Skip to main content
SpringerLink
Log in

Nature of allelic sequence polymorphism at the KIR3DL3 locus

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

Abstract

KIR3DL3 is a framework gene of the Leukocyte Receptor Complex, present in all individuals and haplotypes analysed to date. We describe 17 novel KIR3DL3 alleles, including seven single nucleotide polymorphic (SNP) positions within the coding region. Sequence variation within introns included a VNTR within intron 1. As KIR3DL3 mRNA is known to be expressed in decidual NK cells, we investigated the impact of KIR3DL3 allelic variation on pre-eclampsia. No statistical difference in allele frequency or polymorphism was observed between pre-eclampsia patient and control cohorts. Linkage disequilibrium (LD) analysis of exonic SNPs suggested that recombination may be a mechanism of generating sequence diversity within KIR3DL3. A potential recombination hotspot was located within intron 5. A strong LD was detected between polymorphism in exon 6 of KIR3DL3 and the KIR gene −2DL3 or -2DS2 loci, which define the centromeric end of two main haplotypes (A and B) of the KIR cluster. Comparison of primate KIR sequences indicated that the Ig domains of KIR3DL3 are highly conserved between chimpanzee, gorilla and humans. Investigation of KIR3DL3 dN/dS ratios indicated a greater level of synonymous mutations consistent with purifying selection, although positive selection was detected acting on two sites within the stem region.

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

Similar content being viewed by others

References

  • Abi-Rached L, Parham P (2005) Natural selection drives recurrent formation of activating killer cell immunoglobulin-like receptor and Ly49 from inhibitory homologues. J Exp Med 201:1319–1332

    Article  PubMed  CAS  Google Scholar 

  • Boyington JC, Motyka SA, Schuck P, Brooks AG, Sun PD (2000) Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature 405:537–543

    Article  PubMed  CAS  Google Scholar 

  • Bulmer JN, Morrison L, Longfellow M, Ritson A, Pace D (1991) Granulated lymphocytes in human endometrium: histochemical and immunohistochemical studies. Hum Reprod 6:791–798

    PubMed  CAS  Google Scholar 

  • Bunce M, O’Neill CM, Barnardo MC, Krausa P, Browning MJ, Morris PJ, Welsh KI (1995) Phototyping: comprehensive DNA typing for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 and DQB1 by PCR with 144 primer mixes utilising sequence-specific primers (PCR-SSP). Tissue Antigens 46:355–367

    PubMed  CAS  Google Scholar 

  • Campbell KS, Dessing M, Lopez-Botet M, Cella M, Colonna M (1996) Tyrosine phosphorylation of a human killer inhibitory receptor recruits protein tyrosine phosphatase 1C. J Exp Med 184:93–100

    Article  PubMed  CAS  Google Scholar 

  • Campbell JJ, Qin S, Unutmaz D, Soler D, Murphy KE, Hodge MR, Wu L, Butcher EC (2001) Unique subpopulations of CD56+ NK and NK-T peripheral blood lymphocytes identified by chemokine receptor expression repertoire. J Immunol 166:6477–6482

    PubMed  CAS  Google Scholar 

  • Chaillet JR, Bader DS, Leder P (1995) Regulation of genomic imprinting by gametic and embryonic processes. Genes Dev 9:1177–1187

    PubMed  CAS  Google Scholar 

  • Chen FC, Li WH (2001) Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. Am J Hum Genet 68:444–456

    Article  PubMed  CAS  Google Scholar 

  • Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T, Carson WE, Caligiuri MA (2001) Human natural killer cells: a unique innate immunoregulatory role for the CD56 (bright) subset. Blood 97:3146–3151

    Article  PubMed  CAS  Google Scholar 

  • Crum KA, Logue SE, Curran MD, Middleton D (2000) Development of a PCR-SSOP approach capable of defining the natural killer cell inhibitory receptor (KIR) gene sequence repertoires. Tissue Antigens 56:313–326

    Article  PubMed  CAS  Google Scholar 

  • Dohring C, Samaridis J, Colonna M (1996) Alternatively spliced forms of human killer inhibitory receptors. Immunogenetics 44:227–230

    Article  PubMed  CAS  Google Scholar 

  • Garnier-Gere P, Dillmann C (1992) A computer program for testing pairwise linkage disequilibria in subdivided populations. J Heredity 83:239

    CAS  Google Scholar 

  • Goodman M, Porter CA, Czelusniak J, Page SL, Schneider H, Shoshani J, Gunnell G, Groves CP (1998) Toward a phylogenetic classification of primates based on DNA evidence complemented by fossil evidence. Mol Phylogenet Evol 9:585–598

    Article  PubMed  CAS  Google Scholar 

  • Gumperz JE, Litwin V, Phillips JH, Lanier LL, Parham P (1995) The Bw4 public epitope of HLA-B molecules confers reactivity with natural killer cell clones that express NKB1, a putative HLA receptor. J Exp Med 181:1133–1144

    Article  PubMed  CAS  Google Scholar 

  • Guo SW, Thompson EA (1992) Performing the exact test of Hardy-Weinberg proportion for multiple alleles. Biometrics 48:361–372

    Article  PubMed  CAS  Google Scholar 

  • Hershberger KL, Kurian J, Korber BT, Letvin NL (2005) Killer cell immunoglobulin-like receptors (KIR) of the African-origin sabaeus monkey: evidence for recombination events in the evolution of KIR. Eur J Immunol 35:922–935

    Article  PubMed  CAS  Google Scholar 

  • Hiby SE, Walker JJ, O’Shaughnessy KM, Redman CW, 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 200:957–965

    Article  PubMed  CAS  Google Scholar 

  • Hsu KC, Liu XR, Selvakumar A, Mickelson E, O’Reilly RJ, Dupont B (2002) Killer Ig-like receptor haplotype analysis by gene content: evidence for genomic diversity with a minimum of six basic framework haplotypes, each with multiple subsets. J Immunol 169:5118–5129

    PubMed  Google Scholar 

  • Jeffreys AJ, Neil DL, Neumann R (1998) Repeat instability at human mini-satellites arising from meiotic recombination. Embo J 17:4147–4157

    Article  PubMed  CAS  Google Scholar 

  • Jeffreys AJ, Barber R, Bois P, Buard J, Dubrova YE, Grant G, Hollies CR, May CA, Neumann R, Panayi M, Ritchie AE, Shone AC, Signer E, Stead JD, Tamaki K (1999) Human mini-satellites, repeat DNA instability and meiotic recombination. Electrophoresis 20:1665–1675

    Article  PubMed  CAS  Google Scholar 

  • Kennedy GC, German MS, Rutter WJ (1995) The mini-satellite in the diabetes susceptibility locus IDDM2 regulates insulin transcription. Nat Genet 9:293–298

    Article  PubMed  CAS  Google Scholar 

  • Khakoo SI, Geller R, Shin S, Jenkins JA, Parham P (2002) The D0 domain of KIR3D acts as a major histocompatibility complex class I binding enhancer. J Exp Med 196:911–921

    Article  PubMed  CAS  Google Scholar 

  • King A, Balendran N, Wooding P, Carter NP, Loke YW (1991) CD3- leukocytes present in the human uterus during early placentation: phenotypic and morphologic characterization of the CD56++ population. Dev Immunol 1:169–190

    Article  PubMed  CAS  Google Scholar 

  • King A, Burrows TD, Hiby SE, Bowen JM, Joseph S, Verma S, Lim PB, Gardner L, Le Bouteiller P, Ziegler A, Uchanska-Ziegler B, Loke YW (2000) Surface expression of HLA-C antigen by human extravillous trophoblast. Placenta 21:376–387

    Article  PubMed  CAS  Google Scholar 

  • Koopman LA, Kopcow HD, Rybalov B, Boyson JE, Orange JS, Schatz F, Masch R, Lockwood CJ, Schachter AD, Park PJ, Strominger JL (2003) Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med 198:1201–1212

    Article  PubMed  CAS  Google Scholar 

  • Kosakovsky Pond SL, Frost SD (2005) Not so different after all: a comparison of methods for detecting amino acid sites under selection. Mol Biol Evol 22:1208–1222

    Article  PubMed  CAS  Google Scholar 

  • Kumar S, Tamura K, Nei M (2004) MEGA3: integrated software for molecular evolutionary genetics analysis and sequence alignment. Brief Bioinform 5:150–163

    Article  PubMed  CAS  Google Scholar 

  • Lanier LL, Corliss BC, Wu J, Leong C, Phillips JH (1998) Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature 391:703–707

    Article  PubMed  CAS  Google Scholar 

  • Long EO, Barber DF, Burshtyn DN, Faure M, Peterson M, Rajagopalan S, Renard V, Sandusky M, Stebbins CC, Wagtmann N, Watzl C (2001) Inhibition of natural killer cell activation signals by killer cell immunoglobulin-like receptors (CD158). Immunol Rev 181:223–233

    Article  PubMed  CAS  Google Scholar 

  • Maenaka K, Juji T, Stuart DI, Jones EY (1999) Crystal structure of the human p58 killer cell inhibitory receptor (KIR2DL3) specific for HLA-Cw3-related MHC class I. Struct Fold Des 7:391–398

    Article  CAS  Google Scholar 

  • Mandelboim O, Davis DM, Reyburn HT, Vales-Gomez M, Sheu EG, Pazmany L, Strominger JL (1996) Enhancement of class II-restricted T cell responses by costimulatory NK receptors for class I MHC proteins. Science 274:2097–2100

    Article  PubMed  CAS  Google Scholar 

  • Martin AM, Freitas EM, Witt CS, Christiansen FT (2000) The genomic organization and evolution of the natural killer immunoglobulin-like receptor (KIR) gene cluster. Immunogenetics 51:268–280

    Article  PubMed  CAS  Google Scholar 

  • Maxwell LD, Wallace A, Middleton D, Curran MD (2002) A common KIR2DS4 deletion variant in the human that predicts a soluble KIR molecule analogous to the KIR1D molecule observed in the rhesus monkey. Tissue Antigens 60:254–258

    Article  PubMed  CAS  Google Scholar 

  • Moffett-King A (2002) Natural killer cells and pregnancy. Nat Rev Immunol 2:656–663

    Article  PubMed  CAS  Google Scholar 

  • Moretta A, Sivori S, Vitale M, Pende D, Morelli L, Augugliaro R, Bottino C, Moretta L (1995) Existence of both inhibitory (p58) and activatory (p50) receptors for HLA-C molecules in human natural killer cells. J Exp Med 182:875–884

    Article  PubMed  CAS  Google Scholar 

  • Nagler A, Lanier LL, Cwirla S, Phillips JH (1989) Comparative studies of human FcRIII-positive and negative natural killer cells. J Immunol 143:3183–3191

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Norman PJ, Cook MA, Carey BS, Carrington CV, Verity DH, Hameed K, Ramdath DD, Chandanayingyong D, Leppert M, Stephens HA, Vaughan RW (2004) SNP haplotypes and allele frequencies show evidence for disruptive and balancing selection in the human leukocyte receptor complex. Immunogenetics 56:225–237

    Article  PubMed  Google Scholar 

  • Olerup O, Aldener A, Fogdell A (1993) HLA-DQB1 and -DQA1 typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours. Tissue Antigens 41:119–134

    PubMed  CAS  Google Scholar 

  • Ota T, Nei M (1994) Variance and covariances of the numbers of synonymous and nonsynonymous substitutions per site. Mol Biol Evol 11:613–619

    PubMed  CAS  Google Scholar 

  • Pando MJ, Gardiner CM, Gleimer M, McQueen KL, Parham P (2003) The protein made from a common allele 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 171:6640–6649

    PubMed  CAS  Google Scholar 

  • Rajalingam R, Hong M, Adams EJ, Shum BP, Guethlein LA, Parham P (2001) Short KIR haplotypes in pygmy chimpanzee (Bonobo) resemble the conserved framework of diverse human KIR haplotypes. J Exp Med 193:135–146

    Article  PubMed  CAS  Google Scholar 

  • Rajalingam R, Parham P, Abi-Rached L (2004) Domain shuffling has been the main mechanism forming new hominoid killer cell Ig-like receptors. J Immunol 172:356–369

    PubMed  CAS  Google Scholar 

  • Red-Horse K, Drake PM, Gunn MD, Fisher SJ (2001) Chemokine ligand and receptor expression in the pregnant uterus: reciprocal patterns in complementary cell subsets suggest functional roles. Am J Pathol 159:2199–2213

    PubMed  CAS  Google Scholar 

  • Rousset F, Raymond M (1995) Testing heterozygote excess and deficiency. Genetics 140:1413–1419

    PubMed  CAS  Google Scholar 

  • Sadler AM, Petronzelli F, Krausa P, Marsh SG, Guttridge MG, Browning MJ, Bodmer JG (1994) Low-resolution DNA typing for HLA-B using sequence-specific primers in allele- or group-specific ARMS/PCR. Tissue Antigens 44:148–154

    PubMed  CAS  Google Scholar 

  • Saitou N, Nei M (1987) The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol 4:406–425

    PubMed  CAS  Google Scholar 

  • Sambrook JG, Bashirova A, Palmer S, Sims S, Trowsdale J, Abi-Rached L, Parham P, Carrington M, Beck S (2005) Single haplotype analysis demonstrates rapid evolution of the killer immunoglobulin-like receptor (KIR) loci in primates. Genome Res 15:25–35

    Article  PubMed  CAS  Google Scholar 

  • Selvakumar A, Steffens U, Dupont B (1996) NK cell receptor gene of the KIR family with two IG domains but highest homology to KIR receptors with three IG domains. Tissue Antigens 48:285–294

    Article  PubMed  CAS  Google Scholar 

  • Stephens M, Scheet P (2005) Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. Am J Hum Genet 76:449–462

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Stewart CB, Disotell TR (1998) Primate evolution—in and out of Africa. Curr Biol 8:R582–R588

    Article  PubMed  CAS  Google Scholar 

  • Torkar M, Norgate Z, Colonna M, Trowsdale J, Wilson MJ (1998) Isotypic variation of novel immunoglobulin-like transcript/killer cell inhibitory receptor loci in the leukocyte receptor complex. Eur J Immunol 28:3959–3967

    Article  PubMed  CAS  Google Scholar 

  • Trompeter HI, Gomez-Lozano N, Santourlidis S, Eisermann B, Wernet P, Vilches C, Uhrberg M (2005) 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 174:4135–4143

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Trundley AE, Hiby SE, Chang C, Sharkey AM, Santourlidis S, Uhrberg M, Trowsdale J, Moffett A (2006) Molecular characterization of KIR3DL3. Immunogenetics 1–13

  • Turri MG, Cuin KA, Porter AC (1995) Characterisation of a novel mini-satellite that provides multiple splice donor sites in an interferon-induced transcript. Nucleic Acids Res 23:1854–1861

    PubMed  CAS  Google Scholar 

  • Uhrberg M, Valiante NM, Shum BP, Shilling HG, Lienert-Weidenbach K, Corliss B, Tyan D, Lanier LL, Parham P (1997) Human diversity in killer cell inhibitory receptor genes. Immunity 7:753–763

    Article  PubMed  CAS  Google Scholar 

  • Valiante NM, Uhrberg M, Shilling HG, Lienert-Weidenbach K, Arnett KL, D’Andrea A, Phillips JH, Lanier LL, Parham P (1997) Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors. Immunity 7:739–751

    Article  PubMed  CAS  Google Scholar 

  • Vilches C, Parham P (2002) KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu Rev Immunol 20:217–251

    Article  PubMed  CAS  Google Scholar 

  • Wagtmann N, Rajagopalan S, Winter CC, Peruzzi M, Long EO (1995) Killer cell inhibitory receptors specific for HLA-C and HLA-B identified by direct binding and by functional transfer. Immunity 3:801–809

    Article  PubMed  CAS  Google Scholar 

  • Wilson MJ, Torkar M, Haude A, Milne S, Jones T, Sheer D, Beck S, Trowsdale J (2000) Plasticity in the organization and sequences of human KIR/ILT gene families. Proc Natl Acad Sci USA 97:4778–4783

    Article  PubMed  CAS  Google Scholar 

  • Winter CC, Long EO (1997) A single amino acid in the p58 killer cell inhibitory receptor controls the ability of natural killer cells to discriminate between the two groups of HLA-C allotypes. J Immunol 158:4026–4028

    PubMed  CAS  Google Scholar 

  • Winter CC, Gumperz JE, Parham P, Long EO, Wagtmann N (1998) Direct binding and functional transfer of NK cell inhibitory receptors reveal novel patterns of HLA-C allotype recognition. J Immunol 161:571–577

    PubMed  CAS  Google Scholar 

  • Witt CS, Dewing C, Sayer DC, Uhrberg M, Parham P, Christiansen FT (1999) Population frequencies and putative haplotypes of the killer cell immunoglobulin-like receptor sequences and evidence for recombination. Transplantation 68:1784–1789

    Article  PubMed  CAS  Google Scholar 

  • Witt CS, Whiteway JM, Warren HS, Barden A, Rogers M, Martin A, Beilin L, Christiansen FT (2002) Alleles of the KIR2DL4 receptor and their lack of association with pre-eclampsia. Eur J Immunol 32:18–29

    Article  PubMed  CAS  Google Scholar 

  • Young NT, Uhrberg M, Phillips JH, Lanier LL, Parham P (2001) Differential expression of leukocyte receptor complex-encoded Ig-like receptors correlates with the transition from effector to memory CTL. J Immunol 166:3933–3941

    PubMed  CAS  Google Scholar 

  • Zhang J, Kumar S, Nei M (1997) Small-sample tests of episodic adaptive evolution: a case study of primate lysozymes. Mol Biol Evol 14:1335–1338

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This project was funded by the Leukaemia Research Fund. All experiments performed in this study complied with the current laws of the UK.

Author information

Authors and Affiliations

  1. Division of Immunology, Department of Pathology,, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK

    Des C. Jones, Susan E. Hiby, Ashley Moffett, John Trowsdale & Neil T. Young

Authors
  1. Des C. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susan E. Hiby
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ashley Moffett
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John Trowsdale
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Neil T. Young
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Neil T. Young.

Electronic supplementary material

Below is the link to the electronic supplementary materials. Refer to Table 3 for information on each primer mix. All reactions contain control primers designed to amplify a 256-bp amplicon of the APC gene. The sample shown produced KIR3DL3 SNP-specific amplicons in reactions 5 (due to linkage between 869A and 961C) and 6 (869C/961T).

Figure A

Long-range KIR3DL3 PCR-SSP (GIF 45 kb)

251_2006_130_MOESM2_ESM.pdf

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jones, D.C., Hiby, S.E., Moffett, A. et al. Nature of allelic sequence polymorphism at the KIR3DL3 locus. Immunogenetics 58, 614–627 (2006). https://doi.org/10.1007/s00251-006-0130-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00251-006-0130-5

Keywords

Search

Navigation