Lilli Freischem (she/her)

The identification of essential genes is a key challenge in systems and synthetic biology, particularly for engineering metabolic pathways that convert feedstocks into valuable products. Assessment of gene essentiality at a genome scale requires large and costly growth assays of knockout strains. Here we describe a strategy to predict the essentiality of metabolic genes using binary classification algorithms. The approach combines elements from genome-scale metabolic models, directed graphs, and machine learning into a predictive model that can be trained on small knockout data. We demonstrate the efficacy of this approach using the most complete metabolic model of Escherichia coli and various machine learning algorithms for binary classification.

The identification of essential genes, i.e. those that impair cell survival when deleted, requires large growth assays of knock-out strains. The complexity and cost of such experiments has triggered a growing interest in computational methods for prediction of gene essentiality. In the case of metabolic genes, Flux Balance Analysis (FBA) is widely employed to predict essentiality under the assumption that cells maximize their growth rate. However, this approach assumes that knock-out strains optimize the same objectives as the wild-type, which excludes cases in which deletions cause large physiological changes to meet other objectives for survival. Here, we resolve this limitation with a novel machine learning approach that predicts essentiality directly from wild-type flux distributions. We first project the wild-type FBA solution onto a mass flow graph, a digraph with reactions as nodes and edge weights proportional to the mass transfer between reactions, and then train binary classifiers on the connectivity of graph nodes. We demonstrate the efficacy of this approach using the most complete metabolic model of Escherichia coli, achieving near state-of-the art prediction accuracy for essential genes. Our approach suggests that wild-type FBA solutions contain enough information to predict essentiality, without the need to assume optimality of deletion strains.