For example, since the modifier alleles are likely to be common variants, traditional genetic approaches are problematic, since the same allele could be associated with more than one line of inheritance within a family tree[ 7].
While genes with low-penetrance and/or modifier alleles can be linked to diverse biological processes, the FA/BrCa pathway is still incomplete [ 2, 20].
We thus suggest that further modeling of the effects of choosing starting populations from low-input, high-stress environments with the goal of locating populations with small attenuating networks and little variation in modifier alleles would be productive.
This highlights the importance of analyzing the function of candidate genes in the appropriate tissue and under appropriate stress conditions, as the phenotypic differences of modifier alleles may be subtle or highly specific and therefore easily overlooked in the wrong setting.
Other human diseases are caused by alleles of major effect, but the expression of such alleles is variable and considerably affected by modifier genes, i.e. the genetic background of the individual is important.
Fisher (1928) proposed that dominance of the wild-type alleles is the result of selection on modifier genes, which epistatically mask the action of the mutant allele in a heterozygote.
This indicates that the different expressivity of the zll-1 mutation between Ler-0 and Col alleles is not due to the nature of the mutant alleles, but must be caused by genetic modifiers.
Note that the performance of these alleles is not directly comparable because neither lamG262 or lam04643 escapers were from outcrossed stocks, so their righting reflex phenotypes were almost certainly enhanced by genetic modifiers.
Such mutant alleles are among "modifier genes", the case of cystic fibrosis CFTR gene being the classical example (recent review [ 19]), some of which are capable of altering the phenotype of a large number of other mutations.
It is more common to see modifiers as background effects when defined alleles are "transplanted" into new genomic contexts (Hamilton and Yu 2012); however, it is labor-intensive to identify the allele conferring the newly visible modifier effect in an inbred or ecotype in most model systems.
