Linkage map of three HLA-DR beta-chain genes: evidence for a recent duplication event.

Abstract

The predominant class II, or Ia, antigen of the human major histocompatibility complex is HLA-DR. It consists of an a and a 13 chain, the latter being responsible for the remarkable polymorphism of these Ia antigens. Studies with cloned genes had shown the existence of more than one DR 13-chain locus. We have isolated about 100 kilobases of the HLA-DR 13-chain gene region from a cosmid library generated from a consanguineous homozygous B-cell line of the DR3 haplotype. Three HLA-DR 13-chain genes have been characterized. They are arranged in a head-to-tail orientation. One of the genes lacks the region encoding the first domain of the DR 13 chain. The two other genes are transcribed, as shown by RNA blot hybridization analysis. A striking restriction site homology has been found within the DR 13-chain gene cluster, suggesting a recent duplication event involving at least 25 kilobases of DNA. Moreover, the molecular map of DR 13 chain genes cloned from B-cell lines of two other HLA-DR haplotypes shows extensive homology between alleles of a given DR 1-chain locus.The class II antigens of the major histocompatibility complex are highly polymorphic transmembrane glycoproteins, consisting of an a subunit and a p subunit. These molecules are located predominantly on the surface of macrophages and B cells. They play a key role in the control of the immune response, functioning in cell-cell interactions and antigen presentation to regulatory T lymphocytes. In the human major histocompatibility complex (HLA), the class II molecules have been mapped to the HLA-D region on chromosome 6. Three subregions have been defined, DP, DQ, and DR. The HLA-DR antigen is the predominant surface product and it is the p chain that is responsible for the DR polymorphism (for reviews, see refs. 1 and 2).The molecular organization of the HLA-D region has not yet been elucidated. The restriction map of the DP subregion is known. There are two DP a-and p-chain loci (3) found as a-p pairs with the a and p chain genes in a head-to-head orientation (4-6). The organization of the DQ and DR subregions is not known, although the genetic complexity of these subregions has been documented. There are two DQ a loci (7,8) and two DQ p loci (9, 10). The HLA-DR subregion has been shown to contain only one nonpolymorphic a-chain gene (11,12). Analysis of cDNA clones (13, 14) and genomic clones (10), as well as direct studies of cellular DNA by Southern blot hybridization (15), has allowed us to establish the existence of multiple DR p-chain loci.In this study, we report the characterization of overlapping cosmid clones containing DR p-chain genes isolated from a genomic library prepared from DNA of a HLA-homozygous individual. Three DR p-chain genes in a head-to-tail conformation have been aligned. Two of these genes are transcribed, while the third one appears to be truncated, lacking the first domain. Extensive restriction site homology between DR P-chain genes within the same haplotype has been observed, suggesting a recent duplication event. ...

HLA antigens in Japanese patients with myasthenia gravis.

“…Recent (37). An interesting possibility is that the B44-DRw I 3-DQw 1 haplotype in Japanese and the B8-DR3-DQw2 haplotype in caucasian share or lack a certain ancestral gene, and that the gene confers the susceptibility to MG in two different populations (Fig.…”

“…Four families were intentionally included since two of the families had monozygotic twins, one had dizygotic twins, and the other had two children with MG; however, all the other families were selected at random. Among the 41 families, 21 of the probands (families 1-21) belonged to the subgroup I, 10 (families [22][23][24][25][26][27][28][29][30][31] to the subgroup II, and 10 (families [32][33][34][35][36][37][38][39][40][41] to the subgroup III. In this study, no family with a proband in subgroup IV was included.…”

HLA‐DRB9— Possible Remnant of an Ancient Functional DRB Subregion

“…Whether S2 is also present in the DR3 haplotype is uncertain. The DR3 haplotype is believed to have arisen by duplication of an ancestral segment consisting of the DRB1*03 and DRB2 progenitors [6]. A copy of the ancestral DRB1*03 gene then gave rise to the DRB3 gene, whereas a copy of the ancestral DRB2 gene became truncated and its only remnant is 508 R. Gongora et al Fig.…”

“…A characteristic feature of the DRB segment is its haplotype polymorphism -the existence of multiple forms differing in the number of DRB loci, each form occurring at an appreciable frequency in the human population. The main DRB haplotypes are DR8, consisting of a single functional gene (DRB1*08) [3]; DR1, containing the functional DRB1 gene and the DRB6 pseudogene [4]; DR51, composed of two functional genes (DRB1 and DRB5) as well as one pseudogene (DRB6) [5]; DR52, also consisting of two functional genes (DRB1, DRB3) and one pseudogene (DRB2) [6]; and DR53, containing two functional genes (DRB1, DRB4) and two pseudogenes (DRB7, DRB8) [7,8]. Each of these haplotypes also contains a gene fragment, DRB9 [9].…”

Analysis of HLA-D micropolymorphism by a simple procedure: RNA oligonucleotide hybridization.

“…In man, one recognizes three subregions, DP, DQ, and DR, encoding distinct a/,8 dimers (3, 4). As many as 15 a-or U-chain genes have been identified (see review in 5) and in the case of HLA-DR, at least three polymorphic #-chain loci have been mapped, two of which are expressed into distinct DR :-chains (6).…”