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HLA2024; 103(2); e15387; doi: 10.1111/tan.15387

Diversity of major histocompatibility complex (MHC) and natural killer cell receptor (NKR) genes and their interactions in domestic horses.

Abstract: The immunogenome is the part of the genome that underlies immune mechanisms and evolves under various selective pressures. Two complex regions of the immunogenome, major histocompatibility complex (MHC) and natural killer cell receptor (NKR) genes, play an important role in the response to selective pressures of pathogens. Their importance is expressed by their genetic polymorphism at the molecular level, and their diversity associated with different types of diseases at the population level. Findings of associations between specific combinations of MHC/NKR haplotypes with different diseases in model species suggest that these gene complexes did not evolve independently. No such associations have been described in horses so far. The aim of the study was to detect associations between MHC and NKR gene/microsatellite haplotypes in three horse breed groups (Camargue, African, and Romanian) by statistical methods; chi-square test, Fisher's exact test, Pearson's goodness-of-fit test and logistic regression. Associations were detected for both MHC/NKR genes and microsatellites; the most significant associations were found between the most variable KLRA3 gene and the EQCA-1 or EQCA-2 genes. This finding supports the assumption that the KLRA3 is an important receptor for MHC I and that interactions of these molecules play important roles in the horse immunity and reproduction. Despite some limitations of the study such as low numbers of horses or lack of knowledge of the selected genes functions, the results were consistent across different statistical methods and remained significant even after overconservative Bonferroni corrections. We therefore consider them biologically plausible.
© 2024 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.
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Publication Date: 2024-02-15 PubMed ID: 38358031DOI: 10.1111/tan.15387Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

Overview

  • This study investigates the genetic diversity and interaction of major histocompatibility complex (MHC) and natural killer cell receptor (NKR) genes in domestic horses, aiming to understand how these gene families might co-evolve and influence immunity and reproduction.

Background and Significance

  • The immunogenome encompasses the parts of the genome responsible for immune functions, evolving under pressures from pathogens and environment.
  • Two critical regions in the immunogenome are the MHC and NKR genes, both highly polymorphic and important in pathogen response.
  • Genetic polymorphism in these regions indicates strong selective forces and has been linked to disease susceptibility or resistance in various species.
  • Studies in model organisms have suggested co-evolution or interaction between MHC and NKR gene complexes, influencing immune function, but such associations remain unexplored in horses until now.

Aims of the Study

  • To detect statistical associations between MHC and NKR gene haplotypes in horses.
  • To analyze these associations across three distinct horse breed groups: Camargue, African, and Romanian horses.
  • To examine both gene-based and microsatellite markers to identify patterns of linkage or interaction.

Methodology

  • Sample groups: Three horse populations representing different breeds were selected.
  • Genotyping: Both MHC and NKR gene haplotypes as well as microsatellite markers were typed.
  • Statistical analysis: Multiple statistical tests were employed to validate associations:
    • Chi-square test
    • Fisher’s exact test
    • Pearson’s goodness-of-fit test
    • Logistic regression analysis
  • Correction for multiple testing was applied using the Bonferroni method to control false positives.

Main Findings

  • Significant associations were identified between MHC and NKR gene haplotypes, particularly involving the KLRA3 gene.
  • KLRA3, known for its high variability, showed strong associations with the MHC class I genes EQCA-1 and EQCA-2.
  • This suggests KLRA3 functions as a key receptor interacting with MHC I molecules in horses, analogous to findings in other species.
  • These molecular interactions likely influence immune response mechanisms as well as reproductive processes.
  • The statistical significance persisted across different tests and remained robust after stringent corrections, supporting biological relevance.

Limitations and Considerations

  • Study sample size was relatively small, which can limit the generalizability of the results.
  • Functional roles of some selected genes, including detailed mechanisms of KLRA3, are not fully characterized in horses.
  • Despite these, consistent results from multiple analytic approaches strengthen confidence in findings.

Implications and Future Directions

  • Demonstrates the potential co-evolution and interaction between MHC and NKR genes in horses, a novel finding in this species.
  • Suggests that immune and reproductive fitness in horses may be influenced by specific MHC-NKR gene combinations.
  • Provides a foundation for further functional studies on KLRA3 and other NKR genes in relation to equine immunity and disease resistance.
  • Encourages broader population-level studies with larger cohorts and additional horse breeds.
  • Could inform breeding strategies aimed at enhancing disease resistance and reproductive success through genetic markers.

Cite This Article

APA
Bubenikova J, Plasil M, Futas J, Stejskalova K, Klumplerova M, Oppelt J, Suchentrunk F, Burger PA, Horin P. (2024). Diversity of major histocompatibility complex (MHC) and natural killer cell receptor (NKR) genes and their interactions in domestic horses. HLA, 103(2), e15387. https://doi.org/10.1111/tan.15387

Publication

HLA
ISSN: 2059-2310
NlmUniqueID: 101675570
Country: England
Language: English
Volume: 103
Issue: 2
Pages: e15387

Researcher Affiliations

Bubenikova, Jana
  • Research Group Animal Immunogenomics, CEITEC VETUNI, University of Veterinary Sciences Brno, Brno, Czechia.
Plasil, Martin
  • Research Group Animal Immunogenomics, CEITEC VETUNI, University of Veterinary Sciences Brno, Brno, Czechia.
Futas, Jan
  • Research Group Animal Immunogenomics, CEITEC VETUNI, University of Veterinary Sciences Brno, Brno, Czechia.
Stejskalova, Karla
  • Department of Animal Genetics, Faculty of Veterinary Medicine, University of Veterinary Sciences Brno, Brno, Czechia.
Klumplerova, Marie
  • Research Group Animal Immunogenomics, CEITEC VETUNI, University of Veterinary Sciences Brno, Brno, Czechia.
Oppelt, Jan
  • Research Group Animal Immunogenomics, CEITEC VETUNI, University of Veterinary Sciences Brno, Brno, Czechia.
Suchentrunk, Franz
  • Research Institute of Wildlife Ecology, University of Veterinary Medicine Vienna, Vienna, Austria.
Burger, Pamela A
  • Research Institute of Wildlife Ecology, University of Veterinary Medicine Vienna, Vienna, Austria.
Horin, Petr
  • Research Group Animal Immunogenomics, CEITEC VETUNI, University of Veterinary Sciences Brno, Brno, Czechia.
  • Department of Animal Genetics, Faculty of Veterinary Medicine, University of Veterinary Sciences Brno, Brno, Czechia.

MeSH Terms

  • Animals
  • Horses / genetics
  • Humans
  • Receptors, Natural Killer Cell / genetics
  • Alleles
  • Major Histocompatibility Complex / genetics
  • Polymorphism, Genetic
  • Breeding

Grant Funding

  • DSP_2022_4 / VETUNI Brno
  • Ceitec/Horin/ITA/2020 / VETUNI Brno

References

This article includes 45 references
  1. Akkaya M, Barclay AN. How do pathogens drive the evolution of paired receptors? Eur J Immunol. 2013;43(2):303-313. doi:10.1002/eji.201242896
  2. Tizard IR. Chapter 7 - The mammalian major histocompatibility complex. In: Tizard IR, ed. Comparative Mammalian Immunology. Developments in Immunology. Academic Press; 2023:89-99. doi:10.1016/B978-0-323-95219-4.00011-3
  3. Murphy K, Weaver C. Janeway's Immunobiology. 9th ed. Garland Science. Taylor & Francis Group; 2017.
  4. Trowsdale J, Knight JC. Major histocompatibility complex genomics and human disease. Annu Rev Genomics Hum Genet. 2013;14(1):301-323. doi:10.1146/annurev-genom-091212-153455
  5. Debebe BJ, Boelen L, Lee JC, et al. Identifying the immune interactions underlying HLA class I disease associations. eLife. 2020;9:e54558. doi:10.7554/eLife.54558
  6. Gao X, Nelson GW, Karacki P, et al. Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS. N Engl J Med. 2001;344(22):1668-1675. doi:10.1056/NEJM200105313442203
  7. Takeshima S-n, Sasaki S, Meripet P, Sugimoto Y, Aida Y. Single nucleotide polymorphisms in the bovine MHC region of Japanese Black cattle are associated with bovine leukemia virus proviral load. Retrovirology. 2017;14:24. doi:10.1186/s12977-017-0348-3
  8. Rastislav M, Mangesh B. BoLA-DRB3 exon 2 mutations associated with paratuberculosis in cattle. Vet J. 2012;192(3):517-519. doi:10.1016/j.tvjl.2011.07.005
  9. Minias P, Vinkler M. Selection balancing at innate immune genes: adaptive polymorphism maintenance in toll-like receptors. Mol Biol Evol. 2022;39(5):msac102. doi:10.1093/molbev/msac102
  10. Niskanen AK, Kennedy LJ, Ruokonen M, et al. Balancing selection and heterozygote advantage in major histocompatibility complex loci of the bottlenecked Finnish wolf population. Mol Ecol. 2014;23(4):875-889. doi:10.1111/mec.12647
  11. Rock KL, Reits E, Neefjes J. Present yourself! By MHC class I and MHC class II molecules. Trends Immunol. 2016;37(11):724-737. doi:10.1016/j.it.2016.08.010
  12. Trowsdale J. Genetic and functional relationships between MHC and NK receptor genes. Immunity. 2001;15(3):363-374. doi:10.1016/s1074-7613(01)00197-2
  13. Sambrook JG, Beck S. Evolutionary vignettes of natural killer cell receptors. Curr Opin Immunol. 2007;19(5):553-560. doi:10.1016/j.coi.2007.08.002
  14. Brown MG, Scalzo AA. NK gene complex dynamics and selection for NK cell receptors. Semin Immunol. 2008;20(6):361-368. doi:10.1016/j.smim.2008.06.004
  15. Kelley J, Walter L, Trowsdale J. Comparative genomics of natural killer cell receptor gene clusters. PLoS Genet. 2005;1(2):129-139. doi:10.1371/journal.pgen.0010027
  16. Prugnolle F, Manica A, Charpentier M, Guégan JF, Guernier V, Balloux F. Pathogen-driven selection and worldwide HLA class I diversity. Curr Biol. 2005;15(11):1022-1027. doi:10.1016/j.cub.2005.04.050
  17. Khor CC, Hibberd ML. Host-pathogen interactions revealed by human genome-wide surveys. Trends Genet. 2012;28(5):233-243. doi:10.1016/j.tig.2012.02.001
  18. Orgul G, Dalva K, Dalva-Aydemir S, et al. Significance of inhibitory maternal killer-cell immunoglobulin-like receptor (KIR) and fetal KIR ligand genotype combinations in placenta related obstetric complications. J Reprod Immunol. 2021;148:103425. doi:10.1016/j.jri.2021.103425
  19. Todd ET, Thomson PC, Hamilton NA, et al. A genome-wide scan for candidate lethal variants in Thoroughbred horses. Sci Rep. 2020;10:13153. doi:10.1038/s41598-020-68946-8
  20. Guethlein LA, Norman PJ, Hilton HG, Parham P. Co-evolution of MHC class I and variable NK cell receptors in placental mammals. Immunol Rev. 2015;267(1):259-282. doi:10.1111/imr.12326
  21. de Groot NG, Blokhuis JH, Otting N, Doxiadis GGM, Bontrop RE. Co-evolution of the MHC class I and KIR gene families in rhesus macaques: ancestry and plasticity. Immunol Rev. 2015;267(1):228-245. doi:10.1111/imr.12313
  22. Wroblewski EE, Parham P, Guethlein LA. Two to tango: co-evolution of hominid natural killer cell receptors and MHC. Front Immunol. 2019;10:177. doi:10.3389/fimmu.2019.00177
  23. Kelley J, Trowsdale J. Features of MHC and NK gene clusters. Transpl Immunol. 2005;14(3-4):129-134. doi:10.1016/j.trim.2005.03.001
  24. Pollock NR, Harrison GF, Norman PJ. Immunogenomics of killer cell immunoglobulin-like receptor (KIR) and HLA class I: coevolution and consequences for human health. J Allergy Clin Immunol Pract. 2022;10(7):1763-1775. doi:10.1016/j.jaip.2022.04.036
  25. Kalbfleisch TS, Rice ES, DePriest MS, et al. EquCab3, an Updated Reference Genome for the Domestic Horse. 306928. Published online April 25 2018. doi:10.1101/306928
  26. Plasil M, Oppelt J, Klumplerova M, et al. Newly identified variability of the antigen binding site coding sequences of the equine major histocompatibility complex class I and class II genes. HLA. 2023;102(4):489-500. doi:10.1111/tan.15078
  27. Takahashi T, Yawata M, Raudsepp T, et al. Natural killer cell receptors in the horse: evidence for the existence of multiple transcribed LY49 genes. Eur J Immunol. 2004;34(3):773-784. doi:10.1002/eji.200324695
  28. Futas J, Horin P. Natural killer cell receptor genes in the family Equidae: not only Ly49. PloS One. 2013;8(5):e64736. doi:10.1371/journal.pone.0064736
  29. Futas J, Oppelt J, Janova E, Musilova P, Horin P. Complex variation in the KLRA (LY49) immunity-related genomic region in horses. HLA. 2020;96(3):257-267. doi:10.1111/tan.13939
  30. Horecky C, Horecka E, Futas J, Janova E, Horin P, Knoll A. Microsatellite markers for evaluating the diversity of the natural killer complex and major histocompatibility complex genomic regions in domestic horses. HLA. 2018;91(4):271-279. doi:10.1111/tan.13211
  31. Excoffier L, Lischer HEL. Arlequin suite ver 3.5: a new series of programs to perform population genetics analyses under Linux and Windows. Mol Ecol Resour. 2010;10(3):564-567. doi:10.1111/j.1755-0998.2010.02847.x
  32. Fasano ME, Rendine S, Pasi A, et al. The distribution of KIR-HLA functional blocks is different from North to South of Italy. Tissue Antigens. 2014;83(3):168-173. doi:10.1111/tan.12299
  33. Guinan KJ, Cunningham RT, Meenagh A, et al. Signatures of natural selection and coevolution between killer cell immunoglobulin-like receptors (KIR) and HLA class I genes. Genes Immun. 2010;11(6):467-478. doi:10.1038/gene.2010.9
  34. Pelak K, Need AC, Fellay J, et al. Copy number variation of KIR genes influences HIV-1 control. PLoS Biol. 2011;9(11):e1001208. doi:10.1371/journal.pbio.1001208
  35. Chaisri S, Jayaraman J, Mongkolsapaya J, et al. KIR copy number variations in dengue-infected patients from northeastern Thailand. Hum Immunol. 2022;83(4):328-334. doi:10.1016/j.humimm.2022.01.005
  36. Kulminski AM. Complex phenotypes and phenomenon of genome-wide inter-chromosomal linkage disequilibrium in the human genome. Exp Gerontol. 2011;46(12):979-986. doi:10.1016/j.exger.2011.08.010
  37. Mora-Bitria L, Asquith B. Innate receptors modulating adaptive T cell responses: KIR-HLA interactions and T cell-mediated control of chronic viral infections. Immunogenetics. 2023;75(3):269-282. doi:10.1007/s00251-023-01293-w
  38. Hollenbach JA, Pando MJ, Caillier SJ, Gourraud PA, Oksenberg JR. The killer immunoglobulin-like receptor KIR3DL1 in combination with HLA-Bw4 is protective against multiple sclerosis in African Americans. Genes Immun. 2016;17(3):199-202. doi:10.1038/gene.2016.5
  39. Khakoo SI, Thio CL, Martin MP, et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science. 2004;305(5685):872-874. doi:10.1126/science.1097670
  40. Hiby SE, Apps R, Chazara O, et al. Maternal KIR in combination with paternal HLA-C2 regulate human birth weight. J Immunol. 2014;192(11):5069-5073. doi:10.4049/jimmunol.1400577
  41. Parham P, Abi-Rached L, Matevosyan L, et al. Primate-specific regulation of natural killer cells. J Med Primatol. 2010;39(4):194-212. doi:10.1111/j.1600-0684.2010.00432.x
  42. Stenzel A, Lu T, Koch WA, et al. Patterns of linkage disequilibrium in the MHC region on human chromosome 6p. Hum Genet. 2004;114(4):377-385. doi:10.1007/s00439-003-1075-5
  43. Almawi WY, Nemr R, Finan RR, Saldhana FL, Hajjej A. HLA-A, -B, -C, -DRB1 and -DQB1 allele and haplotype frequencies in Lebanese and their relatedness to neighboring and distant populations. BMC Genomics. 2022;23(1):456. doi:10.1186/s12864-022-08682-7
  44. Jiang X, Peng Y, Liu L, et al. MAIT cells ameliorate liver fibrosis by enhancing the cytotoxicity of NK cells in cholestatic murine models. Liver Int Off J Int Assoc Study Liver. 2022;42(12):2743-2758. doi:10.1111/liv.15445
  45. Vacchini A, Chancellor A, Spagnuolo J, Mori L, De Libero G. MR1-restricted T cells are unprecedented cancer fighters. Front Immunol. 2020;11: 751. Accessed July 28, 2023. https://www.frontiersin.org/articles/10.3389/fimmu.2020.00751

Citations

This article has been cited 1 times.
  1. Vychodilova L, Plasil M, Futas J, Kopecka A, Molinkova D, Wijacki T, Jahn P, Knoll A, Horin P. Genetic susceptibility to sarcoid in Arabian horses: associations with MHC class II and compound MHC class I/KLRA genotypes.. Vet Res Commun 2025 May 1;49(3):184.
    doi: 10.1007/s11259-025-10748-2pubmed: 40310488google scholar: lookup
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