GEARS: Predicting transcriptional outcomes of novel multi-gene perturbations

Cellular response to genetic perturbation is central to numerous biomedical applications from identifying genetic interactions involved in cancer to methods for regenerative medicine. However, the combinatorial explosion in the number of possible multi-gene perturbations severely limits experimental interrogation. Here, we present GEARS, a method that can predict transcriptional response to both single and multi-gene perturbations using single-cell RNA-sequencing data from perturbational screens. GEARS is uniquely able to predict outcomes of perturbing combinations consisting of novel genes that were never experimentally perturbed by leveraging geometric deep learning and a knowledge graph of gene-gene relationships. GEARS has higher precision than existing approaches in predicting five distinct genetic interaction subtypes and can identify the strongest interactions more than twice as well as prior approaches. Overall, GEARS can discover novel phenotypic outcomes to multi-gene perturbations and can thus guide the design of perturbational experiments.