Codon Optimality Is a Major Determinant of mRNA Stability

mRNA degradation represents a critical regulated step in gene expression. Although the major pathways in turnover have been identified, accounting for disparate half-lives has been elusive. We show that codon optimality is one feature that contributes greatly to mRNA stability. Genome-wide RNA decay analysis revealed that stable mRNAs are enriched in codons designated optimal, whereas unstable mRNAs contain predominately non-optimal codons. Substitution of optimal codons with synonymous, non-optimal codons results in dramatic mRNA destabilization, whereas the converse substitution significantly increases stability. Further, we demonstrate that codon optimality impacts ribosome translocation, connecting the processes of translation elongation and decay through codon optimality. Finally, we show that optimal codon content accounts for the similar stabilities observed in mRNAs encoding proteins with coordinated physiological function. This work demonstrates that codon optimization exists as a mechanism to finely tune levels of mRNAs and, ultimately, proteins. [Display omitted] •Codon identity correlates with yeast mRNA half-lives transcriptome wide•Converting non-optimal codons to optimal codons increases mRNA stability•Codon optimality impacts translational elongation rate•Proteins with related function are coordinated at the level of optimal codon content Codon usage impacts gene expression both at the level of translation and mRNA decay, with the balance between optimal and non-optimal codons helping to fine-tune levels of mRNAs and, ultimately, proteins.