Epistasis is a phenomenon in genetics in which the effect of a mutation on a trait is dependent on the presence or absence of mutations at different loci (locations on the genome), that may be on the same gene (intragenic) or on different genes, called modifier genes. In evolutionary genetics, epistasis occurs when the combined effect of two mutations is different from what you would expect by simply adding their individual effects together. This definition can be expanded to more than two loci to study higher-order epistasis, which plays an important role in shaping evolutionary trajectories.
The term epistasis was introduced in 1907 to describe the discrepancy between the prediction of segregation ratios based on the action of individual genes and the actual outcome of a dihybrid cross, and is now widely used in biochemistry, computational biology and evolutionary biology. While the nuanced meaning of the term now differs between researchers studying genetics at a functional, compositional, or at a statistical level, it still describes gene interactions at various levels.
History Understanding of epistasis has changed considerably through the history of genetics and so too has the use of the term. The term was first used in 1907 by William Bateson and his collaborators Florence Durham and Muriel Wheldale Onslow. In early 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. Some introductory courses still teach population genetics this way. Because of the way that the science of population genetics was developed, evolutionary geneticists have tended to think of epistasis as the exception. However, in general, the expression of any one allele depends in a complicated way on many other alleles.
In classical genetics, if genes A and B are mutated, and each mutation by itself produces a unique phenotype but the two mutations together show the same phenotype as the gene A mutation, then gene A is epistatic and gene B is hypostatic. For example, the gene for total baldness is epistatic to the gene for brown hair, because the baldness phenotype masks the expression of the hair color gene. As the study of genetics developed, and with the advent of molecular biology, the focus shifted from simple (and complete) masking effects to the complex, quantitative interactions between genes. Consequently, the definition of epistasis has expanded to describe any non-additive interaction between two or more mutations.
The effects of genes are now commonly quantifiable by assaying the magnitude of a phenotype (e.g. height, pigmentation or growth rate) or by biochemically assaying protein activity (e.g. binding or catalysis). Increasingly sophisticated computational and evolutionary biology models aim to describe the effects of epistasis on a genome-wide scale and the consequences of this for evolution. Since identification of epistatic pairs is challenging both computationally and statistically, many studies have tried to prioritize epistatic pairs. In recent years, however, high throughput experiments and computational assays have allowed researchers to also study higher-order epistasis (where more than two mutations at different loci interact).
Classification
Terminology about epistasis can vary between scientific fields. Additionally, there are differences when looking at epistasis within a single gene and epistasis within a haploid or diploid genome. In general, epistasis is used to denote the departure from 'independence' of the effects of different genetic loci. Confusion often arises due to the varied interpretation of 'independence' among different branches of biology. The classifications below attempt to cover the various terms and how they relate to one another.
Additivity Two mutations are considered to be purely additive if the effect of the double mutation is the "sum of the effects" of the single mutations. This occurs when genes do not interact with each other, for example by acting through different metabolic pathways. Simply, additive traits were studied early on in the history of genetics, however they are relatively rare, with most genes exhibiting at least some level of epistatic interaction.
Note that "sum of effects" is a subjective term that depends on weather the mutation on the trait being studied behaves additively or multiplicatively. The same mutation can behave either ways if the definition of the trait being studied changes. For example, while both Malthusian and Wrightian selection coefficients quantify the fitness effect of a mutation, mutations that are multiplicative in Wrightian fitness behave additively in Malthusian fitness (since Malthusian fitness is the logarithm of Wrightian fitness).
Magnitude epistasis
When the double mutation has a fitter phenotype than expected from the effects of the two single mutations, it is referred to as positive epistasis. Positive epistasis between beneficial mutations generates greater improvements in function than expected. Positive epistasis between deleterious mutations protects against the negative effects to cause a less severe fitness drop.
Conversely, when two mutations together lead to a less fit phenotype than expected from their effects when alone, it is called negative epistasis. Negative epistasis between beneficial mutations causes smaller than expected fitness improvements, whereas negative epistasis between deleterious mutations causes greater-than-additive fitness drops.
Independently, when the effect on fitness of two mutations is more radical than expected from their effects when alone, it is referred to as synergistic epistasis. The opposite situation, when the fitness difference of the double mutant from the wild type is smaller than expected from the effects of the two single mutations, it is called antagonistic epistasis. Therefore, for deleterious mutations, negative epistasis is also synergistic, while positive epistasis is antagonistic; conversely, for advantageous mutations, positive epistasis is synergistic, while negative epistasis is antagonistic.
The term genetic enhancement is sometimes used when a double (deleterious) mutant has a more severe phenotype than the additive effects of the single mutants. Strong positive epistasis is sometimes referred to by creationists as irreducible complexity (although most examples are misidentified).
Sign epistasis Sign epistasis occurs when mutations have the opposite effect when in the presence of other mutations. For example, a large and complex brain is a waste of energy without a range of sense organs, but sense organs are made more useful by a large and complex brain that can better process the information. The absence of sign epistasis causes a fitness landscape to be smooth (also called a Mt Fuji landscape), since every single mutation step towards the optimum genotype would be monotonically adaptive.
At its most extreme, reciprocal sign epistasis occurs when two deleterious genes are beneficial when together. For example, producing a toxin alone can kill a bacterium, and producing a toxin exporter alone can waste energy, but producing both can improve fitness by killing competing organisms. If a fitness landscape has sign epistasis but no reciprocal sign epistasis then it is called semismooth. Reciprocal sign epistasis is a necessary condition for ruggedness (multiple peaks) in a fitness landscape.
Reciprocal sign epistasis can also lead to an extreme form of genetic suppression whereby two individually deleterious mutations are beneficial when present together. A clear example of genetic suppression was the demonstration that in the assembly of bacteriophage T4 two deleterious mutations, each causing a deficiency in the level of a different morphogenetic protein, could interact positively. If a mutation causes a reduction in a particular structural component, this can bring about an imbalance in morphogenesis and loss of viable virus progeny, but production of viable progeny can be restored by a second (suppressor) mutation in another morphogenetic component that restores the balance of protein components.
The term genetic suppression can also apply to sign epistasis where the double mutant has a phenotype intermediate between those of the single mutants, in which case the more severe single mutant phenotype is suppressed by the other mutation or genetic condition. For example, in a diploid organism, a hypomorphic (or partial loss-of-function) mutant phenotype can be suppressed by knocking out one copy of a gene that acts oppositely in the same pathway. In this case, the second gene is described as a "dominant suppressor" of the hypomorphic mutant; "dominant" because the effect is seen when one wild-type copy of the suppressor gene is present (i.e., even in a heterozygote). For most genes, the phenotype of the heterozygous suppressor mutation by itself would be wild type (because most genes are not haplo-insufficient), so that the double mutant (suppressed) phenotype is intermediate between those of the single mutants.
In non reciprocal sign epistasis, fitness of the mutant lies in the middle of that of the extreme effects seen in reciprocal sign epistasis.
When two mutations are viable alone but lethal in combination, it is called Synthetic lethality or unlinked non-complementation.
Haploid organisms In a haploid organism with genotypes (at two loci) ab, Ab, aB or AB, we can think of different forms of epistasis as affecting the magnitude of a phenotype upon mutation individually (Ab and aB) or in combination (AB).
Interaction type ab Ab aB AB No epistasis (additive) 0 1 1 2 AB = Ab + aB + ab Positive (synergistic) epistasis 0 1 1 3 AB > Ab + aB + ab Negative (antagonistic) epistasis 0 1 1 1 AB < Ab + aB + ab Sign epistasis 0 1 -1 2 AB has opposite sign to Ab or aB Reciprocal sign epistasis 0 -1 -1 2 AB has opposite sign to Ab and aB
Diploid organisms Epistasis in diploid organisms is further complicated by the presence of two copies of each gene. Epistasis can occur between loci, but additionally, interactions can occur between the two copies of each locus in heterozygotes. For a two locus, two allele system, there are eight independent types of gene interaction.
Additive A locus Additive B locus Dominance A locus Dominance B locus aaaAAAaaaAAAaaaAAAaaaAAA bb10–1bb111bb–11–1bb–1–1–1 bB10–1bB000bB–11–1bB111 BB10–1BB–1–1–1BB–11–1BB–1–1–1 Additive by Additive Epistasis Additive by Dominance Epistasis Dominance by Additive Epistasis Dominance by Dominance Epistasis aaaAAAaaaAAAaaaAAAaaaAAA bb10–1bb10–1bb1–11bb–11–1 bB000bB–101bB000bB1–11 BB–101BB10–1BB–11–1BB–11–1
Genetic and molecular causes
Additivity This can be the case when multiple genes act in parallel to achieve the same effect. For example, when an organism is in need of phosphorus, multiple enzymes that break down different phosphorylated components from the environment may act additively to increase the amount of phosphorus available to the organism. However, there inevitably comes a point where phosphorus is no longer the limiting factor for growth and reproduction and so further improvements in phosphorus metabolism have smaller or no effect (negative epistasis). Some sets of mutations within genes have also been specifically found to be additive. It is now considered that strict additivity is the exception, rather than the rule, since most genes interact with hundreds or thousands of other genes.
Epistasis between genes