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.
Highlights
Codon usage bias is abundant in every sequenced genome and several theories have been put forward to explain it, depending on the genome or the gene
As humans have a relatively small effective population size, and the efficiency of selection to purge mutations of mild deleterious effect decreases as population size decreases, it has been assumed that the benefit/ cost of codons is not large enough to have a measurable effect on codon choice
We show that codons with the lowest amount of tRNA are clustered in gene sequences more often than anticipated
Summary
Codon usage bias is abundant in every sequenced genome and several theories have been put forward to explain it, depending on the genome or the gene. In many organisms, including bacteria, yeast and Drosophila species, the strongest factor determining codon bias is selection for maximizing translation speed and accuracy [1,2,3,4,5,6]. Those genes that are the most highly expressed exhibit a bias towards codons that have the most abundant cognate tRNAs. Those genes that are the most highly expressed exhibit a bias towards codons that have the most abundant cognate tRNAs It is not the case, that a maximal rate of translation always results in optimal protein production. In bacteria and yeast there are several well-studied mechanisms by which local variations in translation rate are an essential regulator of protein production [9,10,11]
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