Prediction of Synergism from Chemical-Genetic Interactions by Machine Learning Journal Articles uri icon

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abstract

  • The structure of genetic interaction networks predicts that, analogous to synthetic lethal interactions between non-essential genes, combinations of compounds with latent activities may exhibit potent synergism. To test this hypothesis, we generated a chemical-genetic matrix of 195 diverse yeast deletion strains treated with 4,915 compounds. This approach uncovered 1,221 genotype-specific inhibitors, which we termed cryptagens. Synergism between 8,128 structurally disparate cryptagen pairs was assessed experimentally and used to benchmark predictive algorithms. A model based on the chemical-genetic matrix and the genetic interaction network failed to accurately predict synergism. However, a combined random forest and Naive Bayesian learner that associated chemical structural features with genotype-specific growth inhibition had strong predictive power. This approach identified previously unknown compound combinations that exhibited species-selective toxicity toward human fungal pathogens. This work demonstrates that machine learning methods trained on unbiased chemical-genetic interaction data may be widely applicable for the discovery of synergistic combinations in different species.

authors

  • Wildenhain, Jan
  • Spitzer, Michaela
  • Dolma, Sonam
  • Jarvik, Nick
  • White, Rachel
  • Roy, Marcia
  • Griffiths, Emma
  • Bellows, David S
  • Wright, Gerard
  • Tyers, Mike

publication date

  • December 2015