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.[2] 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 different gene.[3]
The concept of epistasis originated in genetics in 1907
History
Understanding of epistasis has changed considerably through the
In
The effects of genes are now commonly quantifiable by assaying the magnitude of a phenotype (e.g.
Classification
Terminology about epistasis can vary between scientific fields.
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.[18][19]
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.[10][11] Positive epistasis between deleterious mutations protects against the negative effects to cause a less severe fitness drop.[13]
Conversely, when two mutations together lead to a less fit phenotype than expected from their effects when alone, it is called negative epistasis.[20][21] Negative epistasis between beneficial mutations causes smaller than expected fitness improvements, whereas negative epistasis between deleterious mutations causes greater-than-additive fitness drops.[12]
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.[15] 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
Sign epistasis
Sign epistasis
At its most extreme, reciprocal sign epistasis
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.[25] 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
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.[26]
Haploid organisms
In a
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
Additive A locus | Additive B locus | Dominance A locus | Dominance B locus | ||||||||||||||||
aa | aA | AA | aa | aA | AA | aa | aA | AA | aa | aA | AA | ||||||||
bb | 1 | 0 | –1 | bb | 1 | 1 | 1 | bb | –1 | 1 | –1 | bb | –1 | –1 | –1 | ||||
bB | 1 | 0 | –1 | bB | 0 | 0 | 0 | bB | –1 | 1 | –1 | bB | 1 | 1 | 1 | ||||
BB | 1 | 0 | –1 | BB | –1 | –1 | –1 | BB | –1 | 1 | –1 | BB | –1 | –1 | –1 | ||||
Additive by Additive Epistasis | Additive by Dominance Epistasis | Dominance by Additive Epistasis | Dominance by Dominance Epistasis | ||||||||||||||||
aa | aA | AA | aa | aA | AA | aa | aA | AA | aa | aA | AA | ||||||||
bb | 1 | 0 | –1 | bb | 1 | 0 | –1 | bb | 1 | –1 | 1 | bb | –1 | 1 | –1 | ||||
bB | 0 | 0 | 0 | bB | –1 | 0 | 1 | bB | 0 | 0 | 0 | bB | 1 | –1 | 1 | ||||
BB | –1 | 0 | 1 | BB | 1 | 0 | –1 | BB | –1 | 1 | –1 | BB | –1 | 1 | –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
Epistasis between genes
Epistasis within the genomes of organisms occurs due to interactions between the genes within the genome. This interaction may be direct if the genes encode proteins that, for example, are separate components of a multi-component protein (such as the
Epistasis within genes
Just as mutations in two separate genes can be non-additive if those genes interact, mutations in two
Also intragenic suppression can occur when the
Proteins are held in their
In enzymes, the protein structure orients a few, key amino acids into precise geometries to form an active site to perform chemistry.[35] Since these active site networks frequently require the cooperation of multiple components, mutating any one of these components massively compromises activity, and so mutating a second component has a relatively minor effect on the already inactivated enzyme. For example, removing any member of the catalytic triad of many enzymes will reduce activity to levels low enough that the organism is no longer viable.[36][37][38]
Heterozygotic epistasis
Similarly, at the protein level, proteins that function as
Evolutionary consequences
Fitness landscapes and evolvability
In
A
If all mutations are additive, they can be acquired in any order and still give a continuous uphill trajectory. The landscape is perfectly smooth, with only one peak (
High epistasis is usually considered a constraining factor on evolution, and improvements in a highly epistatic trait are considered to have lower
The frustration of adaptive evolution by rugged fitness landscapes was recognized as a potential force for the evolution of evolvability. Michael Conrad in 1972 was the first to propose a mechanism for the evolution of evolvability by noting that a mutation which smoothed the fitness landscape at other loci could facilitate the production of advantageous mutations and hitchhike along with them.[46][47] Rupert Riedl in 1975 proposed that new genes which produced the same phenotypic effects with a single mutation as other loci with reciprocal sign epistasis would be a new means to attain a phenotype otherwise too unlikely to occur by mutation.[48][49]
Rugged, epistatic fitness landscapes also affect the trajectories of evolution. When a mutation has a large number of epistatic effects, each accumulated mutation drastically changes the set of available
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. This hypothesis was proposed by Alexey Kondrashov, and is sometimes known as the deterministic mutation hypothesis[52] and has also been tested using artificial gene networks.[20]
However, the evidence for this hypothesis has not always been straightforward and the model proposed by Kondrashov has been criticized for assuming mutation parameters far from real world observations.[53] In addition, in those tests which used artificial gene networks, negative epistasis is only found in more densely connected networks,[20] whereas empirical evidence indicates that natural gene networks are sparsely connected,[54] and theory shows that selection for robustness will favor more sparsely connected and minimally complex networks.[54]
Methods and model systems
Regression analysis
Quantitative genetics focuses on genetic variance due to genetic interactions. Any two locus interactions at a particular gene frequency can be decomposed into eight independent genetic effects using a weighted regression. In this regression, the observed two locus genetic effects are treated as dependent variables and the "pure" genetic effects are used as the independent variables. Because the regression is weighted, the partitioning among the variance components will change as a function of gene frequency. By analogy it is possible to expand this system to three or more loci, or to cytonuclear interactions[55]
Double mutant cycles
When assaying epistasis within a gene, site-directed mutagenesis can be used to generate the different genes, and their protein products can be assayed (e.g. for stability or catalytic activity). This is sometimes called a double mutant cycle and involves producing and assaying the wild type protein, the two single mutants and the double mutant. Epistasis is measured as the difference between the effects of the mutations together versus the sum of their individual effects.[56] This can be expressed as a free energy of interaction. The same methodology can be used to investigate the interactions between larger sets of mutations but all combinations have to be produced and assayed. For example, there are 120 different combinations of 5 mutations, some or all of which may show epistasis...
Computational prediction
Numerous computational methods have been developed for the detection and characterization of epistasis. Many of these rely on machine learning to detect non-additive effects that might be missed by statistical approaches such as linear regression.[57] For example,
See also
- Co-adaptation
- Epistasis and functional genomics
- Mutation
- Synthetic viability
- Synthetic lethality
- Quantitative trait locus
- Interactome (Genetic interaction network)
- Fitness landscape
- Evolvability
- Pleiotropy
- Evolution of sexual reproduction
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External links
- INTERSNP - a software for genome-wide interaction analysis (GWIA) of case-control and case-only SNP data, including analysis of quantitative traits.
- Science Aid: Epistasis High school (GCSE, Alevel) resource.
- GeneticInteractions.org
- Epistasis.org