Reproduced from Nature Genet. 38, 896–903 © (2006) Macmillan Publishers.
A thorough investigation of the molecular interactions that take place in, arguably, the most interesting of animal cells — our own — is currently beyond our practical means. But while technologies catch up, simpler eukaryotes can tell us a great deal about the nature of genetic networks in animals. The first systematic study of such interactions to be carried out on a large scale in any animal has now been reported for Caenorhabditis elegans. The most striking general finding to emerge from this RNAi screen — which tested 
65,000 pairwise interactions — is that a handful of genes interact with an unexpectedly large number of signalling pathways, and so might be common modifiers of different developmental processes.
The new screen, reported by Ben Lehner and colleagues, was designed to detect interactions between a member of an RNAi library and genes that were individually mutated in 'query' strains. In practice, one of a library of RNAi reagents was delivered to both mutant and wild-type worms, and the treated animals were then scored for a synthetic phenotype. The assay, therefore, involved asking: is the phenotype caused by combining a library RNAi reagent and any mutant allele more severe than the product of the phenotype seen in the mutant and in the library-treated wild-type worm alone? If the answer is yes, then an interaction between the two genes is deemed to be likely.
The authors were particularly interested in assessing the interaction between components of signalling pathways, as there is much evidence that, when mutated, these molecules cause disease in mammals. The RNAi library consisted of about 1,750 genes that, based on sequence homology, are involved in signal transduction; likewise, each of the 37 query strains carried a mutation in a known signalling molecule. Of the 65,000 pairwise interactions that were tested 350 interactions, involving 162 genes, were identified.
The resulting interaction map is notable for two reasons. First, it highlights an unexpected level of sharing between pathways: six genes interacted with all the pathways tested, and so might modify more than one signalling network. Second, all of these six so-called 'hub' genes are chromatin-modifying proteins. These genes are conserved across animals and there is evidence to suggest that they can enhance the strength or penetrance of loss-of-function phenotypes of genes with diverse biological functions in other animals in addition to C. elegans.
If genetic hub genes also exist in humans (and they most probably will) then they might function as modifier genes in seemingly unrelated genetic diseases. Hub genes, therefore, make excellent candidate genes for disease association studies.
The genetic interaction map also has a direct application in identifying genes that were unknown to interact with a pathway. The functional characterization of these interactors should open up opportunities for developing testable hypotheses about the biological basis of cellular signalling and disease.