Epistasis between promoter activity and coding mutations shapes gene evolvability

The evolution of protein-coding genes proceeds as mutations act on two main dimensions: regulation of transcription level and the coding sequence. The extent and impact of the connection between these two dimensions are largely unknown because they have generally been studied independently. By measuring the fitness effects of all possible mutations on a protein complex at various levels of promoter activity, we show that expression at the optimal level for the WT protein masks the effects of both deleterious and beneficial coding mutations. Mutants that are deleterious at low expression but masked at optimal expression are slightly destabilizing for individual subunits and binding interfaces. Coding mutations that increase protein abundance are beneficial at low expression but incur a fitness cost at high expression. We thereby demonstrate that expression level can dictate which coding mutations are beneficial or deleterious.