A large case-control study of malaria in West African children shows that a human leucocyte class I antigen (HLA-Bw53) and an HLA class II haplotype (DRB1*1302-DQB1*0501), common in West Africans but rare in other racial groups, are independently associated with protection from severe malaria. In this population they account for as great a reduction in disease incidence as the sickle-cell haemoglobin variant. These data support the hypothesis that the extraordinary polymorphism of major histocompatibility complex genes has evolved primarily through natural selection by infectious pathogens.

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Common West African HLA antigens are associated with protection from severe malaria

The major histocompatibility complex (MHC) has become a paradigm for how selection can act to maintain adaptively important genetic diversity in natural populations. Here, we review the contribution of studies on the MHC in non-model species to our understanding of how selection affects MHC diversity, emphasising how ecological and ethological processes influence the tempo and mode of evolution at the MHC, and conversely, how variability at the MHC affects individual fitness, population dynamics and viability. We focus on three main areas: the types of information that have been used to detect the action of selection on MHC genes; the relative contributions of parasite-mediated and sexual selection on the maintenance of MHC diversity; and possible future lines of research that may help resolve some of the unanswered issues associated with MHC evolution.

/pdf/the-evolutionary-ecology-of-the-major-histocompatibility-20e94rlsvi.pdf

The evolutionary ecology of the major histocompatibility complex.

Genetic studies have typically inferred the effects of human impact by documenting patterns of genetic differentiation and levels of genetic diversity among potentially isolated populations using selective neutral markers such as mitochondrial control region sequences, microsatellites or single nucleotide polymorphism (SNPs). However, evolutionary relevant and adaptive processes within and between populations can only be reflected by coding genes. In vertebrates, growing evidence suggests that genetic diversity is particularly important at the level of the major histocompatibility complex (MHC). MHC variants influence many important biological traits, including immune recognition, susceptibility to infectious and autoimmune diseases, individual odours, mating preferences, kin recognition, cooperation and pregnancy outcome. These diverse functions and characteristics place genes of the MHC among the best candidates for studies of mechanisms and significance of molecular adaptation in vertebrates. MHC variability is believed to be maintained by pathogen-driven selection, mediated either through heterozygote advantage or frequency-dependent selection. Up to now, most of our knowledge has derived from studies in humans or from model organisms under experimental, laboratory conditions. Empirical support for selective mechanisms in free-ranging animal populations in their natural environment is rare. In this review, I first introduce general information about the structure and function of MHC genes, as well as current hypotheses and concepts concerning the role of selection in the maintenance of MHC polymorphism. The evolutionary forces acting on the genetic diversity in coding and non-coding markers are compared. Then, I summarise empirical support for the functional importance of MHC variability in parasite resistance with emphasis on the evidence derived from free-ranging animal populations investigated in their natural habitat. Finally, I discuss the importance of adaptive genetic variability with respect to human impact and conservation, and implications for future studies.

/pdf/the-importance-of-immune-gene-variability-mhc-in-4yulbv2kgg.pdf

The importance of immune gene variability (MHC) in evolutionary ecology and conservation

Disease and evolution

In the 1960s, when population geneticists first began to collect data on the amount of genetic variation in natural populations, balancing selection was invoked as a possible explanation for how such high levels of molecular variation are maintained. However, the predictions of the neutral theory of molecular evolution have since become the standard by which cases of balancing selection may be inferred. Here we review the evidence for balancing selection acting on the major histocompatibility complex (MHC) of vertebrates, a genetic system that defies many of the predictions of neutrality. We apply many widely used tests of neutrality to MHC data as a benchmark for assessing the power of these tests. These tests can be categorized as detecting selection in the current generation, over the history of populations, or over the histories of species. We find that selection is not detectable in MHC datasets in every generation, population, or every evolutionary lineage. This suggests either that selection on the MHC is heterogeneous or that many of the current neutrality tests lack sufficient power to detect the selection consistently. Additionally, we identify a potential inference problem associated with several tests of neutrality. We demonstrate that the signals of selection may be generated in a relatively short period of microevolutionary time, yet these signals may take exceptionally long periods of time to be erased in the absence of selection. This is especially true for the neutrality test based on the ratio of nonsynonymous to synonymous substitutions. Inference of the nature of the selection events that create such signals should be approached with caution. However, a combination of tests on different time scales may overcome such problems.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.0014-3820.2003.tb00580.x

Perspective: detecting adaptive molecular polymorphism: lessons from the MHC.

Lines of chickens selected from a common ancestral population for either resistance or susceptibility to Marek's disease developed contrasting frequencies of particular B alloalleles. Comparison of inoculated sibs in backcross-families revealed that the B alloalleles characterizing the two lines accounted for an eightfold difference in tumor incidence. This genetic difference in tumorigenesis associated with the alloalleles of the major histocompatibility complex is probably expressed through the cell-mediated immune system.

https://science.sciencemag.org/content/sci/195/4274/193.full.pdf

RK Cole

Papers

Marek's disease: effects of B histocompatibility alloalleles in resistant and susceptible chicken lines