Environmental changes dictate selection and nonspecific epistasis in an empirical phenotype-environment-fitness landscape

The fitness landscape, a function that maps genotypic and phenotypic changes to their effects on fitness, is an invaluable concept in evolutionary biochemistry. Though widely discussed, measurements of phenotype-fitness landscapes in proteins remain scarce. Here, we quantify all single mutational effects on fitness and phenotype (antibiotic resistance level) of VIM-2 {beta}-lactamase (5600 variants) across a 64-fold range of ampicillin concentrations by deep mutational scanning. We then construct a phenotype-fitness landscape that takes variations in environmental selection pressure into account (a phenotype-environment-fitness landscape). We found that a simple, empirical landscape accurately models the ~39,000 mutational data points, which suggests the evolution of VIM-2 can be predicted based on the selection environment. Our landscape provides new quantitative knowledge on the evolution of the {beta}-lactamases and proteins in general, particularly their evolutionary dynamics under sub-inhibitory antibiotic concentrations, as well as the mechanisms and environmental dependence of nonspecific epistasis.