Perhaps the most interesting discovery in the study of the major histocompatibility complex (MHC) in the past ten years was the demonstration that genes encoding class I presenting molecules (class Ia) are genetically linked to class I 'processing' genes, including proteases that generate peptides to bind to class Ia (lmp) and transporters (TAP) that convey peptides from the cytosol into the ER lumen. In mammals, however, it is somehow incongruous that the class I 'processing' genes are embedded in the MHC class II region. In several non-mammalian vertebrates including zebrafish, chicken and the frog Xenopus, however, the class I 'processing' and 'presenting' genes do appear to be closely linked, suggesting a primordial MHC organization. Ancient allelic lineages of Xenopus class I processing and preventing genes are also suggestive of a primordial association of these genes. In zebrafish, in contrast to all other vertebrates examined, the class I and class II regions are not genetically linked, leading to one proposal that these regions, in some way, came together in an ancestor of the tetrapods. We think this proposition is unlikely, and plan to solidify the ideas of 1) a 'class I processing and presenting region' and 2) a primordial genetic association of class I and class II, by examining the MHC in a representative (shark) of the most primitive class of vertebrates--the cartilaginous fish--shown to display an adaptive immune response orchestrated by bona fide immunoglobulin and T cell receptors. Studies of gene silencing in polyploid species of Xenopus, and of class Ib genes in Xenopus and sharks, also will be done to gain an understanding of the early nature of the MHC.
The specific aims are: 1) to establish MHC linkage groups from members of all vertebrate classes concentrating on i) whether class I and class II regions were linked in the original MHC, ii) class Ia/TAP/lmp genes form a primordial linkage group, and iii) class Ib gene complexes are genetically and functionally independent of MHC; 2) to determine the significance of the two ancient allelic lineages of class Ia/lmp7/TAP2 in Xenopus; 3) to examine the mode of silencing of MHC genes in polyploid Xenopus to determine whether the same genetic regions are affected after each polyploidization event; and 4) to continue an analysis of lass Ib genes and determine whether class Ib lineages are expressed in a tissue specific fashion and perhaps have novel functions in non-mammalian vertebrates.
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