Abstract
Human killer immunoglobulin-like receptors (KIR) are expressed on natural killer (NK) cells and are involved in their immunoreactivity. While KIR with a long cytoplasmic tail deliver an inhibitory signal when bound to their respective major histocompatibility complex class I ligands, KIR with a short cytoplasmic tail can activate NK responses. The expansion of the KIR gene family originally appeared to be a phenomenon restricted to primates (human, apes, and monkeys) in comparison to rodents, which via convergent evolution have numerous C-type lectin-like Ly49 molecules that function analogously. Further studies have shown that multiple KIR are also present in cow and horse. In this study, we have identified by comparative genomics the first and possibly only KIR gene, named KIR2DL1, in the domesticated pig (Sus scrofa) allowing further evolutionary comparisons to be made. It encodes a protein with two extracellular immunoglobulin domains (D0 + D2), and a long cytoplasmic tail containing two inhibitory motifs. We have mapped the pig KIR2DL1 gene to chromosome 6q. Flanked by LILRa, LILRb, and LILRc, members of the leukocyte immunoglobulin-like receptor (LILR) family, on the centromeric end, and FCAR, NCR1, NALP7, NALP2, and GP6 on the telomeric end, pig demonstrates conservation of synteny with the human leukocyte receptor complex (LRC). Both the porcine KIR and LILR genes have diverged sufficiently to no longer be clearly orthologous with known human LRC family members.
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
Anderson SI, Lopez-Corrales NL, Gorick B, Archibald AL (2000) A large-fragment porcine genomic library resource in a BAC vector. Mamm Genome 11:811–814
Ashurst JL, Chen CK, Gilbert JG, Jekosch K, Keenan S, Meidl P, Searle SM, Stalker J, Storey R, Trevanion S, Wilming L, Hubbard T (2005) The Vertebrate Genome Annotation (Vega) database. Nucleic Acids Res 33:D459–D465
Bankier AT, Weston KM, Barrell BG (1987) Random cloning and sequencing by the M13/dideoxynucleotide chain termination method. Methods Enzymol 155:51–93
Bonfield JK, Smith K, Staden R (1995) A new DNA sequence assembly program. Nucleic Acids Res 23:4992–4999
Canavez F, Young NT, Guethlein LA, Rajalingam R, Khakoo SI, Shum BP, Parham P (2001) Comparison of chimpanzee and human leukocyte Ig-like receptor genes reveals framework and rapidly evolving genes. J Immunol 167:5786–5794
Davoli R, Fontanesi L, Zambonelli P, Bigi D, Gellin J, Yerle M, Milc J, Braglia S, Cenci V, Cagnazzo M, Russo V (2002) Isolation of porcine expressed sequence tags for the construction of a first genomic transcript map of the skeletal muscle in pig. Anim Genet 33:3–18
Denyer MS, Wileman TE, Stirling CM, Zuber B, Takamatsu HH (2006) Perforin expression can define CD8 positive lymphocyte subsets in pigs allowing phenotypic and functional analysis of Natural Killer, Cytotoxic T, Natural Killer T and MHC un-restricted cytotoxic T-cells. Vet Immunol Immunopathol 110:325–330
Ewing B, Hillier L, Wendl MC, Green P (1998) Base-calling of automated sequencer traces using phred. I. Accuracy assessment. Genome Res 8:175–185
Fan QR, Mosyak L, Winter CC, Wagtmann N, Long EO, Wiley DC (1997) Structure of the inhibitory receptor for human natural killer cells resembles haematopoietic receptors. Nature 389:96–100
Gagnier L, Wilhelm BT, Mager DL (2003) Ly49 genes in non-rodent mammals. Immunogenetics 55:109–115
Guethlein LA, Flodin LR, Adams EJ, Parham P (2002) NK cell receptors of the orangutan (Pongo pygmaeus): a pivotal species for tracking the coevolution of killer cell Ig-like receptors with MHC-C. J Immunol 169:220–229
Hershberger KL, Shyam R, Miura A, Letvin NL (2001) Diversity of the killer cell Ig-like receptors of rhesus monkeys. J Immunol 166:4380–4390
Hoelsbrekken SE, Nylenna O, Saether PC, Slettedal IO, Ryan JC, Fossum S, Dissen E (2003) Cutting edge: molecular cloning of a killer cell Ig-like receptor in the mouse and rat. J Immunol 170:2259–2263
Kelley J, Walter L, Trowsdale J (2005) Comparative genomics of natural killer cell receptor gene clusters. PLoS Genet 1:129–139
Khakoo SI, Rajalingam R, Shum BP, Weidenbach K, Flodin L, Muir DG, Canavez F, Cooper SL, Valiante NM, Lanier LL, Parham P (2000) Rapid evolution of NK cell receptor systems demonstrated by comparison of chimpanzees and humans. Immunity 12:687–698
Koren HS, Amos DB, Kim YB (1978) Natural killing and antibody-dependent cellular cytotoxicity are independent immune functions in the Minnesota miniature swine. Proc Natl Acad Sci USA 75:5127–5131
Kumar S, Tamura K, Jakobsen IB, Nei M (2001) MEGA2: molecular evolutionary genetics analysis software. Bioinformatics 17:1244–1245
Mager DL, McQueen KL, Wee V, Freeman JD (2001) Evolution of natural killer cell receptors: coexistence of functional Ly49 and KIR genes in baboons. Curr Biol 11:626–630
Marra MA, Kucaba TA, Dietrich NL, Green ED, Brownstein B, Wilson RK, McDonald KM, Hillier LW, McPherson JD, Waterston RH (1997) High throughput fingerprint analysis of large-insert clones. Genome Res 7:1072–1084
Marsh SG, Parham P, Dupont B, Geraghty DE, Trowsdale J, Middleton D, Vilches C, Carrington M, Witt C, Guethlein LA, Shilling H, Garcia CA, Hsu KC, Wain H (2003) Killer-cell immunoglobulin-like receptor (KIR) nomenclature report, 2002. Immunogenetics 55:220–226
Martin MP, Bashirova A, Traherne J, Trowsdale J, Carrington M (2003) Cutting edge: expansion of the KIR locus by unequal crossing over. J Immunol 171:2192–2195
Martin AM, Kulski JK, Gaudieri S, Witt CS, Freitas EM, Trowsdale J, Christiansen FT (2004) Comparative genomic analysis, diversity and evolution of two KIR haplotypes A and B. Gene 335:121–131
McQueen KL, Wilhelm BT, Harden KD, Mager DL (2002) Evolution of NK receptors: a single Ly49 and multiple KIR genes in the cow. Eur J Immunol 32:810–817
Rajagopalan S, Long EO (2005) Understanding how combinations of HLA and KIR genes influence disease. J Exp Med 201:1025–1029
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
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
Rice P, Longden I, Bleasby A (2000) EMBOSS: the European Molecular Biology Open Software Suite. Trends Genet 16:276–277
Rosenblum BB, Lee LG, Spurgeon SL, Khan SH, Menchen SM, Heiner CR, Chen SM (1997) New dye-labeled terminators for improved DNA sequencing patterns. Nucleic Acids Res 25:4500–4504
Rutherford K, Parkhill J, Crook J, Horsnell T, Rice P, Rajandream MA, Barrell B (2000) Artemis: sequence visualization and annotation. Bioinformatics 16:944–945
Saitou N, Nei M (1987) The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol 4:406–425
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
Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74:5463–5467
Searle SM, Gilbert J, Iyer V, Clamp M (2004) The otter annotation system. Genome Res 14:963–970
Storset AK, Slettedal IO, Williams JL, Law A, Dissen E (2003) Natural killer cell receptors in cattle: a bovine killer cell immunoglobulin-like receptor multigene family contains members with divergent signaling motifs. Eur J Immunol 33:980–990
Takahashi T, Yawata M, Raudsepp T, Lear TL, Chowdhary BP, Antczak DF, Kasahara M (2004) Natural killer cell receptors in the horse: evidence for the existence of multiple transcribed LY49 genes. Eur J Immunol 34:773–784
Volz A, Wende H, Laun K, Ziegler A (2001) Genesis of the ILT/LIR/MIR clusters within the human leukocyte receptor complex. Immunol Rev 181:39–51
Welch AY, Kasahara M, Spain LM (2003) Identification of the mouse killer immunoglobulin-like receptor-like (Kirl) gene family mapping to chromosome X. Immunogenetics 54:782–790
Wende H, Colonna M, Ziegler A, Volz A (1999) Organization of the leukocyte receptor cluster (LRC) on human chromosome 19q13.4. Mamm Genome 10:154–160
Wernersson R, Schierup MH, Jorgensen FG, Gorodkin J, Panitz F, Staerfeldt HH, Christensen OF, Mailund T, Hornshoj H, Klein A, Wang J, Liu B, Hu S, Dong W, Li W, Wong GK, Yu J, Bendixen C, Fredholm M, Brunak S, Yang H, Bolund L (2005) Pigs in sequence space: a 0.66X coverage pig genome survey based on shotgun sequencing. BMC Genomics 6:70
Williams AP, Bateman AR, Khakoo SI (2005) Hanging in the balance. KIR and their role in disease. Mol Interv 5:226–240
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
Yim D, Jie HB, Sotiriadis J, Kim YS, Kim KS, Rothschild MF, Lanier LL, Kim YB (2001) Molecular cloning and characterization of pig immunoreceptor DAP10 and NKG2D. Immunogenetics 53:243–249
Acknowledgements
DNA sequencing at the Sanger Institute is supported by the Wellcome Trust. We wish to thank all members of the Sequencing Division. We thank Brian McTeir for his technical assistance. ALA and TW were supported by the BBSRC.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sambrook, J.G., Sehra, H., Coggill, P. et al. Identification of a single killer immunoglobulin-like receptor (KIR) gene in the porcine leukocyte receptor complex on chromosome 6q. Immunogenetics 58, 481–486 (2006). https://doi.org/10.1007/s00251-006-0110-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00251-006-0110-9