bioRxiv : the preprint server for biologySep 24, 2026

Codon pairs influence mRNA stability through their role in protein production beyond individual codon effects

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Updated Sep 25, 2026

Abstract

Codon pairs and amino acid pairs regulate mRNA stability beyond individual codons.

Codon context and amino acid interactions influence mRNA decay in a translation-dependent manner.
The identity and order of neighboring codons impact the stability of the mRNA sequence.
Machine learning can quantify the contributions of specific codon and amino acid combinations to mRNA stability.
Endogenous mRNAs are also regulated by codon pairs, affecting gene regulation and biological functions.
The decay process relies on deadenylation and decapping actions mediated by specific proteins.

Simplified

The coding sequence of an mRNA directs its own decay, yet how codons, codon context, and amino acids collectively regulate mRNA stability remains poorly understood. Here we use a massively parallel reporter assay to decode this regulatory layer in zebrafish embryos. We find that codon pairs and amino acid pairs regulate mRNA stability beyond the level of individual codons. This regulation depends on the identity and order of neighboring codons and their encoded amino acids in a translation-dependent manner. The relative contributions of codon and amino acid combinations to mRNA stability can be quantified using machine learning. We further found that endogenous mRNAs are regulated by codon pairs, thereby governing developmental gene regulation and biological function. This codon context-dependent decay requires deadenylation and decapping by Cnot7 and Dcp2, with Upf1 acting on long non-optimal ORFs. Together, our results redefine codon optimality as a context-dependent, pair-level code with implications for RNA biology and therapeutic mRNA design.

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Codon pairs influence mRNA stability through their role in protein production beyond individual codon effects

Abstract

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