title: Nonlinear fitness landscape of a molecular pathway.
abstract: Genes are regulated because their expression involves a fitness cost to the organism. The production of proteins by transcription and translation is a well-known cost factor, but the enzymatic activity of the proteins produced can also reduce fitness, depending on the internal state and the environment of the cell. Here, we map the fitness costs of a key metabolic network, the lactose utilization pathway in Escherichia coli. We measure the growth of several regulatory lac operon mutants in different environments inducing expression of the lac genes. We find a strikingly nonlinear fitness landscape, which depends on the production rate and on the activity rate of the lac proteins. A simple fitness model of the lac pathway, based on elementary biophysical processes, predicts the growth rate of all observed strains. The nonlinearity of fitness is explained by a feedback loop: production and activity of the lac proteins reduce growth, but growth also affects the density of these molecules. This nonlinearity has important consequences for molecular function and evolution. It generates a cliff in the fitness landscape, beyond which populations cannot maintain growth. In viable populations, there is an expression barrier of the lac genes, which cannot be exceeded in any stationary growth process. Furthermore, the nonlinearity determines how the fitness of operon mutants depends on the inducer environment. We argue that fitness nonlinearities, expression barriers, and gene-environment interactions are generic features of fitness landscapes for metabolic pathways, and we discuss their implications for the evolution of regulation.
authors.affiliation: Institut für Genetik, Universität zu Köln, Cologne, Germany.
authors.forename: Lilia
authors.initials: L
authors.lastname: Perfeito
authors.forename: Stéphane
authors.initials: S
authors.lastname: Ghozzi
authors.forename: Johannes
authors.initials: J
authors.lastname: Berg
authors.forename: Karin
authors.initials: K
authors.lastname: Schnetz
authors.forename: Michael
authors.initials: M
authors.lastname: Lässig
mesh_terms: D005075:Biological Evolution; D004777:Environment; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D056084:Genetic Fitness; D005838:Genotype; D007763:Lac Operon / Q000502:physiology; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D010641:Phenotype
chemical_list: D029968:Escherichia coli Proteins