Higher-order genetic interactions and their contribution to complex traits

•Most work on genetic interactions focuses on relatively simple cases involving only two loci.•Higher-order genetic interactions (HGIs) involving three or more loci also occur and can have major phenotypic effects.•Crossing experiments in model organisms are starting to provide crucial insights into the architecture, prevalence, and mechanisms of HGIs.•Continued work on HGIs will improve our basic understanding of the relationship between genotype and phenotype.

The contribution of genetic interactions involving three or more loci to complex traits is poorly understood. These higher-order genetic interactions (HGIs) are difficult to detect in genetic mapping studies, therefore, few examples of them have been described. However, the lack of data on HGIs should not be misconstrued as proof that this class of genetic effect is unimportant. To the contrary, evidence from model organisms suggests that HGIs frequently influence genetic studies and contribute to many complex traits. Here, we review the growing literature on HGIs and discuss the future of research on this topic.