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Immunogenetics

, Volume 64, Issue 3, pp 165–175 | Cite as

Signatures of historical demography and pathogen richness on MHC class I genes

  • Nouar QutobEmail author
  • Francois Balloux
  • Towfique Raj
  • Hua Liu
  • Sophie Marion de Procé
  • John Trowsdale
  • Andrea Manica
Original Paper

Abstract

The extreme polymorphism of MHC class I has been argued to be driven by balancing selection from pathogens, with the prediction that populations exposed to a wider variety of diseases should have higher diversity. We assembled a global database of allotype frequencies for MHC class I genes and investigated possible drivers of genetic diversity, measured in different ways. We first looked for a decline in diversity with distance from Africa (a consequence of drift during human expansions) and then investigated the link with pathogen richness once the effect of drift had been corrected for. Using heterozygosity, we recovered a clear decline in diversity from Africa and confirmed the positive relationship between genetic diversity and pathogen richness for all three classical MHC class I genes. However, when we considered a sequence-based measure of genetic diversity, the correlation with geographic distance from Africa vanished for HLA-C, and the correlations with pathogen richness for the three MHC class I genes were much weaker. HLA-C is known to consist of two functional classes of allotypes (classified with respect to the 80th residue), which interact with different KIR receptors. While this separation provided some improvement in the fit between genetic diversity and distance from Africa for one class, much clearer and consistent patterns were recovered when we used the 90th residue to separate HLA-C allotypes into two new classes. This suggests that this residue, which is also involved in the binding of KIR, might have had an important evolutionary role that has been overlooked.

Keywords

MHC MHC diversity Dempography Pathogen richness Natural selection 

Notes

Acknowledgments

This work was supported by the Wellcome Trust (RG56540), the Medical Research Council (G0800681 and G0901682), the Biotechnology and Biological Sciences Research Council (BB/H005854/1 and BB/H008802/1), the Leverhulme Trust (Philip Leverhulme Award), the Karim Rida Said foundation (Karim Rida Said Scholarship‬) and the Cambridge Overseas Trust and in part by the Cambridge NIHR Biomedical Research Centre. We would like to thank Derek Smith, Rufus Johnstone, Stuart Piertney and two anonymous referees for the comments on the manuscript. We would also like to thank Thibaut Jombart for his help with the statistical analyses.

Supplementary material

251_2011_576_MOESM1_ESM.pdf (113 kb)
ESM Table 1 (PDF 113 kb)
251_2011_576_MOESM2_ESM.pdf (78 kb)
ESM Table 2 (PDF 78 kb)
251_2011_576_MOESM3_ESM.pdf (5 kb)
ESM Table 3 (PDF 5 kb)
251_2011_576_MOESM4_ESM.xls (107 kb)
ESM Table 4 (XLS 107 kb)
251_2011_576_MOESM5_ESM.pdf (63 kb)
ESM Table 5 (PDF 62 kb)

References

  1. Alcaide M, Edwards SV, Negro JJ, Serrano D, Tella JL (2008) Extensive polymorphism and geographical variation at a positively selected MHC class II B gene of the lesser kestrel (Falco naumanni). Mol Ecol 17:2652–2665PubMedCrossRefGoogle Scholar
  2. Alcaide M, Lemus JA, Blanco G, Tella JL, Serrano D, Negro JJ, Rodríguez A, García-Montijano M (2010) MHC diversity and differential exposure to pathogens in kestrels (Aves: Falconidae). Mol Ecol 19:691–705PubMedCrossRefGoogle Scholar
  3. Allendorf FW (1986) Genetic drift and the loss of alleles versus heterozygosity. Zoo Biology 5:181–190CrossRefGoogle Scholar
  4. Anfossi N, Andre P, Guia S, Falk CS, Roetnynck S, Stewart CA, Breso V, Frassati C, Reviron D, Middleton D, Romagne F, Ugolini S, Vivier E (2006) Human NK cell education by inhibitory receptors for MHC class I. Immunity 25:331–342PubMedCrossRefGoogle Scholar
  5. Apanius V, Penn D, Slev PR, Ruff LR, Potts WK (1997) The nature of selection on the major histocompatibility complex. Crit Rev Immunol 17:179–224PubMedGoogle Scholar
  6. Appanna R, Ponnampalavanar S, Lum Chai See L, Sekaran S (2010) Susceptible and protective HLA class 1 alleles against dengue fever and dengue hemorrhagic fever patients in a Malaysian population. 5(9):e13029Google Scholar
  7. Arnaiz-Villena J, Moscoso JI, Serrano-Vela J, Martinez-Laso (2006) The uniqueness of Amerindians according to HLA genes and the peopling of the Americas. Inmunología 25:13–24Google Scholar
  8. Betti L, Balloux F, Amos W, Hanihara T, Manica A (2009) Distance from Africa, not climate, explains within-population phenotypic diversity in humans. Proc Roy Soc B 276:809–814CrossRefGoogle Scholar
  9. Bodmer JG, Marsh SGE, Parham P, Erlich HA, Albert E, Bodmer WF, Dupont B, Mach B, Mayr WR, Sasazuki T, Schreuder GMT, Strominger JL, Svejgaard A, Terasaki PI (1990) Nomenclature for factors of the HLA system. Tissue Antigens 35:1–8PubMedCrossRefGoogle Scholar
  10. Boyton RJ, Altmann DM (2007) Natural killer cells, killer immunoglobulin-like receptors and human leukocyte antigen class I in disease. Clin Exp Immunol 149:1–8PubMedCrossRefGoogle Scholar
  11. Carrington M, Martin MP (2006) The impact of variation at the KIR gene cluster on human disease. Curr Top Microbiol Immunol 298:225–257PubMedCrossRefGoogle Scholar
  12. Carrington M, Nelson GW, Martin MP, Kissner T, Vlahov D, Goedert JJ, Kaslow R, Buchbinder S, Hoots K, O'Brian J (1999) HLA and HIV I: heterozygote advantage and B*35-Cw*04 disadvantage. Science 283(5408):1748–1752PubMedCrossRefGoogle Scholar
  13. Cella M, Longo A, Ferrara GB, Strominger JL, Colonna M (1994) NK3-specific natural killer cells are selectively inhibited by Bw4-positive HLA alleles with isoleucine 80. J Exp Med 180:1235–1242PubMedCrossRefGoogle Scholar
  14. Coetzee V, Barrett L, Greeff JM, Henzi SP, Perrett DI, David I, Wadee AA (2007) Common HLA alleles associated with health, but not with facial attractivenss. PLoS One 2:e640PubMedCrossRefGoogle Scholar
  15. Doherty PC, Zinkernagel RM (1975) Enhanced immunological surveillance in mice heterozygous at the H-2 gene complex. Nature 256:50–52PubMedCrossRefGoogle Scholar
  16. Duhamel S, Jacquet S (2005) Flow cytometric analysis of bacteria- and virus-like particles in lake sediments. J Microbiol Meth 64(3):316–323CrossRefGoogle Scholar
  17. Fan QR, Wiley DC (1999) Structure of human histocompatibility leukocyte antigen (HLA)-Cw4, a ligand for the KIR2D natural killer cell inhibitory receptor. J Exp Med 190:113PubMedCrossRefGoogle Scholar
  18. Gao X, O’Brien TR, Welzel TM, Marti D, Qi Y, Goedert JJ, Phair J, Pfeiffer R, Carrington M (2010) HLA-B alleles associate consistently with HIV heterosexual transmission, viral load, and progression to AIDS, but not susceptibility to infection. AIDS 24(12):1835–1840PubMedCrossRefGoogle Scholar
  19. Gendzekhadze K, Norman PJ, Abi-Rached L, Graef T, Moesta AK, Layrisse Z, Parham P (2001) Co-evolution of KIR2DL3 with HLA-C in a human population retaining minimal essential diversity of KIR and HLA class I ligands. Proc Nati Acad Sci USA 106(44):18692–18697CrossRefGoogle Scholar
  20. Gendzekhadze K, Norman PJ, Abi-Rached L, Graef T, Moesta AK, Layrisse Z, Parham P (2009) Co-evolution of KIR2DL3 with HLA-C in a human population retaining minimal essential diversity of KIR and HLA class I ligands. Proc Natl Acad Sci USA 106:18692–18697PubMedCrossRefGoogle Scholar
  21. Godot V, Harraga S, Beurton I, Deschaseaux M, Sarciron E, Gottstein B, Vuitton DA (2000) Resistance/susceptibility to Echinococcus multilocularis infection and cytokine profile in humans. I. Comparison of patients with progressive and abortive lesions. Clin Exp Immunol 121:484–490PubMedCrossRefGoogle Scholar
  22. Graef T, Moesta AK, Norman PJ, Abi-Rached L, Vago L, Older Aguilar AM, Gleimer M, Hammond JA, Guethlein LA, Bushnell DA, Robinson PJ, Parham P (2009) KIR2DS4 is a product of gene conversion with KIR3DL2 that introduced specificity for HLA-A*11 while diminishing avidity for HLA-C. J Exp Med 206(11):2557–2572PubMedCrossRefGoogle Scholar
  23. Guernier V, Hochberg ME, Guégan JF (2004) Ecology drives the worldwide distribution of human diseases. PLoS Biol 2:740–746CrossRefGoogle Scholar
  24. Guivier E, Galan M, Male P, Kallio E, Voutilainen L, Henttonen H, Olsson G, Lundkvist A, Tersago K, Augot D, Cosson J, Charbonnel N (2010) Associations between MHC genes and Puumala virus infection in Myodes glareolus are detected in wild populations, but not from experimental infection data. J Gen Virol 91(10):2507–2512PubMedCrossRefGoogle Scholar
  25. Hansasuta P, Dong T, Thananchai H, Weekes M, Willberg C, Aldemir H, Rowland-Jones S, Braud VM (2004) Recognition of HLA-A3 and HLA-A11 by KIR3DL2 is peptide-specific. Mol Immunol 34:1673–1679Google Scholar
  26. Hiby SE, Walker JJ, O'shaughnessy KM, Redman CWG, Carrington M, Trowsdale J, Moffett A (2004) Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med 200(8):957–965PubMedCrossRefGoogle Scholar
  27. Hiby SE, Apps R, Sharkey AM, Farrell LE, Gardner L, Mulder A, Claas FH, Walker JJ, Redman CW, Morgan L, Tower C, Regan L, Moore GE, Carrington M, Moffett A (2010) Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2. J Clin Invest 120(11):4102–4010PubMedCrossRefGoogle Scholar
  28. Hill AV, Allsopp CEM, Kwiatkowski DK, Anstey NM, Twumasi P, Rowe PA, Bennett S, Brewster D, McMichael AJ, Greenwood BM (1991) Common west African HLA antigens are associated with protection from severe malaria. Nature 352:595–600PubMedCrossRefGoogle Scholar
  29. Hoglund P, Brodin P (2009) Current perspectives of natural killer cell education by MHC class I molecules. Nat Rev Immunol 10:724–734CrossRefGoogle Scholar
  30. Jones DT, Taylor WR, Thornton JM (1992) The rapid generation of mutation data matrices from protein sequences. Comput Appl Biosci 8:275–282PubMedGoogle Scholar
  31. Khakoo SI, Carrington M (2006) KIR and disease: a model system or system of models. Immunol Rev 214:186–201PubMedCrossRefGoogle Scholar
  32. Kidd KK, Pakstis AJ, Speed WC, Kidd JR (2004) Understanding human DNA sequence variation. J Hered 95(5):406–420PubMedCrossRefGoogle Scholar
  33. Koehler RN, Walsh AM, Saathoff E, Tovanabutra S, Arroyo MA, Currier JR, Maboko L, Hoelsher M, Robb ML, Michael NL, McCutchan F, Kim J, Kijak G (2010) Class I HLA-A*7401 is associated with protection from HIV-1 acquisition and disease progression in Mbeya, Tanzania. J Infect Dis 202:1562–1566PubMedCrossRefGoogle Scholar
  34. Kulkarni S, Savan R, Qi Y, Gao X, Yuki Y, Bass SE, Martin MP, Hunt P, Deeks SG, Telenti A, Pereyra F, Goldstein D, Wolinsky S, Walker B, Young HA, Carrington M (2011) Differential microRNA regulation of HLA-C expression and its association with HIV control. Nature 472(7344):495–498PubMedCrossRefGoogle Scholar
  35. Lechler R (1994) HLA and diseases. Academic press limited, London, pp 1–186Google Scholar
  36. Liu H, Prugnolle F, Manica A, Balloux F (2006) A geography explicit genetic model of worldwide human-settelment history. Am J Hum Genet 79:230–237PubMedCrossRefGoogle Scholar
  37. Mandelboim O, Reyburn HT, Sheu EG, Vales-Gomez M, Davis DM, Pazmany L, Strominger JL (1997) The binding site of NK receptors on HLA-C molecules. Immunity 6(3):341–350PubMedCrossRefGoogle Scholar
  38. Manica A, Prugnolle F, Balloux F (2005) Geography is a better determinant of human genetic differentiation than ethnicity. Hum Genet 118:366–371PubMedCrossRefGoogle Scholar
  39. Manica A, Amos W, Balloux F, Hanihara T (2007) The effect of ancient bottenecks on human phenotype variation. Nature 448:346–348PubMedCrossRefGoogle Scholar
  40. McAdam SN, Boyson JE, Liu X, Garber TL, Hughes AL, Bontrop RE, Watkins DI (1994) A uniquely high level of recombination at the HLA-B locus. Proc Natl Acad Sci USA 91:5893–5897PubMedCrossRefGoogle Scholar
  41. McClelland EE, Penn DJ, Potts WK (2003) Major histocompatibility complex heterozygote superiority during coinfection. Infect Immun 71(4):2079–2086PubMedCrossRefGoogle Scholar
  42. Meyer D, Mack SJ (2006) Major histocompatibility complex (MHC) genes: polymorphism. Encyclopedia of Life SciencesGoogle Scholar
  43. Meyer D, Thomson G (2001) How selection shapes variation of the human major histocompatibility complex: a review. Ann Hum Genet 65:1–26PubMedCrossRefGoogle Scholar
  44. Nei M (1978) Estimation of average heterozygosity and genetic distance from a small number of individuals. Genetics 89:583–590PubMedGoogle Scholar
  45. Parham P (2005) MHC I molecules and KIRs in human history, healthy and survival. Nat Rev Immunol 5:201–214PubMedCrossRefGoogle Scholar
  46. Parham P, Guethlein LA (2010) Pregnancy immunogenetics: NK cell education in the womb? J Clin Invest 1(120):3801–3804CrossRefGoogle Scholar
  47. Paterson S, Wilson K, Pemberton JM (1998) Major histocompatibility complex variation associated with juvenile survival and parasite resistance in a large unmanaged ungulate population. Proc Natl Acad Sci USA 95:3714–3719PubMedCrossRefGoogle Scholar
  48. Penn DJ, Damjanovich K, Potts WK (2002) MHC heterozygosity confers a selective advantage against multiple-strain infections. Proc Nati Acad Sci USA 99:11260–11264CrossRefGoogle Scholar
  49. Piertney SB, Oliver MK (2006) The evolutionary ecology of the major histocompatibility complex. Heredity 96:7–21PubMedGoogle Scholar
  50. Prugnolle F, Manica A, Balloux F (2005a) Geography predicts neutral genetic diversity of human populations. Curr Biol 15:R159–R160PubMedCrossRefGoogle Scholar
  51. Prugnolle F, Manica A, Charpentier M, Guegan J, Balloux F (2005b) Pathogen-driven selection and worldwide HLA class 1 diversity. Curr Biol 15:1022–1027PubMedCrossRefGoogle Scholar
  52. R Development Core Team (2005) R: A language and environment for statistical computing. R Foundation for Statistical Computing.Google Scholar
  53. Rajagopalan S, Long EO (2005) Understanding how combinations of HLA and KIR genes influence disease. J Exp Med 201(7):1025–1029PubMedCrossRefGoogle Scholar
  54. Rajalingam R, Krausa P, Shilling HG, Stein JB, Balamurugan A, McGinnis MD, Cheng NW, Mehra NK, Parham P (2002) Distinctive KIR and HLA diversity in a panel of North Indian Hindus. Immunogenetics 53:1009–1019PubMedCrossRefGoogle Scholar
  55. Ramachandran S, Deshpande O, Roseman CC, Rosenberg NA, Feldman MW, Cavalli-Sforza LL (2005) Support from the relationship of genetic and geographic distance in human populations for a serial founder effect originating in Africa. Proc Natl Acad Sci USA 102:15942–15947PubMedCrossRefGoogle Scholar
  56. Robinson J, Waller MJ, Parham P, de Groot N, Bontrop R, Kennedy LJ, Stoehr P, Marsh SG (2003) IMGT⁄HLA and IMGT⁄MHC: sequence databases for the study of the major histocompatibility complex. Nucleic Acids Res 31:311–314PubMedCrossRefGoogle Scholar
  57. Romero IG, Manica A, Goudet J, Handley LL, Balloux F (2009) How accurate is the current picture of human genetic variation? Heredity 102:120–126PubMedCrossRefGoogle Scholar
  58. Simmonds MJ, Howson JM, Heward JM, Carr-Smith J, Franklyn JA, Todd JA, Gough SC (2007) A novel and major association of HLA-C in Graves' disease that eclipses the classical HLA-DRB1 effect. Hum Mol Genet 16(18):2149–2153PubMedCrossRefGoogle Scholar
  59. Single RM, Martin MP, Ga X, Meyer D, Yeager M, Kidd JR, Kidd KK, Carrington M (2007) Global diversity and evidence for coevolution of KIR and HLA. Nat Genet 39(9):1114–1119PubMedCrossRefGoogle Scholar
  60. Sommer S (2005) The importance of immune gene variability in evolutionary ecology and evolution. Frontiers in Zoology 2:16PubMedCrossRefGoogle Scholar
  61. Stephen JO, Gao X, Carrington M (2001) HLA and AIDS: a cautionary tale. Trends Mol Med 7(9):379–381CrossRefGoogle Scholar
  62. Stern M, Ruggeri L, Capanni M, Mancusi A, Velardi A (2008) Human leukocyte antigens A23, A24, and A32 but not A25 are ligands for KIR3DL1. Blood 112(3):708–710PubMedCrossRefGoogle Scholar
  63. Tamura K, Dudley J, Nei M, Kumar S (2007) MEGA4: molecular evolutionary genetics analysis, version 4.0. Mol Biol Evol 24(8):1596–1599PubMedCrossRefGoogle Scholar
  64. Thananchai H, Gillespie G, Martin MP, Bashirova A, Yawata N, Yawata M, Easterbrook P, McVicar DW, Maenaka K, Parham P, Carrington M, Dong T, Rowland-Jones S (2007) Cutting edge: allele specific and peptide-dependent interactions between KIR3DL1 and HLA-A and HLA-B. J Immunol 178:33–37PubMedGoogle Scholar
  65. Thomas R, Apps R, Qi Y, Gao X, Male V, O'hUigin C, O'Connor G, Ge D, Fellay J, Martin JN, Margolick J, Goedert JJ, Buchbinder S, Kirk GD, Martin MP, Telenti A, Deeks SG, Walker BD, Goldstein D, McVicar DW, Moffett A, Carrington M (2009) HLA-C cell surface expression and control of HIV/AIDS correlate with a variant upstream of HLA-C. Nat Genet 41(12):1290–1294PubMedCrossRefGoogle Scholar
  66. Thursz MR, Kwiatkowski D, Allsopp CEM, Greenwood BM, Thomas HC, Hill AVS (1995) Association between an MHC class II allele and clearance of hepatitis B virus in the Gambia. N Engl J Med 332:1065–1069PubMedCrossRefGoogle Scholar
  67. Thursz MR, Thomas HC, Greenwood BM, Hill AV (1997) Heterozygote advantage for HLA-class II type in hepatitis B virus infection. Nat Genet 17(1):11–12PubMedCrossRefGoogle Scholar
  68. Trachtenberg E, Korber B, Sollars C, Kepler TB, Hraber PT, Hayes E, Funkhouser R, Fugate M, Theiler J, Hsu YS, Kunstman K, Wu S, Phair J, Erlich H, Wolinsky S (2003) Advantage of rare HLA supertype in HIV disease progression. Nat Med 9:928–935PubMedCrossRefGoogle Scholar
  69. Williams AP, Bateman AR, Khakoo SI (2005) Hanging in the balance: KIR and their role in disease. Mol Interv 5:226–240PubMedCrossRefGoogle Scholar
  70. Yang Z (1996) Among-site variation and its impact of phylogenetic analysis. Trends Ecol Evol 11:367–372PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Nouar Qutob
    • 1
    Email author
  • Francois Balloux
    • 2
  • Towfique Raj
    • 3
    • 4
  • Hua Liu
    • 5
  • Sophie Marion de Procé
    • 6
  • John Trowsdale
    • 7
  • Andrea Manica
    • 1
  1. 1.Department of ZoologyUniversity of CambridgeCambridgeUK
  2. 2.MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease EpidemiologyImperial College Faculty of MedicineLondonUK
  3. 3.Harvard School of Public HealthBostonUSA
  4. 4.Division of Genetics, Department of Medicine, Brigham & Women’s HospitalHarvard Medical SchoolBostonUSA
  5. 5.Department of GeneticsUniversity of CambridgeCambridgeUK
  6. 6.Institute of Evolutionary BiologyUniversity of EdinburghEdinburghUK
  7. 7.Department of PathologyUniversity of CambridgeCambridgeUK

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