An Asymmetric Model of Heterozygote Advantage at Major Histocompatibility Complex Genes: Degenerate Pathogen Recognition and Intersection Advantage

Abstract

We characterize the function of MHC molecules by the sets of pathogens that they recognize, which we call their ''recognition sets.'' Two features of the MHC-pathogen interaction may be important to the theory of polymorphism construction at MHC loci: First, there may be a large degree of overlap, or degeneracy, among the recognition sets of MHC molecules. Second, when infected with a pathogen, an MHC genotype may have a higher fitness if that pathogen belongs to the overlapping portion, or intersection, of the two recognition sets of the host, when compared with a genotype that contains that pathogen in only one of its recognition sets. We call this benefit ''intersection advantage,'' g, and incorporate it, as well as the degree of recognition degeneracy, m, into a model of heterozygote advantage that utilizes a set-theoretic definition of fitness. Counterintuitively, we show that levels of polymorphism are positively related to m and that a high level of recognition degeneracy is necessary for polymorphism at MHC loci under heterozygote advantage. Increasing g reduces levels of polymorphism considerably. Hence, if intersection advantage is significant for MHC genotypes, then heterozygote advantage may not explain the very high levels of polymorphism observed at MHC genes.

Distinct evolutionary strategies of human leucocyte antigen loci in pathogen-rich environments

“…The loss of PBS role in antigen recognition (i.e. recognition degeneracy like described by Stoffels & Spencer [55]) would have been essential for HLA-DQ to guarantee immune protection against a large variety of pathogens despite the existence of only a few stable ab heterodimers. A further conclusion is that HLA loci submitted to different selective forces-balancing selection in the case of HLA-A, -B, -C and -DRB1, and purifying selection in the case of HLA-DQA1 and -DQB1-would have followed distinct evolutionary strategies to provide efficient immune protection in pathogen-rich environments.…”

Major histocompatibility complex (MHC) heterozygote superiority to natural multi-parasite infections in the water vole ( Arvicola terrestris )

“…Whereas our findings support an overdominant mode of MHC evolution, some theoretical studies predict that overdominance is inadequate or only capable of maintaining high levels of MHC variation under assumptions that are arguably unrealistic, such as all heterozygotes being of equivalent fitness . In a given system, the evolutionary dynamics between MHC variation and parasites is likely to depend on a number of parameters, including the number of MHC alleles, allelic divergence and parasite variability (Richman et al 2001;Hedrick 2002;Stoffels & Spencer 2008). Therefore, there exists a considerable empirical challenge to make the findings between studies comparable, both in the interpretation of results and using appropriate analytical techniques.…”

Signals of major histocompatibility complex overdominance in a wild salmonid population

“…But why should such a signal be observed in this population when numerous other studies have failed to detect such an association? A recent simulation study (Stoffels & Spencer 2008) provides a possible answer to this question. Namely, by characterizing the function of MHC molecules by the sets of parasites they recognize (recognition sets) as well as considering the effects of effective population size and genetic drift, Stoffels & Spencer were able to demonstrate that for populations with N e ¼ 1000 (the smallest N e considered), the number of alleles expected to be maintained at an MHC locus can be less than five, even with a relatively strong heterozygote advantage.…”