Chromosomal Localization and Arrangement of the MHC Genes

CHROMOSOMAL LOCALIZATION AND ARRANGEMENT OF THE MHC GENES

The mapping of the MHC region has been established based on the study of crossover gene products and on in situ hybridization studies with DNA probes. The MHC genes are located on chromosome 6 of humans and on chromosome 17 of the mouse. In both cases, the MHC genes are located between the centromere and the telomere of the short arm of the respec-tive chromosomes. A simplified map of human chromosome 6 is shown in Fig. 3.4.

The MHC genes can be grouped in the same classes as the antigens detected in cell membranes, i.e., MHC class I and class II genes. The MHC region occupies 0.5 (mice) and 1.8 centimorgans (humans) of their respective chromosomes. The larger size of the human HLA region suggests that it includes more genes and is more polymorphic than the murine H2.

In mice, the H2-K locus and the H2-L/H2-D loci (class la genes) are the most poly-morphic. In contrast, class lb genes—which include H2M3 and Qa1—are much less poly-morphic and devoted to the presentation of formylated peptides (H2M3) or peptides de-rived from the signal sequence of MHC molecules (Qa1). They are followed by the I region, which includes two loci: I-A and I-E (class II genes). One related locus (locus S) codes for the C4 molecule of the complement system and is located between the H-2K and H-2D loci.

The organization of the HLA gene complex in humans is similar. The class I genes are also divided into two groups: la, which includes the polymorphic HLA-A and B genes and the less polymorphic HLA-C, and group lb, which includes HLA-E-F and G, which are almost monomorphic. Furthermore, in humans the class II genes are closer to the GLO1 lo-cus (coding for one isoenzyme of glyoxylase) and followed by several loci coding for pro-teins related to the complement cascade such as Bf, C2, and C4 and by the HLA, B, and C loci (class I genes). The human MHC region includes other non-MHC genes such as those coding for tumor necrosis factor (TNF) and lymphotoxin- (LT-α , TNF-β ) , which are located near the C4 genes. The two C4 alleles are separated from each other by the genes coding for the enzyme 21α -hydroxylase (Fig. 3.4). In addition, the MHC-II region includes genes that code for proteins involved in cleaving and loading peptides into MHC molecules . The complete sequence of the 3.6 Mb of the human MHC on chromosome 6p21.31 was published at the end of 1999. In addition to the previously identified 200 loci, sequence analysis revealed many genes of yet unknown significance in the flanking regions of class I, class II. It also stressed that the content of immune-related genes in the MHC region is 39.8%.