In Silico Prediction of Synthetic Lethality by Meta-Analysis of Genetic Interactions, Functions, and Pathways in Yeast and Human Cancer

Abstract

A major goal in cancer medicine is to find selective drugs with reduced side effect. A pair of genes is called synthetic lethality (SL) if mutations of both genes will kill a cell while mutation of either gene alone will not. Hence, a gene in SL interactions with a cancer-specific mutated gene will be a promising drug target with anti-cancer selectivity. Wet-lab screening approach is still so costly that even for yeast only a small fraction of gene pairs has been covered. Computational methods are therefore important for large-scale discovery of SL interactions. Most existing approaches focus on individual features or machine-learning methods, which are prone to noise or overfitting. In this paper, we propose an approach named MetaSL for predicting yeast SL, which integrates 17 genomic and proteomic features and the outputs of 10 classification methods. MetaSL thus combines the strengths of existing methods and achieves the highest area under the Receiver Operating Characteristics (ROC) curve (AUC) of 87.1% among all competitors on yeast data. Moreover, through orthologous mapping from yeast to human genes, we then predicted several lists of candidate SL pairs in human cancer. Our method and predictions would thus shed light on mechanisms of SL and lead to discovery of novel anti-cancer drugs. In addition, all the experimental results can be downloaded from http://www.ntu.edu.sg/home/zhengjie/data/MetaSL .