, Volume 37, Issue 1, pp 1–11 | Cite as

Mhc-DRB diversity of the chimpanzee (Pan troglodytes)

  • M. Kenter
  • N. Otting
  • J. Anholts
  • M. Jonker
  • R. Schipper
  • R. E. Bontrop
Original articles


Fifty-four chimpanzee Patr-DRB and five human HLA-DRB second exons were cloned and sequenced from thirty-five chimpanzees and four B-cell lines and compared with known Mhc-DRB sequences of these two species. Equivalents of the HLA-DRB1 * 02,-DRB1 * 03, -DRB1 * 07 allelic lineages and the HLA-DRB3,-DRB4, -DRB5, -DRB6, and -DRB7 loci were all found in the chimpanzee. In addition, two chimpanzee Patr-DRB lineages (Patr-DRBX and -DRBY) were found for which no human counterparts have been described. None of the Patr-DRB sequences is identical to known HLA-DRB sequences. The Patr-DRB1 * 0702 and HLA-DRB1 * 0701 alleles are the most similar sequences in a comparison between the two species and differ by only two nucleotides out of 246 sequences. Equivalents of the HLA-DRB1 * 01,-DRB1 * 04, and -DRB1 * 09 alleles were not found in our sample of chimpanzees. A per locus comparison of the number of Patr-DRB alleles with the HLA-DRB alleles shows that the Patr-DRB3, -DRB4, -DRB5, and -DRB6 locus are, thus far, more polymorphic than ther human homologs. The polymorphism of the Patr-DRB1 locus seems to be less extensive than that reported for the HLA-DRB1 locus. Nevertheless, the Patr-DRB1 locus seems to be the most polymorphic of the Patr-DRB loci. Phylogenetic analyses indicate that the HLA-DRB1 * 09 allele may have originated from a recombination between a Mhc-DRB5 allele and the DRB1 allele of a Mhc-DR7 haplotype. Although recombination seems to increase the diversity of the Patr-DRB alleles, its contribution to the generation of Patr-DRB variation is probably low. Hence, most Patr-DRB diversity presumably accumulated via recurrent point mutations. Finally, two distinct PAtr-DRB haplotypes are deduced, one of which (the chimpanzee equivalent of the HLA-Dr7 haplotype) is probably older than 6–8 million years.


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  1. Andersson, G., Larhammer, 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, 1987Google Scholar
  2. Andrews, P.: Fossil evidence on human origins and dispersal. Cold spring Harb Symp Biol: 419–428, 1986Google Scholar
  3. Böhme, J., Andersson, M., Andersson, G., Möller, E., Peterson, P. A., and Rask, L.: HLA-DRβ genes vary in number between different DR specificities, whereas the number of DQβ genes in constant. J Immunol 135: 2149–2155, 1985Google Scholar
  4. Bontrop, R. E., Otting, N., Broos, L. A. M., Noort, M. C., Kenter, M., and Jonker, M.: RFLP analysis of the HLA-, ChLA-, and RhLA-DQ alpha chain gene regions: conservation of restriction sites during evolution. Immunogenetics 30: 432–439, 1989Google Scholar
  5. Bontrop, R. E., Broos, L. A. M., Pham, K., Bakas, R., Otting, N., and Jonker, M.: The chimpanzee major histocompatibility complex class II DR subregion contains an unexpectedly high number of beta-chain genes. Immunogenetics 32: 272–290, 1990Google Scholar
  6. Brown, J. H., Jerdetzky, T., Saper, M. A., Samraoui, B., Bjorkman, P. J., and Wiley, D. C.: A hypothetical model of the foreign antigen binding site of class II histocompatibility molecules. Nature 332: 845–850, 1988CrossRefPubMedGoogle Scholar
  7. Bullock, W. O., Fernandez, J. M., and Short, J. M.: XL1-Blue: a high efficiency plasmid transformation rec A Escherichia coli strain with beta-galactosidase selection. Biotechniques 5: 376–378, 1987Google Scholar
  8. Corell, A., Martin-Villa, J.-M., Morales, P., de Juan, M. D., Varela, P., Vicario, J. L., Martinez-Laso, J., and Arnaiz-Villena, A.: Exon-2 nucleotide sequences, polymorphism, and haplotypes distribution of a new HLA-DRB gene: HLA-DRBδ. Mol Immunol 28: 533–543, 1991Google Scholar
  9. Deverex, J., Haeberli, P., and Smithies, O.: A comprehensive set of sequence analysis programs for the VAX. Nucleic Acid Res 12: 387–395, 1984Google Scholar
  10. Fan, W., Kasahara, M., Gutknecht, J., Klein, D., Mayer, W. E., Jonker, M., and Klein, J.: Shared class II MHC polymorphism between humans and chimpanzees. Hum Immunol 26: 107–121, 1989Google Scholar
  11. Felsenstein, J.: Confidence limits on phylogenies: an approach using the bootstrap. Evolution 39: 783–791, 1985Google Scholar
  12. Figueroa, F., O'hUigin, C., Inoko, H., and Klein, J.: Primate DRB6 pseudogenes — clue to the evolutionary origin of the HLA-DR2 haplotype. Immunogenetics 34: 324–337, 1991Google Scholar
  13. Gorski, J. and Mach, B.: Polymorphism of human Ia antigens: gene conversion between two DRβ loci results in a new HLA-D/DR specificity. Nature 322: 67–70, 1986Google Scholar
  14. Gyllensten, U. B., Sundvall, M., and Erlich, H.: Allelic diversity is generated by intraexon sequence exchange at the DRB1 locus of primates. Proc Natl Acad Sci USA 88: 3686–3690, 1991aGoogle Scholar
  15. Gyllensten, U., Sundvall, M., Ezcurra, I., and Erlich, H.: Genetic diversity at class II DRB loci of the primate MHC. J Immunol 146: 4368–4376, 1991bGoogle Scholar
  16. Haas, D. A., Boss, J. M., Strominger, J. L., and Spies, T.: A highly deverged β1 exon in the DR region of the human MHC: sequence and evolutionary implications. Immunogenetics 25: 15–20, 1987Google Scholar
  17. Higgins, D. G., Bleasy, A. J., and Fuchs, R.: CLUSTAL V: improved software for multiple sequence alignments. CABIOS 8: 189–191, 1992Google Scholar
  18. Hughes, A. L. and Nei, M.: Nucleotide substitutions at major histocompatibility complex class II loci: evidence for overdominant selection. Proc Natl Acad Sci USA 86: 958–962, 1989PubMedGoogle Scholar
  19. Hughes, A. L.: Testing for interlocus genetic exchange in the MHC a reply to Andersson and co-workers. Immunogenetics 33: 243–246, 1991Google Scholar
  20. Kapper, D. and Strominger, J. L.: Human class II major histocompatibility complex genes and proteins. Annu Rev Biochem 57: 991–1028, 1988Google Scholar
  21. 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, 1990Google Scholar
  22. Kelly, A. P., Monaca, J. J., Cho, S., and Trowsdale, J.: A new human HLA class II locus, DM. Nature 353: 571–573, 1991CrossRefPubMedGoogle Scholar
  23. Kenter, M., Anholts, J., Ruff, G., Otting, N., and Bontrop, R. E. Selective inactivation of the primate Mhc-DQA2 locus. In J. Klein and D. Klein (eds.): Molecular Evolution of the Major Histocompatibility Complex, pp. 213–220, Springer Verlag, Heidelberg, 1991Google Scholar
  24. Kenter, M., Otting, N., Anholts, J., Leunissen, J., Jonker, M., and Bontrop, R. E.: Evolutionary relationships among the primate Mhc-DQA1 and DQA2 alleles. Immunogenetics 36: 71–78, 1992Google Scholar
  25. Kieny, M. P., Lathe, R., and Lecocq, J. P.: New versatile cloning and sequencing vectors based on bacteriophage M13. Gene 26: 91–99, 1983Google Scholar
  26. Kimura, M.: Estimation of evolutionary distances between nucleotide sequences. Proc Natl Acad Sci USA 78: 454–458, 1981Google Scholar
  27. King, L. B., Sharma, S., and Corley, R. B.: Complete coding region sequence of Eβk cDNA clones: Lack of polymorphism in the NH2-terminus between Eβk and Eβb molecules. J of Immunogenetics 15: 209–214, 1988Google Scholar
  28. Klein, J.: Origin of major histocompatibility complex polymorphism: the trans species hypothesis. Hum Immunol 19: 155–162, 1987CrossRefPubMedGoogle Scholar
  29. 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, 1990PubMedGoogle Scholar
  30. Klein, D., Vincek, V., Kasahara, M., Schönbach, C., O'hUigin, C., Klein, J.: Gorilla major histocompatibility complex-DRB pseudogene orthologous to HLA-DRBVIII. Hum Immunol 32: 211–220, 1991aGoogle Scholar
  31. Klein, J., O'hUigin, C., Kasahara, M., Vincek, V., Klein, D., and Figueroa, F.: Frozen haplotypes in Mhc evolution. In J. Klein and D. Klein (eds.): Molecular Evolution of the Major Histocompatibility Complex, pp. 261–286, Springer-Verlag, Heidelberg, 1991bGoogle Scholar
  32. Klein, J., Satta, Y., O'hUigin, C., Mayer, W. E., and Takahata, N.: Evolution of the primate DRB region. In T. Sasazuki (ed.): HLA 1991, Vol 2, Proceedings of the 11th International Histocompatibility Workshop, Yokohama, Japan. Oxford University Press, Oxford, 1992Google Scholar
  33. Larhammer, D., Servenius, B., Rask, L., and Peterson, P. A.: Characterization of an HLA-DRβ pseudogene. Proc Natl Acad Sci USA 82: 1475–1479, 1985PubMedGoogle Scholar
  34. Maniatis, T., Fritsch, E. F., and Sambrook, J.: Molecular cloning: A laboratory manual. Cold Spring Harbor Laboratory, New York, 1982Google Scholar
  35. Marsh, S. G. E. and Bodmer, J. G.: HLA Class II Nucleotide Sequences 1991. Hum Immunol 31: 207–227, 1991Google Scholar
  36. Meunier, H. F., Carson, S., Bodmer, W. F., and Trowsdale, J.: An isolated β1 exon next to the DRα gene in the HLA-D region. Immunogenetics 23: 172–180, 1986Google Scholar
  37. Nei, M. and Gojobori, T.: Simple methods for estimating the number of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol 3: 418–426, 986Google Scholar
  38. Nei, M. and Rzhetsky, A.: Reconstruction of phylogenetic trees and evolution of major histocompatibility complex genes. In J. Klein and D. Klein (eds.): Molecular Evolution of the Major Histocompatibility Complex, pp. 13–27, Springer Verlag, Heiderlberg, 1991Google Scholar
  39. Olerup, O., Troye-Blomberg, M., Schreuder, G. M. T., and Riley, E. M.: HLA-DR and -DQ gene polymorphism in West Africans is twice extensive as in North European Caucasians: Evolutionary implication. Proc Natl Acad Sci USA 88: 8480–8484, 1991Google Scholar
  40. Otting, N., Kenter, M., van Weeren, P., Jonker, M., and Bontrop, R. E.: Mhc-DQB repertoire variation in hominoid and Old World primate species. J Immunol, in press, 1992Google Scholar
  41. Rollini, P., Mach, B., and Gorski, J.: Linkage map of three HLA-DRβ chain genes: Evidence for a recent duplication event. Proc Natl Acad Sci USA 82: 7197–7201, 1985Google Scholar
  42. Rollini, P., Gorski, J., and Mach, B.: Characterization of an HLA-DRβ pseudogene in the DRw52 supertypic group. Immunogenetics 25: 336–342, 1987Google Scholar
  43. Ruvolo, M., Disorell, T., Allard, M. W., Brown, W. M., and Honeycutt, R. L.: Resolution of the African hominoid trichotomy by use of a mitochondrial gene sequence. Proc Natl Acad Sci USA 88: 1570–1574, 1991Google Scholar
  44. Saiki, R. K., Scharf, S., Faloona, F., Mullis, K. B., Horn, G. T., Erlich, H. A., and Arnheim, N.: Enzymatic amplification of β-globin genomic sequences and restriction site analysis of sickle cell anaemia. Science 230: 1350–1354, 1985Google Scholar
  45. Saiki, R. K., Gelfand, D. H., Stoffel, S., Scharf, S. J., Higuchi, R., Horn, G. T., Mullis, K. B., and Erlich, H. A.: Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239: 487–491, 1988PubMedGoogle Scholar
  46. Saitou, N. and Nei, M.: The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol 4: 406–425, 1987PubMedGoogle Scholar
  47. Sanger, F., Nicklen, S., and Carlson, R.: DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 77: 5463–5467, 1977Google Scholar
  48. Trowsdale, J., Ragoussis, J., and Campbell, R. D.: Map of the human MHC. Immunol Today 12: 443–446, 1991Google Scholar
  49. Vincek, V., Klein, D., Figueroa, F., Hauptvield, V., Kasahara, M., O'hUigin, C., Mach, B., and Klein, J.: The evolutionary origin of the HLA-DR3 haplotype. Immunogenetics 35: 263–271, 1992Google Scholar
  50. WHO Nomenclature Committee: Nomenclature for factors of the HLA system, 1991. Tissue Antigens 39: 1–13, 1992Google Scholar
  51. Wu, S., Sauders, T. L., and Bach, F.: Polymorphism of human Ia antigens generated by reciprocal intergenic exchange between two DRβ loci. Nature 324: 676–679, 1986Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • M. Kenter
    • 1
    • 2
  • N. Otting
    • 1
  • J. Anholts
    • 2
  • M. Jonker
    • 1
  • R. Schipper
    • 2
  • R. E. Bontrop
    • 1
  1. 1.ITRI-TNOHV RijswijkThe Netherlands
  2. 2.Department of Immunohematology and Blood BankLeiden University HospitalThe Netherlands

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