Here we report the sequence of the region that determines rapid allograft rejection in chickens, the chicken major histocompatibility complex (MHC) This 92-kilobase region of the B locus contains only 19 genes, making the chicken MHC roughly 20-fold smaller than the human MHC Virtually all the genes have counterparts in the human MHC, defining a minimal essential set of MHC genes conserved over 200 million years of divergence between birds and mammals They are organized differently, with the class III region genes located outside the class II and class I region genes The absence of proteasome genes is unexpected and might explain unusual peptide-binding specificities of chicken class I molecules The presence of putative natural killer receptor gene(s) is unprecedented and might explain the importance of the B locus in the response to the herpes virus responsible for Marek's diseases The small size and simplicity of the chicken MHC allows co-evolution of genes as haplotypes over considerable periods of time, and makes it possible to study the striking MHC-determined pathogen-specific disease resistance at the molecular level

The chicken B locus is a minimal essential major histocompatibility complex

The major histocompatibility complex (MHC) is the center of the immune universe. Genes in the MHC determine which antigens are processed and presented. Not surprisingly, the MHC contributes the major genetic component to important autoimmune diseases and will no doubt, although evidence is limited, contribute to resistance to infectious disorders. Vertebrates all seem to have MHC genes and it should be possible to determine, within the next few years, whether the clustering of antigen processing and presenting genes in this region is a conserved feature. One could imagine an evolutionary advantage to maintaining the MHC as a unit, either to coordinate expression of the genes in different tissues, or to coordinate T-cell selection during thymic ontogeny, since inheriting a linked set of polymorphic gene products may help to avoid conflicts during positive and negative selection. 153 refs., 9 figs., 3 tabs.

“Both man & bird & beast”: comparative organization of MHC genes

The high polymorphism of classical Mhc molecules found in mammals is not simply the result of strong selection for pathogen resistance in the recent past, since there are virtually no examples of diseases caused by infectious pathogens for which resistance is determined by particular Mhc haplotypes, and in the best-studied case, a particular aspect of malaria in humans, the selection is remarkably weak. We discuss three possibilities to explain high polymorphism in mammals: accumulating, merging and boosting. The mammalian Mhc is complicated and redundant, so that every Mhc haplotype may give some level of resistance due to multiple classical Mhc genes as well as other disease resistance genes; this frustrates the attempts to demonstrate selection for disease resistance. We have looked at two vertebrate groups that may represent two extreme examples of selection for Mhc polymorphism. Birds, like mammals, have highly a polymorphic Mhc that determines strong allograft rejection. However, chickens have a much smaller, compact and simpler Mhc than mammals, as though the Mhc has been stripped down to the essentials during evolution. The selection on a single Mhc gene should be much stronger than on a large multigene family and, in fact, there are a number of viral diseases for which resistance and susceptibility are determined by particular chicken Mhc haplotypes. We have determined the peptide motifs for the chicken class I molecules from a number of haplotypes, which may explain some disease associations quite simply. On the other hand, salamanders have very low Mhc polymorphism and slow allograft rejection. We have isolated axolotl Mhc molecules and shown that they cosegregate with the locus that determines graft rejection in the axolotl, have only a few alleles and only weakly stimulate axolotl T lymphocytes in mixed lymphocyte culture. We believe that salamanders have classical Mhc molecules but most T cells do not recognize them, so that there is no strong selection for polymorphism.

A “Minimal Essential Mhc” and an “Unrecognized Mhc”: Two Extremes in Selection for Polymorphism

Malaria parasites are a widespread and species-rich group infecting many wild populations of mammals, birds and reptiles. Studies on humans have demonstrated that genetic factors play a key role in the susceptibility and outcome of malaria infections. Until the present study, it has not been examined whether genetic variation in hosts is important for the outcome of malaria infections in natural avian populations. We investigated associations between major histocompatibility complex (MHC) genes and prevalence of three different avian malaria parasites (Haemoproteus payevskyi (GRW1), Plasmodium sp. (GRW2) and Plasmodium sp. (GRW4)) in a long-term study of great reed warblers Acrocephalus arundinaceus. We hypothesized that the MHC genes could either give full protection against a malaria infection, or confer protection against lethal malaria and direct the infection towards being milder. We found a positive association between numbers of MHC class I alleles (a measure of level of heterozygosity) and prevalence of the GRW2 parasite, suggesting the latter scenario. There was also a positive association between a specific MHC allele (B4b), previously shown to be under frequency-dependent selection in the study population, and prevalence of GRW2. These associations suggest that individuals carrying either a large number of MHC alleles or a specific MHC allele are protected against lethal malaria infections.

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Associations between malaria and MHC genes in a migratory songbird

The MHC is highly polymorphic in most vertebrates and the suggested selective mechanisms responsible for the maintenance of this variation are several, including maternal‐fetal interaction, parasite resistance, and negative-assortative mating. Evidence for these mechanisms is reviewed and estimates of the amount of selection in a number of studies are given. Although there is much yet to be understood about the mechanism and extent of balancing selection at MHC, new advances in molecular genetic technology and increasing interest in MHC from many types of biologists promise answers in the near future.

Balancing selection and MHC.

The major histocompatibility complex (MHC) of chicken is the B complex, originally described as a blood group system. Its three classes of cell membrane antigens have been clearly defined by serological, histogenetic, biochemical, and molecular biological methods. Two of these classes are homologous to classes I and II of mammals (B-F and B-L respectively), while the third--B-G antigen--has not so far been detected in mammals. The possible role of this antigen is discussed. The genes of the MHC play important roles in the regulation of immune response, disease resistance, and regression of Rous sarcomas.

J. Plachy

Papers

Biology of the chicken MHC (B complex).