Integration of graph neural networks and genome-scale metabolic models for predicting gene essentiality

Genome-scale metabolic models are powerful tools for understanding cellular physiology. Flux balance analysis (FBA), in particular, is a popular optimization approach for predicting metabolic phenotypes under genetic and environmental perturbations. In model microbes such as Escherichia coli , FBA has been successful at predicting essential genes, i.e. those genes that impair survival when deleted. A central assumption in this approach, however, is that both wild type and deletion strains optimize the same fitness objective. While the optimality assumption may hold for the wild type metabolic network, deletion strains are not subject to the same evolutionary pressures and knock-out mutants may steer their metabolism to meet other objectives for survival. Here, we present FlowGAT, a hybrid FBA-machine learning strategy for predicting essentiality directly from wild type metabolic phenotypes. The approach is based on graph-structured representation of metabolic fluxes predicted by FBA, where nodes correspond to enzymatic reactions and edges quantify the propagation of metabolite mass flow between a reaction and its neighbours. We integrate this information into a graph neural network that can be trained on knock-out fitness assay data. Comparisons across different model architectures reveal that FlowGAT predictions for E. coli are close to those of FBA for several growth conditions. This suggests that gene essentiality can be accurately predicted by exploiting the network structure of metabolism, without additional assumptions beyond optimality of the wild type. Our approach demonstrates the benefits of combining the mechanistic insights afforded by genome-scale models with the ability of deep learning models to extract patterns from complex data.