Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Novel insights in the genomic organization and hotspots of recombination in the human KIR locus through analysis of intergenic regions

Genes & Immunity volume 16, pages 103–111 (2015)Cite this article

Subjects

Abstract

The Killer Immunoglobulin-like Receptor (KIR) proteins constitute a family of highly homologous surface receptors involved in the regulation of the innate cytotoxicity of natural killer (NK) cells. Within the human genome, 17 KIR genes are present, many of which show large variation across the population owing to the high number of allelic variants and copy number variation (CNV). KIR genotyping and CNV determination were used to map the KIR locus in a large cohort of >400 Caucasian individuals. Gene order and structure was determined by sequence-specific polymerase chain reaction of the intergenic regions. In this way, we could show that KIR3DL1 and KIR2DS4 gene variants are linked and that—contrary to current views—the gene KIR2DS5 is only present in the telomeric half of the KIR locus. Our study revealed novel insights in the highly organized distribution of KIR genes. Novel recombination hotspots were identified that contribute to the diversity of KIR gene distribution in the Caucasian population. Next-generation sequencing of the KIR intergenic regions allowed for a detailed single-nucleotide polymorphism analysis, which demonstrated several gene-specific as well as haplotype-specific nucleotides for a more accurate genotyping of this notoriously complex gene cluster.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. O'Leary JG, Goodarzi M, Drayton DL, von Adrian UH . T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nat Immunol 2006; 7: 507–516.

    Article  CAS  Google Scholar 

  2. Paust S, Senman B, Von Andrian UH . Adaptive immune responses mediated by natural killer cells. Immunol Rev 2010; 235: 286–296.

    Article  CAS  Google Scholar 

  3. Béziat V, Liu LL, Malmberg JA, Ivarsson MA, Sohlberg E, Björklund AT et al. NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs. Blood 2013; 121: 2678–2688.

    Article  Google Scholar 

  4. Kunert K, Seiler M, Mashreghi MF, Klippert K, Schönemann C, Neumann K et al. KIR/HLA Ligand incompatibility in kidney transplantation. Transplantation 2007; 84: 1527–1533.

    Article  CAS  Google Scholar 

  5. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097–2100.

    Article  CAS  Google Scholar 

  6. van Bergen J, Thompson A, Haasnoot GW, Roodnat JI, de Fijter JW, Claas FHJ et al. KIR-Ligand mismatches are associated with reduced long-term graft survival in HLA-compatible kidney transplantation. Am J Transplant 2011; 11: 1959–1964.

    Article  CAS  Google Scholar 

  7. Venstrom JM, Zheng J, Noor N, Danis KE, Yeh AW, Cheung IY et al. KIR and HLA genotypes are associated with disease progression and survival following autologous hematopoietic stem cell transplantation for high-risk neuroblastoma. Clin Cancer Res 2009; 15: 7330–7334.

    Article  CAS  Google Scholar 

  8. Trowsdale J . Genetic and functional relationships between MHC and NK receptor genes. Immunity 2001; 15: 363–374.

    Article  CAS  Google Scholar 

  9. 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  Google Scholar 

  10. Uhrberg M, Valiante NM, Shum BP, Shilling HG, Lienert-Weidenbach K, Corliss B et al. Human diversity in killer cell inhibitory receptor genes. Immunity 1997; 7: 753–763.

    Article  CAS  Google Scholar 

  11. Jiang W, Johnson C, Jayaraman J, Simecek N, Noble J, Moffatt MF et al. Copy number variation leads to considerable diversity for B but not A haplotypes of the human KIR genes encoding NK cell receptors. Genome Res 2012; 22: 1845–1854.

    Article  CAS  Google Scholar 

  12. Vendelbosch S, de Boer M, Gouw RATW, Ho CKY, Geissler J, Swelsen WTN et al. Extensive variation in gene copy number at the killer immunoglobulin-like receptor locus in humans. PLoS ONE 2013; 8: e67619.

    Article  CAS  Google Scholar 

  13. Pyo CW, Guethlein LA, Vu Q, Wang R, Abi-Rached L, Norman PJ et al. Different patterns of evolution in the centromeric and telomeric regions of group A and B haplotypes of the human killer cell Ig-like receptor locus. PLoS ONE 2010; 5: e15115.

    Article  CAS  Google Scholar 

  14. 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  Google Scholar 

  15. Vierra-Green C, Roe D, Hou L, Hurley CK, Rajalingam R, Reed E et al. Allele-level haplotype frequencies and pairwise linkage disequilibrium for 14 KIR loci in 506 European-American individuals. PLoS ONE 2012; 7: e47491.

    Article  CAS  Google Scholar 

  16. Shilling HG, Young N, Guethlein LA, Cheng NW, Gardiner CM, Tyan D et al. Genetic control of human NK cell repertoire. J Immunol 2002; 169: 239–247.

    Article  CAS  Google Scholar 

  17. Martin M, Single R, Wilson M, 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  Google Scholar 

  18. Pando MJ, Gardiner CM, Gleimer M, McQueen KL, Parham P . The protein Madm from a common Aalele of KIR3DL1 (3DL1*004) is poorly expressed at cell surfaces due to substitution at positions 86 in Ig domain 0 and 182 in Ig domain 1. J Immunol 2003; 171: 6640–6649.

    Article  CAS  Google Scholar 

  19. Gonzalez-Galarza FF, Christmas S, Middleton D, Jones AR . Allele frequency net: a database and online repository for immune gene frequencies in worldwide populations. Nucleic Acids Res 2011; 39: D913–D919.

    Article  CAS  Google Scholar 

  20. Gomez-Lozano N, Gardiner C, Parham P, Vilches C . Some human KIR haplotypes contain two KIR2DL5 genes: KIR2DL5A and KIR2DL5B. Immunogenetics 2002; 54: 314–319.

    Article  CAS  Google Scholar 

  21. van Heeringen SJ, Veenstra GJ . GimmeMotifs: a de novo motif prediction pipeline for ChIP-sequencing experiments. Bioinformatics 2010; 27: 270–271.

    Article  Google Scholar 

  22. Davies GE, Locke SM, Wright PW, Li H, Hanson RJ, Miller JS et al. Identification of bidirectional promoters in the human KIR genes. Genes Immun 2007; 8: 245–253.

    Article  CAS  Google Scholar 

  23. Li H, Pascal V, Martin MP, Carrington M, Anderson SK . Genetic control of variegated KIR gene expression: polymorphisms of the bi-directional KIR3DL1 promoter are associated with distinct frequencies of gene expression. PLoS Genet 2008; 4: e1000254.

    Article  Google Scholar 

  24. Presnell SR, Zhang L, Ramilo CA, Chan HW, Lutz CT . Functional redundancy of transcription factor-binding sites in the killer cell Ig-like receptor (KIR) gene promoter. Int Immunol 2006; 18: 1221–1232.

    Article  CAS  Google Scholar 

  25. Trompeter HI, Gómez-Lozano N, Santourlidis S, Eisermann B, Wernet P, Vilches C et al. Three structurally and functionally divergent kinds of promoters regulate expression of clonally distributed killer cell Ig-like receptors (KIR), of KIR2DL4, and of KIR3DL3. J Immunol 2005; 174: 4135–4143.

    Article  CAS  Google Scholar 

  26. vanBergen J, Stewart CA, vandenElsen PJ, Trowsdale J . Structural and functional differences between the promoters of independently expressed killer cell Ig-like receptors. Eur J Immunol 2005; 35: 2191–2199.

    Article  CAS  Google Scholar 

  27. Gómez-Lozano N, Trompeter HI, de Pablo R, Estefanía E, Uhrberg M, Vilches C . Epigenetic silencing of potentially functional KIR2DL5 alleles: implications for the acquisition of KIR repertoires by NK cells. Eur J Immunol 2007; 37: 1954–1965.

    Article  Google Scholar 

  28. Gómez-Lozano N, Estefanía E, Williams F, Halfpenny I, Middleton D, Solís R et al. The silent KIR3DP1 gene (CD158c) is transcribed and might encode a secreted receptor in a minority of humans, in whom the KIR3DP1, KIR2DL4 and KIR3DL1/KIR3DS1 genes are duplicated. Eur J Immunol 2005; 35: 16–24.

    Article  Google Scholar 

  29. Martin MP, Bashirova A, Traherne J, Trowsdale J, Carrington M . Cutting edge: expansion of the KIR locus by unequal crossing over. J Immunol 2003; 171: 2192–2195.

    Article  CAS  Google Scholar 

  30. Trundley AE, Hiby SE, Chang C, Sharkey AM, Santourlidis S, Uhrberg M et al. Molecular characterization of KIR3DL3. Immunogenetics 2006; 57: 904–916.

    Article  CAS  Google Scholar 

  31. Norman P, Cook M, Carey BS, Carrington C, Verity D, Hameed K et al. SNP haplotypes and allele frequencies show evidence for disruptive and balancing selection in the human leukocyte receptor complex. Immunogenetics 2004; 56: 225–237.

    Article  Google Scholar 

  32. Giebel S, Nowak I, Wojnar J, Krawczyk-Kulis J, Holowiecki J, Kyrc-Krzemien P et al. Association of KIR2DS4 and its variant KIR1D with leukemia. Leukemia 2008; 22: 2129–2130.

    Article  CAS  Google Scholar 

  33. Cichocki F, Miller JS, Anderson SK, Bryceson YT . Epigenetic regulation of NK cell differentiation and effector functions. Front Immunol 2013; 4: 55.

    Article  Google Scholar 

  34. Uhrberg M . Shaping the human NK cell repertoire: an epigenetic glance at KIR gene regulation. Mol Immunol 2005; 42: 471–475.

    Article  CAS  Google Scholar 

  35. Norman PJ, Hollenbach JA, Nemat-Gorgani N, Guethlein LA, Hilton HG, Pando MJ et al. Co-evolution of human leukocyte antigen (HLA) class I ligands with killer-cell immunoglobulin-like receptors (KIR) in a genetically diverse population of sub-Saharan Africans. PLoS Genet 2013; 9: e1003938.

    Article  Google Scholar 

  36. Traherne JA, Martin M, Ward R, Ohashi M, Pellett F, Gladman D et al. Mechanisms of copy number variation and hybrid gene formation in the KIR immune gene complex. Hum Mol Genet 2010; 19: 737–751.

    Article  CAS  Google Scholar 

  37. Batzer MA, Deininger PL . Alu repeats and human genomic diversity. Nat Rev Genet 2002; 3: 370–379.

    Article  CAS  Google Scholar 

  38. Du Z, Sharma SK, Spellman S, Reed EF, Rajalingam R . KIR2DL5 alleles mark certain combination of activating KIR genes. Genes Immun 2008; 9: 470–480.

    Article  CAS  Google Scholar 

  39. 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  Google Scholar 

  40. Gardiner CM, Guethlein LA, Shilling HG, Pando M, Carr WH, Rajalingam R et al. Different NK cell surface phenotypes defined by the DX9 antibody are due to KIR3DL1 gene polymorphism. J Immunol 2001; 166: 2992–3001.

    Article  CAS  Google Scholar 

  41. Hall TA . BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucleic Acids Symp Ser 1999; 41: 95–98.

    CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the Sanquin Blood Supply Foundation, The Netherlands, Grant number PPOC-09-018. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author Contributions

SV designed and performed experiments and analyzed the data; MdB, KvL, FP and JG performed experiments; and TKvdB and TWK provided intellectual input. All authors contributed to writing the manuscript.

Author information

Authors and Affiliations

  1. Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands

    S Vendelbosch, M de Boer, K van Leeuwen, F Pourfarzad, J Geissler, T K van den Berg & T W Kuijpers

  2. Department of Pediatric Hematology, Emma Children’s Hospital, Immunology and Infectious diseases, Academic Medical Center, Amsterdam, The Netherlands

    T W Kuijpers

Authors
  1. S Vendelbosch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M de Boer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K van Leeuwen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F Pourfarzad
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Geissler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T K van den Berg
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T W Kuijpers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Vendelbosch.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on Genes and Immunity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vendelbosch, S., de Boer, M., van Leeuwen, K. et al. Novel insights in the genomic organization and hotspots of recombination in the human KIR locus through analysis of intergenic regions. Genes Immun 16, 103–111 (2015). https://doi.org/10.1038/gene.2014.68

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2014.68

This article is cited by

Search

Advanced search

Quick links