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Characterising context-dependent gene functions is crucial for understanding the genetic bases of health and disease. To date, inference of gene functions from large-scale genetic perturbation screens is based on ad hoc analysis pipelines involving unsupervised clustering and functional enrichment. We present Knowledge- and Context-driven Machine Learning (KCML), a framework that systematically predicts multiple context-specific functions for a given gene based on the similarity of its perturbation phenotype to those with known function. As a proof of concept, we test KCML on three datasets describing phenotypes at the molecular, cellular and population levels and show that it outperforms traditional analysis pipelines. In particular, KCML identified an abnormal multicellular organisation phenotype associated with the depletion of olfactory receptors, and TGFβ and WNT signalling genes in colorectal cancer cells. We validate these predictions in colorectal cancer patients and show that olfactory receptors expression is predictive of worse patient outcomes. These results highlight KCML as a systematic framework for discovering novel scale-crossing and context-dependent gene functions. KCML is highly generalisable and applicable to various large-scale genetic perturbation screens.

Original publication




Journal article


Molecular systems biology

Publication Date





Department of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Oxford, UK.


Cell Line, Tumor, HCT116 Cells, Humans, Colorectal Neoplasms, Transforming Growth Factor beta, Receptors, Odorant, Prognosis, Systems Biology, Signal Transduction, Gene Expression Regulation, Neoplastic, Phenotype, Gene Regulatory Networks, Neoplasm Grading, Wnt Signaling Pathway, MCF-7 Cells, Support Vector Machine