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 (G6G) interaction [1]. By analogy to genotype-by-environment (G6E) interactions that occur when different genotypes respond differently to environmental change, G6G interactions occur when the response of host genotypes differs across pathogen genotypes. Although the concept of G6G 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 G6G 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 G6G 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. In some instances, the specificity of host–pathogen associations can be explained to a large extent by major genes of hosts and pathogens, as in the gene-forgene model of plant–pathogen compatibility [5,6]. In general, however, multiple genes and epistatic interactions among these genes determine the infection outcome [7–9]. A recent meta-analysis of 500 published studies reporting quantitative trait loci (QTL) for host resistance to pathogens in plants and animals revealed that the genetic architecture of this trait varies dramatically across different combinations of host and pathogen genotypes [9]. Thus, different host–pathogen associations involve different QTL and epistatic interactions, indicating that a substantial portion of phenotypic variation derives from the specific interaction between the two genomes. This is made even more complex when multiple pathogen species or strains infect the same host [10] and/or when G6G interactions are environmentdependent [11,12]. It is striking that, to date, quantitative genetic studies of host–pathogen systems have neglected the specific component of the interaction. Dissecting the genetic architecture of complex infection traits has traditionally relied on QTL mapping strategies [7,9] and more recently on association analyses of candidate gene polymorphisms [8]. A major caveat of these QTL mapping and association studies is that they focus on either the host or the pathogen genome. Because they consider variation in only one of the two interacting organisms, these studies ignore specific host genome by pathogen genome interactions. In order to fully dissect the genetic architecture and explore the molecular landscape of host– pathogen interactions, it will be necessary to account for the specific component of the relationship. This should be made possible by recent developments in molecular strategies combining host and pathogen genetics [13–15] and in quantitative genetic models of host–pathogen interactions allowing detection of host QTL by pathogen QTL interactions [16,17]. Advantage could also be taken from existing methods for analysis of gene–gene and gene–environment interactions [18–21]. A critical (and limiting) aspect for investigating genetic specificity is the need to include different combinations of host and pathogen genotypes in the experimental design. From a fundamental standpoint, improved knowledge of the genetic architecture of host–pathogen specificity has important implications for our understanding of the ecology and evolution of host–pathogen associations. The genetic specificity of host–pathogen interactions is thought to promote the maintenance of host and pathogen genetic diversity via frequency-dependent coevolutionary cycles [22–25], which in turn favor higher rates of mutation, recombination, and sexual reproduction [26]. Unraveling the genetic architecture and molecular landscape of host–pathogen specificity, combined with molecular evolution analyses, will shed light on the mechanistic basis of the infection process and the biochemistry of host–pathogen recognition [27–30]. The genetic model and precise epistatic interactions underlying host–pathogen specificity are critical determinants of