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Epistasis is the interaction between genes, and was first described by Dr. Rivers Wallace. Epistasis takes place when the action of one gene is modified by one or several other genes, which are sometimes called modifier genes. The gene whose phenotype is expressed is said to be epistatic, while the phenotype altered or suppressed is said to be hypostatic.

In general, the fitness increment of any one gene depends in a complicated way on many other genes; but, because of the way that the science of population genetics was developed, evolutionary scientists tend to think of epistasis as the exception to the rule. In the first models of natural selection devised in the early 20th century, each gene was considered to make its own characteristic contribution to fitness, against an average background of other genes. In introductory college courses, population genetics is still taught this way.

Epistasis and genetic interaction refer to the same phenomenon; however, epistasis is widely used in population genetics and refers especially to the statistical properties of the phenomenon.

Examples of tightly linked genes having epistatic effects on fitness are found in supergenes and the human major histocompatibility complex genes. The effect can occur directly at the genomic level, where one gene could code for a protein preventing transcription of the other gene. Alternatively, the effect can occur at the phenotypic level. For example, the gene causing albinism would hide the gene controlling color of a person's hair. In another example, a gene coding for a widow's peak would be hidden by a gene causing baldness. Fitness epistasis (where the affected trait is fitness) is one cause of linkage disequilibrium.

Studying genetic interactions can reveal gene function, the nature of the mutations, functional redundancy, and protein interactions. Because protein complexes are responsible for most biological functions, genetic interactions are a powerful tool.

Diagram illustrating different relationships between numbers of mutations and fitness. Synergistic epistasis is the red line - each mutation has a disproportionately large effect on the organism's fitness. Antagonistic epistasis is the blue line. See Evolution of Sex

Two-locus epistatic interactions can be either synergistic (positive) or antagonistic (negative). In the example of a haploid organism with genotypes (at two loci) AB, Ab, aB and ab, we can think of the following trait values where higher values suggest greater expression of the characteristic (the exact values are simply given as examples):

Hence, we can classify thus:

Understanding whether the majority of genetic interactions are synergistic or antagonistic will help solve such problems as the evolution of sex.

Negative epistasis and sex are thought to be intimately correlated. Experimentally, this idea has been tested in using digital simulations of asexual and sexual populations. Over time, sexual populations move towards more negative epistasis, or the lowering of fitness by two interacting alleles. It is thought that negative epistasis allows individuals carrying the interacting deleterious mutations to be removed from the populations efficiently. This removes those alleles from the population, resulting in an overall more fit population. Thus the idea is that sex selects for negative epistasis.^[1]

However, this view is not agreed by many others. For example, see Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12801-6. Coevolution of robustness, epistasis, and recombination favors asexual reproduction. MacCarthy T, Bergman A.

Publications from Otto and Feldman also disagree with Azaevedo et al.

• Genetic suppression - the double mutant has a less severe phenotype than either single mutant.
• Genetic enhancement - the double mutant has a more severe phenotype than one predicted by the additive effects of the single mutants.
• Synthetic lethality or unlinked non-complementation - two mutations fail to complement and yet do not map to the same locus.
• Intragenic complementation, allelic complementation, or interallelic complementation - two mutations map to the same locus, yet the two alleles complement in the heteroallelic diploid. Causes of intragenic complementation include:
  • homology effects such as transvection, where, for example, an enhancer from one allele acts in trans to activate transcription from the promoter of the second allele.
  • trans-splicing of two mutant RNA molecules to produce a functional RNA.
  • At the protein level, another possibility involves proteins that normally function as dimers. In a heteroallelic diploid, two different abnormal proteins could form a functional dimer if each can compensate for the lack of function in the other.

• Co-adaptation
• Mutation

1. ^ Azevedo R, Lohaus R, Srinivasan S, Dang K, Burch C (2006). "Sexual reproduction selects for robustness and negative epistasis in artificial gene networks". Nature 440 (7080): 87-90. PMID 16511495. 

• GeneticInteractions.org
• Epistasis.org