Experimental determination of codon usage‐dependent selective pressure on high copy‐number genes in Saccharomyces cerevisiae

• Published in: Yeast (Chichester, England) Vol. 36; no. 1; pp. 43 - 51
• Main Authors: Jossé, Lyne, Singh, Tarun, Haar, Tobias
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.01.2019
• Subjects: codon usage; Copy number; evolution; Evolutionary genetics; Gene expression; Growth rate; Interferon; Molecular modelling; plasmid copy number; Protein biosynthesis; recombinant gene expression; Reproductive fitness; Saccharomyces cerevisiae; selective pressure; Yeast; selective pressure; recombinant gene expression; evolution; codon usage; yeast; plasmid copy number
• ISSN: 0749-503X; 1097-0061
• DOI: 10.1002/yea.3373

One of the central hypotheses in the theory of codon usage evolution is that in highly expressed genes, particular codon usage patterns arise because they facilitate efficient gene expression and are thus selected for in evolution. Here, we use plasmid copy number assays and growth rate measurements to explore details of the relationship between codon usage, gene expression level, and selective pressure in Saccharomyces cerevisiae. We find that when high expression levels are required, optimal codon usage is beneficial and provides a fitness advantage, consistent with evolutionary theory. However, when high expression levels are not required, optimal codon usage is surprisingly and strongly selected against. We show that this selection acts at the level of protein synthesis, and we exclude a number of molecular mechanisms as the source for this negative selective pressure including nutrient and ribosome limitations and proteotoxicity effects. These findings deepen our understanding of the evolution of codon usage bias, as well as the design of recombinant protein expression systems.