Target discovery in the postgenomic era

Genetic screens can reveal new pathway modifier genes that would be difficult to uncover using other experimental approaches. The conservation of biochemical pathways and ability to quickly screen large numbers of candidate target genes strongly supports the use of model system genetics. We have carried out large-scale genetic screens in Drosophila melanogaster, Caenorhabditis elegans, and cells to identify modifier genes of cancer-related pathways and phenotypes. Genetic screens can identify the function of novel genes, and establish functional links between genes that may have been previously identified, but whose role in a process was not understood. Invertebrate genetic screens are carried out in animals or cells with mutations in cancer genes that produce a measureable phenotype. In Drosophila we typically perform tissue-specific screens, in the eye or the wing, so that the cancer mutations do not affect viability or fertility of the organism. These sensitized genetic backgrounds are then screened to identify genes that modify the visible phenotype. Modifier genes can be identified through reverse genetic approaches, including transposon insertions and RNA interference. The availability of fully sequenced genomes and the use of reverse genetic tools such as RNA interference enables genetic screens to be focused on classes of proteins which are amenable to drug discovery, thus enhancing the efficiency of target identification. Genetic screens will help build a better understanding of signal transduction pathways and gene function on a large scale.