Abstract
The existence of epistasis in humans was first predicted by Bateson in 1909. Epistasis describes the non-linear, synergistic interaction of two or more genetic loci, which can substantially modify disease severity or result in entirely new phenotypes. The concept has remained controversial in human genetics because of the lack of well-characterized examples. In humans, it is only possible to demonstrate epistasis if two or more genes are mutated. In most cases of epistasis, the mutated gene products are likely to be constituents of the same physiological pathway leading to severe disruption of a cellular function such as antibody production. We have recently described a digenic family, who carry mutations of TNFRSF13B/TACI as well as TCF3 genes. Both genes lie in tandem along the immunoglobulin isotype switching and secretion pathway. We have shown they interact in an epistatic way causing severe immunodeficiency and autoimmunity in the digenic proband. With the advent of next generation sequencing, it is likely other families with digenic inheritance will be identified. Since digenic inheritance does not always cause epistasis, we propose an epistasis index which may help quantify the effects of the two mutations. We also discuss the clinical implications of digenic inheritance and epistasis in humans with primary immunodeficiency disorders.
Highlights
Since digenic inheritance does not always cause epistasis, we propose an epistasis index which may help quantify the effects of the two mutations
We suggest that positive and negative epistasis are grouped as quantitative epistasis while gene–gene interactions resulting in a new phenotype are termed qualitative epistasis
Unlike individuals bearing a single gene defect, we suggest that epistatic effects of digenic disorders can only be fully evaluated in an informative family (Table 1)
Summary
Epistasis was a term coined by Bateson in 1909 [1]. Based on a series of experiments, Bateson predicted there would be interactions between two or more genetic loci to produce novel phenotypes. Bateson and Punnett undertook experiments on the genetics of flower color in peas and comb morphology in roosters. When white pea flowers were crossed, all of the F1 hybrid was purple, a new phenotype. When the purple F1 hybrids were crossed, the result was unexpected: a ratio of 9:7 purple to white colored flowers. This result could not be explained by Mendelian genetics [2]. Bateson and Punnett described a similar phenomenon in the comb morphology of roosters They speculated there must be at least two genes, which were interacting in order to explain their observations. Homozygous null mutations of either enzyme result in white colored pea flowers.
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