epistasis
Mackay TFC 2014 Epistasis and quantitative traits: using model organisms to study gene-gene interactions. Nat Rev Genet 15:22-33.
- the role of epistasis in the genetic architecture of quantitative traits is controversial
- this controversy arises because most genetic variation for quantitative traits is additive
- additive variance is consistent with pervasive epistasis
- additivity can be an emergent property of underlying genetic interaction networks
- epistasis causes hidden quantitative genetic variation in natural populations and could be responsible for the small additive effects, missing heritability and the lack of replication that are typically observed for human complex traits
- efforts to chart the genotype–phenotype map for quantitative traits using both linkage and association study designs have mainly focused on estimating additive effects of single loci
- epistasis (that is, nonlinear interactions between segregating loci) is a biologically plausible feature of the genetic architecture of quantitative traits
- most observed genetic variance for quantitative traits is additive
- such genetic variance could be either 'real'
- or 'apparent' from non-zero main effects that arise from epistatic gene action at many loci
- this distinction is not important if the goal is to estimate heritability, to predict phenotype from genetic relationships among individuals16,17 or to predict short-term response to artificial and natural selection because all of these depend on additive variance that is specific to the population of interest
- knowing whether additive variance is an emergent property of underlying epistasis becomes crucial if the goals are to functionally dissect the genotype–phenotype map, to determine genetic interaction networks, to understand the effects of mutational perturbations on standing variation, to predict long-term responses to artificial and natural selection, and to understand the consequences of genetic drift and inbreeding on quantitative traits
- properties of genetic interaction networks
- network hub genes have the following characteristics compared with genes that have fewer interactions:
- they are more important for fitness
- they are more pleiotropic
- their mRNAs are expressed at higher levels
- they are more sensitive to environmental perturbations
- they are more evolutionarily conserved
- genetic interaction networks are mostly decoupled from protein–protein interaction networks
- although properties of genetic network architecture are conserved across species, the network connectivities are not conserved
