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...

Major histocompatibility complex (MHC) glycoproteins bind processed fragments of proteins and present them to the receptors of T lymphocytes. The extraordinary polymorphism of class I MHC molecules in man (HLA-A, B and C) and mouse (H-2 K, D and L) poses many questions concerning their diversification and evolution. Comparison of allelic sequences within a species suggests diversity is generated by the assortment of point mutations into varied combinations by mechanisms of recombination and gene conversion. We have now compared class I MHC alleles in two closely related species: humans (Homo sapiens) and chimpanzees (Pan troglodytes). Chimpanzee homologues of HLA-A, HLA-B and a non-classical gene have been identified. No features distinguishing human and chimpanzee alleles could be found. Individual HLA-A or B alleles are more closely related to individual chimpanzee alleles than to other HLA-A or B alleles. These results show that a considerable proportion of contemporary HLA-A and B polymorphism existed before divergence of the chimpanzee and human lines. The stability of the polymorphism indicates that hyper-mutational mechanisms are not necessary to account for HLA-A, B and C diversity.

14 gorilla class I major histocompatibility complex (MHC) alleles have been isolated, sequenced, and compared to their counterparts in humans and chimpanzees. Gorilla homologues of HLA-A, -B, and -C were readily identified, and four Gogo-A, four Gogo-B, and five Gogo-C alleles were defined. In addition, an unusual Gogo class I gene with features in common with HLA-A and its related pseudogene, HLA-H, is described. None of the gorilla alleles is identical or even closely related to known class I alleles and each encodes a unique antigen recognition site. However, the majority of polymorphic substitutions and sequence motifs of gorilla class I alleles are shared with the human or chimpanzee systems. In particular, elements shared with HLA-A2 and HLA-B27 are found in Gogo-A and -B alleles. Diversity at the Gogo-B locus is less than at the Gogo-A locus, a trend the opposite of that seen for HLA-A and -B. The Gogo-C locus also appears to have limited polymorphism compared to Gogo-A. Two basic Gogo-C motifs were found and they segregate with distinctive sets of HLA-C alleles. HLA-A allels are divided into five families derived from two ancient lineages. All chimpanzee A alleles derived from one of these lineages and all gorilla alleles derive from the other. Unlike chimpanzee Patr-A alleles, the Gogo-A alleles do not clearly partition with one of the HLA-A families but have similarities with two. Overall, gorilla class I diversity appears from this sampling to show more distinctions from class I HLA than found for chimpanzee class I.

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