Nature of polymorphism in HLA-A, -B, and -C molecules.

Abstract

Diversity in 39 HLA-A, -B, and -C molecules is derived from 20 amino acid positions of high variability and 71 positions of low variability. Variation in the structurally homologous a, and a2 domains is distinct and may correlate with partial segregation of peptide and T-cell receptor binding functions. Comparison of 15 HLA-A with 20 HLA-B molecules reveals considerable locus-specific character, due primarily to differences at polymorphic residues. The results indicate that genetic exchange between alleles of the same locus has been a more important mechanism in the generation of HLA-A, -B, and -C diversity than genetic exchange events between alleles of different loci.Class I major histocompatibility complex glycoproteins are peptide-binding proteins that present processed antigens to cytotoxic T lymphocytes. The genes coding for these molecules are the most polymorphic loci known in higher vertebrates and for humans a total of 19 HLA-A, 37 HLA-B, and 8 HLA-C molecules have been defined (1). Although the basic features of class I molecules are well defined (2), accumulation of allelic sequences has been slow. The paucity of sequences has limited our understanding of the scope of the polymorphism, its function, and its generation. We present here a comparison of 39 HLA-A, -B, and -C sequences and a general assessment of their patterns of diversity. MATERIALS AND METHODSGenomic clones encoding HLA-A1, -B8, -B14, -B18, -Bw4l, -Bw42, -B44.2, -Bw65, and -Cw2.2 were isolated from the following cell lines: S. Gar (HLA-Aw24,3;B18,w41;Cw6), BB (HLA-Aw68.2,30;Bw42,w6S), FMB (HLA-AJ,32;$44,w57; Cw5,w6), MRWC (HLA-A2,32$JA,27;Cw2), MVL (HLAAw32;B27;Cw2), and LCL721 (HLA-Ai,2$.i,5). The cloned genes are underlined. Construction of libraries, isolation and identification of genes, and sequencing of genes with exonspecific oligonucleotide primers were as described (3). Genomic clones encoding HLA-A1 and HLA-B8 were kindly provided by H. T. Orr (University of Minnesota) (4).RESULTS AND DISCUSSION Variability in HLA-A, -B, and -C Molecules. Genes encoding HLA-A1, -B8, -B14, -B18, -B44, -Bw4l, -Bw42, -Bw65, and -Cw2 were isolated, and the exons were sequenced. The sequences of the HLA-B44 and HLA-Cw2 proteins each differ by 3 amino acids from identically typed molecules isolated from other cell lines (5, 6). These represent distinct subtypes, and we have designated them as HLA-B44.2 and HLA-Cw2.2 compared to HLA-B44.1 and HLA-Cw2.1 for the published sequences (5, 6). (a,, a2, and a3) that interact with antigenic peptides, the T-cell receptor, and the CD8 molecule. As single residues predominate at most positions, a consensus sequence can be made (Fig. 1). Individual molecules differ from the consensus by [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] residues, showing all have considerably diverged from a common ancestor.Without knowing the total number of alleles, it is difficult to predict how many sequences are required to gain an accurate description of HLA-A, -B, and -C polymorphism...

Allelic variation in HLA-B and HLA-C sequences and the evolution of the HLA-B alleles

“…One exception is the HLA-B40* antigen which was postulated to have lost the epitope encompassing amino acids 177 and 180 by gene conversion, a result which supports this evolutionary relationship of HLA-B alleles. The relationship is also observed when comparing the leader sequences of the HLA-B7 and -B8 genes (only Parham et al 1988), JY328 (Srivastava et al 1985), and Cx52 (Takata et al 1988). Cw2.2 only differs from Cw2.1 at position 49/50 (A/P in place of G/R).…”

Detecting excess radical replacements in phylogenetic trees

“…Each branch was subjected to the positive selection test on the cleft subsequences. Branches in boldface indicate positive selection at p < 0.01. of the antigen recognition site, consists of 29 residues (Parham et al, 1988). The phylogenetic tree for MHC class I sequences is given in Fig.…”

HLA-G and its role in implantation (review)

“…Although it is expressed as a membrane-bound exhibiting a very restricted tissue distribution limited to extravillous cytotrophoblast cells in the placenta, as well as in maternal spiral arteries, endothelial cells of fetal vessels in the chorionic villi, amnion cells, thymus, and on interferon-γ-stimulated blood monocytes [9][10][11][12][13][14]. The HLA-G protein product has 86% sequence identity to the class I consensus sequence [15]. HLA-G has a lower molecular mass (37-39 kDa) than class 1a molecules due to a stop codon in exon 6 that results in the deletion of all but 6 amino acids in the cytoplasmic tail [16].…”