ArticlePLoS genetics2018
Synonymous mutations make dramatic contributions to fitness when growth is limited by a weak-link enzyme.
Article in PLoS genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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55 citing papers in PubMed, 128 citations in OpenAlex.
- Synonymous codon-optimized multiplex qPCR for simultaneous detection ofJournal of clinical microbiology · 2026Article
- Prime editor-based high-throughput screening reveals functional synonymous mutations in human cells.Nature biotechnology · 2026Article
- Preliminary study of genetic variation in the CYP26B1 gene coding region in Bali cattle bulls.Open veterinary journal · 2026Article
- Rare KDM4C variants and reduced expression underlie epigenetic dysregulation in rheumatoid arthritis.Immunologic research · 2026Article
- Functional synonymous mutations and their evolutionary consequences.Nature reviews. Genetics · 2025Review
- Reannotation of cancer mutations based on expressed RNA transcripts reveals functional non-coding mutations in melanoma.American journal of human genetics · 2025Article
- High-throughput method characterizes hundreds of previously unknown antibiotic resistance mutations.Nature communications · 2025Article
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- Further Evidence for Strong Nonneutrality of Yeast Synonymous Mutations.Molecular biology and evolution · 2024Article
- SynonymousNAR genomics and bioinformatics · 2024Article
- A new era of mutation rate analyses: Concepts and methods.Zoological research · 2024Review
- Cetuximab chemotherapy resistance: Insight into the homeostatic evolution of head and neck cancer (Review).Oncology reports · 2024Review
- CRISPR-Cas9-assisted genome editing inbioRxiv : the preprint server for biology · 2024Article
- Fitness difference between two synonymous mutations of Phytophthora infestans ATP6 gene.BMC ecology and evolution · 2024Article
- Fitness benefits of a synonymous substitution in an ancient EF-Tu gene depend on the genetic background.Journal of bacteriology · 2024Article
- Genetic determinants of SARS-CoV-2 and the clinical outcome of COVID-19 in Southern Bangladesh.Immunity, inflammation and disease · 2024Article
- Synonymous edits in theProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Molecular bases for strong phenotypic effects of single synonymous codon substitutions in the E. coli ccdB toxin gene.BMC genomics · 2023Article
- Polymorphism in ovineAnimal biotechnology · 2023Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Synonymous mutations do not alter the specified amino acid but may alter the structure or function of an mRNA in ways that impact fitness. There are few examples in the literature, however, in which the effects of synonymous mutations on microbial growth rates have been measured, and even fewer for which the underlying mechanism is understood. We evolved four populations of a strain of Salmonella enterica in which a promiscuous enzyme has been recruited to replace an essential enzyme. A previously identified point mutation increases the enzyme's ability to catalyze the newly needed reaction (required for arginine biosynthesis) but decreases its ability to catalyze its native reaction (required for proline biosynthesis). The poor performance of this enzyme limits growth rate on glucose. After 260 generations, we identified two synonymous mutations in the first six codons of the gene encoding the weak-link enzyme that increase growth rate by 41 and 67%. We introduced all possible synonymous mutations into the first six codons and found substantial effects on growth rate; one doubles growth rate, and another completely abolishes growth. Computational analyses suggest that these mutations affect either the stability of a stem-loop structure that sequesters the start codon or the accessibility of the region between the Shine-Dalgarno sequence and the start codon. Thus, these mutations would be predicted to affect translational efficiency and thereby indirectly affect mRNA stability because translating ribosomes protect mRNA from degradation. Experimental data support these hypotheses. We conclude that the effects of the synonymous mutations are due to a combination of effects on mRNA stability and translation efficiency that alter levels of the weak-link enzyme. These findings suggest that synonymous mutations can have profound effects on fitness under strong selection and that their importance in evolution may be under-appreciated.
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