Dissecting the Genetic Architecture of Host–Pathogen Specificity

In this essay, I argue that unraveling the full genetic architecture (i.e., the number, position, effect, and interactions among genes underlying phenotypic variation) and molecular landscape of host–pathogen interactions can only be achieved by accounting for their genetic specificity. Indeed, the outcome of host–pathogen interactions often depends on the specific pairing of host and pathogen genotypes [1]. In such cases, the infection phenotype does not merely result from additive effects of host and pathogen genotypes, but also from a specific interaction between the two genomes (Box 1). This specific component, which can be measured by the interaction term in a two-way statistical analysis of phenotypic variation as a function of host and pathogen genotypes, is referred to as a genotype-by-genotype (G×G) interaction [1]. By analogy to genotype-by-environment (G×E) interactions that occur when different genotypes respond differently to environmental change, G×G interactions occur when the response of host genotypes differs across pathogen genotypes. Although the concept of G×G interactions has mostly been used by evolutionary ecologists to describe the specificity of host immune defenses against pathogens [2], it can be applied to any phenotype resulting from the specific interaction between two genomes. The general definition of G×G interactions allows its use to characterize phenotypes ranging from macroscopic traits such as lifespan [3] to the level of gene expression [4]. Here, the genetic specificity of host–pathogen associations is defined in the sense of G×G interactions. This definition differs from that of immunological specificity, which is the ability of a host to recognize and mount an immune response against a particular pathogen genotype or antigen. Whereas immunological specificity often depends on infection history (i.e., past exposure to a pathogen), genetic specificity describes the intrinsic compatibility between host and pathogen genotypes and occurs independently of infection history.