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

Nature Reviews Genetics volume 9, pages 855–867 (2008)Cite this article

Key Points

  • 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.

Abstract

Epistasis, or interactions between genes, has long been recognized as fundamentally important to understanding the structure and function of genetic pathways and the evolutionary dynamics of complex genetic systems. With the advent of high-throughput functional genomics and the emergence of systems approaches to biology, as well as a new-found ability to pursue the genetic basis of evolution down to specific molecular changes, there is a renewed appreciation both for the importance of studying gene interactions and for addressing these questions in a unified, quantitative manner.

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Figure 1: Different viewpoints of epistasis.
Figure 2: Reconstructing genetic pathways using epistasis analysis.
Figure 3: Epistasis in complex traits.
Figure 4: Three different views of the generation of epistasis under natural selection.

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Acknowledgements

This work was initiated while the author was a sabbatical visitor at the Gulbenkian Institute of Science. I gratefully acknowledge their support. I also deeply appreciate input from H. Hoekstra, S. Otto, J. Thornton and three anonymous reviewers, as well as a long-term synergistic interaction with M. Whitlock. This work was supported by a fellowship from the Guggenheim Foundation, and by grants from the National Institutes of Health and the National Science Foundation.

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  1. Center for Ecology and Evolution, University of Oregon, Eugene, 97403, Oregon, USA

    Patrick C. Phillips

  2. Instituto Gulbenkian de Ciência, Apartado 14, P-2781-901, Oeiras, Portugal

    Patrick C. Phillips

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Glossary

Admixture

The pattern of genetic variation that occurs when a population is derived from founders that originated from more than one ancestral population.

Punnett square

A method of calculating the outcomes of a genetic cross by multiplying the expected frequency of gametes from a mother by the expected frequency of gametes from the father.

Hardy–Weinberg equilibrium

A theoretical description of the relationship between genotype and allele frequencies that is based on expectation in a stable population undergoing random mating in the absence of selection, new mutations and gene flow; under these conditions (and in the absence of linkage disequilibrium) the genotype frequencies are equal to the product of the allele frequencies.

Dauer larva

A developmentally arrested, immature, long-lived and non-feeding form of Caenorhabditis elegans that forms under conditions of food scarcity and high population density, and that resumes development if food levels increase.

Synthetic-lethal mutations

Two mutations are considered to be synthetically lethal if they result in death when both are present, whereas an individual with either mutation alone is viable.

Chromatin immunoprecipitation

A technique used to identify potential regulatory sequences by isolating soluble DNA chromatin extracts (complexes of DNA and protein) using antibodies that recognize specific DNA-binding proteins.

Linkage disequilibrium

A measure of whether alleles at two loci coexist in a population in a non-random fashion. Alleles that are in linkage disequilibrium are found together on the same haplotype more often than would be expected under a random combination of alleles.

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Phillips, P. Epistasis — the essential role of gene interactions in the structure and evolution of genetic systems. Nat Rev Genet 9, 855–867 (2008). https://doi.org/10.1038/nrg2452

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