MHC genes are the most polymorphic loci known in vertebrates and this diversity is thought to be maintained via antagonistic coevolution with pathogens. However, for antagonistic coevolution to operate as such a mechanism the following predictions must be confirmed. First, adaptations that benefit pathogen fitness in one host MHC genotype are predicted to be costly to pathogen fitness in another unfamiliar host MHC. Second, these genotype-specific patterns of adaptation must produce correlated patterns of virulence. Using serial passage, I induced pathogen adaptation in three MHC-congenic lines of BALB/c mice. Results from cross-infection studies of adapted pathogens support these predictions and provide the first experimental confirmation of antagonistic coevolution as a mechanism capable of explaining the extreme levels of genetic diversity at MHC.

In order to test the relative contribution of genetic diversity in the MHC region versus genetic diversity elsewhere in the genome as a target of pathogen adaptation, I serially passaged a pathogen through inbred genotypes of mice that were matched across the genome but different at the MHC, or completely different across the entire genome. Cross-infection studies comparing the fitness tradeoffs suffered by adapted pathogens infecting unfamiliar hosts from one of these two treatments support the MHC as a primary target of pathogen adaptation. In fact, MHC differences alone were responsible for approximately 72% of the fitness tradeoffs suffered by adapted pathogens.

To test the prediction that genetic diversity in host populations creates an impediment to pathogen adaptation, we compared patterns of adaptation between pathogens serially passaged through a series of genetically identical hosts or through alternating host genotypes. Rapid pathogen adaptation and virulence evolution was observed in pathogens serially exposed to genetically identical hosts only. Thus, host genetic diversity is an impediment to pathogen adaptation, which, consequently, also reduces the severity of infectious disease.

Recent evidence suggests that MHC diversity has costs associated with it in both viability and fecundity. Fitness benefits and costs associated with MHC diversity imply tradeoffs, and suggest that maximal diversity may not always be optimal. Using a review of the recent literature, I crafted a synthetic argument outlining multiple physiological costs associated with MHC diversity that may explain the paradox of why individuals within a vertebrate population harbor only a small fraction of the MHC allelic diversity observed in their population.