nonlinear fitness landscape of a molecular pathway非线性健身景观的分子途径.pdfVIP

Nonlinear Fitness Landscape of a Molecular Pathway 1,2 ´ 2 2 1 ¨ 2 Lilia Perfeito *, Stephane Ghozzi , Johannes Berg , Karin Schnetz , Michael Lassig * ¨ ¨ ¨ ¨ ¨ ¨ 1 Institut fur Genetik, Universitat zu Koln, Cologne, Germany, 2 Institut fur Theoretische Physik, Universitat zu Koln, Cologne, Germany 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