Abstract
BackgroundNatural selection has traditionally been understood as a force responsible for pushing genes to states of higher translational efficiency, whereas lower translational efficiency has been explained by neutral mutation and genetic drift. We looked for evidence of directional selection resulting in increased unpreferred codon usage (and presumably reduced translational efficiency) in three divergent clusters of eukaryotic genomes using a simple optimal-codon-based metric (Kp/Ku).ResultsHere we show that for some genes natural selection is indeed responsible for causing accelerated unpreferred codon substitution, and document the scope of this selection. In Cryptococcus and to a lesser extent Drosophila, we find many genes showing a statistically significant signal of selection for unpreferred codon usage in one or more lineages. We did not find evidence for this type of selection in Saccharomyces. The signal of positive selection observed from unpreferred synonymous codon substitutions is coincident in Cryptococcus and Drosophila with the distribution of upstream open reading frames (uORFs), another genic feature known to reduce translational efficiency. Functional enrichment analysis of genes exhibiting low Kp/Ku ratios reveals that genes in regulatory roles are particularly subject to this type of selection.ConclusionThrough genome-wide scans, we find recent selection for unpreferred codon usage at approximately 1% of genetic loci in a Cryptococcus and several genes in Drosophila. Unpreferred codons can impede translation efficiency, and we find that genes with translation-impeding uORFs are enriched for this selection signal. We find that regulatory genes are particularly likely to be subject to selection for unpreferred codon usage. Given that expression noise can propagate through regulatory cascades, and that low translational efficiency can reduce expression noise, this finding supports the hypothesis that translational efficiency may be suppressed in some cases to reduce stochastic noise in gene expression.
Highlights
Natural selection has traditionally been understood as a force responsible for pushing genes to states of higher translational efficiency, whereas lower translational efficiency has been explained by neutral mutation and genetic drift
An unpreferred codon that changes into a preferred synonymous codon would be classified as a preferred synonymous substitution, and the opposite directionality of change would be classified as an unpreferred synonymous substitution
Upstream Open Reading Frame analysis We find an association between genes with low Kp and Ku (Kp/Ku) ratios and upstream open reading frames. uORFs are short open reading frames located in the transcribed 5' leader sequence of genes [23]. uORFs are capable of repressing protein translation by inhibiting ribosome reinitiation at the downstream protein-coding start site, decreasing mRNA transcript stability, or encoding a cisacting peptide capable of stalling the ribosome [24]
Summary
Natural selection has traditionally been understood as a force responsible for pushing genes to states of higher translational efficiency, whereas lower translational efficiency has been explained by neutral mutation and genetic drift. TRNAs can significantly decrease translation rate [7,8] has likewise motivated many reports claiming evidence for the downward modulation of expression level through the use of inefficiently translated codons [9,10,11,12,13]. Though this analogous argument for down-regulation of expression through codon usage, known as the 'expression-regulation theory,' has a symmetric appeal, it has been strongly and repeatedly challenged [9,14,15]. Many early studies in favor of the expression-regulation theory failed to document a significant enrichment of translationally inefficient codons in genes thought to be subject to translational repression [14], leading to the 'selection-mutation-drift theory' that weak codon bias results from an absence of selection for translational efficiency, rather than from selection in the opposite direction
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