Epistasis
Encyclopedia
In genetics
, epistasis is the phenomenon where the effects of one gene are modified by one or several other genes, which are sometimes called modifier genes. The gene whose phenotype
is expressed is called epistatic, while the phenotype altered or suppressed is called hypostatic. 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 fitness increment 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. For further discussion of the definitions of epistasis, and the history of these definitions, see.
Examples of tightly linked genes having epistatic effects on fitness are found in supergene
s 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.
) 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):
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
.
, and is sometimes known as the deterministic mutation hypothesis
and has also been tested using artificial gene networks
.
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. For example, see MacCarthy and Bergman. In addition, in those tests which used artificial gene networks, negative epistasis is only found in more densely connected networks, whereas empirical evidence indicates that natural gene networks are sparsely connected, and theory shows that selection for robustness will favor more sparsely connected and minimally complex networks.
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
, epistasis is the phenomenon where the effects of one gene are modified by one or several other genes, which are sometimes called modifier genes. The gene whose phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
is expressed is called epistatic, while the phenotype altered or suppressed is called hypostatic. Epistasis can be contrasted with dominance, which is an interaction
Interaction
Interaction is a kind of action that occurs as two or more objects have an effect upon one another. The idea of a two-way effect is essential in the concept of interaction, as opposed to a one-way causal effect...
between alleles at the same gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
. Epistasis is often studied in relation to Quantitative Trait Loci
Quantitative trait locus
Quantitative traits refer to phenotypes that vary in degree and can be attributed to polygenic effects, i.e., product of two or more genes, and their environment. Quantitative trait loci are stretches of DNA containing or linked to the genes that underlie a quantitative trait...
(QTL) and polygenic inheritance.
In general, the fitness increment of any one allele depends in a complicated way on many other alleles; but, because of the way that the science of population genetics
Population genetics
Population genetics is the study of allele frequency distribution and change under the influence of the four main evolutionary processes: natural selection, genetic drift, mutation and gene flow. It also takes into account the factors of recombination, population subdivision and population...
was developed, evolutionary scientists tend to think of epistasis as the exception to the rule. In the first models of natural selection
Natural selection
Natural selection is the nonrandom process by which biologic traits become either more or less common in a population as a function of differential reproduction of their bearers. It is a key mechanism of evolution....
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
Population genetics
Population genetics is the study of allele frequency distribution and change under the influence of the four main evolutionary processes: natural selection, genetic drift, mutation and gene flow. It also takes into account the factors of recombination, population subdivision and population...
this way.
Epistasis and genetic interaction refer to different aspects of the same phenomenon. The term epistasis is widely used in population genetics
Population genetics
Population genetics is the study of allele frequency distribution and change under the influence of the four main evolutionary processes: natural selection, genetic drift, mutation and gene flow. It also takes into account the factors of recombination, population subdivision and population...
and refers especially to the statistical
Statistics
Statistics is the study of the collection, organization, analysis, and interpretation of data. It deals with all aspects of this, including the planning of data collection in terms of the design of surveys and experiments....
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. For further discussion of the definitions of epistasis, and the history of these definitions, see.
Examples of tightly linked genes having epistatic effects on fitness are found in supergene
Supergene
A supergene is a group of neighbouring genes on a chromosome which are inherited together because of close genetic linkage and are functionally related in an evolutionary sense, although they are rarely co-regulated genetically....
s and the human major histocompatibility complex
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
genes. The effect can occur directly at the genomic level, where one gene could code for a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
preventing transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
of the other gene. Alternatively, the effect can occur at the phenotypic level. For example, the gene causing albinism
Albinism
Albinism is a congenital disorder characterized by the complete or partial absence of pigment in the skin, hair and eyes due to absence or defect of an enzyme involved in the production of melanin...
would hide the gene controlling color of a person's hair. In another example, a gene coding for a widow's peak
Widow's peak
A widow's peak is a distinct point in the hairline in the center of the forehead. This hair anomaly is a result of a lower-than-usual position of the intersection of the bilateral periorbital fields of hair-growth suppression on the forehead.-Definition:...
would be hidden by a gene causing baldness. Fitness
Fitness (biology)
Fitness is a central idea in evolutionary theory. It can be defined either with respect to a genotype or to a phenotype in a given environment...
epistasis (where the affected trait is fitness) is one cause of linkage disequilibrium
Linkage disequilibrium
In population genetics, linkage disequilibrium is the non-random association of alleles at two or more loci, not necessarily on the same chromosome. It is also referred to as to as gametic phase disequilibrium , or simply gametic 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.
Classification by fitness or trait value
Two-locus epistatic interactions can be either synergistic (enhancing the effectiveness) or antagonistic (reducing the activity). In the example of a haploid organism with genotypes (at two lociLocus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
) 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 + aB − ab | No epistasis, additive inheritance |
| AB > Ab + aB − ab | Synergistic epistasis |
| AB < Ab + aB − ab | Antagonistic epistasis |
Understanding whether the majority of genetic interactions are synergistic or antagonistic will help solve such problems as the evolution of sex
Evolution of sex
The evolution of sexual reproduction is currently described by several competing scientific hypotheses. All sexually reproducing organisms derive from a common ancestor which was a single celled eukaryotic species. Many protists reproduce sexually, as do the multicellular plants, animals, and fungi...
.
Epistasis and 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 KondrashovAlexey Kondrashov
Alexey S. Kondrashov is a professor at the University of Michigan in Ann Arbor, MI.He has worked on a variety of subjects in evolutionary genetics...
, and is sometimes known as the deterministic mutation hypothesis
and has also been tested using artificial gene networks
Gene regulatory network
A gene regulatory network or genetic regulatory network is a collection of DNA segments in a cell whichinteract with each other indirectly and with other substances in the cell, thereby governing the rates at which genes in the network are transcribed into mRNA.In general, each mRNA molecule goes...
.
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. For example, see MacCarthy and Bergman. In addition, in those tests which used artificial gene networks, negative epistasis is only found in more densely connected networks, whereas empirical evidence indicates that natural gene networks are sparsely connected, and theory shows that selection for robustness will favor more sparsely connected and minimally complex networks.
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. 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.
- Synthetic lethalitySynthetic lethalitySynthetic lethality arises when a combination of mutations in two or more genes leads to cell death, whereas a mutation in only one of these genes does not, and by itself is said to be viable In a synthetic lethal genetic screen, it is necessary to begin with a mutation that does not kill the cell,...
or unlinked non-complementation - two mutations fail to complementComplementation (genetics)In genetics, complementation refers to a relationship between two different strains of an organism which both have homozygous recessive mutations that produce the same phenotype . These strains are true breeding for their mutation...
and yet do not map to the same locusLocus (genetics)In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
. - Intragenic complementation, allelic complementation, or interallelic complementation - two mutations map to the same locusLocus (genetics)In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
, yet the two alleles complement in the heteroallelic diploid. Causes of intragenic complementation include:- homology effects such as transvectionTransvection (genetics)Transvection is an epigenetic phenomenon that results from an interaction between an allele on one chromosome and the corresponding allele on the homologous chromosome. Transvection can lead to either gene activation or repression...
, 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.
- homology effects such as transvection
See also
- Co-adaptationCo-adaptationIn biology, co-adaptation, or coadaptation refers to the mutual adaptation of:* Species: see mutualism, symbiosis* organs: see the evolution of the eye.* Genes or gene complexes: see Linkage disequilibrium, epistasis...
- Epistasis and functional genomicsEpistasis and Functional GenomicsEpistasis refers to genetic interactions in which the mutation of one gene masks the phenotypic effects of a mutation at another locus. Systematic analysis of these epistatic interactions can provide insight into the structure and function of genetic pathways. By examining the phenotypes resulting...
- MutationMutationIn molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
- Quantitative trait locusQuantitative trait locusQuantitative traits refer to phenotypes that vary in degree and can be attributed to polygenic effects, i.e., product of two or more genes, and their environment. Quantitative trait loci are stretches of DNA containing or linked to the genes that underlie a quantitative trait...
External links
- Science Aid: Epistasis High school (GCSE, Alevel) resource.
- GeneticInteractions.org
- Epistasis.org