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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

The sliding window profile of FOXF2: a lung and placenta specific transcription factor.Although there is large variation across the gene, the ACA score at the 5′ region is very unlikely to have occurred by chance (P<0.001).
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pgen-1000548-g002: The sliding window profile of FOXF2: a lung and placenta specific transcription factor.Although there is large variation across the gene, the ACA score at the 5′ region is very unlikely to have occurred by chance (P<0.001).

Mentions: To identify regions of genes that have the greatest potential to minimize the translation rate, we devised a measurement of corresponding tRNA abundance (the anti-codon abundance score). This score assumes that there is a direct correlation between tRNA abundance and the number of tRNA genes; an assumption that previous investigations have shown is justified [2],[28],[29]. This scoring method allows us to directly compare the different amino acids within the same gene. We employed a sliding window analysis across 13,793 human genes and calculated the average anti-codon abundance score (ACA score) for each window (see Methods and Figure 2). The region of the gene with the lowest score was deemed to have the greatest putative role in the reduction of translation rate. This classification differs from other methods that found the regions of the greatest codon bias when compared to the codon usage of the whole genome, a method that does not guarantee that the region identified limits the translation rate. Our method identifies the absolute rate-limiting position within the gene, the region most likely to cause translation related regulatory effects. To test if the window with the lowest ACA score was expected given the underlying nucleotide content of the gene, or whether it occurred due to factors other than chance alone, we implemented a randomization analysis. For each gene, the existing codons were shuffled 1,000 times, maintaining the underlying gene codon usage and nucleotide biases, and the sliding window analysis was repeated. We identified 1703 genes with an original ACA score that was lower than at least 95% of the randomizations for that gene and 148 genes with an ACA score that was lower than 99.9% of the randomizations (Figure 3).


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

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

The sliding window profile of FOXF2: a lung and placenta specific transcription factor.Although there is large variation across the gene, the ACA score at the 5′ region is very unlikely to have occurred by chance (P<0.001).
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1000548-g002: The sliding window profile of FOXF2: a lung and placenta specific transcription factor.Although there is large variation across the gene, the ACA score at the 5′ region is very unlikely to have occurred by chance (P<0.001).
Mentions: To identify regions of genes that have the greatest potential to minimize the translation rate, we devised a measurement of corresponding tRNA abundance (the anti-codon abundance score). This score assumes that there is a direct correlation between tRNA abundance and the number of tRNA genes; an assumption that previous investigations have shown is justified [2],[28],[29]. This scoring method allows us to directly compare the different amino acids within the same gene. We employed a sliding window analysis across 13,793 human genes and calculated the average anti-codon abundance score (ACA score) for each window (see Methods and Figure 2). The region of the gene with the lowest score was deemed to have the greatest putative role in the reduction of translation rate. This classification differs from other methods that found the regions of the greatest codon bias when compared to the codon usage of the whole genome, a method that does not guarantee that the region identified limits the translation rate. Our method identifies the absolute rate-limiting position within the gene, the region most likely to cause translation related regulatory effects. To test if the window with the lowest ACA score was expected given the underlying nucleotide content of the gene, or whether it occurred due to factors other than chance alone, we implemented a randomization analysis. For each gene, the existing codons were shuffled 1,000 times, maintaining the underlying gene codon usage and nucleotide biases, and the sliding window analysis was repeated. We identified 1703 genes with an original ACA score that was lower than at least 95% of the randomizations for that gene and 148 genes with an ACA score that was lower than 99.9% of the randomizations (Figure 3).

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