Abstract
The human HLA-DR3 haplotype consists of two functional genes (DRB1*03 and DRB3*01) and one pseudogene (DRB2), arranged in the order DRB1... DRB2... DRB3 on the chromosome. To shed light on the origin of the haplotype, we sequenced 1480 nucleotides of the HLA-DRB2 gene and aong stretches of two other genes, Gogo-DRB2 from a gorilla, “Sylvia” and Patr-DRB2 from a chimpanzee, “Hugo”. All three sequences (HLA-DRB2, Gogo-DRB2, Patr-DRB2) are pseudogenes. The HLA-DRB2 and Gogo-DRB2 pseudogenes lack exon 2 and contain a twenty-nucleotide deletion in exon 3, which destroys the correct translational reading frame and obliterates the highly conserved cysteine residue at position 173. The Patr-DRB2 pseudogene lacks exons 1 and 2; it does not contain the twenty-nucleotide deletion, but does contain a characteristic duplication of that part of exon 6 which codes for the last four amino acid residues of the cytoplasmic region. When the nucleotide sequences of these three genes are compared to those of all other known DRB genes, the HLA-DRB2 is seen as most closely related to Gogo-DRB2, indicating orthologous relationship between the two sequences. The Patr-DRB2 gene is more distantly related to these two DRB2 genes and whether it is orthologous to them is uncertain. The three genes are in turn most closely related to HLA-DRBVI (the pseudogene of the DR2 haplotype) and Patr-DRB6 (another pseudogene of the Hugo haplotype), followed by HLA-DRB4 (the functional but nonpolymorphic gene of the DR4 haplotype). These relationships suggest that these six genes evolved from a common ancestor which existed before the separation of the human, gorilla, and chimpanzee lineages. The DRB2 and DRB6 have apparently been pseudogenes for at least six million years (myr). In the human and the gorilla haplotype, the DRB2 pseudogene is flanked on each side by what appear to be related genes. Apparently, the DR3 haplotype has existed in its present form for more than six myr.
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References
Andersson, G., Larhammar, D., Widmark, E., Servenius, B., Peterson, P. A., and Rask, L.: Class II genes of the human major histocompatibility complex. Organization and evolutionary relationship of the DRβ genes. J Biol Chem 262: 8748–8758, 1987
Bell, J. I., Estess, P., John, T. St., Saiki, R., Watling, D., Erlich, H. A., and McDevitt, H. O.: DNA sequence and characterization of human class II major histocompatibility complex β chains from the DR1 haplotype. Proc Natl Acad Sci USA 82: 3405–3409, 1985
Böhme, J., Andersson, M., Andersson, G., Möller, E., Peterson, P. A., and Rask, L.: HLA-DR β genes vary in number between different DR specificities, whereas the number of DQ β genes is constant. J Immunol 135: 2149–2155, 1985
Brändle,UU., Ono, H., Figueroa, F., and Klein, J.: Trans-species evolution of MHC-DRB haplotype polymorphism in primates: Organization of DRB genes in the chimpanzee. Immunogenetics 35, in press, 1992
Breathnach, R. and Chambon, P.: Organization and expression of eucaryotic split genes coding for proteins. Annu Rev Biochem 50: 349–383, 1981
Carson, S. and Trowsdale, J.: Molecular organization of the class II genes of the human and mouse major histocompatibility complexes. Oxford Surv Eukaryot Genes 3: 63–94, 1986
Evans, G. A. and Wahl, G. M.: Cosmid vectors for genomic walking and rapid restriction mapping. Methods Enzymol 152: 604–610, 1987
Fan, W., Kasahara, M., Gutknecht, J., Klein, D., Mayer, W. E., Jonker, M., and Klein, J.: Shared class II Mhc polymorphisms between human and chimpanzees. Hum Immunol 26: 107–121, 1989
Felsenstein, J.: Phylogenies from molecular sequences: Inference and reliability. Annu Rev Genet 22: 521–565, 1988
Figueroa, F., O'hUigin, C., Inoki, H., and Klein, J.: Primate DRB6 pseudogenes: clue to the evolutionary origin of the HLA-DR2 haplotype. Immunogenetics 34: 324–337, 1991
Gorski, J.: The HLA-DRw8 lineage was generated by a deletion in the DRB region followed by first domain diversification. J Immunol 142: 4041–4045, 1989
Gorski, J., Tosi, R., Strubin, M., Rabourdin-Combe, C., and Mach, B.: Serological and immunochemical analysis of the products of a single HLA-DRα- and DRβ chain gene expressed in a mouse cell line after DNA-mediated cotransformation reveals that the β chain carries a known supertypic specificity. J Exp Med 162: 105–116, 1985
Gorski, J., Rollini, P., and Mach, B.: Structural comparison of the genes of two HLA-DR supertypic groups. The loci encoding DRw52 and DRw53 are not truly allelic. Immunogenetics 25: 397–402, 1987
Gregersen, P. K., Shen, M., Song, Q.-L., Merryman, P., Degar, S., Seki, T., Maccari, J., Goldberg, D., Murphy, H., Schwenzer, J., Wang, C. Y., Winchester, R. J., Nepom, G. T., and Silver, J.: Molecular diversity of HLA-DR4 haplotypes. Proc Natl Acad Sci USA 83: 2642–2646, 1986
Grosveld, F. G., Lund, T., Murray, E. J., Mellor, A. L., Dahl, J. J. M., and Flavell, R. A.: The construction of cosmid libraries which can be used to transform eukaryotic cells. Nucl Acids Res 10: 6715–6732, 1982
Groves, C. P.: Systematics of the great apes. In D. R. Swindler and J. Erwin (eds.): Comparative Primate Biology, Vol 1, pp. 187–217. Liss, New York, 1986
Gustafsson, K., Wiman, K., Emmoth, E., Larhammar, D., Göhme, J., Hyldig-Nielsen, J. J., Ronne, H., Peterson, P. A., and Rask, L.: Mutations and selection in the generation of class II histocompatibility antigen polymorphism. EMBO J 3: 1655–1661, 1984
Hughes, A. L. and Nei, M.: Pattern of nucleotide substitutions at major histocompatibility complex class I loci reveals overdominant selection. Nature 335: 167–170, 1988
Hughes, A. L. and Nei, M.: Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection. Proc Natl Acad Sci USA 86: 958–962, 1989
Jonsson, A.-K., Andersson, L., and Rask, L.: A cellular and functional split in the DRw8 haplotype is due to a single amino acid replacement (DRβser57-asp57). Immunogenetics 29: 308–316, 1989
Kasahara, M., Klein, D., Fan, W., and Gutknecht, J.: Evolution of the class II major histocompatibility complex alleles in higher primates. Immunol Rev 113: 65–82, 1990
Kasahara, M., Klein, D., Vincek, V., Sarapata, D. E., and Klein, J.: The DRB subregion of the gorilla major histocompatibility complex: evidence for linkage disequilibrium conserved across species. Submitted, 1991
Kawai, J., Ando, A., Sato, T., Nakatsuji, T., Tsuji, K., and Inoko, H.: Analysis of gene structure and antigen determinants of DR2 antigens using DR gene transfer into mouse L cells. J Immunol 142: 312–317, 1989
Kimura, J.: A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences. J Mol Evol 16: 111–120, 1980
Klein, J.: Natural History of the Major Histocompatibility Complex. Wiley, New York 1986
Klein, J.: Of HLA, tryps, and selection. An essay on coevolution of Mhc and parasites. Hum Immunol 30: 247–258, 1991
Klein, J., Bontrop, R. E., Dawkins, R. L., Erlich, H. A., Gyllensten, U. B., Heise, E. R., Jones, P. P., Parham, P., Wakeland, E. K., and Watkins, D. I.: Nomenclature for the major histocompatibility complexes of different species: a proposal. Immunogenetics 31: 217–219, 1990
Klein, J., Kasahara, M., Gutknecht, J., and Schönbach, C.: Phylogeny of primate Mhc DRB alleles. Hum Immunol 31: 28–33, 1991
Klein, J. and Takahata, N.: The major histocompatibility complex and the quest for origins. Immunol Rev 113: 5–25, 1990
Klein, D., Vincek, V., Kasahara, M., Schönbach, C., O'hUigin, C., and Klein, J.: Gorilla Mhc-DRB pseudogene orthologous to HLA-DRBVIII. Hum Immunol 32: 211–220, 1991
Larhammar, D., Servenius, B., Rask, L., and Peterson, P. A.: Characterization of an HLA-DRβ pseudogene. Proc Natl Acad Sci USA 82: 1475–1479, 1986
Lee, S., Nunez-Roldan, A., Dwyer, E., Pompeo, L., and Winchester, R.: Definition of DRw10 by restriction fragment length polymorphism. Tissue Antigens 33: 466–474, 1989
Lock, C. B., So, S. K. L., Welsh, K. I., Parkes, J. D., and Trowsdale, J.: MHC class II sequences of an HLA-DR2 narcoleptic. Immunogenetics 27: 449–455, 1988
Long, E. O., Wake, C. T., Gorski, J., and Mach, B.: Complete sequence of an HLA-DR β chain deduced from cDNA clone and identification of multiple non-allelic DR β chain genes. EMBO J 2: 389–394, 1983
Low, K. B., The Recombination of Genetic Material. Academic, San D Diego, 1988
Maniatis, T., Fritsch, E. F., and Sambrook, J.: Molecular Cloning. A Laboratory Manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1982
Martin, R. D.: Primate Origins and Evolution. A Phylogenetic Reconstruction. Chapman and Hall, London 1990
Mayer, W. E., Jonker, M., Klein, D., Ivanyi, P., van Seventer, G., and Klein, J.: Nucleotide sequences of chimpanzee MHC class I alleles: evidence for trans-species mode of evolution. EMBO J 7: 2765–2774, 1988
Mellars, P. and Stringer, C.: The Human Revolution. Princeton University Press, Princeton, 1989
Merryman, P., Gregersen, P. K., Lee, S., Silver, J., Nunez-Roldan, N., Crapper, R., and Winchester, R.: Nucleotide sequence of a DRw10 β chain cDNA clone. Identify of the third D region with that of the DRw53 allele of the β2 locus and as the probable site encoding a polymorphic MHC class II epitope. J Immunol 140: 2447–2452, 1988
Messing, J.: New M13 vectors for cloning. Methods Enzymol 101: 20–77, 1983
Navarrete, C., Seki, T., Miranda, A., Winchester, R., and Gregersen, P. K.: DNA sequence analysis of the HLA-DRw12 allele. Hum Immunol 25: 51–58, 1989
Rollini, P., Mach, B., and Gorski, J.: Linkage map of three HLA-DR β-chain genes. Evidence for a recent duplication event. Proc Natl Acad Sci USA 82: 7197–7201, 1985
Rollini, P., Mach, B., Gorski, J.: Characterization of an HLA-DRβ pseudogene in the DRw52 supertypic group. Immunogenetics 25: 336–342, 1987
Saitou, N. and Nei, M.: The neighbor-joining method. A new method for reconstructing phylogenetic trees. Mol Biol Evol 4: 406–425, 1987
Sanger, F., Nicklen, S., and Coulson, A. R.: DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74: 5463–5467, 1977
Spies, T., Sorrentino, R., Boss, J. M., Okada, K., and Strominger, J. L.: Structural organization of the DR subregion of the human major histocompatibility complex. Proc Natl Acad Sci USA 82: 5165–5169, 1985
Steinmetz, M., Stephen, D., Dastoornikoo, G. R., Gibb, E., and Romaniuk, R.: Methods in molecular immunology: Chromosomal walking in the major histocompatibility complex. Immunol Meth 3: 1–19, 1985
Steinmetz, M., Uematsu, Y., and Fischer-Lindahl, K.: Hotspots of homologous recombination in mammalian genomes. Trends Genet 3: 7–20, 1987
Vierra, J. and Messing, J.: The pUC plasmids, an M13mp17-derived system for insertion mutagenesis and sequencing with universal primers. Gene 19: 259, 1982
WHO Committee for Factors of the HLA System: Nomenclature for Factors of the HLA System, 1990. Immunogenetics 33: 301–309, 1991
Young, J. A. T., Wilkinson, D., Bodmer, W. F., and Trowsdale, J.: Sequence and evolution of HLA-DR7-and DRw53-associated A chain genes. Proc Natl Acad Sci USA 84: 4929–4933, 1987
Zhu, Z., Vincek, V., Figueroa, F., Schönbach, C., and Klein, J.: Mhc-DRB genes of the pigtail macaque (Macaca nemestrina). Implications for the evolution of human DRB genes. Mol Biol Evol 8: 563–578, 1991
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The nucleotide sequence data reported in this paper have been submitted to the GenBank nucleotide sequence database and have been assigned the accession number M86691–94.
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Vincek, V., Klein, D., Figueroa, F. et al. The evolutionary origin of the HLA-DR3 haplotype. Immunogenetics 35, 263–271 (1992). https://doi.org/10.1007/BF00166832
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DOI: https://doi.org/10.1007/BF00166832