In This Article Expand or collapse the "in this article" section Epistasis and Evolution

  • Introduction
  • General Overviews
  • History of the Concept
  • Statistical Epistasis

Evolutionary Biology Epistasis and Evolution
Joachim Krug
  • LAST MODIFIED: 28 July 2021
  • DOI: 10.1093/obo/9780199941728-0137


The concept of epistasis was introduced into evolutionary theory more than a hundred years ago. Its history is marked by controversies regarding its importance for the evolutionary process, as exemplified by the debate between Ronald Fisher and Sewall Wright in the wake of the modern synthesis. In this case the disagreement was about the shape of the adaptive landscape, which is determined by epistasis. Wright believed that epistasis causes the adaptive landscape to be rugged with many local peaks, whereas Fisher viewed evolution as a smooth, steady progression toward a unique optimum. Even today, the different meanings attributed to epistasis continue to spawn confusion. Nevertheless, a consensus is emerging, according to which the term should be used to designate interactions between genetic effects on phenotypes in the broadest sense. Stated differently, in the presence of epistasis the phenotypic effects of a gene depend on its genetic context. In evolutionary theory the phenotype of primary interest is organismal fitness, but principally the concept applies to any genotype-phenotype map. Reflecting the Fisherian view, throughout the 20th century epistasis was often considered to be a residual perturbation on the main effects of individual genes. Following the advent of sequencing techniques providing insights into the molecular basis of genotype-phenotype maps, over the past two decades it has become clear, however, that epistasis is the rule rather than an exception. This has motivated a large number of empirical studies exploring the patterns and evolutionary consequences of epistasis across a wide range of scales of organismal and genomic complexity. Correspondingly, mathematical and computational tools have been developed for the analysis of experimental data, and models have been constructed to elucidate the mechanistic and statistical origins of genetic interactions. Despite a certain inherent vagueness, the concept takes center stage in modern evolutionary thought as a framework for organizing the accumulating understanding of the relationship among genotype, phenotype, and organism.

General Overviews

Because classical population genetics has focused on independent gene effects, most textbooks cover epistasis only in passing (but see Statistical Epistasis). Undergraduate texts in evolutionary biology tend to briefly mention epistasis as a generalization of the concept of dominance from genetic interaction within a locus to interactions between loci. The collection Wolf, et al. 2000 marks the beginning of a paradigm shift toward an increased appreciation of the importance of genetic interactions for the evolutionary process. Phillips 2008; de Visser, et al. 2011; and Domingo, et al. 2019 are review articles that give a good overview of the state of the field at their respective dates of publication.

  • de Visser, J. A. G. M., T. F. Cooper, and S. F. Elena. 2011. The causes of epistasis. Proceedings of the Royal Society B 278:3617–3624.

    DOI: 10.1098/rspb.2011.1537

    A short review discussing patterns and mechanisms of epistasis from the perspective of experimental microbial evolution.

  • Domingo, J., P. Baeza-Centurion, and B. Lehner. 2019. The causes and consequences of genetic interactions (epistasis). Annual Review of Genomics and Human Genetics 20:17.1–17.28.

    DOI: 10.1146/annurev-genom-083118-014857

    The most recent of the reviews cited in this section, this article elaborates on the distinction between specific and nonspecific epistasis, which is emerging as a central theme in the field (see also Global Epistasis). The focus is on molecular systems, such as proteins and RNA.

  • Phillips, P. C. 2008. Epistasis: The essential role of gene interactions in the structure and evolution of genetic systems. Nature Reviews Genetics 9:855–867.

    DOI: 10.1038/nrg2452

    Starting from a lucid exposition of the often confusing terminology and its historical origins, this still authoritative review introduces the modern perspective on epistasis in evolutionary genetics through a series of illustrative examples. An excellent starting point for further reading.

  • Wolf, J. B., E. D. Brodie III, and M. J. Wade, eds. 2000. Epistasis and the evolutionary process. Oxford: Oxford Univ. Press.

    A highly readable collection of articles advocating a transition from the traditional view of evolution centered on independent gene effects toward a recognition of the importance of genetic interactions. The volume combines contributions on the historical and conceptual foundations with applications to topics such as development, the evolution of sex, and speciation.

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