Penetrance and expressivity

Penetrance (according to wikipedia) is the proportion of individuals with the variant (allele) that also express an associated trait (phenotype).

Expressivity (according to this note) is the degree to which the trait expression differs among individuals. For instance, there is a polydactyly (extra toes) trait in inbreeding cats. Individual carriers may have different number of extra toes. Therefore expressivity is only meaningful when the trait is quantitatively measurable in some sense. An extreme case is that the trait/disease is binary, in which the expressivity for an individual is the trait/disease state. And its population average is penetrance.

Genetic background effect and examples

It has been found that there are cases where the individual carries the Mendelian disease causing mutation but has no disease symptom. It implies that the incomplete penetrance may depend on the genetic background. The genetic background includes the genes that affect/interact with the disease causing genes.

Also, the same disease with the same mutated genes (involves multiple loci), the expressivity is different among loci, which can also result from the various genetic background.

Cystic fibrosis is monogenic disease. 50% patients carry the same disease causing allele but the disease symptoms are highly variable because of the modifier background genes. There is also case where pedigree-specific phenotype is found. In such case, the same exon deletion causes one syndrome in one pedigree but a more severe one in another.

Single gene mutations depend on multiple background loci

The idea is that the expressivity and penetrance of a mutation \(M\) is the function of \(M\) and the interaction between \(M\) and \(B\). There are experimental support of \(M \times B\) effect in fruit flies and mice.

Genome-wide and molecular insights into background interactions

Using RNAi researchers have looked for the background interaction in \(C. elegans\). The studies indicate that

1. The effect of background interact is small individually but big together.
2. The effect may depend on the expression level of the affected gene

Cryptic genetic variants

Cryptic genetic variants are SNVs that show phenotypic effect under atypical conditions. Such studies imply that gene regulatory network may play a role in genetic background effects. Also, disease-related signaling pathway may be enriched for CGVs.

The contribution of genetic background is ignored by current genetic research

The effect of genetic background can confound the result so geneticists tend to remove such confounding factor by using organisms with single genetic background. This strategy is to maximize the reproducibility but it miss the genetic background effect which is of great importance in understanding the phenotypic variability of human diseases.

The author points out the general experimental framework to study genetic background effect using model organism. With two populations, \(M \times B_1\) and \(M \times B_2\) where both of them have disease causing mutation but only one of them has phenotype. By crossing the two populations and performing linkage analysis, the locus associated with the background effect can be identified.

Besides genetic background effects, the phenotypic effects of a mutation can differ in the population with the same genetic background due to environmental effects and stochastic effects.