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Identifying Amino Acid Overproducers Using Rare-Codon-Rich Markers
Published on: June 24, 2019
Limitations of the 'ambush hypothesis' at the single-gene scale: what codon biases are to blame?
Robert L Bertrand1, Mona Abdel-Hameed, John L Sorensen
1Department of Chemistry, University of Manitoba, Winnipeg, R3T 2N2, Canada, bertrarl@cc.umanitoba.ca.
Abstract:
Ribosomal frameshifting, a translational error, catastrophically alters the amino acid composition of the nascent protein by shifting the reading frame from the intended contiguous trinucleotide reading. Frameshift events waste energy and resources, and peptide products have unpredictable cytotoxic effects. The 'Ambush Hypothesis' (Seligmann and Pollock 2004, DNA Cell Biol 23:701-5) suggests there is a selective pressure favouring the evolution of out-of-frame ('hidden') stop codons. Although this hypothesis has gained empirical support through whole-genome studies, it is presently unknown whether it can be applied at a single-gene scale. Herein, we report such an investigation using the gene, polyketide synthase (PKS), among species of fungi. Contrary to expectation, genes presented with significantly lower number of hidden stop codons than expected in a selection-neutral model (p < 0.0005), suggesting both non-adherence to the ambush hypothesis as well as suppression of hidden stop codon evolution. It is known that there are multiple adaptive considerations determining codon selection during evolution, and that the information-holding potential of the genetic code is finite. We hypothesize that the reason for low hidden stops in PKS genes is due to competing 'codon biases' that are prioritized over the selective pressure favouring the emergence of hidden stops. Future studies of the ambush hypothesis in the context of other drivers of codon bias may allow this hypothesis to be molded into a comprehensive genetic theory that can be integrated within the broader genetic theory of codon bias and applied to the genetic code at any scale of analysis.
Insights
Ribosomal frameshifting causes errors in protein synthesis. Our study on fungal PKS genes found fewer hidden stop codons than expected, challenging the Ambush Hypothesis.
Area of Science:
- Molecular Biology
- Evolutionary Genetics
- Bioinformatics
Background:
- Ribosomal frameshifting is a translational error that alters protein sequences, leading to wasted cellular resources and potentially cytotoxic peptides.
- The Ambush Hypothesis proposes selective pressure favors hidden stop codons to mitigate frameshifting costs.
- Previous genomic studies supported the Ambush Hypothesis, but its applicability at the single-gene level remained unexplored.
Purpose of the Study:
- To investigate the prevalence of hidden stop codons in fungal polyketide synthase (PKS) genes.
- To determine if the Ambush Hypothesis applies to individual genes.
- To explore potential reasons for deviations from the Ambush Hypothesis in PKS genes.
Main Methods:
- Analysis of PKS genes across various fungal species.
- Statistical comparison of observed hidden stop codon frequencies against a neutral evolution model.
- Bioinformatic assessment of codon usage biases within PKS genes.
Main Results:
- Fungal PKS genes exhibited significantly fewer hidden stop codons than predicted by a neutral model (p < 0.0005).
- This finding contradicts the predictions of the Ambush Hypothesis at the single-gene scale.
- Evidence suggests suppression of hidden stop codon evolution in PKS genes.
Conclusions:
- The Ambush Hypothesis may not universally apply to all genes, particularly at the single-gene level.
- Competing codon biases in PKS genes likely override the selective pressure for hidden stop codons.
- Further research integrating the Ambush Hypothesis with codon bias drivers is needed for a comprehensive genetic theory.
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