The major histocompatibility complex (MHC) plays key roles in controlling both adaptive and innate immune systems. In the adaptive immune system, both MHC class I and class II antigens recognize, bind and present peptides to cytotoxic and helper T-cells, respectively, and initiate cell-to-cell communication between antigen presenting cells and T-cells by forming immunological synapses and activating both subtypes of T-cells for both cellular and humoral immune systems. In addition, a number of gene clusters in this complex encode proteins which play important roles for antigen processing (proteosome subunit, LMP2 and 7, antigen transporter, TAP1 and 2, antigen loading for class I antigen, Tapasin, antigen loading for class II antigens, DM and DO molecules). In the innate immune system, both classical (HLA-A,-B,-C in human) and non-classical class I (HLA-E) antigens, plus class I-related molecules (MIC-A, -B) interact with natural killer (NK) receptors (Killer immunoglobulin-like receptor genes KIR and natural killer cell lectin-like receptors NKG antigens in human and Ly-49 and NKG antigens in mouse) and inhibit and activate NK-cell functions. In addition to the immunological importance, the MHC provides important tools to study molecular evolution. Extremely polymorphic features of both class I and class II antigens identified in most vertebrates provide numerous numbers of peptide binding grooves for MHC class I and II antigens in order to adapt various pathogens. Natural and balancing selections play pivotal roles to generate and maintain these polymorphisms. The nature of multigene clusters of the MHC genes also provides a number of theories to explain the genesis of the MHC. Also, paralogous chromosomal regions found in three other locations in human (chr. 6p21.3 for MHC, 9q33-34, 1, 19 for the others) and jawed vertebrates raises questions for the origin of the MHC. A large-scale sequencing project for the HLA has been launched and completed for the 3.6 Mb of the classical class I, II, and III regions to reveal the molecular history of this important gene complex, and has identified 224 tightly linked genes, including 128 expressed genes, and 96 pseudogenes. More recently, the MHC expands to 4.6 Mb, including five subregions: 1) extended class II (280 kb); 2) class II (700 kb); 3) class III (1000 kb); 4) class I (1600 kb); and 5) extended class I (1000 kb). In contrast of this large complex structure in HLA, the chicken MHC B-locus presents a """"""""minimal essential MHC"""""""" disposition extending 92 kb and including 19 functional genes, raising questions about the structure of other MHC systems. The feline MHC has been studied for an approach to comparative gene organization of this multigene cluster in mammals. A 3.1 Mbp sequencing ready bacterial artificial/P1 artificial chromosomes (BAC/PAC) contig map and sequence drafts for the feline MHC, including 800 kb extended and classical class II region (HSET to BTLII), 700 kb class III region (Notch 4 to BAT 1) and classical (1,400 kb) and extended (300 kb) class I region (class I gene adjacent to BAT 1 to OLFR) has been completed. Unlike genomic structures of other mammalian MHC so far been studied, the domestic cat MHC has an unique gene organization with a split within tripartite motif containing (TRIM) gene cluster located between HLA-E and HLA-A class I regions in human. The first Feline Leukocyte Antigen (FLA) fragment includes extended and classical class II, class III, and class I region from HLA-B associated transcript 1(BAT1) through TRIM39 genes. The other includes TRIM26 gene through myelin oligodendrocyte glycoprotein (MOG), gamma-aminobatyric acid receptor (GABAR), ubiquitin D (UBD) in classical class I region plus entire extended class I region. Two Color Fluorescent In situ Hybridization (FISH) using BAC clones which contain TRIM39 gene and TRIM26 gene, respectively revealed that the first FLA fragment resides near centromeric region of chromosome B2 (B2Cen), while the second half of FLA fragment resides near telomeric region of a short arm of the same chromosome (B2pTel). A radiation hybrid mapping study of the chromosome B2 using markers including MHC genes indicated a chromosomal inversion in the entire short arm of B2 chromosome at the breakpoint within the TRIM gene cluster of the MHC occurred in the cat. Recently two sequence drafts for an entire canine MHC have been generated as a part of the 7x dog genome sequencing project. One supercontig_38195 which is 9472360 bp in size includes two thirds of MHC genes (DAXX to TRIM39 in extended and classical class II, class III and a part of class I regions) in 2.9 Mbp region. The other supercontig_40588 which is 2661921 bp in size maintains the rest of one third of MHC genes (TRIM26 to olfactory receptor genes in the rest of class I and extended class I regions) in approximately 1 Mbp region. Detailed Refn database search indicated that the canine MHC has a similar split gene organization found in feline MHC, where the split occurred between TRIM 39 and TRIM26 in TRIM gene cluster. The comparison of gene contents in these sequences and published canine radiation hybrid (RH) map suggested that the first two thirds of canine MHC genes locates on canine chromosome 12 (Cfa 12) and the other one third of MHC is on Cfa 35. Both RH map and G banding pattern showed canine Cfa12 and Cfa 35 chromosomes are syntenic with feline Fca B2 chromosome, suggesting this unique split gene organization of MHC found in these two species occurred before a divergence of feline and canine species (more than 40 MYA) as a single event and maintained throughout the species evolution. Sequence comparison of feline and canine MHC showed both remarkable conservation and difference of gene organization in these two MHC systems. Highly conserved regions were found through entire extended class II (DAXX to COL11A2) and a part of classical class II (DP to DOB) regions (approx. 290 Kb), class III region from NOTCH4 through BAT1 genes (approx. 667 Kb), classical class I region from OCT3 through TRIM39 ( approx. 610 Kb), and three regions in distal and extended class I region (150, 87 and 87 Kb). However, gene organization in DQ/DR class II region and B/C class I region were clearly different in these MHC systems. The feline MHC class II region lacks the entire DQ region and but maintains three DRA/four DRB genes, while the canine class II maintains at least a pair of DQA/B and DRA/B genes. In class I B/C region, feline MHC has 18 class I genes/gene fragments with 3 possible classical class I genes, while canine class I B/C region only maintains 4 class I genes. Two canine class I genes were identified by Basic local alignment search tool (BLAST) search on two other chromosome (Cfa 7 and Cfa 18). Both feline and canine MHC lacks entire class I A region, where at least 11 class I genes locates in human HLA. In extended class I region, canine MHC has a olfactory receptor gene cluster, however, the size of this cluster is at least three times smaller than that of human olfactorg receptor (OLFR) region (145 Kb vs. 523 Kb).

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Division of Basic Sciences - NCI (NCI)
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