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 & 7, antigen transporter, TAP1 & 2, antigen loading for class I antigen, Tapasin, antigen loading for class II antigens, DM & 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 (KIR & 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, & 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 BAC/PAC contig map 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. The domestic cat MHC has a relatively smaller but a similar class organization as found in human MHC (3.1 Mbp versus 4.6 Mbp, in cat and human MHC, and class order: extended & classical class II, class III, class I and extended class I regions). Sequence drafts for 22 BAC clones, spanning the entire classical class I region (1,800 kb), from TNF C gene to three olfactory receptor genes have been completed. Thirty eight framework genes, which include TNFC, TNFA, TNFB, IkBL, ATP6G, BAT1, HNRNPA1, 2 MIClike1, 2 MIClike2, OCT3, SC1, HCR, SPR1, Corneodesmosin (S), VaryltRNA Synthtase, DDR1 kinase, Multispanning Nucleolar Envelope Protein, FLOTILLIN, TUB, KIAA0170, DBP2 PTD017, FB9, ABC50, HSR1, EF1A, RNF23, TRIM31, ZNF173, RFB30, PPP1R11, MOG, UBD, OLFRA, OLFRB, OLFRC plus twenty class I genes/gene fragments were identified by GENSCAN and BLASTN/P algorithms. Three class I genes appear to encode classical class I antigens based on predicted amino acid sequences. Comparative analysis between cat and human class I region revealed that although gene contents and orders of framework genes in both MHC systems are very similar, positions of class I gene clusters are unique in each MHCs. The cat MHC lacks class I gene cluster in human HLA-A region. Instead, the cat MHC has 18 class I genes/gene fragments in human HLA-B, -C region, whereas human MHC maintains 4 and 11 class I genes, in HLA-B, -C, and HLA-A region, respectively. Identification of unique gene amplification units, which carries class I gene and BAT1 gene fragment (exon 7,8,9) in cat MHC plus phylogenetic analysis of feline and human class I peptides suggests separate origins of class I multi-genes in each species. Sequence drafts for 7 BAC clones, spanning the entire class III region (800 kb), from BTL2 to BAT1 gene have been also determined. Forty nine framework genes, including BTL2, BTN1A1, BTN2A1, NOTCH4, PBX2, AGER, RNF5, AGPAT1, PPT2, NG5, FKBPL, CREBL1, TNXB, CYP21A2, C4B, DOM3Z, SKIV2L, C2, NG36, HSPA1A, HSPA1L, NEU3, C6orf29, bioref, VARS2, MSH5, CLIC1, DDAH2, G6B, G6C, G6D, G6E, BAT5, G5C, G5B, CSNK2B, BAT4, G4, APOM, BAT3, AIF1, BAT2, LTB, TNF, LTA, NFKBIL1, ATP6G, HNRPA1, and BAT1 genes were identified by GENSCAN and BLASTN/P algorithms. Comparative sequence analysis of feline, murine and human class III regions showed highly conserved gene organization in this region. In innate immune systems in mammals, two gene complexes have been found to play crucial roles in controlling NK cell functions. One gene complex, LRC encodes approximately 45 genes in one mega base region of human chromosome 19q13. Of these genes, 14 genes encode KIR (killer-cell Ig-like receptor) molecules and 15 others encode Ig-like receptors (leukocyte Ig-like receptor:LILR, leukocyte-associated Ig-like receptor:LAIR). The other gene complex, NKC encodes 8 calcium dependent lectin type NK receptors (NKG2 A-H) on human chromosome 12p13. Both Ig-like and c-lectin type receptors interact with MHC class I and class I like molecules in order to control NK cell functions. Interestingly, mouse genome lacks entire KIR genes in LRC, instead employs Ly49 c-lectin type receptors in addition to NKG2 type receptors in NKC. We have analyzed five BAC clones in feline LRC region and one BAC clone in feline NKC region by seven to ten fold shotgun sequencing and found at least 10 Ig-like receptor sequences and 3 c-lectin type receptor sequences. Phylogenetic analysis of these feline Ig-like receptor sequences plus canine sequences obtained from tblastn search through canine wgs (whole genome shotgun) sequences using human KIR 2DL, bovine KIR 2DL, & X-linked murine KIR like sequences (kirl1) indicated that no KIR like genes in the feline LRC or 1.5 X whole genome shotgun sequence of the canine genome.

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Division of Basic Sciences - NCI (NCI)
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