Genomic Anatomy of a Premier Major Histocompatibility Complex Paralogous Region on Chromosome 1q21–q22

The 3.6-Mb human Major Histocompatibility Complex (MHC; also known as the Human leukocyte antigen, HLA) on chromosome 6p21.3 is a critical repository for immune response genes. This 230-gene–rich segment has taught us a great deal about immunity as well as about the evolutionary dynamics of compact genomic segments (Campbell and Trowsdale 1997; The MHC Sequencing Consortium 1999; Shiina et al. 1999). Extensive analysis of the genomic organization of the HLA region has revealed that at least 27 of its resident genes possess duplicated copies in at least one of three other restricted regions on chromosomes 1q21–q25, 9q33–q34, and 19p13.1–p13.4 (Sugaya et al. 1994, 1997; Kasahara et al. 1996; Katsanis et al. 1996; Endo et al. 1997; Hughes 1998; Kasahara 1999). ABC transporter gene family members are located on 6p21.3 (TAP1, TAP2), 1q25 ({"type":"entrez-protein","attrs":{"text":"EST31252","term_id":"558540113","term_text":"EST31252"}}EST31252), and 9q34 (ABC2), proteasome β-type subunit loci can be found on 6p21.3 (LMP2, LMP7) as well as 9q34 (PSMB7), pre-B cell leukemia transcription factors are readily identified on 6p21.3 (PBX2), 1q23 (PBX1), and 9q33–q34 (PBX3), and NOTCH genes are located on 6p21.3 (NOTCH4), 9q34.3 (NOTCH1) and 19p13.2–p13.1 (NOTCH3). These observations suggest that these four paralogous regions were generated from a common ancestor after two rounds of chromosomal duplication. Moreover, these large-scale duplications possibly enabled at least one of these quadruplicate regions to be relaxed from functional constraints, allowing the formation of the present-day vertebrate MHC, the sophisticated machinery at the heart of the acquired immune system (Abi-Rached et al. 1999). A number of indirect evidences, especially the sequence comparison as well as phylogenetic tree analysis of a number of paralogous genes, allows tracing back these duplicatives events to a common ancestor of jawed vertebrates, from the lineage leading to hagfish and lamprey (Kasahara 1999). Among the above-mentioned paralogous regions, that of 1q21–q25 is unique because it is the only one outside the MHC carrying divergent, yet genuine histocompatibility-like loci, CD1 and MR1 (Albertson et al. 1988; Hashimoto et al. 1995; Riegert et al. 1998). CD1 molecules are cell surface glycoproteins structurally and functionally similar to MHC class I molecules (Calabi and Millstein 1986; Martin et al. 1986). The main difference between these two classes of antigen-presenting loci is indeed their “cargo” peptides in the case of 6p-located MHC class I molecules, and a diverse admixture of glycolipids (issued mainly by various pathogens) in the case of CD1 molecules. This diversification of the presentation capacity of MHC molecules greatly enhances the surveillance capacity of patrolling cytotoxic T cells (Sieling et al. 1995; Burdin et al. 1998). There are five CD1 genes, CD1A to CD1E, originally identified within a 190-kb cosmid segment (Calabi and Milstein 1986; Martin et al. 1987; Calabi et al. 1989; Yu and Milstein 1989). Based on sequence divergence, the CD1 genes can be ordered into three groups: (1) CD1A, CD1B, and CD1C, (2) CD1D, and (3) CD1E (Hughes 1991). Only homologs of human CD1D have been identified in the mouse (Balk et al. 1991), and the rat (Ichimiya et al. 1994). CD1D might be a vestige of the ancestral CD1, which plausibly created the present-day human CD1 cluster through sequential duplications (Yu and Mulatein 1989). Furthermore, paralleling the chromosome 6 HLA region, the CD1 region is of great biomedical importance, as a number of disease-susceptibility loci have been mapped to 1q21–q23; these include genes for elliptocytosis-2, spherocytosis, pyropoikilocytosis (Gallagher et al. 1992), autosomal dominant nonsyndoromic deafness, autosomal dominant nonsyndromic sensorineural 7 (Fagerheim et al. 1996), familial hemiplegic migraine (Ducrons et al. 1997), familial partial lipodystrophy (Jackson et al. 1998), and familial schizophrenia (Brzustowicz et al. 2000). This region has also been implicated in a number of chromosomal translocations; for example t (1; 19) (q23; p13) in lymphoblastic leukemias and t (X; 1) (p11; q21) in papillary renal cell carcinoma (Williams et al. 1984; Weterman et al. 1996). To clarify the genomic organization of this paralogous CD1 region, and to understand the evolutionary process through which the MHC system acquired its present-day structure, we aimed to establish a comprehensive gene map of a critical 1.7-Mb region. A composite YAC, BAC, and PAC contig was thus constructed, and a core segment of 1.1 Mb encompassing the CD1 genes was completely sequenced. This 1.7-Mb region was found to contain 10 known genes and 31 newly mapped genes or gene candidates including 20 ORctory receptors.