Understanding how essential genes function in networks presents a challenge — because knocking them out causes lethality, their function must instead be carefully manipulated to probe their interactions. Rising to this challenge, one group has now studied an extensive set of interactions for essential genes in Saccharomyces cerevisiae, indicating an unforeseen complexity of genetic networks.

Davierwala and colleagues made conditional expression alleles or conditional temperature-sensitive alleles for over half the essential genes in S. cerevisiae. Expression of both types of allele can be controlled so that levels of the gene products are decreased, but not abolished. These strains were crossed to a panel of 30 others, carrying similarly derived mutant alleles of either essential or non-essential genes. The fitness of the double mutants was scored relative to the parent strains, as quantified by colony growth, which revealed a network of 567 interactions among 286 essential genes. Only two of these interactions were already documented, highlighting the power of this approach to identify new relationships.

The most remarkable aspect of the network was the number of interactions it contained. On average, essential genes take part in about five times as many interactions as their non-essential counterparts — significantly more than previously estimated. This indicates that the overall network in budding yeast might be twice as dense as previously thought.

Notably, many of the conditional alleles of essential genes had little or no phenotype as single mutants, but combined with interacting alleles they produced more severe effects. If other gene networks are organized in a similar way, such interactions might underlie variation in many complex traits — including non-Mendelian disease in humans.