Molecular Evolution in Large Genetic Networks: Connectivity Does not Equal Importance

Biological networks are extremely robust to many different perturbations. Both drastic environmental changes and loss-of-function mutations in a variety of genes often have no detectable effect on the phenotype of an organism, even if the lost gene is considered “a priori” to be important for cellular activity. This robustness may be a function of a network’s architecture: power-law distributions of the number of interactors observed in genetic networks have been hypothesized to confer robustness against mutations. We evaluate this hypothesis for two genetic networks, that of the “E. coli” core intermediary metabolism and that of the yeast protein interaction network. Specifically, we test the hypothesis through one of its key predictions: highly connected proteins should be more important to the cell, and thus be subject to severe selective and evolutionary constraints. We find that highly connected proteins can tolerate just as many amino acid substitutions as other proteins, and thus conclude that power laws in cellular networks do not reflect selection for mutational robustness.