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Signatures of natural selection and coevolution between killer cell immunoglobulin-like receptors (KIR) and HLA class I genes

Genes & Immunity volume 11, pages 467–478 (2010)Cite this article

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Abstract

Natural killer (NK) cells are lymphocytes of the innate immune system. In humans, NK cell activities are partly controlled by the diverse killer immunoglobulin-like receptor (KIR) gene family. The importance of NK cells in both immunity to infection and reproduction makes KIR strong candidates for genes undergoing dynamic evolution in the human genome. Using high-resolution allelic typing, we investigated the potential role of natural selection in the diversification of KIR in the Irish population. Higher diversity than expected is observed at several loci, consistent with a history of balancing selection acting to maintain several allelic variants at high frequency in the population. KIR diversity is enhanced further at the haplotype level with functional polymorphisms at KIR2DL4, KIR3DL1 and KIR2DS4 defining nine ‘core’ haplotypes. Analysis of these core haplotypes in combination with human leukocyte antigen (HLA) class I ligands revealed several nonrandom associations. In particular, the KIR:HLA association for the core haplotype defined by KIR3DL1*01502 was female specific and a likely consequence of negative selection acting against KIR3DL1*01502 on an HLA-C1/C1 background. Many of the associations between KIR and HLA in the Irish differ from those previously reported, which argues against universal selective pressures for specific KIR:HLA combinations in diverse human populations.

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References

  1. Parham P . The genetic and evolutionary balances in human NK cell receptor diversity. Semin Immunol 2008; 20: 311–316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hanna J, Goldman-Wohl D, Hamani Y, Avraham I, Greenfield C, Natanson-Yaron S et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med 2006; 12: 1065–1074.

    Article  CAS  PubMed  Google Scholar 

  3. O'Connor GM, Hart OM, Gardiner CM . Putting the natural killer cell in its place. Immunology 2006; 117: 1–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gardiner CM . Killer cell immunoglobulin-like receptors on NK cells: the how, where and why. Int J Immunogenet 2008; 35: 1–8.

    Article  CAS  PubMed  Google Scholar 

  5. Lanier LL . Activating and inhibitory NK cell receptors. Adv Exp Med Biol 1998; 452: 13–18.

    Article  CAS  PubMed  Google Scholar 

  6. Hiby SE, Regan L, Lo W, Farrell L, Carrington M, Moffett A . Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage. Hum Reprod 2008; 23: 972–976.

    Article  CAS  PubMed  Google Scholar 

  7. Hiby SE, Walker JJ, O'Shaughnessy KM, Redman CW, Carrington M, Trowsdale J et al. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med 2004; 200: 957–965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sharkey AM, Gardner L, Hiby S, Farrell L, Apps R, Masters L et al. Killer Ig-like receptor expression in uterine NK cells is biased toward recognition of HLA-C and alters with gestational age. J Immunol 2008; 181: 39–46.

    Article  CAS  PubMed  Google Scholar 

  9. Trowsdale J, Moffett A . NK receptor interactions with MHC class I molecules in pregnancy. Semin Immunol 2008; 20: 317–320.

    Article  CAS  PubMed  Google Scholar 

  10. Martin MP, Single RM, Wilson MJ, Trowsdale J, Carrington M . KIR haplotypes defined by segregation analysis in 59 Centre d'Etude Polymorphisme Humain (CEPH) families. Immunogenetics 2008; 60: 767–774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hsu KC, Chida S, Geraghty DE, Dupont B . The killer cell immunoglobulin-like receptor (KIR) genomic region: gene-order, haplotypes and allelic polymorphism. Immunol Rev 2002; 190: 40–52.

    Article  CAS  PubMed  Google Scholar 

  12. Trowsdale J, Barten R, Haude A, Stewart CA, Beck S, Wilson MJ . The genomic context of natural killer receptor extended gene families. Immunol Rev 2001; 181: 20–38.

    Article  CAS  PubMed  Google Scholar 

  13. Ahlenstiel G, Martin MP, Gao X, Carrington M, Rehermann B . Distinct KIR/HLA compound genotypes affect the kinetics of human antiviral natural killer cell responses. J Clin Invest 2008; 118: 1017–1026.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Alter G, Martin MP, Teigen N, Carr WH, Suscovich TJ, Schneidewind A et al. Differential natural killer cell-mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes. J Exp Med 2007; 204: 3027–3036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kim S, Sunwoo JB, Yang L, Choi T, Song YJ, French AR et al. HLA alleles determine differences in human natural killer cell responsiveness and potency. Proc Natl Acad Sci USA 2008; 105: 3053–3058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Single RM, Martin MP, Gao X, Meyer D, Yeager M, Kidd JR et al. Global diversity and evidence for coevolution of KIR and HLA. Nat Genet 2007; 39: 1114–1119.

    Article  CAS  PubMed  Google Scholar 

  17. Guinan K, Cunningham RT, Meenagh A, Dring MM, Middleton D, Gardiner CM . Receptor systems controlling natural killer cell function are genetically stratified in Europe. Genes Immun 2010; 11: 67–78.

    Article  CAS  PubMed  Google Scholar 

  18. Yawata M, Yawata N, Draghi M, Little AM, Partheniou F, Parham P . Roles for HLA and KIR polymorphisms in natural killer cell repertoire selection and modulation of effector function. J Exp Med 2006; 203: 633–645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cornuet JM, Luikart G . Description and power analysis of two tests for detecting recent population bottlenecks from allele frequency data. Genetics 1996; 144: 2001–2014.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Gaunt TR, Rodriguez S, Zapata C, Day IN . MIDAS: software for analysis and visualisation of interallelic disequilibrium between multiallelic markers. BMC Bioinformatics 2006; 7: 227.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Stephens M, Donnelly P . A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003; 73: 1162–1169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Stephens M, Smith NJ, Donnelly P . A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978–989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Middleton D, Meenagh A, Gourraud PA . KIR haplotype content at the allele level in 77 Northern Irish families. Immunogenetics 2007; 59: 145–158.

    Article  CAS  PubMed  Google Scholar 

  24. Sabeti PC, Reich DE, Higgins JM, Levine HZ, Richter DJ, Schaffner SF et al. Detecting recent positive selection in the human genome from haplotype structure. Nature 2002; 419: 832–837.

    Article  CAS  PubMed  Google Scholar 

  25. Martin AM, Kulski JK, Gaudieri S, Witt CS, Freitas EM, Trowsdale J et al. Comparative genomic analysis, diversity and evolution of two KIR haplotypes A and B. Gene 2004; 335: 121–131.

    Article  CAS  PubMed  Google Scholar 

  26. Yawata M, Yawata N, Abi-Rached L, Parham P . Variation within the human killer cell immunoglobulin-like receptor (KIR) gene family. Crit Rev Immunol 2002; 22: 463–482.

    Article  CAS  PubMed  Google Scholar 

  27. Gutierrez-Rodriguez ME, Sandoval-Ramirez L, Diaz-Flores M, Marsh SG, Valladares-Salgado A, Madrigal JA et al. KIR gene in ethnic and Mestizo populations from Mexico. Hum Immunol 2006; 67: 85–93.

    Article  CAS  PubMed  Google Scholar 

  28. Norman PJ, Abi-Rached L, Gendzekhadze K, Korbel D, Gleimer M, Rowley D et al. Unusual selection on the KIR3DL1/S1 natural killer cell receptor in Africans. Nat Genet 2007; 39: 1092–1099.

    Article  CAS  PubMed  Google Scholar 

  29. Ferrer-Admetlla A, Bosch E, Sikora M, Marques-Bonet T, Ramirez-Soriano A, Muntasell A et al. Balancing selection is the main force shaping the evolution of innate immunity genes. J Immunol 2008; 181: 1315–1322.

    Article  CAS  PubMed  Google Scholar 

  30. Ucisik-Akkaya E, Dorak MT . A study of natural killer cell lectin-like receptor K1 gene (KLRK1/NKG2D) region polymorphisms in a European population sample. Tissue Antigens 2009; 73: 177–183.

    Article  CAS  PubMed  Google Scholar 

  31. McMillen MM . Differential mortality by sex in fetal and neonatal deaths. Science 1979; 204: 89–91.

    Article  CAS  PubMed  Google Scholar 

  32. Vatten LJ, Skjaerven R . Offspring sex and pregnancy outcome by length of gestation. Early Hum Dev 2004; 76: 47–54.

    Article  PubMed  Google Scholar 

  33. Eiben B, Bartels I, Bahr-Porsch S, Borgmann S, Gatz G, Gellert G et al. Cytogenetic analysis of 750 spontaneous abortions with the direct-preparation method of chorionic villi and its implications for studying genetic causes of pregnancy wastage. Am J Hum Genet 1990; 47: 656–663.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Ober C, Loisel DA, Gilad Y . Sex-specific genetic architecture of human disease. Nat Rev Genet 2008; 9: 911–922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Korbel DS, Norman PJ, Newman KC, Horowitz A, Gendzekhadze K, Parham P et al. Killer Ig-like receptor (KIR) genotype predicts the capacity of human KIR-positive CD56dim NK cells to respond to pathogen-associated signals. J Immunol 2009; 182: 6426–6434.

    Article  CAS  PubMed  Google Scholar 

  36. Miller SA, Dykes DD, Polesky HF . A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 1215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Middleton D, Curran M, Maxwell L . Natural killer cells and their receptors. Transpl Immunol 2002; 10: 147–164.

    Article  CAS  PubMed  Google Scholar 

  38. Middleton D, Williams F, Halfpenny IA . KIR genes. Transpl Immunol 2005; 14: 135–142.

    Article  CAS  PubMed  Google Scholar 

  39. Keaney L, Williams F, Meenagh A, Sleator C, Middleton D . Investigation of killer cell immunoglobulin-like receptor gene diversity III. KIR2DL3. Tissue Antigens 2004; 64: 188–194.

    Article  CAS  PubMed  Google Scholar 

  40. Meenagh A, Williams F, Sleator C, Halfpenny IA, Middleton D . Investigation of killer cell immunoglobulin-like receptor gene diversity V. KIR3DL2. Tissue Antigens 2004; 64: 226–234.

    Article  CAS  PubMed  Google Scholar 

  41. Maxwell LD, Williams F, Gilmore P, Meenagh A, Middleton D . Investigation of killer cell immunoglobulin-like receptor gene diversity: II. KIR2DS4. Hum Immunol 2004; 65: 613–621.

    Article  CAS  PubMed  Google Scholar 

  42. Williams F, Meenagh A, Sleator C, Middleton D . Investigation of killer cell immunoglobulin-like receptor gene diversity: I. KIR2DL4. Hum Immunol 2004; 65: 31–38.

    Article  CAS  PubMed  Google Scholar 

  43. Halfpenny IA, Middleton D, Barnett YA, Williams F . Investigation of killer cell immunoglobulin-like receptor gene diversity: IV. KIR3DL1/S1. Hum Immunol 2004; 65: 602–612.

    Article  CAS  PubMed  Google Scholar 

  44. Meenagh A, Gonzalez A, Sleator C, McQuaid S, Middleton D . Investigation of killer cell immunoglobulin-like receptor gene diversity, KIR2DL1 and KIR2DS1. Tissue Antigens 2008; 72: 383–391.

    Article  CAS  PubMed  Google Scholar 

  45. Gonzalez A, Meenagh A, Sleator C, Middleton D . Investigation of killer cell immunoglobulin-like receptor (KIR) gene diversity: KIR2DL2, KIR2DL5 and KIR2DS5. Tissue Antigens 2008; 72: 11–20.

    Article  CAS  PubMed  Google Scholar 

  46. Gonzalez A, McErlean C, Meenagh A, Shovlin T, Middleton D . Killer cell immunoglobulin-like receptor allele discrimination by high-resolution melting. Hum Immunol 2009; 70: 858–863.

    Article  CAS  PubMed  Google Scholar 

  47. Middleton D, Halfpenny I, Meenagh A, Williams F, Sivula J, Tuomilehto-Wolf E . Investigation of KIR gene frequencies in type 1 diabetes mellitus. Hum Immunol 2006; 67: 986–990.

    Article  CAS  PubMed  Google Scholar 

  48. Fredsted T, Villessen P . Fast and reliable sexing of prosimian and human DNA. Am J Primatol 2004; 64: 345–350.

    Article  CAS  PubMed  Google Scholar 

  49. Halliburton R . Quantifying genetic variation. In: T RC (ed). Introduction to Population Genetics, vol. International edn. Pearson Education, Inc.: Upper Saddle River, 2004.

    Google Scholar 

  50. Bernstein F . Uber die Erblichkeit der Blutgruppen. Zeitschrift für induktive Abstammungs und Vererbungslehre. 1930; 54: 400–426.

    Google Scholar 

  51. Van Oosterhout C, Weetman D, Hutchinson WF . Estimation and adjustment of microsatellite null alleles in nonequilibrium populations. Molecular Ecology Notes 2006; 6: 255–256.

    Article  Google Scholar 

  52. Mueller JC, Andreoli C . Plotting haplotype-specific linkage disequilibrium patterns by extended haplotype homozygosity. Bioinformatics 2004; 20: 786–787.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by an Ireland–Northern Ireland Co-operation grant funded jointly by the Irish Health Research Board and the Northern Ireland R&D Office. CMG is also supported by the Science Foundation Ireland. We also acknowledge Dr Anthony W Ryan, Dr Pardis D Sabeti, Dr Aisling M O'Halloran, Dr Cock van Oosterhout, Maria Morrison and Dr Brian McSharry for their helpful discussions about the study.

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  1. R T Cunningham

    Present address: 4Current address: Institute of Agri-Food & Land Use, Queen's University, David Keir Building, Stranmillis Road, Belfast BT9 5AG, Northern Ireland.,

Authors and Affiliations

  1. School of Biochemistry and Immunology, Trinity College, Dublin, Ireland

    K J Guinan, M M Dring, B W McGuinness & C M Gardiner

  2. Histocompatibility and Immunogenetics Laboratory, Belfast City Hospital, Belfast, Northern Ireland, UK

    R T Cunningham, A Meenagh & A Gonzalez

  3. Royal Liverpool University Hospital and School of Infection and Host Defense, Liverpool University, Liverpool, UK

    D Middleton

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  1. K J Guinan
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Correspondence to C M Gardiner.

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Guinan, K., Cunningham, R., Meenagh, A. et al. Signatures of natural selection and coevolution between killer cell immunoglobulin-like receptors (KIR) and HLA class I genes. Genes Immun 11, 467–478 (2010). https://doi.org/10.1038/gene.2010.9

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