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Why Gene x Gene Interactions – Epistasis - Matters Now
Epistasis refers to the observation that some phenotypes only arise when specific alleles of two (or in some cases, more) genes are present in the same individual. Epistasis may be caused by a variety of underlying mechanisms. For instance, proteins that participate in a complex with other proteins may exhibit epistasis: the activity of protein (encoded by an allele of one gene) is altered due to its interaction with another protein (encoded by a second gene). The strength of interacting effect depends upon the specific alleles encoding each of the individual proteins: the A allele of gene 1 alters the activity of the Y allele of gene 2, but the B allele of gene 1 has no effect on the activity of the Y allele of gene 2.
Examples of Epistasis in Obesity
In little more than a decade, eleven different genes have been shown to cause Mendelian forms of human obesity and more than 52 genes have been shown to cause obesity in knockout or transgenic mice (1). However, other data suggest that a substantial fraction of the underlying biology of obesity still remains undiscovered because little is known about specific networks of interacting genes involved in gene x gene epistasis (2).
A substantial number of literature reports using animal models indicates that epistasis influences the physiological effects of virtually all obesity genes. Much of this evidence is an unintentional byproduct of studies using transgenic and knockout mice (2) rather than concerted efforts by laboratories to study epistasis. Although it may not be obvious, every investigator who reports that the phenotype effects of their knockout or transgene differs with mouse strain background is also reporting the existence of an epistatic interaction. The interactions are between the transgenic/knockout gene and at least one other gene whose functional alleles vary between inbred mouse strains. Obesity phenotypes, as a general observation, vary depending on the inbred strain background which means that every one of the genes studied also is involved in at least one epistatic interaction.
In support of epistatitic interactions, one recent paper concluded that interacting networks are causal for obesity in mice. (3). Additionally, other investigators have also observed significant epistasis for obesity (4, 5).
The number of studies of gene x gene epistasis and obesity in humans is much smaller than the animal models literature. Nevertheless, several studies confirm the existence of gene x gene epistasis as a cause of human obesity. For instance, researchers using a positional genetics approach identified TBC1D1 (a protein containing a domain that may function as a GTPase activator) as a human obesity gene.(6). They also reported an epistatic interaction that is only detectable in people with specific genotypes for TBC1D1. Another group reported epistatic interactions influencing obesity in a human quantitative trait locus (QTL) linkage study (7).
Although it is clear that epistasis contributes to both the biological basis of obesity in animal models and variations in human obesity, almost nothing is known about the specific genes and mechanisms that are. Identification of genes involved in epistasis is therefore a largely unexploited component of the worldwide search for the underlying causes of obesity. Studies designed to find genes for epistasis are particularly important because animal models mapping experiments frequently identify loci with epistatic effects but no direct effects by themselves on the studied phenotype (3-5). These genes (alleles) would therefore be undetectable in studies focused only on direct effects.
Experiments designed to find genes involved in epistasis are essential for the discovery of one major underlying cause of obesity. Although some genes with epistatic effects will be discovered because they have both direct and indirect (epistatic) effects, other genes with epistatic effects will only be discovered by experiments intentionally designed for this purpose. One of the major barriers to studies of epistasis is inadequate statistical power, since the study of gene x gene interactions requires much larger sample sizes than studies of direct effects. A practical approach to find genes involved in epistasis is to use animal models (because the genotypes are known and reproducible) for the positional cloning of epistasis genes. The rapidly decreasing cost genotyping may finally make it practical to study gene x gene epistasis directly in humans.
1. Rankinen T, Zuberi A, Chagnon YC, et al. 2006. The human obesity gene map: the 2005 update. Obesity 14, 529 - 644. PMID: 16741264
2. Warden CH, Yi N, Fisler J. 2004. Epistasis among genes is a universal phenomenon in obesity: evidence from rodent models. Nutrition 20, 74 - 77. PMID: 14698018
3. Stylianou IM, Korstanje R, Li R, Sheehan S, Paigen B, Churchill GA. 2006. Quantitative trait locus analysis for obesity reveals multiple networks of interacting loci. Mamm Genome 17, 22 - 36. PMID: 16416088 Free Access
4. Yi N, Diament A, Chiu S, et al. 2004. Characterization of epistasis influencing complex spontaneous obesity in the BSB model. Genetics 167, 399 - 409. PMID: 15166164 Free Access
5. Cheverud JM, Vaughn TT, Pletscher LS, et al. 2001. Genetic architecture of adiposity in the cross of LG/J and SM/J inbred mice. Mamm Genome 12, 3 - 12. PMID: 11178736 Free Access
6. Stone S, Abkevich V, Russell DL, et al. 2006. TBC1D1 is a candidate for a severe obesity gene and evidence for a gene/gene interaction in obesity predisposition. Hum Mol Genet. PMID: 16893906 Free Access
7. Dong C, Wang S, Li WD, Li D, Zhao H, Price RA. 2003. Interacting genetic loci on chromosomes 20 and 10 influence extreme human obesity. Am J Hum Genet 72, 115 - 24 PMID: 12478478 Free Access
Contributed by: Craig Warden, University of California Davis