Should evolutionary geneticists worry about higher-order epistasis?

Curr Opin Genet Dev. 2013 Dec;23(6):700-7. doi: 10.1016/j.gde.2013.10.007. Epub 2013 Nov 27.


Natural selection drives evolving populations up the fitness landscape, the projection from nucleotide sequence space to organismal reproductive success. While it has long been appreciated that topographic complexities on fitness landscapes can arise only as a consequence of epistatic interactions between mutations, evolutionary genetics has mainly focused on epistasis between pairs of mutations. Here we propose a generalization to the classical population genetic treatment of pairwise epistasis that yields expressions for epistasis among arbitrary subsets of mutations of all orders (pairwise, three-way, etc.). Our approach reveals substantial higher-order epistasis in almost every published fitness landscape. Furthermore we demonstrate that higher-order epistasis is critically important in two systems we know best. We conclude that higher-order epistasis deserves empirical and theoretical attention from evolutionary geneticists.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Epistasis, Genetic*
  • Escherichia coli / genetics
  • Evolution, Molecular*
  • Fungi / genetics
  • Genetic Fitness
  • Genetics, Population
  • Models, Genetic*
  • Mutation / genetics*
  • Selection, Genetic