Edge-based sensitivity analysis of signaling networks by using Boolean dynamics.

Motivation: Biological networks are composed of molecular components and their interactions represented by nodes and edges, respectively, in a graph model. Based on this model, there were many studies with respect to effects of node-based mutations on the network dynamics, whereas little attention was paid to edgetic mutations so far. Results: In this paper, we defined an edgetic sensitivity measure that quantifies how likely a converging attractor is changed by edge-removal mutations in a Boolean network model. Through extensive simulations based on that measure, we found interesting properties of highly sensitive edges in both random and real signaling networks. First, the sensitive edges in random networks tend to link two end nodes both of which are susceptible to node-knockout mutations. Interestingly, it was analogous to an observation that the sensitive edges in human signaling networks are likely to connect drug-target genes. We further observed that the edgetic sensitivity predicted drug-targets better than the node-based sensitivity. In addition, the sensitive edges showed distinguished structural characteristics such as a lower connectivity, more involving feedback loops and a higher betweenness. Moreover, their gene-ontology enrichments were clearly different from the other edges. We also observed that genes incident to the highly sensitive interactions are more central by forming a considerably large connected component in human signaling networks. Finally, we validated our approach by showing that most sensitive interactions are promising edgetic drug-targets in p53 cancer and T-cell apoptosis networks. Taken together, the edgetic sensitivity is valuable to understand the complex dynamics of signaling networks.