Major Histocompatibility Complex (MHC) Diversity and its implications in human and wildlife health and Conservation


  • Oluwakayode Michael COKER Department of Wildlife and Ecotourism Management, University of Ibadan, Nigeria
  • Osamede Henry OSAIYUWU Department of Animal Science, University of Ibadan, Nigeria
  • Abraham Oladiran FATOKI Department of Animal Science, University of Ibadan, Nigeria



Biodiversity health, Conservation, Genetic variations, Immune genes


It is clear that the global environment has changed and is still changing. The results of climate change, pollution, human use, and misuse of natural resources are tolling on humans and global biodiversity. The appropriate response(s) to these changes can be attributed to the immune system’s efficacy. The Major Histocompatibility Complex (MHC) has a key role in maintaining global biodiversity in the face of the obvious threats they face. Genetic variation, especially those within MHC proteins has been known to influence the ability of individuals to cope with various pathogens. This review, therefore, explores the diversities within the MHC in wildlife, highlights the importance of MHC to wildlife and human health, emphasizes the need to conserve MHC diversity for adequate conservation, and opens a discussion on whether the diversity within the MHC genes and disease resistance is a question of quantity or quality. For most jawed vertebrates, classical MHC genes are the most gene-dense and polymorphic. This polymorphism in the MHC genes can be explained by host-pathogen coevolution, providing an excellent tool for determining a population's or species' immunological fitness. Their variation is undoubtedly adaptively important, and there is strong evidence that pathogen-imposed balancing selection is the primary cause of its maintenance. Over the years, variants in the major histocompatibility complex (MHC) have been reported as major risk factors for autoimmune and infectious diseases in humans and wildlife species of conservation concern. It has been observed that, though high diversity within the MHC proffers some protection on most natural populations, this seems not to be universal. The influence of this high diversity on the survival of natural populations should be further investigated. As the debate lingers, there is a dire need to protect the present diversity at the locus. This will definitely play a very important role in maintaining the health of both humans and animals and ensuring the conservation of biodiversity in response to the inevitable changes in our world.


Akiyama T. Kohyama TI. Nishida C. Onuma M. Momose K. Masuda R 2017. Genetic variation of major histocompatibility complex genes in the endangered red-crowned crane. Immunogenetics, 69(7), 451–462. DOI:10.1007/s00251-017-0994-6

Al Hadra B. Lukanov TI and Ivanova MI 2022. HLA class I chain-related MICA and MICB genes polymorphism in healthy individuals from the Bulgarian population. Human Immunology, 83(7), 551-555 ISSN 0198-8859. DOI:10.1016/j.humimm.2022.04.006

Alcaide M. Lemus JA. Blanco G. Tella JL. Serrano D. Negro JJ. Rodriguez A. Garcia-Montijano M 2010. MHC diversity and differential exposure to pathogens in kestrels Aves: Falconidae) Molecular Ecology, 19, 691–705. DOI:10.1111/j.1365-294X.2009.04507.x.

Amiel JL. 1967. Study of leucocyte phenotypes in Hodgkins' disease. Histocompatibility testing 1967 79-81.

Averdam A. Kuschal C. Otto N. Westphal N. Roos C. Reinhardt R. Walter L 2011. Sequence analysis of the grey mouse lemur Microcebus murinus) MHC class II DQ and DR region. Immunogenetics,63:85–93. DOI:10.1007/s00251-010-0487-3

Babik W. Durka W. and Radwan J. 2005. Sequence diversity of the MHC DRB gene in the Eurasian beaver Castor fiber Molecular Ecology, 14: 4249–4257. DOI:10.1111/j.1365-294x.2005.02751.x

Becker L. Nieberg C. Jahreis K and Peters E. 2009. MHC class II variation in the endangered European mink Mustela lutreola L. 1761)—Consequences for species conservation. Immunogenetics, 61, 281–288. DOI:10.1007/s00251-009-0362-2

Biedrzycka A and Radwan J 2008. Population fragmentation and major histocompatibility complex variation in the spotted suslik Spermophilus suslicus. Molecular Ecology, 17, 4801–4811. DOI:10.1111/j.1365-294X.2008-03955.x

Bose B. Johnson DV. Campbell SB 2013. Transplantation antigens and histocompatibility matching. In: Rath T ed. Current Issues and Future Direction in Kidney Transplantation. InTech, 371–90. ISBN: 978-953-51-0985-3.

Bowen L. Aldridge BM. Gulland F. Van Bonn W. DeLong R. Melin S. Johnson ML 2004. Class II multiformity generated by variable MHC-DRB region configurations in the California sea lion Zalophus californianus Immunogenetics, 56: 12–27. DOI:10.1007/s00251-004-0655-4

Bravo MJ. Colmenero JD. Martín J. Alonso A. Caballero A 2007. Polymorphism of the transmembrane region of the MICA gene and human brucellosis. Tissue Antigens 69: 358–360. PMID: 17389022. DOI: 10.1111/j.1399-0039.2007-00823.x

Brewerton DA. Hart FD. Nicholls A. Caffrey M. James DCO. Sturrock RD 1973. Ankylosing Spondylitis and HL-A 27. The Lancet 301(7809) 904–907. DOI:10.1016/s0140-6736(73)91360-3

Burri R. Salamin N. Studer RA. Roulin A. Fumagalli L 2010. Adaptive divergence of ancient gene duplicates in the avian MHC class II beta. Molecular Biology and Evolution, 27 2360–2374. DOI: 10.1093/molbev/msq120

Castillo S. Srithayakumar V. Meunier V. Kyle CJ 2010. Characterization of Major Histocompatibility Complex MHC) DRB Exon 2 and DRA Exon 3 Fragments in a Primary Terrestrial Rabies Vector Procyon lotor PLoS ONE 5(8): e12066. DOI:10.1371/journal.pone.0012066

Castro-Prieto A. Wachter B. Sommer S 2011. Cheetah Paradigm Revisited: MHC Diversity in the World’s Largest Free-Ranging Population Molecular Biology and Evolution, 28(4):1455–1468. 2011. DOI: 10.1093/molbev/msq330

Chu X. Yang M. Song ZJ. Dong Y. Li C. Shen M. Huang W 2018. Fine mapping MHC associations in Graves’ disease and its clinical subtypes in Han Chinese. Journal of Medical Genetics, 0:1–8. DOI:10.1136/jmedgenet-2017-105146

Cohen R. Metzger S. Nahir M. Chajek-Shaul T 2002. Association of the MIC-A gene and HLA-B51 with Behçet's disease in Arabs and non-Ashkenazi Jews in Israel. Annals of the Rheumatic Diseases 61: 157–160. PMID: 11796403. DOI: 10.1136/ard.61.2.157

Dadi H. Le M. Dinka H. Nguyen D. Choi H. Cho H. Park C 2015. Genetic Diversity and mRNA Expression of Porcine MHC Class I Chain-Related 2 SLA-MIC2) Gene and Development of a High-Resolution Typing Method. PLOS ONE 10(8) e0135922. DOI: 10.1371/journal.pone.0135922

De Bruyn M. Allendorf FW. Luikart G 2007. Conserving Global Biodiversity? Conservation and the Genetics of Populations. Conservation Genetics, 9(2) 437–438. DOI:10.1007/s10592-007-9330-2

De Groot N. Stanbury K. de Vos-Rouweler AJM. de Groot NG. Poirier N. Blancho G. Bontrop RE 2017. A quick and robust MHC typing method for free-ranging and captive primate species. Immunogenetics, 69(4) 231–240. DOI:10.1007/s00251-016-0968-0

De la Herrán-Arita AK and García-García F 2014. Narcolepsy as an Immune-Mediated Disease. Sleep Disorders, 1–6. DOI:10.1155/2014/792687

Delgado JC. Yunis DE. Bozón MV. Salazar M. Deulofeut R. Turbay D. Yunis EJ 1996. MHC class II alleles and haplotypes in patients with pemphigus vulgaris from India. Tissue Antigens, 48(6), 668–672. DOI:10.1111/j.1399-0039.1996-tb02690.x

Ejsmond MJ and Radwan J 2011. MHC diversity in bottlenecked populations: a simulation model. Conservation Genetics, 12:129–137 DOI 10.1007/s10592-009-9998-6

Evans ML. Neff BD. Heath DD 2009. MHC genetic structure and divergence across populations of Chinook salmon Oncorhynchus tshawytscha. Heredity, 104(5), 449–459. DOI:10.1038/hdy.2009.121

Fernando MMA. Freudenberg J. Lee A. Morris DL. Boteva L. Rhodes B 2012. Transancestral mapping of the MHC region in systemic lupus erythematosus identifies new independent and interacting loci at MSH5 HLA-DPB1 and HLA-G. Annals of the Rheumatic Diseases, 71(5) 777–784. DOI:10.1136/annrheumdis-2011-200808

Fernando MMA. Stevens CR. Sabeti PC. Walsh EC. McWhinnie AJM. Shah A. Vyse TJ 2007. Identification of Two Independent Risk Factors for Lupus within the MHC in United Kingdom Families. PLoS Genetics, 3(11) e192. DOI: 10.1371/journal.pgen.0030192

Fleischnick E. Raum D. Alosco S. Gerald P. Yunis E. Awdeh Z. Alper C 1983. Extended Mhc Haplotypes In 21-Hydroxylase-Deficiency Congenital Adrenal Hyperplasia: Shared Genotypes in Unrelated Patients. The Lancet, 321(8317), 152–156. DOI:10.1016/s0140-

Froeschke G and Sommer S 2005. MHC Class II DRB constitution and parasite load in the striped mouse Rhabdomys pumilio in the Southern Kalahari. Molecular Biology and Evolution. 22:1254-1259.

Gaigher A. Burri R. Gharib W. Taberlet P. Roulin A. Fumagalli L. 2016. Family-assisted inference of the genetic architecture of major histocompatibility complex variation. Molecular Ecology Resources, 16(6), 1353–1364. DOI: 10.1111/1755-0998.12537

Gorodezky C. Alaez C. Munguı́a A. Cruz R. Vazquez A. Camacho A. Rodriguez O 2004. Molecular mechanisms of MHC linked susceptibility in leprosy: towards the development of synthetic vaccines. Tuberculosis. 84(1-2), 82–92. DOI:10.1016/

Gutierrez-Achury J. Zhernakova A. Pulit SL. Trynka G. Hunt KA. Romanos J. de Bakker PIW 2015. Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease. Nature Genetics, 47(6), 577–578. DOI:10.1038/ng.3268

Hedrick P 2003. The major histocompatibility complex MHC) in declining populations: An example of adaptive variation. In W. V. Holt A. R. Pickard J. C. Rodger and D. E. Wildt Eds.) Reproduction science and integrated conservation pp. 97–113 Cambridge UK: Cambridge University Press.

Hedrick PW 2002. Pathogen resistance and genetic variation at MHC loci. Evolution, 56: 1902–1908. DOI: 10.1111/j.0014-3820.2002.tb00116.x

Hedrick PW and Thomson G 1988. Maternal-Fetal Interactions and the Maintenance of HLA Polymorphism. Genetics 119: 206-212. DOI: 10.1093/genetics/119.1.205

Hjelmström P and Sanjeevi CB 2000. Molecular Mechanisms of MHC Associations with Myasthenia Gravis. In: Christadoss P. eds) Myasthenia Gravis. Springer Dordrecht. DOI: 10.1007/978-94-011-4060-7_9

Holderegger R. Kamm U. Gugerli F 2006. Adaptive vs. neutral genetic diversity: implications for landscape genetics. Landsc Ecol 21: 797-807. Landscape Ecology. 21(6), 797-807. DOI:10.1007/s10980-005-5245-9

Howell WM 2013. HLA and disease: guilt by association. International Journal of Immunogenetics, 41(1), 1–12. DOI:10.1111/iji.12088

Huchard E. Cowlishaw G. Raymond MI. Weill M. Knapp LA 2006. Molecular study of Mhc-DRB in wild chacma baboons reveals high variability and evidence for trans-species inheritance. Immunogenetics, 58: 805–816. DOI: 10.1007/s00251-006-0156-8

Hughes AL and Hughes MK 1995. Natural selection on the peptide-binding regions of major histocompatibility complex molecules. Immunogenetics 42: 233–243. DOI: 10.1007/BF00176440

Hughes AL. Ota T. Nei M 1990. Positive Darwinian selection promotes charge profile diversity in the antigen-binding cleft of class I major-histocompatibility-complex molecules. Mol. Biol. Evol. 7 515–524. DOI: 10.1093/oxfordjournals.molbev.a040626

Janeway Jr CA. Travers P. Walport M. Shlomchik MJ 2001. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science. The Front Line of Host Defense.

Jinushi M. Vanneman M. Munshi NC. Tai YT. Prabhala RH. Ritz J. Dranoff G 2008. MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma. Proceedings of the National Academy of Sciences, 105(4) 1285–1290. DOI:10.1073/pnas.0711293105

Judson MA. 2018. A sarcoidosis clinician’s perspective of MHC functional elements outside the antigen binding site. Human Immunology. DOI:10.1016/j.humimm.2018.05.007

Kalbe M. Eizaguirre C. Dankert I. Reusch TBH. Sommerfeld RD. Wegner KM. Milinski M 2009. Lifetime reproductive success is maximized with optimal major histocompatibility complex diversity. Proceedings of the Royal Society of London Series B: Biological Sciences 276 925–934.

Kelly A and Trowsdale J 2017. Introduction: MHC/KIR and governance of specificity. Immunogenetics 69(8-9) 481–488. DOI:10.1007/s00251-017-0986-6

Khor CC. Chau TNB. Pang J. Davila S. Long HT. Ong RTH. Simmons CP 2011. Genome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1. Nature Genetics 43(11) 1139–1141. DOI:10.1038/ng.960

Kohyama TI. Akiyama T. Nishida C. Takami K. Onuma M. Momose K. Masuda R 2015. Isolation and characterization of major histocompatibility complex class II B genes in cranes. Immunogenetics 67: 705–710

Lan H. Zhou T. Wan QH. Fang SG 2019. Genetic Diversity and Differentiation at Structurally Varying MHC Haplotypes and Microsatellites in Bottlenecked Populations of Endangered Crested Ibis. 8(4), 377. DOI:10.3390/cells8040377

Loewe L and Hill WG 2010. The population genetics of mutations: good bad and indifferent. Philosophical Transactions of the Royal Society B: Biological Sciences 365(1544) 1153–1167. DOI:10.1098/rstb.2009.0317

Madsen T and Ujvari B 2006. MHC Class I associates with parasite resistance and longevity in tropical pythons. Journal of Evolutionary Biology, 19(6), 1973–1978. DOI: 10.1111/j.1420-9101.2006.01158.x

Manlik O. Krützen M. Kopps AM. Mann J. Bejder L. Allen SJ. Sherwin WB 2019. Is MHC diversity a better marker for conservation than neutral genetic diversity? A case study of two contrasting dolphin populations. Ecology Evolution, 9:6986–6998. DOI: 10.1002/ece3.5265

Mason RA. Browning TL. Eldridge MDB 2011. Reduced MHC class II diversity in island compared to mainland populations of the black-footed rock-wallaby Petrogale lateralis lateralis. Conservation Genetics, 12, 91–103. DOI 10.1007/s10592-009-9993-y

Mikko S and Andersson L 1995. Low major histocompatibility complex class II diversity in European and North American moose. Proceedings of the National Academy of Sciences. 92(10), 4259–4263. DOI:10.1073/pnas.92.10.4259

Miller HC. Allendorf F. Daugherty CH 2010. Genetic diversity and differentiation at MHC genes in island populations of tuatara Sphenodon spp. Molecular Ecology, 19, 3894–3908. DOI: 10.1111/j.1365-294X.2010.04771.x

Milner CM. Smith SV. Carrillo MB. Taylor GL. Hollinshead M. Campbell RD 1997. Identification of a Sialidase Encoded in the Human Major Histocompatibility Complex. Journal of Biological Chemistry, 272(7), 4549–4558. DOI:10.1074/jbc.272.7.4549

Molinero LL. Fuertes MB. Rabinovich GA. Fainboim L. Zwirner NW 2002. Activation-induced expression of MICA on T lymphocytes involves engagement of CD3 and CD28. Journal of Leukocyte Biology, 71: 791–797. PMID: 11994503

Morran MP. Vonberg A. Khadra A. Pietropaolo M 2015. Immunogenetics of type 1 diabetes mellitus. Molecular Aspects of Medicine, 42, 42–60. DOI:10.1016/j.mam.2014.12.004

Morris KM. Wright B. Grueber CE. Hoggt C. Belov K 2015. Lack of genetic diversity across diverse immune genes in an endangered mammal the Tasmanian devil Sarcophilus harrisii Molecular Ecology, 24, 3860–3872. DOI: 10.1111/mec.13291

Newton J. Harney S. Wordsworth B. Brown M 2004. A review of the MHC genetics of rheumatoid arthritis. Genes & Immunity 5(3) 151–157. DOI:10.1038/sj.gene.6364045

Niskanen AK. Kennedy LJ. Ruokonen M. Kojola I. Lohi H. Isomursu M. Jansson E. Pyhäjärvi T. Aspi J 2014. Balancing selection and heterozygote advantage inmajor histocompatibility complex loci of the bottlenecked Finnish wolf population. Molecular Ecology, 23:875–889. DOI: 10.1111/mec.12647

Peacock MM and Smith AT 1997. The effects of habitat fragmentation on dispersal patterns mating behavior and genetic variation in a pica Ochotona princeps) metapopulation. O.ecologia, 112:524-533. DOI:10.1007/s004420050341

Piertney SB and Oliver MK 2006. The evolutionary ecology of the major histocompatibility complex. Heredity 96: 7–21. DOI: 10.1038/sj.hdy.6800724

Piertney SB and Webster LMI 2010. Characterizing functionally important and ecologically meaningful genetic diversity using a candidate gene approach. Genetica, 138(4) 419–432. DOI:10.1007/s10709-008-9322-2

Radwan J. Babik W. Kaufman J. Lenz TL. Winternitz J 2020. Advances in the Evolutionary Understanding of MHC Polymorphism. Trends in Genetics, 36(4) DOI:10.1016/j.tig.2020.01.008

Radwan J. Biedrzycka A. Babik W 2010. Does reduced MHC diversity decrease viability of vertebrate populations? Biology and Conservation, 143:537–544. DOI: 10.1016/j.biocon.2009.07.026

Ramagopalan SV and Ebers GC 2009. Multiple sclerosis: major histocompatibility complexity and antigen presentation. Genome Medicine, 1(11), 105. DOI:10.1186/gm105

Reche PA and Reinherz EL 2003. Sequence variability analysis of human class I and class II MHC molecules: Functional and structural correlates of amino acid polymorphisms. Journal of Molecular Biology, 331, 623–641. DOI: 10.1016/s0022-2836(03)00750-2

Reith W and Mach B 2001. The Bare Lymphocyte Syndrome and The Regulation of MHC Expression. Annual Review of Immunology, 19(1), 331–373. DOI:10.1146/annurev.immunol.19.1.331

Riley EM. Olerup O. Bennett S. Rowe P. Allen SJ. Blackman MJ. Greenwood BM 1992. MHC and malaria: the relationship between HLA class II alleles and immune responses to Plasmodium falciprum. International Immunology, 4(9), 1055–1063. DOI:10.1093/intimm/4.9.1055

Robinson J. Halliwell JA. Hayhurst JH. Flicek P. Parham P. Marsh SGE 2015. The IPD and IMGT/HLA database: allele variant databases. Nucleic Acids Research, 43: D423–D431. DOI: 10.1093/nar/gku1161

Sanjuán R and Domingo-Calap P 2019. Genetic Diversity and Evolution of Viral Populations. Reference Module in Life Sciences. DOI:10.1016/b978-0-12-809633-8.20958-8

Schwensow N. Fietz J. Dausmann KH. Sommer S 2007. Neutral versus adaptive genetic variation in parasite resistance: importance of major histocompatibility complex supertypes in a free-ranging primate. Heredity, 99: 265–277. DOI: 10.1038/sj.hdy.6800993

Sommer S. 2005. The importance of immune gene variability MHC in evolutionary ecology and conservation. Frontiers in Zoology. 2005, 2:16. DOI: 10.1186/1742-9994-2-16

Thoss M. Ilmonen K. Musolf K. Penn DJ 2011. Major histocompatibility complex heterozygosity enhances reproductive success. Molecular Ecology, 20, 1546–1557.

Truedsson L. Alper CA. Awdeh ZL. Johansen P. Sjöholm AG Sturfelt G 1993. Characterization of type I complement C2 deficiency MHC haplotypes. Strong conservation of the complotype/HLA-B-region and absence of disease association due to linked class II genes. Journal of Immunology, 15; 151(10):5856-63. PMID: 7901282.

Tsai S and Santamaria P 2013. MHC class II polymorphisms autoreactive T-cells and Autoimmunity. Frontiers in Immunology. Antigen Presenting Cell Biolog, 4:321 DOI: 10.3389/fimmu.2013.00321

Tsuji H. Taniguchi Y. Ishizuka S. Matsuda H. Yamada T. Naito K. Iwaisaki H 2017. Structure and polymorphisms of the major histocompatibility complex in the Oriental stork Ciconia boyciana. Sci. Rep. 2017 7 42864.

Ujvari B and Belov K 2011. Major Histocompatibility Complex MHC) Markers in Conservation Biology. International Journal of Molecular Sciences, 12, 5168–5186. DOI:10.3390/ijms12085168

Walford RL. Finkelstein S. Neerhout R. Konrad P. Shanbrom E 1970. Acute Childhood Leukaemia in Relation to the HL–A Human Transplantation Genes. Nature, 225(5231), 461–462. DOI:10.1038/225461a0

Wang N. Shen N. Vyse TJ. Anand V. Gunnarson I. Sturfelt G. Hammarström L 2011. Selective IgA Deficiency in Autoimmune Diseases. Molecular Medicine, 17(11-12) 1383–1396. DOI:10.2119/molmed.2011.00195

Wang S. Liu C. Wilson AB. Zhao N. Li X. Zhu W. Gao X. Liu X. Li Y 2017. Pathogen richness and abundance predict patterns of adaptive MHC variation in insular amphibians. Molecular Ecology, 26, 4671–4685. DOI: 10.1111/mec.14242

Weber DS. Stewart BS. Schienman J. Lehman N 2004. Major histocompatibility complex variation at three class II loci in the northern elephant seal. Molecular Ecology, 13(3), 711–718. DOI:10.1111/j.1365-294x.2004-02095.x

Wong CGT. Scherer SW. Snead III OC. Hampson DR 2001. Localization of the human mGluR4 gene within an epilepsy susceptibility locus. Molecular Brain Research, 87(1), 109–116. DOI:10.1016/s0169-328x(00)00283-7

Yamaguchi T and Dijkstra JM 2019. Major Histocompatibility Complex MHC) Genes and Disease Resistance in Fish. Cells, 8(4), 378. DOI:10.3390/cells8040378

Zeisset I and Beebee TJC 2009. Molecular characterization of major histocompatibility complex class II alleles in the common frog Rana temporaria. Molecular Ecology Resources, 9: 738–745.

Zeng CJ. Pan HJ. Gong SB. Yu JQ. Wan QH. Fang SG 2007. Giant panda BAC library construction and assembly of a 650-kb contig spanning major histocompatibility complex class II region. BMC Genomics, 8: 315. DOI:10.1186/1471-2164-8-315

Zhang J. Wei Z. Cardinale CJ. Gusareva ES. Van Steen K. Sleiman P 2019. Multiple Epistasis Interactions Within MHC Are Associated With Ulcerative Colitis. Frontiers in Genetics, 10. DOI:10.3389/fgene.2019.00257

Zhou F and Zhang X 2018. Major Histocompatibility Complex and Psoriasis. Journal of Investigative Dermatology Symposium Proceedings, 19(2), S79–S80. DOI:10.1016/j.jisp.2018.09.006

Ziegler A. Kentenich H. Uchanska-Ziegler B 2005. Female choice and the MHC. Trends in Immunology, 26:496–502. DOI: 10.1016/




How to Cite

COKER, O. M., OSAIYUWU , O. H., & FATOKI, A. O. (2023). Major Histocompatibility Complex (MHC) Diversity and its implications in human and wildlife health and Conservation. Genetics & Biodiversity Journal, 7(2), 1–11.



Review Article