Epistasis
Epistasis is a phenomenon in genetics in which the effect of a gene mutation is dependent on the presence or absence of mutations in one or more other genes, respectively termed modifier genes. In other words, the effect of the mutation is dependent on the genetic background in which it appears. Epistatic mutations therefore have different effects on their own than when they occur together. Originally, the term epistasis specifically meant that the effect of a gene variant is masked by that of a different gene.
The concept of epistasis originated in genetics in 1907 but is now used in biochemistry, computational biology and evolutionary biology. The phenomenon arises due to interactions, either between genes or within them, leading to non-linear effects. Epistasis has a great influence on the shape of evolutionary landscapes, which leads to profound consequences for evolution and for the evolvability of phenotypic traits.
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. In this sense, epistasis can be contrasted with genetic dominance, which is an interaction between alleles at the same gene locus. As the study of genetics developed, and with the advent of molecular biology, epistasis started to be studied in relation to quantitative trait loci and polygenic inheritance.
The effects of genes are now commonly quantifiable by assaying the magnitude of a phenotype or by biochemically assaying protein activity. 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, some studies try to prioritize epistatic pairs.
Classification
Terminology about epistasis can vary between scientific fields. Geneticists often refer to wild type and mutant alleles where the mutation is implicitly deleterious and may talk in terms of genetic enhancement, synthetic lethality and genetic suppressors. Conversely, a biochemist may more frequently focus on beneficial mutations and so explicitly state the effect of a mutation and use terms such as reciprocal sign epistasis and compensatory mutation. 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.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 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.
Sign epistasis
Sign epistasis occurs when one mutation has the opposite effect when in the presence of another mutation. This occurs when a mutation that is deleterious on its own can enhance the effect of a particular beneficial mutation. 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. If a fitness landscape has no sign epistasis then it is called smooth.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 also leads to genetic suppression whereby two deleterious mutations are less harmful together than either one on its own, i.e. one compensates for the other. 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 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 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. For most genes, the phenotype of the heterozygous suppressor mutation by itself would be wild type, so that the double mutant 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.