Complex genetic interactions underlie much of biology and are at the root of many human diseases. However, most frequently, our analysis in model organisms of the genetic basis for phenotypic traits involves the perturbation of single genes, rather than the systematic examination of gene interactions. We are attempting to explore genetic interactions more systematically using screens for synthetic lethals. A synthetic lethal interaction between two genes, A and B, occurs if deleting either A or B yields a viable organism, whereas removing both A and B is lethal. In yeast, systematic screens for pairs of synthetic lethal genes have uncovered a large amount about the wiring of basic cellular biology. We are identifying synthetic lethals in C. elegans by comparing the sets of lethal genes generated by RNAi in wild-type and in mutant backgrounds. To screen sufficient numbers of genes, we have developed an efficient high-throughput method for inducing RNAi by feeding and also for the automated microscopic analysis of the resulting phenotypes. We induce RNAi by feeding dsRNA-expressing bacteria to worms growing in liquid culture this can be done in 96-well format and is as efficient as other ways of RNAi by feeding. To analyse phenotypes, we have set up an automated image analysis system which we will describe this generates precise quantitative measurements of sterile and lethal phenotypes. These RNAi feeding and analysis protocols allow us to analyse ~1200 genes targeted by RNAi per day. We present the results of screens for genes that are synthetic lethal with
efl-1/EF2 gene; this gene is part of the
lin-35/Retinoblastoma complex that is involved in regulation of the cell cycle regulation and of vulval development. We find multiple novel biological connections including
ncl-1 and a component of SWI/SNF and with SynMuv genes. We will present these data and discuss our results.