate.We observed a significant reduction in the substitution rate between the human RTS clusters and their orthologous chimp sequence, when compared to non-RTS cluster sequences.As genes that regulate transcription in lower eukaryotes are known to be involved in translation on demand, this suggests that the mechanism of translation level expression regulation also exists within the human genome.

View Article: PubMed Central - PubMed

Affiliation: Centre for Molecular and Biomolecular Informatics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. J.Parmley@cmbi.ru.nl

ABSTRACT
In species with large effective population sizes, highly expressed genes tend to be encoded by codons with highly abundant cognate tRNAs to maximize translation rate. However, there has been little evidence for a similar bias of synonymous codons in highly expressed human genes. Here, we ask instead whether there is evidence for the selection for codons associated with low abundance tRNAs. Rather than averaging the codon usage of complete genes, we scan the genes for windows with deviating codon usage. We show that there is a significant over representation of human genes that contain clusters of codons with low abundance cognate tRNAs. We name these regions, which on average have a 50% reduction in the amount of cognate tRNA available compared to the remainder of the gene, RTS (rare tRNA score) clusters. We observed a significant reduction in the substitution rate between the human RTS clusters and their orthologous chimp sequence, when compared to non-RTS cluster sequences. Overall, the genes with an RTS cluster have higher tissue specificity than the non-RTS cluster genes. Furthermore, these genes are functionally enriched for transcription regulation. As genes that regulate transcription in lower eukaryotes are known to be involved in translation on demand, this suggests that the mechanism of translation level expression regulation also exists within the human genome.

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Related in: MedlinePlus

Correlation between tRNA gene copy number and genome codon usage.There is an overall trend for codons with high genome usage to have more cognate tRNA gene copies. However, the codons with the fewest cognate tRNA genes are not the most rare within the genome.
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pgen-1000548-g001: Correlation between tRNA gene copy number and genome codon usage.There is an overall trend for codons with high genome usage to have more cognate tRNA gene copies. However, the codons with the fewest cognate tRNA genes are not the most rare within the genome.

Mentions: Regions of genes that may regulate the folding of mature proteins, by means of rare codon clusters, have been identified in two studies [26],[27]. Widmann et al. assessed the usage of rare codons in genes from two families of α/β proteins and found that synonymous mutations in these clusters induce protein mis-folding [27]. The protein families investigated were those most likely to undergo co-translational protein folding, and thus, these results do not represent the incidence of any genome-wide phenomena. Clarke and Clark proposed a large-scale method for identifying gene segments of highly biased codons (when compared to their potential maximum bias) [26]. Both these studies (mentioned above) attributed the clustering of rare codons to constraints on protein folding. However, these two investigations may suffer from the assumptions that they have made. Firstly, both groups assume that the codons used most infrequently in the genome are those that will be the least translationally optimal. There is no evidence for this. If we take the number of cognate tRNA gene copies as a proxy for the rate of translation of the codon, then codons with the fewest tRNAs, and thus the lowest rate of translation, do not have the lowest genome frequency (Figure 1). Secondly, both groups identify codon bias within the genes relative to the whole genome codon usage, and ignore the variations in local GC content across the human genome. This approach may fall foul of isochore effects in mammalian genomes.


Clustering of codons with rare cognate tRNAs in human genes suggests an extra level of expression regulation.

Parmley JL, Huynen MA - PLoS Genet. (2009)

Correlation between tRNA gene copy number and genome codon usage.There is an overall trend for codons with high genome usage to have more cognate tRNA gene copies. However, the codons with the fewest cognate tRNA genes are not the most rare within the genome.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2697378&req=5

pgen-1000548-g001: Correlation between tRNA gene copy number and genome codon usage.There is an overall trend for codons with high genome usage to have more cognate tRNA gene copies. However, the codons with the fewest cognate tRNA genes are not the most rare within the genome.
Mentions: Regions of genes that may regulate the folding of mature proteins, by means of rare codon clusters, have been identified in two studies [26],[27]. Widmann et al. assessed the usage of rare codons in genes from two families of α/β proteins and found that synonymous mutations in these clusters induce protein mis-folding [27]. The protein families investigated were those most likely to undergo co-translational protein folding, and thus, these results do not represent the incidence of any genome-wide phenomena. Clarke and Clark proposed a large-scale method for identifying gene segments of highly biased codons (when compared to their potential maximum bias) [26]. Both these studies (mentioned above) attributed the clustering of rare codons to constraints on protein folding. However, these two investigations may suffer from the assumptions that they have made. Firstly, both groups assume that the codons used most infrequently in the genome are those that will be the least translationally optimal. There is no evidence for this. If we take the number of cognate tRNA gene copies as a proxy for the rate of translation of the codon, then codons with the fewest tRNAs, and thus the lowest rate of translation, do not have the lowest genome frequency (Figure 1). Secondly, both groups identify codon bias within the genes relative to the whole genome codon usage, and ignore the variations in local GC content across the human genome. This approach may fall foul of isochore effects in mammalian genomes.

Bottom Line: In species with large effective population sizes, highly expressed genes tend to be encoded by codons with highly abundant cognate tRNAs to maximize translation rate.We observed a significant reduction in the substitution rate between the human RTS clusters and their orthologous chimp sequence, when compared to non-RTS cluster sequences.As genes that regulate transcription in lower eukaryotes are known to be involved in translation on demand, this suggests that the mechanism of translation level expression regulation also exists within the human genome.

View Article: PubMed Central - PubMed

Affiliation: Centre for Molecular and Biomolecular Informatics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. J.Parmley@cmbi.ru.nl

ABSTRACT
In species with large effective population sizes, highly expressed genes tend to be encoded by codons with highly abundant cognate tRNAs to maximize translation rate. However, there has been little evidence for a similar bias of synonymous codons in highly expressed human genes. Here, we ask instead whether there is evidence for the selection for codons associated with low abundance tRNAs. Rather than averaging the codon usage of complete genes, we scan the genes for windows with deviating codon usage. We show that there is a significant over representation of human genes that contain clusters of codons with low abundance cognate tRNAs. We name these regions, which on average have a 50% reduction in the amount of cognate tRNA available compared to the remainder of the gene, RTS (rare tRNA score) clusters. We observed a significant reduction in the substitution rate between the human RTS clusters and their orthologous chimp sequence, when compared to non-RTS cluster sequences. Overall, the genes with an RTS cluster have higher tissue specificity than the non-RTS cluster genes. Furthermore, these genes are functionally enriched for transcription regulation. As genes that regulate transcription in lower eukaryotes are known to be involved in translation on demand, this suggests that the mechanism of translation level expression regulation also exists within the human genome.

Show MeSH
Related in: MedlinePlus