Higher Order Genetic Interactions and Complex Trait Variation

Abstract

Abstract Genetic variants that segregate within species can cause individuals to show heritable phenotypic differences. Some of these polymorphisms act the same regardless of the other variants with which they co‐occur. However, many of these polymorphisms exhibit genetic (or epistatic) interactions with each other and thus show different effects across genetic backgrounds. These interactions represent a potentially important source of heritable trait variation, but are difficult to identify in most genetic mapping studies. For this reason, researchers typically focus on two‐locus interactions, which are the least complex and easiest to identify form of interaction. Although two‐locus interactions are undoubtedly important, higher order genetic interactions (HGIs) involving three or more loci can also occur. In this article, we discuss the phenotypic effects, underlying molecular mechanisms and potential biological significance of these HGIs. Key Concepts Higher order genetic interactions (HGIs) occur when three or more polymorphisms collectively exhibit unexpected phenotypic effects. Detecting HGIs is difficult, especially as the number of involved loci increases. Evidence suggests that genetically complex perturbation of gene regulatory networks might be the major source of HGIs. HGIs can cause individuals to show different susceptibilities to environmental change and mutation.