Principles of modifier Genetics

The effect of modifier and target genes on phenotype are not additive (i.e. there is genetic interaction between the two). As shown in the above figure, modifier itself would not lead to phenotype. Taking another view, phenotype is the outcome of the integration of not only so called disease-causing genes but also environmental context and genetic background.

Types of target genes

It can be single target gene ot multigenic but the number of modifier-affected genes are largely unknown thanks to the lack of knowledge of genetic architecture and gene regulatory network.

Types of modifier effects

1. Penetrance: The modifier gene changes the penetrance of the disease-causing variant
2. Expressivity: The modifier gene changes the expressivity of the disease-causing variant
3. Dominance: Dominance measures the genetic dosage required for a phenotype (complete dominant means heterozygous and homozygous have exactly the same phenotype). The modifier gene changes the dominance of the disease-causing variant
4. Pleiotropy: When the modifier gene presents, it induces novel phenotypes

Modifiers of complex traits

For single-gene phenotype, modifier study use multigenic background among a population sharing the same target variant. But for complex trait, only single modifier variant can be tested in a genetically clean population for differential phenotype. Note that the modifier effect is also context-dependent.

To identify genetic modifier in humans

Two strategies are i) Look for shared variants between individuals with disease-causing variants without disease; iii) Perform target sequencing on disease gene to identify candidate with causal variant but phenotypically unaffected.

Through sequencing, researchers have found the reason of low penetrance of a disease-causing variant in a family where the occurrence of a common variant along with the disease-causing variant reaches 100% penetrance. Also, another research reported that the over-expression of one gene is protective to a LoF variant of disease gene.

GWAS type of study takes the strategy that collect a population which share the same disease-causing variant but with various phenotypic outcome (severity, age of onset, etc). Also, the same strategy can be used in family-based study (linkage study) where the signal-noise ratio is better.

To identify genetic modifiers in mice

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Nature of sequence variation

The number of identified modifier variants is small but it has suggested considerable heterogeneity. The following lists several outcomes of modifier variants:

1. Partial or complete loss of function (missense mutation or gene deletion)
2. Enhanced function (increased protein stability)
3. Gain of alternative function (novel protein-protein interaction)

Currently discovered modifier variants often occur in protein-coding exon but may act as regulatory variant (UTRs or promoters). In general, any variant that affect gene function by affecting interaction with other genes and networks is modifier variant.

Nature of modifier functions

One interesting question is that whether modifier genes tend to alter a general regulatory process or affect the target gene locally. It turns out that the latter is the case according to current data.

Mutational buffering

Here the authors discussed a general mechanism to suppress the effect of deleterious mutations by chaperones. But there is not mapping study showing that chaperone is modifier gene, but it is clear that the change of chaperone can modify the effect of a causal variant.

Global modifier refers to the genes that regulate the outcome of variant via general mechanisms, such as chaperones, chromatin modifiers, and transcriptional regulators.

It seems that global modifiers respond to generalized stress and modifier genes target specific dysfunctions.