Epistasis — the essential role of gene interactions in the structure and evolution of genetic systems

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Abstract
Epistasis has been used to describe a number of phenomena, including the functional interaction between genes, the genetic outcome of mutations acting within the same genetic pathway, and the statistical deviation from additive gene action. Converging interests across genetics suggests that it is now time to develop a more unified view of epistasis and gene interactions. One of the traditional uses of epistasis analysis has been to order genes within developmental and metabolic pathways. These approaches have recently become much more systematic through the use of high-throughput genetic screens, especially in yeast. These studies show that gene interactions are ubiquitous and can be used to help understand the structure of complex genetic networks. The major limitation of comprehensive analyses of gene interactions is the total number of interactions that must ultimately be tested, which grows at approximately the square of the number of genes (for example, >18 million interactions in the Saccharomyces cerevisiae genome). Future work in this area will need to focus on particular subsets of this interaction space using information from other sources, such as functional genomics. Epistasis can be a major barrier to inferring the genetic basis of complex traits within natural populations. The effects of many QTLs might be obscured by interactions with other loci, which can make mapping difficult. Human genetic disease is one area in which epistasis seems to be fairly common, although we have few examples in which the functional basis of a particular interaction has been demonstrated. Epistasis is one possible explanation for why human mapping results can be difficult to replicate. Epistasis arises as a natural by-product of the evolutionary process, as all subsequent evolutionary change is built upon genetic changes that have occurred previously. There is clear evidence that epistasis helps to structure the possible pathways that evolution can follow but, even after nearly a century of debate on the topic, we still do not know if epistasis creates a major barrier to evolutionary change. An increased focus on the quantitative effects of gene interactions will provide the basis for a unified approach to studies of gene interaction, while providing a point of articulation between genetics, functional genomics, evolutionary genetics and systems biology.