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Preferred synonymous codons are translated more accurately: Proteomic evidence, among-species variation, and mechanistic basis.

ABSTRACT: A commonly stated cause of unequal uses of synonymous codons is their differential translational accuracies. A key prediction of this long-standing translational accuracy hypothesis (TAH) of codon usage bias is higher translational accuracies of more frequently used synonymous codons, which, however, has had no direct evidence beyond case studies. Analyzing proteomic data from Escherichia coli, we present direct, global evidence for this prediction. The experimentally measured codon-specific translational accuracies validate a sequence-based proxy; this proxy provides support for the TAH from the vast majority of over 1000 taxa surveyed in all domains of life. We find that the relative translational accuracies of synonymous codons vary substantially among taxa and are strongly correlated with the amounts of cognate transfer RNAs (tRNAs) relative to those of near-cognate tRNAs. These and other observations suggest a model in which selections for translational efficiency and accuracy drive codon usage bias and its coevolution with the tRNA pool.

SUBMITTER: Sun M

PROVIDER: S-EPMC9258949 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Preferred synonymous codons are translated more accurately: Proteomic evidence, among-species variation, and mechanistic basis.

Sun Mengyi M Zhang Jianzhi J

Science advances 20220706 27

A commonly stated cause of unequal uses of synonymous codons is their differential translational accuracies. A key prediction of this long-standing translational accuracy hypothesis (TAH) of codon usage bias is higher translational accuracies of more frequently used synonymous codons, which, however, has had no direct evidence beyond case studies. Analyzing proteomic data from <i>Escherichia coli</i>, we present direct, global evidence for this prediction. The experimentally measured codon-speci ...[more]

PMID: 35857447

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Project description:Synonymous rare codons are considered to be sub-optimal for gene expression because they are translated more slowly than common codons. Yet surprisingly, many protein coding sequences include large clusters of synonymous rare codons. Rare codons at the 5' terminus of coding sequences have been shown to increase translational efficiency. Although a general functional role for synonymous rare codons farther within coding sequences has not yet been established, several recent reports have identified rare-to-common synonymous codon substitutions that impair folding of the encoded protein. Here we test the hypothesis that although the usage frequencies of synonymous codons change from organism to organism, codon rarity will be conserved at specific positions in a set of homologous coding sequences, for example to tune translation rate without altering a protein sequence. Such conservation of rarity-rather than specific codon identity-could coordinate co-translational folding of the encoded protein. We demonstrate that many rare codon cluster positions are indeed conserved within homologous coding sequences across diverse eukaryotic, bacterial, and archaeal species, suggesting they result from positive selection and have a functional role. Most conserved rare codon clusters occur within rather than between conserved protein domains, challenging the view that their primary function is to facilitate co-translational folding after synthesis of an autonomous structural unit. Instead, many conserved rare codon clusters separate smaller protein structural motifs within structural domains. These smaller motifs typically fold faster than an entire domain, on a time scale more consistent with translation rate modulation by synonymous codon usage. While proteins with conserved rare codon clusters are structurally and functionally diverse, they are enriched in functions associated with organism growth and development, suggesting an important role for synonymous codon usage in organism physiology. The identification of conserved rare codon clusters advances our understanding of distinct, functional roles for otherwise synonymous codons and enables experimental testing of the impact of synonymous codon usage on the production of functional proteins.

Dataset Information

Preferred synonymous codons are translated more accurately: Proteomic evidence, among-species variation, and mechanistic basis.

Publications

Preferred synonymous codons are translated more accurately: Proteomic evidence, among-species variation, and mechanistic basis.

Similar Datasets

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