Epistasis is the phenomenon of the effect
of one gene being dependent on the presence
of one or more 'modifier genes', the genetic
background.
Thus, epistatic mutations have different effects
in combination than individually.
It was originally a concept from genetics
but is now used in biochemistry, computational
biology and evolutionary biology.
It arises due to interactions, either between
genes, or within them, leading to non-additive[clarification
needed] effects.
Epistasis has a large influence on the shape
of evolutionary landscapes, which leads to
profound consequences for evolution and evolvability
of phenotype traits.
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.[21]
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 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 ribosome), inhibit each other's activity,
or if the protein encoded by one gene modifies
the other (such as by phosphorylation).
Alternatively the interaction may be indirect,
where the genes encode components of a metabolic
pathway or network, developmental pathway,
signalling pathway or transcription factor
network.
For example, the gene encoding the enzyme
that synthesizes penicillin is of no use to
a fungus without the enzymes that synthesize
the necessary precursors in the metabolic
pathway.
Just as mutations in two separate genes can
be non-additive if those genes interact, mutations
in two codons within a gene can be non-additive.
In genetics this is sometimes called intragenic
complementation when one deleterious mutation
can be compensated for by a second mutation
within that gene.
This occurs when the amino acids within a
protein interact.
Due to the complexity of protein folding and
activity, additive mutations are rare.
Proteins are held in their tertiary structure
by a distributed, internal network of cooperative
interactions (hydrophobic, polar and covalent).[22]
Epistatic interactions occur whenever one
mutation alters the local environment of another
residue (either by directly contacting it,
or by inducing changes in the protein structure).[23]
For example, in a disulphide bridge, a single
cysteine has no effect on protein stability
until a second is present at the correct location
at which point the 
two cysteines form a chemical bond which enhances
the stability of the protein.[24] This would
be observed as positive epistasis where the
double-cysteine variant had a much higher
stability than either of the single-cysteine
variants.
Conversely, when deleterious mutations are
introduced, proteins often exhibit mutational
robustness whereby as stabilising interactions
are destroyed the protein still functions
until it reaches some stability threshold
at which point further destabilising mutations
have large, detrimental effects as the protein
can no longer fold.
This leads to negative epistasis whereby mutations
that have little effect alone have a large,
deleterious effect together.[25][26]
In enzymes, the protein structure orients
a few, key amino acids into precise geometries
to form an active site to perform chemistry.[27]
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.
Diploid organisms contain two copies of each
gene.
If these are different (heterozygous / heteroallelic),
the two different copies of the allele may
interact with each other to cause epistasis.
This is sometimes called allelic complementation,
or interallelic complementation.
It may be caused by several mechanisms, for
example transvection, where an enhancer from
one allele acts in trans to activate transcription
from the promoter of the second allele.
Alternately, trans-splicing of two non-functional
RNA molecules may produce a single, functional
RNA.
Similarly, at 
the protein level, proteins that function
as dimers may form a heterodimer composed
of one protein from each alternate gene and
may display different 
properties 
to 
the homodimer of one or 
both variants.
