Introduction to Focus Issue: Genetic Interactions

Abstract

The perturbation of a gene in an organism's genome often causes changes in the organism's observable properties or phenotypes. It is not obvious a priori whether the simultaneous perturbation of two genes produces a phenotypic change that is easily predictable from the changes caused by individual perturbations. In fact, this is often not the case: the nonlinearity and interdependence between genetic variants in determining phenotypes, also known as epistasis, is a prevalent phenomenon in biological systems. This focus issue presents recent developments in the study of epistasis and genetic interactions, emphasizing the broad implications of this phenomenon in evolutionary biology, functional genomics, and human diseases. © 2010 American Institute of Physics. ͓doi:10.1063/1.3456057͔A long-standing question in biology is how the instructions written in the heritable blueprint of a living system (its genotype) determine its observable properties (its phenotype).1,2 The genotype-phenotype mapping is important for many reasons, from gaining fundamental understanding of how evolution works, 1,3 to uncovering the molecular mechanisms of genetic disease, 4,5 and identifying the "Achilles' heels" of microbial pathogens.6,7 One way of probing this mapping is to study how different versions of the genotype (either naturally occurring or artificially generated) produce different phenotypes. 8,9This focus issue brings together different viewpoints and approaches to understanding epistasis, 3,10-12 i.e., the nonlinearities often present in the genotype-phenotype mapping.To introduce the concept of epistasis, let us start with a highly oversimplified view where the myriad instructions written in a genome can be thought of as discrete, binary units ͑"genes"͒, whose values determine an array of quantitative phenotypic traits. Assume for simplicity that an unperturbed organism has all genes set to zero. Single perturbation experiments may then be performed, switching individual genes to the value one. In a "first order" approximation of biology, one may be satisfied with knowing how the perturbation of each gene affects the phenotypes. For example, imagine that gene A exerts some control over metabolic rate, such that switching A from zero to one decreases the metabolic rate by 10%. It may be the case that another gene B influences metabolic rate to the same extent. The first order approximation might still work if the perturbations of multiple genes combine according to a simple, general law. For example, the metabolic rate may be affected additively, so that simultaneous switching of A or B decreases metabolic rate by 20%.Yet, since the early days of genetics, it is known that living systems can deviate quite dramatically from such a simple linear behavior. An extreme case is one in which the effect of a double perturbation is drastically enhanced relative to the effects of individual perturbations ͑synergistic effect͒. In the example above, this may mean that the simultaneous switching of A and B gives a metabolic rate of zer...