Network-assisted target identification for haploinsufficiency and homozygous profiling screens

PLoS Comput Biol. 2017 Jun 2;13(6):e1005553. doi: 10.1371/journal.pcbi.1005553. eCollection 2017 Jun.

Abstract

Chemical genomic screens have recently emerged as a systematic approach to drug discovery on a genome-wide scale. Drug target identification and elucidation of the mechanism of action (MoA) of hits from these noisy high-throughput screens remain difficult. Here, we present GIT (Genetic Interaction Network-Assisted Target Identification), a network analysis method for drug target identification in haploinsufficiency profiling (HIP) and homozygous profiling (HOP) screens. With the drug-induced phenotypic fitness defect of the deletion of a gene, GIT also incorporates the fitness defects of the gene's neighbors in the genetic interaction network. On three genome-scale yeast chemical genomic screens, GIT substantially outperforms previous scoring methods on target identification on HIP and HOP assays, respectively. Finally, we showed that by combining HIP and HOP assays, GIT further boosts target identification and reveals potential drug's mechanism of action.

MeSH terms

  • Antifungal Agents / pharmacology
  • Biological Assay
  • Drug Discovery
  • Gene Expression Profiling / methods*
  • Gene Expression Regulation, Fungal / drug effects
  • Gene Targeting
  • Genome, Fungal / genetics
  • Haploinsufficiency / genetics
  • Homozygote
  • Network Meta-Analysis*
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*

Substances

  • Antifungal Agents