From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics of Health

Abstract

Phenotypes are rarely consistent across genetic backgrounds and environments, but instead vary in many ways depending on allelic variants, unlinked genes, epigenetic factors, and environmental exposures. In the extreme, individuals carrying the same causal DNA sequence variant but on different backgrounds can be classified as having distinct conditions. Similarly, some individuals that carry disease alleles are nevertheless healthy despite affected family members in the same environment. These genetic background effects often result from the action of so-called "modifier genes" that modulate the phenotypic manifestation of target genes in an epistatic manner. While complicating the prospects for gene discovery and the feasibility of mechanistic studies, such effects are opportunities to gain a deeper understanding of gene interaction networks that provide organismal form and function as well as resilience to perturbation. Here, we review the principles of modifier genetics and assess progress in studies of modifier genes and their targets in both simple and complex traits. We propose that modifier effects emerge from gene interaction networks whose structure and function vary with genetic background and argue that these effects can be exploited as safe and effective ways to prevent, stabilize, and reverse disease and dysfunction.

Figure 1

Targets and Modifiers in a Hypothetical 10-Gene Genome Blue and red boxes highlight allelic variants that have potential modifier or target effects, respectively, on a phenotype of interest. (A) No modifier or target alleles affecting the baseline phenotype. (B) A gene 7 variant changes the basic phenotype but the genetic background does not also carry a variant with modifier activity. (C) The potential of a gene 3 variant to modify the phenotype cannot be realized because the genome does not carry an appropriate gene 7 allele. (D) Only where both modifier and target alleles occur together is the hypothetical phenotype altered. The arrow shows the functional relation between the modifier (gene 3) and its target (gene 7).

Figure 2

Classes of Modifier Effects (A) In this hypothetical example, the mutant allele m acts in a recessive manner to cause obesity and impaired glucose tolerance with complete penetrance in homozygotes. (B) A dominance modifier allele causes heterozygous m/+ mice to develop obesity and glucose tolerance phenotypes indistinguishable from homozygotes. (C) A genetic modifier of penetrance decreases the frequency of obesity and impaired glucose tolerance in m/m individuals. Some are unaffected, while others display phenotypes as extreme as the original m/m population. The resultant increased inter-individual variability within the population shifts the m/m glucose tolerance test (GTT) plot toward the basal phenotype but with an increase in standard deviation. (D) An expressivity modifier allele decreases trait severity in all m/m individuals, producing a phenotype intermediate between the original +/+ and m/m populations. The m/m GTT plot shift has the same magnitude as with the penetrance modifier (C), but without the associated increase in standard deviation due to relative phenotypic homogeneity within the population. (E) A genetic modifier of pleiotropy eliminates the impaired glucose tolerance phenotype without affecting obesity in m/m individuals.

Figure 3

Continuous Genetic Complexity of Modifiers and Targets in a Hypothetical 10-Gene Genome (A) Classic one modifier (blue), one target (red) case. (B) Three distinct genomes showing different modifiers (genes 1, 3, and 4) that modulate the phenotype associated with a gene 7 allele. (C) A modifier (gene 3) acting on three targets (genes 7, 8, and 10). (D) Example of complex epistasis with multiple genes (genes 1, 3, 4, 7, 8, and 10) that interact in various ways (some directional, others bidirectional). Red-blue checked boxes indicate genes that can act as both modifier and target.