Understanding synergy in genetic interactions.

Synergy occurs when the contribution of two mutations to the phenotype of a double mutant exceeds the expectations from the additive effects of the individual mutations. The molecular characterization of genes involved in synergistic interactions has revealed that synergy mainly results from mutations in functionally related genes. Recent research in Arabidopsis thaliana has advanced our understanding of the scenarios resulting in synergistic phenotypes. Those involving homologous loci usually result from various levels of functional redundancy. Some of these loci fail to complement each other or become dose-dependent in certain multiple mutant combinations, suggesting that the effects of haploinsufficiency and redundancy can combine. Synergy involving non-homologous genes probably reflects the topology of the regulatory or metabolic networks and can arise when pathways that converge at a node are disrupted. The Hub genes provide a remarkable example, these genes have an extraordinary number of connections and mutations that interact with many unrelated pathways.