Skip to main content
SpringerLink
Log in

Polymorphism, haplotype composition, and selection in the Mhc-DRB of wild baboons

  • Original Paper
  • Published:
Immunogenetics Aims and scope Submit manuscript

Abstract

General patterns of organization in the major histocompatibility complex (MHC) have been successfully explained by the model of birth-and-death evolution, but understanding why certain MHC genes are maintained together into specific haplotypes remains challenging. The haplotype configurations of the functionally important class II DR region have been described in few primates and display important interspecific variability with respect to the extent of allelic variation, the number of loci and/or combinations of loci present. Understanding the evolutionary mechanisms driving such variation is conditional upon characterizing haplotypes in new species and identifying the selective pressures acting on haplotypes. This study explores the variability of haplotype configurations in the Mhc-DRB region (exon 2) for the first time in wild non-human primates, chacma baboons (Papio ursinus). Paur-DRB haplotypes were characterized through segregation studies and linkage disequilibrium. 23 Paur-DRB sequences and 15 haplotype configurations were identified in 199 animals. The Paur-DRB exon 2 is shown to be subjected to intense positive selection and frequent recombination. An approach recently developed for human vaccine studies was used to classify Paur-DRB sequences into supertypes, based on the physico-chemical properties of amino acids that are positively selected, thus most probably involved in antigen recognition. Sequences grouped into the same supertype (thus presumably sharing antigen-binding affinities) are non-randomly distributed within haplotypes, leading to an increased individual diversity of supertypes. Our results suggest that selection favoring haplotypes with complementary sets of DRB supertypes shapes functionally tuned haplotypes in this natural baboon population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Alper CA, Larsen CE, Dubey DP, Awdeh ZL, Fici DA, Yunis EJ (2006) The haplotype structure of the human major histocompatibility complex. Hum Immunol 67:73–84 doi:10.1016/j.humimm.2005.11.006

    Article  PubMed  CAS  Google Scholar 

  • Anisimova M, Nielsen R, Yang ZH (2003) Effect of recombination on the accuracy of the likelihood method for detecting positive selection at amino acid sites. Genetics 164:1229–1236

    PubMed  CAS  Google Scholar 

  • Apanius V, Penn D, Slev P, Ruff LR, Potts WK (1997) The nature of selection on the major histocompatibility complex. Crit Rev Immunol 17:179–224

    PubMed  CAS  Google Scholar 

  • Bodmer WF (1972) Evolutionary significance of the HL-A system. Nature 237:139–183 doi:10.1038/237139a0

    Article  PubMed  CAS  Google Scholar 

  • Bontrop RE, Otting N, de Groot NG, Doxiadis GGM (1999) Major histocompatibility complex class II polymorphisms in primates. Immunol Rev 167:339–350 doi:10.1111/j.1600-065X.1999.tb01403.x

    Article  PubMed  CAS  Google Scholar 

  • Brown JH, Jardetzky TS, Gorga JC, Stern LJ, Urban RG, Strominger JL et al (1993) Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature 364:33–39 doi:10.1038/364033a0

    Article  PubMed  CAS  Google Scholar 

  • Consuegra S, Megens HJ, Schaschl H, Leon K, Stet RJM, Jordan WC (2005) Rapid evolution of the MH class I locus results in different allelic compositions in recently diverged populations of Atlantic salmon. Mol Biol Evol 22:1095–1106 doi:10.1093/molbev/msi096

    Article  PubMed  CAS  Google Scholar 

  • Cowlishaw G (1999) Ecological and social determinants of spacing behaviour in desert baboon groups. Behav Ecol Sociobiol 45:67–77 doi:10.1007/s002650050540

    Article  Google Scholar 

  • de Groot N, Doxiadis GG, de Groot NG, Otting N, Heijmans C, Rouweler AJM et al (2004) Genetic makeup of the DR regions in rhesus macaques: gene content, transripts, and pseudogenes. J Immunol 172:6152–6157

    PubMed  Google Scholar 

  • Delguercio MF, Sidney J, Hermanson G, Perez C, Grey HM, Kubo RT et al (1995) Binding of a peptide antigen to multiple Hla alleles allows definition of an A2-like supertype. J Immunol 154:685–693

    CAS  Google Scholar 

  • Doherty PC, Zinkernagel RM (1975) Enhanced immunological surveillance in mice heterozygous at the H-2 gene complex. Nature 256:50–52 doi:10.1038/256050a0

    Article  PubMed  CAS  Google Scholar 

  • Doxiadis GGM, Otting N, de Groot N, Noort MC, Bontrop RE (2000) Unprecedented poluymorphism of Mhc-DRB region configurations in rhesus macaques. J Immunol 164:3193–3199

    PubMed  CAS  Google Scholar 

  • Doxiadis GGM, Otting N, de Groot N, Bontrop RE (2001) Differential evolutionary MHC class II strategies in humans and rhesus macaques: relevance for biomedical studies. Immunol Rev 183:77–85 doi:10.1034/j.1600-065x.2001.1830106.x

    Article  Google Scholar 

  • Doxiadis GGM, Otting N, de Groot NG, de Groot N, Rouweler AJM, Noort R et al (2003) Evolutionary stability of MHC class II haplotypes in diverse rhesus macaque populations. Immunogenetics 55:540–551 doi:10.1007/s00251-003-0590-9

    Article  PubMed  CAS  Google Scholar 

  • Doytchinova IA, Flower DR (2005) In silico identification of supertypes for class II MHCs. J Immunol 174:7085–7095

    PubMed  CAS  Google Scholar 

  • Doytchinova IA, Guan PP, Flower DR (2004) Identifiying human MHC supertypes using bioinformatic methods. J Immunol 172:4314–4323

    PubMed  CAS  Google Scholar 

  • Gu X, Nei M (1999) Locus specificity of polymorphic alleles and evolution by a birth-and-death process in mammalian MHC genes. Mol Biol Evol 16:147–156

    PubMed  CAS  Google Scholar 

  • Hedrick PW, Kim KJ (2000) Genetics of the complex polymorphisms: parasites and maintenance of the major histocompatibility complex variation. In: Singh RS, Krimbas CB (eds) Evolutionary genetics: from molecules to morphology. Cambridge University Press, Cambridge, pp 204–234

    Google Scholar 

  • Huchard E, Cowlishaw G, Raymond M, Weill M, Knapp LA (2006) Molecular study of Mhc-DRB in wild chacma baboons reveals high variability and evidence for trans-species inheritance. Immunogenetics 58:805–816 doi:10.1007/s00251-006-0156-8

    Article  PubMed  CAS  Google Scholar 

  • Hudson RR (2001) Two-locus sampling distributions and their application. Genetics 159:1805–1817

    PubMed  CAS  Google Scholar 

  • Hughes AL, Yeager M (1998) Natural selection at major histocompatibility complex loci of vertebrates. Annu Rev Genet 32:415–432 doi:10.1146/annurev.genet.32.1.415

    Article  PubMed  CAS  Google Scholar 

  • Jeffery KJM, Bangham CRM (2000) Do infectious diseases drive MHC diversity? Microbes Infect 2:1335–1341 doi:10.1016/S1286-4579(00)01287-9

    Article  PubMed  CAS  Google Scholar 

  • Jukes TH, Cantor CR (1969) Evolution of protein molecules. In: Munro HN (ed) Mammalian protein metabolism. Academic, New York, pp 21–132

    Google Scholar 

  • Khazand M, Peiberg C, Nagy M, Sauermann U (1999) Mhc-DQ-DRB haplotype analysis in the rhesus macaque: evidence for a number of different haplotypes displaying a low allelic polymorphism. Tissue Antigens 54:615–624 doi:10.1034/j.1399-0039.1999.540612.x

    Article  PubMed  CAS  Google Scholar 

  • Knapp LA, Cadavid LF, Eberle ME, Knechtle SJ, Bontrop RE, Watkins DI (1997) Identification of new Mamu-DRB alleles using DGGE and direct sequencing. Immunogenetics 45:171–179 doi:10.1007/s002510050186

    Article  PubMed  CAS  Google Scholar 

  • Kumar S, Koichiro T, Jakobsen IB Nei M (2001) MEGA2: molecular evolutionary genetics analysis software. Bioinformatics Application Note 17:1244–1245

    CAS  Google Scholar 

  • Kundu S, Faulkes CG (2004) Patterns of MHC selection in African mole-rats, family Bathyergidae: the effects of sociality and habitat. Proc R Soc Lond B Biol Sci 271:273–278 doi:10.1098/rspb.2003.2584

    Article  Google Scholar 

  • Lund O, Nielsen M, Kesmir C, Petersen AG, Lundegaard C, Worning P et al (2004) Definition of supertypes for HLA molecules using clustering of specificity matrices. Immunogenetics 55:797–810 doi:10.1007/s00251-004-0647-4

    Article  PubMed  CAS  Google Scholar 

  • Madden DR (1995) The 3-dimensional structure of peptide-Mhc complexes. Annu Rev Immunol 13:587–622 doi:10.1146/annurev.iy.13.040195.003103

    Article  PubMed  CAS  Google Scholar 

  • Marsh SGE (2005) Nomenclature for factors of the HLA system, update June 2005. Tissue Antigens 66:338–340 doi:10.1111/j.1399-0039.2005.00479.x

    Article  PubMed  CAS  Google Scholar 

  • McVean G, Awadalla P, Fearnhead P (2002) A coalescent-based method for detecting and estimating recombination from gene sequences. Genetics 160:1231–1241

    PubMed  CAS  Google Scholar 

  • Myers RM, Fischer SG, Lerman LS, Maniatis T (1987) Nearly all single base substitutions in DNA fragments joined to GC-clamp can be detected by denaturing gradient gel electrophoresis. Nucleic Acids Res 13:3131–3145 doi:10.1093/nar/13.9.3131

    Article  Google Scholar 

  • Nei M, Gojobori T (1986) Simple methods for estimating the number of synonymous and non-synonymous nucleotide substitutions. Mol Biol Evol 3:418–426

    PubMed  CAS  Google Scholar 

  • Nei M, Gu X, Sitnikova T (1997) Evolution by the birth-and-death process in multigene families of the vertebrate immune system. Proc Natl Acad Sci U S A 94:7799–7806 doi:10.1073/pnas.94.15.7799

    Article  PubMed  CAS  Google Scholar 

  • Nei M, Hughes AL (1992) Balanced polymorphism and evolution by the birth-and-death process in the MHC loci. In: Tsuji K, Aizawa M, Sasazuki T (eds) Eleventh histocompatibility workshop and conference. Oxford University Press, Oxford, England, pp 27–38

    Google Scholar 

  • Nei M, Kumar S (2000) Molecular evolution and phylogenetics. Oxford University Press, Oxford

    Google Scholar 

  • Nuismer SL, Otto SP (2004) Host–parasite interactions and the evolution of ploidy. Proc Natl Acad Sci U S A 101:11036–11039 doi:10.1073/pnas.0403151101

    Article  PubMed  CAS  Google Scholar 

  • Otting N, de Groot NG, Noort MC, Doxiadis GGM, Bontrop RE (2000) Allelic diversity of Mhc-DRB alleles in rhesus macaques. Tissue Antigens 56:58–68 doi:10.1034/j.1399-0039.2000.560108.x

    Article  PubMed  CAS  Google Scholar 

  • Piontkivska H, Nei M (2003) Birth-and-death evolution in primate MHC Class I genes: divergence time estimates. Mol Biol Evol 20:601–609 doi:10.1093/molbev/msg064

    Article  PubMed  CAS  Google Scholar 

  • Richman AD, Herrera LG, Nash D (2003a) Evolution of MHC class II E beta diversity within the genus Peromyscus. Genetics 164:289–297

    Article  PubMed  CAS  Google Scholar 

  • Richman AD, Herrera LG, Nash D, Schierup MH (2003b) Relative roles of mutation and recombination in generating allelic polymorphism at an MHC class II locus in Peromyseus maniculatus. Genet Res 82:89–99 doi:10.1017/S0016672303006347

    Article  PubMed  CAS  Google Scholar 

  • Robinson J, Waller MJ, Parham P, de Groot N, Bontrop RE, Kennedy LJ et al (2003) IMGT/HLA and IMGT/MHC: sequence databases for the study of the major histocompatibility complex. Nucleic Acids Res 31:311–314 doi:10.1093/nar/gkg070

    Article  PubMed  CAS  Google Scholar 

  • Sandberg M, Eriksson L, Jonsson J, Sjostrom M, Wold S (1998) New chemical descriptors relevant for the design of biologically active peptides. A multivariate characterization of 87 amino acids. J Med Chem 41:2481–2491 doi:10.1021/jm9700575

    Article  PubMed  CAS  Google Scholar 

  • Schad J, Sommer S, Ganzhorn JU (2004) MHC variability of a small lemur in the littoral forest fragments of southeastern Madagascar. Conserv Genet 5:299–309 doi:10.1023/B:COGE.0000031137.50239.d3

    Article  CAS  Google Scholar 

  • Schaschl H, Suchentrunk F, Hammer S, Goodman SJ (2005) Recombination and the origin of sequence diversity in the DRB MHC class II locus in chamois (Rupicapra spp.). Immunogenetics 57:108–115 doi:10.1007/s00251-005-0784-4

    Article  PubMed  CAS  Google Scholar 

  • Schwensow N, Fietz J, Dausmann KH, Sommer S (2007) Neutral versus adaptive genetic variation in parasite resistance: importance of major histocompatibility complex supertypes in a free-ranging primate. Heredity 99:265–277 doi:10.1038/sj.hdy.6800993

    Article  PubMed  CAS  Google Scholar 

  • Sette A, Sidney J (1998) HLA supertypes and supermotifs: a functional perspective on HLA polymorphism. Curr Opin Immunol 10:478–482 doi:10.1016/S0952-7915(98)80124-6

    Article  PubMed  CAS  Google Scholar 

  • Sette A, Sidney J (1999) Nine major HLA class I supertypes account for the vast preponderance of HLA-A and -B polymorphism. Immunogenetics 50:201–212 doi:10.1007/s002510050594

    Article  PubMed  CAS  Google Scholar 

  • Sette A, Livingston B, McKinney D, Appella E, Fikes J, Sidney J et al (2001) The development of multi-epitope vaccines: Epitope identification, vaccine design and clinical evaluation. Biologicals 29:271–276 doi:10.1006/biol.2001.0297

    Article  PubMed  CAS  Google Scholar 

  • Sette A, Newman M, Livingston B, McKinney D, Sidney J, Ishioka G et al (2002) Optimizing vaccine design for cellular processing, MHC binding and TCR recognition. Tissue Antigens 59:443–451 doi:10.1034/j.1399-0039.2002.590601.x

    Article  PubMed  CAS  Google Scholar 

  • Seutin G, White BN, Boag PT (1990) Preservation of avian blood and tissue samples for DNA analysis. Can J Zool 69:82–90 doi:10.1139/z91-013

    Article  Google Scholar 

  • Sidney J, Howard MG, Kubo RT, Sette A (1996) Practical, biochemical and evolutionary implications of the discovery of HLA class I supermotifs. Immunol Today 17:261–266 doi:10.1016/0167-5699(96)80542-1

    Article  PubMed  CAS  Google Scholar 

  • Slierendregt BL, Otting N, van Besouw N, Jonker M, Bontrop RE (1994) Expansion and contraction of rhesus macaque DRB regions by duplication and deletion. J Immunol 152:2298–2307

    PubMed  CAS  Google Scholar 

  • Slierendregt BL, van Noort JT, Bakas RM, Otting N, Jonker M, Bontrop RE (1992) Evolutionary stability of transpecies major histocompatibility complex class II DRB lineages in humans and rhesus monkeys. Hum Immunol 35:29–39 doi:10.1016/0198-8859(92)90092-2

    Article  PubMed  CAS  Google Scholar 

  • Southwood S, Sidney J, Kondo A, del Guercio MF, Appella E, Hoffman S et al (1998) Several common HLA-DR types share largely overlapping peptide binding repertoires. J Immunol 160:3363–3373

    PubMed  CAS  Google Scholar 

  • Stern LJ, Brown JH, Jardetzky TS, Gorga JC, Urban RG, Strominger JL et al (1994) Crystal-structure of the human class-Ii Mhc protein Hla-Dr1 complexed with an influenza-virus peptide. Nature 368:215–221 doi:10.1038/368215a0

    Article  PubMed  CAS  Google Scholar 

  • Sturn A, Quackenbush J, Trajanoski Z (2002) Genesis: cluster analysis of microarray data. Bioinformatics 18:207–208 doi:10.1093/bioinformatics/18.1.207

    Article  PubMed  CAS  Google Scholar 

  • Trachtenberg E, Korber B, Sollars C, Kepler TB, Hraber PT, Hayes E et al (2003) Advantage of rare HLA supertype in HIV disease progression. Nat Med 9:928–935 doi:10.1038/nm893

    Article  PubMed  CAS  Google Scholar 

  • Wong WSW, Yang ZH, Goldman N, Nielsen R (2004) Accuracy and power of statistical methods for detecting adaptive evolution in protein coding sequences and for identifying positively selected sites. Genetics 168:1041–1051 doi:10.1534/genetics.104.031153

    Article  PubMed  CAS  Google Scholar 

  • Yang ZH (1997) PAML: a program package for phylogenetic analysis by maximum likelihood. Comput Appl Biosci 13:555–556

    PubMed  CAS  Google Scholar 

  • Yang ZH, Bielawski JP (2000) Statistical methods for detecting molecular adaptation. Trends Ecol Evol 15:496–503 doi:10.1016/S0169-5347(00)01994-7

    Article  PubMed  Google Scholar 

  • Yang ZH, Nielsen R, Goldman N, Pedersen AMK (2000) Codon-substitution models for heterogeneous selection pressure at amino acid sites. Genetics 155:431–449

    PubMed  CAS  Google Scholar 

Download references

Acknowledgment

We would like to thank Arnaud Berthomieu and Jo Osborn for technical assistance in the lab and Alexandre Courtiol for help in the resampling tests. We thank the Ministry of Lands and Resettlement for permission to work at Tsaobis Leopard Park, the Desert Research Foundation of Namibia for affiliation, and the Ministry of Environment and Tourism for research permission. We confirm that we have adhered to the Guidelines for the Use of Animals in Behavioural Research and Teaching (Animal Behaviour, 65:249–255, 2003) and the legal requirements of the country (Namibia) in which the work was carried out. This work was funded by a Natural Environment Research Council (UK) grant awarded to G.C. and a Ministère de l’Education et de la Recherche (France) Studentship awarded to E.H. G.C. was funded by a NERC Advanced Fellowship during the writing of this paper. This paper is a publication of the ZSL Institute of Zoology’s Tsaobis Baboon Project. Contribution ISEM 2008-054.

Author information

Authors and Affiliations

  1. CNRS, Institut des Sciences de l’Evolution, Université Montpellier 2, CC 065, Place Eugène Bataillon, 34095, Montpellier Cedex 05, France

    Elise Huchard, Mylene Weill & Michel Raymond

  2. Institute of Zoology, Zoological Society of London, Regent’s Park, London, NW1 4RY, UK

    Elise Huchard & Guy Cowlishaw

  3. Department of Biological Anthropology, University of Cambridge, Downing Street, Cambridge, CB2 3DZ, UK

    Leslie A. Knapp

Authors
  1. Elise Huchard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mylene Weill
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guy Cowlishaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michel Raymond
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Leslie A. Knapp
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elise Huchard.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huchard, E., Weill, M., Cowlishaw, G. et al. Polymorphism, haplotype composition, and selection in the Mhc-DRB of wild baboons. Immunogenetics 60, 585–598 (2008). https://doi.org/10.1007/s00251-008-0319-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00251-008-0319-x

Keywords

Search

Navigation