GSGS: a computational approach to reconstruct signaling pathway structures from gene sets.

Reconstruction of signaling pathway structures is essential to decipher complex regulatory relationships in living cells. Existing approaches often rely on unrealistic biological assumptions and do not explicitly consider signal transduction mechanisms. Signal transduction events refer to linear cascades of reactions from cell surface to nucleus and characterize a signaling pathway. We propose a novel approach, Gene Set Gibbs Sampling, to reverse engineer signaling pathway structures from gene sets related to pathways. We hypothesize that signaling pathways are structurally an ensemble of overlapping linear signal transduction events which we encode as Information Flows (IFs). We infer signaling pathway structures from gene sets, referred to as Information Flow Gene Sets (IFGSs), corresponding to these events. Thus, an IFGS only reflects which genes appear in the underlying IF but not their ordering. GSGS offers a Gibbs sampling procedure to reconstruct the underlying signaling pathway structure by sequentially inferring IFs from the overlapping IFGSs related to the pathway. In the proof-of-concept studies, our approach is shown to outperform existing network inference approaches using data generated from benchmark networks in DREAM. We perform a sensitivity analysis to assess the robustness of our approach. Finally, we implement GSGS to reconstruct signaling mechanisms in breast cancer cells.