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Epistatic

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Epistatic

Not to be confused with epistaxis, epitaxis, or epitasis.

In genetics, epistasis is a phenomenon in which the expression of one gene depends on the presence of one or more 'modifier genes'. A gene whose phenotype is expressed is called epistatic, while one whose phenotype is altered or suppressed is called hypostatic. If two epistatic 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 to gene B. Epistasis can be contrasted with dominance, which is an interaction between alleles at the same gene locus. Epistasis is often studied in relation to Quantitative Trait Loci (QTL) and polygenic inheritance.

In general, the expression of any one allele depends in a complicated way on many other alleles; 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. Some introductory college courses still teach population genetics this way.

Epistasis and genetic interaction refer to different aspects of the same phenomenon. The term epistasis is widely used in population genetics and refers especially to the statistical properties of the phenomenon, and does not necessarily imply biochemical interaction between gene products. However, 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' between different branches of biology.[1]

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 between loci that are not necessarily physically close to each other.

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.

Classification by fitness or trait value

Two-locus epistatic interactions can be either synergistic (enhancing the effectiveness) or antagonistic (reducing the activity).[4][5] In the example of a haploid organism with genotypes (at two loci) AB, Ab, aB or 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):

AB Ab aB ab
No epistasis (additive across loci)  2 1 1 0
Synergistic epistasis 3 1 1 0
Antagonistic epistasis 1 1 1 0

Hence, we can classify thus:

Trait values Type of epistasis
AB = Ab + aBab  No epistasis, additive inheritance
Synergistic epistasis
AB < Ab + aBab  Antagonistic epistasis

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

Alternate classification by sign

Studies where the effect of epistasis is determined quantitatively based on changes in some quantitative measure of phenotypes may favor classifying epistasis as either positive or negative, depending on whether the actual phenotype is greater or smaller than the expected additive phenotype, respectively. This classification is not only simpler but also preferable in evolutionary genetics, since the absolute sign of epistasis matters more than relationship between sign of epistasis and sign of individual loci's effect on phenotype. Under this classification, sign epistasis refers to the phenomenon where the sign of epistatic and individual effect on phenotype differs because the individual alleles' effect on phenotype changes depending on the genetic context.[6]

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[7] and has also been tested using artificial gene networks.[4]

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.[8] In addition, in those tests which used artificial gene networks, negative epistasis is only found in more densely connected networks,[4] whereas empirical evidence indicates that natural gene networks are sparsely connected,[9] and theory shows that selection for robustness will favor more sparsely connected and minimally complex networks.[9]

Functional or mechanistic classification

  • Genetic suppression
the double mutant has a less severe phenotype than either single mutant. [This term can also apply to a case 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 heterozigote). 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.]
  • Genetic enhancement
the double mutant has a more severe phenotype than one predicted by the additive effects of the single mutants.
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.

See also

References

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
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