Dissecting the Genetic Architecture of Host–Pathogen Specificity

In this essay, I argue that unraveling thefull genetic architecture (i.e., the number,position, effect, and interactions amonggenes underlying phenotypic variation)and molecular landscape of host–pathogeninteractions can only be achieved byaccounting for their genetic specificity.Indeed, the outcome of host–pathogeninteractions often depends on the specificpairing of host and pathogen genotypes[1]. In such cases, the infection phenotypedoes not merely result from additive effectsof host and pathogen genotypes, but alsofrom a specific interaction between thetwo genomes (Box 1). This specific com-ponent, which can be measured by theinteraction term in a two-way statisticalanalysis of phenotypic variation as afunction of host and pathogen genotypes,is referred to as a genotype-by-genotype(G6G) interaction [1]. By analogy togenotype-by-environment (G6E) interac-tions that occur when different genotypesrespond differently to environmentalchange, G6G interactions occur whenthe response of host genotypes differsacross pathogen genotypes. Although theconcept of G6G interactions has mostlybeen used by evolutionary ecologists todescribe the specificity of host immunedefenses against pathogens [2], it can beapplied to any phenotype resulting fromthe specific interaction between two ge-nomes. The general definition of G6Ginteractions allows its use to characterizephenotypes ranging from macroscopictraits such as lifespan [3] to the level ofgene expression [4]. Here, the geneticspecificity of host–pathogen associations isdefined in the sense of G6G interactions.This definition differs from that of immu-nological specificity, which is the ability ofa host to recognize and mount an immuneresponse against a particular pathogengenotype or antigen. Whereas immuno-logical specificity often depends on infec-tion history (i.e., past exposure to apathogen), genetic specificity describesthe intrinsic compatibility between hostand pathogen genotypes and occurs inde-pendently of infection history.In some instances, the specificity ofhost–pathogen associations can be ex-plained to a large extent by major genesof hosts and pathogens, as in the gene-for-gene model of plant–pathogen compati-bility [5,6]. In general, however, multiplegenes and epistatic interactions amongthese genes determine the infection out-come [7–9]. A recent meta-analysis of 500published studies reporting quantitativetrait loci (QTL) for host resistance topathogens in plants and animals revealedthat the genetic architecture of this traitvaries dramatically across different combi-nations of host and pathogen genotypes[9]. Thus, different host–pathogen associ-ations involve different QTL and epistaticinteractions, indicating that a substantialportion of phenotypic variation derivesfrom the specific interaction between thetwo genomes. This is made even morecomplex when multiple pathogen speciesor strains infect the same host [10] and/orwhen G6G interactions are environment-dependent [11,12]. It is striking that, to date, quantitativegenetic studies of host–pathogen systemshave neglected the specific component ofthe interaction. Dissecting the geneticarchitecture of complex infection traitshas traditionally relied on QTL mappingstrategies [7,9] and more recently onassociation analyses of candidate genepolymorphisms [8]. A major caveat ofthese QTL mapping and associationstudies is that they focus on either thehost or the pathogen genome. Becausethey consider variation in only one of thetwo interacting organisms, these studiesignore specific host genome by pathogengenome interactions. In order to fullydissect the genetic architecture and ex-plore the molecular landscape of host–pathogen interactions, it will be necessaryto account for the specific component ofthe relationship. This should be madepossible by recent developments in molec-ular strategies combining host and patho-gen genetics [13–15] and in quantitativegenetic models of host–pathogen interac-tions allowing detection of host QTL bypathogen QTL interactions [16,17]. Ad-vantage could also be taken from existingmethods for analysis of gene–gene andgene–environment interactions [18–21]. Acritical (and limiting) aspect for investigat-ing genetic specificity is the need toinclude different combinations of hostand pathogen genotypes in the experi-mental design.From a fundamental standpoint, im-proved knowledge of the genetic architec-ture of host–pathogen specificity hasimportant implications for our under-standing of the ecology and evolution ofhost–pathogen associations. The geneticspecificity of host–pathogen interactions isthought to promote the maintenance ofhost and pathogen genetic diversity viafrequency-dependent coevolutionary cy-cles [22–25], which in turn favor higherrates of mutation, recombination, andsexual reproduction [26]. Unraveling thegenetic architecture and molecular land-scape of host–pathogen specificity, com-bined with molecular evolution analyses,will shed light on the mechanistic basis ofthe infection process and the biochemistryof host–pathogen recognition [27–30]. The genetic model and precise epistaticinteractions underlying host–pathogenspecificity are critical determinants of