Higher Order Genetic Interactions and Complex Trait Variation


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.

Keywords: genetic interaction; epistasis; higher order genetic interaction; complex traits; heritability; gene regulatory network; cryptic genetic variation; phenotypic capacitance; phenotypic selection

Figure 1. Comparison of three additive loci to three loci involved in an HGI. In (a), three additive loci with equal effects affect a phenotype. In contrast, (b) shows a situation where three loci that interact collectively influence a phenotype. For both panels, an individual's genotype at a specific locus is shown as either blue or orange squares and corresponds to the two segregating alleles of a locus that would segregate in a cross. The same colouring scheme is used throughout this article. The different genotypes across the involved loci are shown on the x‐axis, and the quantitative change in trait value among individuals with a given genotype is shown in the y‐axis. For simplicity, we use haploids in this figure, as well as in all subsequent figures.
Figure 2. Factors that limit the statistical power of tests for HGIs. In (a), the numbers of statistical tests involved in genome‐wide scans for additive effects or genetic interactions of varying complexities across 1000 loci are shown. To enable visualisation of the large number of tests, the values are plotted on a log10 scale on the y‐axis. In (b), all possible genotype classes that can exist with increasing number of interacting alleles are displayed. As more loci are involved, the number of possible genotype combinations increases. Thus, fewer individuals with a specific multi‐locus genotype class will be present in a mapping population, reducing statistical power to detect HGIs.
Figure 3. Role of gene regulatory networks in HGIs. One way HGIs can occur is if genetic variants are found in genes that are involved in a gene regulatory network that determines the transcript level of a phenotypically important gene. (a) Individuals with blue alleles at all three interacting loci collectively suppress the expression of the gene. (b) The gene regulatory network in individuals with one orange allele is altered such that there is low transcription of the gene, but transcript abundance is not high enough to cause a phenotype change. (c) The gene regulatory network is further modified in individuals with three orange alleles. The phenotypically important gene is now highly transcribed, leading to a change in phenotype. In this figure, the darkness of an arrow indicates the intensity of a molecular effect.
Figure 4. Involvement of HGIs in phenotypic capacitance. Individuals can carry cryptic genetic variants, which may not exhibit any visible phenotypic effects under normal conditions (a). However, when individuals carrying the alleles involved in an HGI are exposed to atypical conditions, such as a spontaneous mutation or a sudden change in environment, then their effects may be uncovered, causing a change in phenotype (b). Individuals with different genotype classes and their phenotypes, depicted as either a grey circle or a green box, are shown here. Under normal conditions, all genetically distinct individuals exhibit the same phenotype. However, when they are exposed to an atypical condition, the individual with the three orange alleles now exhibits a different phenotype.


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Matsui, Takeshi, and Ehrenreich, Ian M(Feb 2016) Higher Order Genetic Interactions and Complex Trait Variation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026374]