Ontogeny and Phylogeny of the MHC

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DESCRIPTION (provided by applicant): In the past several years, there have been several entire vertebrate genomes sequenced, specifically those of human, mouse, and bony fish (e.g. the pufferfish). In the vertebrate tree, the cartilaginous fish (elasmobranchs including the sharks, skates, and rays) and amphibians are at important phylogenetic junctures, but these animals have not been well studied at the genetic level. Cartilaginous fish are at the base of the jawed vertebrate tree and are the oldest vertebrates to have an adaptive immune system based on the presence of immunoglobulins, T cell receptors, and the major histocompatibility complex (MHC). Amphibians, the first land vertebrates, have been one of the favored non-mammalian models for the study of the adaptive immune system (especially the frog Xenopus, a well known model for developmental biologists). Our analyses of nurse shark and Xenopus MHCs have shown that unlike the bony fish, but like humans, class I, class II, and class III genes are all present in their MHC; thus, representative animals from these vertebrate classes seemingly more accurately represent the hypothetical ancestral vertebrate MHC than the better studied bony fish (e.g. zebrafish). However, unlike humans, there are deep lineages of genes involved in the production (immunoproteasome), transport (TAP1/2), and display (classical class I proteins) of peptides in the MHC class I pathway, at least in Xenopus and probably also in shark. These genes are tightly linked in a true 'class I region,' which likely reflects the situation in the primordial MHC. In Xenopus as well, there is a series of polyploid individuals ranging from 2n-12n, which no doubt arose by genome-wide duplication events (allopolyploidization); the genes of the adaptive immune system become diploidized in the polyploids, presumably to maintain an optimal number of expressed MHC molecules. In order to study the evolution of MHC genetics and the apparent functional consequences of gene organization on the immune system our specific aims are: 1) To compile comparative maps of the MHC in representatives of all vertebrate classes, with an emphasis on nurse shark (cartilaginous fish or elasmobranch) and Xenopus (amphibian); 2) Examine the significance of Xenopus ancient biallelic class I region lineages, specifically by studying the specificity of immunoproteasome subunits, class I peptide-binding, TAP 1/2biochemistry and peptide transport, and in transgenic frogs; and 3) Study gene silencing in polyploid Xenopus: with the advent of genomic sequencing projects in Xenopus (especially the true diploid X. tropicalis), we will begin to analyze the modes of silencing in the tetraploids and eventually the higher order octo- and dodecaploid individuals.