ArticleProceedings of the National Academy of Sciences of the United States of America2013
Differential requirements for mRNA folding partially explain why highly expressed proteins evolve slowly.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.
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79 citing papers in PubMed.
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- Codon Usage Bias: A Potential Factor Affecting VGLUT Developmental Expression and Protein Evolution.Molecular neurobiology · 2025Article
- Correlations of gene expression, codon usage bias, and evolutionary rates of the mitochondrial genome show tissue differentiation in Ophioglossum vulgatum.BMC plant biology · 2025Article
- Synthetic rational design of live-attenuated Zika viruses based on a computational model.Nucleic acids research · 2025Article
- Further Evidence for Strong Nonneutrality of Yeast Synonymous Mutations.Molecular biology and evolution · 2024Article
- Patterns of Change in Nucleotide Diversity Over Gene Length.Genome biology and evolution · 2024Article
- Population Genomics of the Facultatively Sexual Liverwort Marchantia polymorpha.Genome biology and evolution · 2023Article
- Genome-wide probing of eukaryotic nascent RNA structure elucidates cotranscriptional folding and its antimutagenic effect.Nature communications · 2023Article
- Growth-dependent Gene Expression Variation Influences the Strength of Codon Usage Biases.Molecular biology and evolution · 2023Article
- Article
- Growth-dependent gene expression variation influences the strength of codon usage biases.bioRxiv : the preprint server for biology · 2023Article
- Chloroplast gene expression level is negatively correlated with evolutionary rates and selective pressure while positively with codon usage bias in Ophioglossum vulgatum L.BMC plant biology · 2022Article
19 more citing papers are in PubMed but not listed here.
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4 authors.
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Abstract
The cause of the tremendous among-protein variation in the rate of sequence evolution is a central subject of molecular evolution. Expression level has been identified as a leading determinant of this variation among genes encoded in the same genome, but the underlying mechanisms are not fully understood. We here propose and demonstrate that a requirement for stronger folding of more abundant mRNAs results in slower evolution of more highly expressed genes and proteins. Specifically, we show that: (i) the higher the expression level of a gene, the greater the selective pressure for its mRNA to fold; (ii) random mutations are more likely to decrease mRNA folding when occurring in highly expressed genes than in lowly expressed genes; and (iii) amino acid substitution rate is negatively correlated with mRNA folding strength, with or without the control of expression level. Furthermore, synonymous (d(S)) and nonsynonymous (d(N)) nucleotide substitution rates are both negatively correlated with mRNA folding strength. However, counterintuitively, d(S) and d(N) are differentially constrained by selection for mRNA folding, resulting in a significant correlation between mRNA folding strength and d(N)/d(S), even when gene expression level is controlled. The direction and magnitude of this correlation is determined primarily by the G+C frequency at third codon positions. Together, these findings explain why highly expressed genes evolve slowly, demonstrate a major role of natural selection at the mRNA level in constraining protein evolution, and reveal a previously unrecognized and unexpected form of nonprotein-level selection that impacts d(N)/d(S).
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