Synthetic lethal analysis of Caenorhabditis elegans posterior embryonic patterning genes identifies conserved genetic interactions

Forward and reverse genetic screens in flies and worms indicate that most genes are not essential to the development or viability of the organism [1-4]. Two primary explanations for such phenotypic robustness to mutation have been offered: homologous gene products may directly compensate for one another's function, or indirect compensation of function may occur through regulatory networks via non-homologous genes acting in alternative pathways or feedback mechanisms [5,6]. In both Saccharomyces cerevisiae and C. elegans, genes with at least one homolog are less likely than unique genes to have a loss-of-function phenotype [7,8]. However, homology accounts for no more than two thirds of the observed phenotypic robustness to mutation in S. cerevisiae and even less in C. elegans, indicating a significant role of the regulatory network in genetic buffering [7,8]. By identifying gene disruptions that are viable in wild type but lethal in a specific mutant background, synthetic lethal screens can shed light on how regulatory networks buffer gene function [9]. Although genetic interactions are being mapped on a genome-wide scale in yeast [9], no such efforts have been reported for an animal system. We report here the use of existing mutants and RNA interference (RNAi) to assemble a synthetic lethal matrix in C. elegans. Our aim was to build on prior knowledge by focusing on a characterized set of genes likely to have interactions among them.The C blastomere is one of five somatic founder blastomeres in the C. elegans embryo. Each founder blastomere produces a characteristic set of cell types via an invariant lineage; the C blastomere predominantly gives rise to muscle and epidermal cells [10]. Maternal and zygotic activities of the homeodomain protein PAL-1 specify the identity and maintain the development of the C-blastomere lineage [11,12]. We have identified genes whose expression depends either directly or indirectly on PAL-1 function ('PAL-1 targets') and shown that t