Active Interaction Mapping Reveals the Hierarchical Organization of Autophagy

We have developed a general progressive procedure, Active Interaction Mapping, to guide assembly of the hierarchy of functions encoding any biological system. Using this process, we assemble an ontology of functions comprising autophagy, a central recycling process implicated in numerous diseases. A first-generation model, built from existing gene networks in Saccharomyces, captures most known autophagy components in broad relation to vesicle transport, cell cycle, and stress response. Systematic analysis identifies synthetic-lethal interactions as most informative for further experiments; consequently, we saturate the model with 156,364 such measurements across autophagy-activating conditions. These targeted interactions provide more information about autophagy than all previous datasets, producing a second-generation ontology of 220 functions. Approximately half are previously unknown; we confirm roles for Gyp1 at the phagophore-assembly site, Atg24 in cargo engulfment, Atg26 in cytoplasm-to-vacuole targeting, and Ssd1, Did4, and others in selective and non-selective autophagy. The procedure and autophagy hierarchy are at http://atgo.ucsd.edu/. [Display omitted] •Diverse -omics data integrated to assemble a unified hierarchical model of autophagy•Post hoc analysis prioritizes the most informative future data types•Consequently, 156,364 genetic interactions measured in autophagy-activating conditions•Multiple new functions involve Gyp1, Atg24, Atg26, Ssd1, Did4, Stp22, and others Kramer et al. present a general procedure that guides molecular interaction mapping to assemble a hierarchical model of any biological system. Application to autophagy reveals the hierarchical organization of this process, including many new biological components and functions. This work provides an archetype for future studies in systems biology.