An important part of the defense against parasites is the specific immune response of the host. The stimulus initiating the response is the binding of parasite-derived antigenic fragments to major histocompatibility (MHC) molecules and their presentation by these molecules to T lymphocytes. The MHC molecules vary from one individual to another and this variability is encoded in polymorphic Mhc genes. Some of the variant molecules are apparently incapable of presenting certain peptides to T lymphocytes and in such situations the capability of the host to respond to a parasitic infestation could be impaired. It is therefore important to understand the nature of the polymorphic variation in the Mhc genes. The main objective of the proposed research is to explain the origins, persistence, and significance of the Mhc polymorphism.
The specific aims of this research are to determine what proportion of the allelic variation pre-and postdates the formation of a species; to define the mechanisms of Mhc diversification; to estimate the age of human allelic and haplotype polymorphisms; to identify the mechanisms possibly maintaining the Mhc polymorphism in natural populations; to provide evidence that parasites are indeed the main driving force behind the Mhc diversification; to establish the part played by population structure in the long-term persistence of Mhc polymorphism; and to formulate an all-encompassing theory of Mhc polymorphism. The research will be carried out on 3 model systems: the primates, the mouse, and the zebra fish. It will include both molecular analyses of the Mhc genes and the study of the Mhc in natural and model populations.
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