Skip to main content
SpringerLink
Log in

Evolutionary and polymorphism analyses reveal the central role of BTN3A2 in the concerted evolution of the BTN3 gene family

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

Abstract

The butyrophilin 3 (BTN3) receptors are implicated in the T lymphocytes regulation and present a wide plasticity in mammals. In order to understand how these genes have been diversified, we studied their evolution and show that the three human BTN3 are the result of two successive duplications in Primates and that the three genes are present in Hominoids and the Old World Monkey groups. A thorough phylogenetic analysis reveals a concerted evolution of BTN3 characterized by a strong and recurrent homogenization of the region encoding the signal peptide and the immunoglobulin variable (IgV) domain in Hominoids, where the sequences of BTN3A1 or BTN3A3 are replaced by BTN3A2 sequence. In human, the analysis of the diversity of these genes in 1683 individuals representing 26 worldwide populations shows that the three genes are polymorphic, with more than 46 alleles for each gene, and marked by extreme homogenization of the IgV sequences. The same analysis performed for the BTN2 genes shows also a concerted evolution; however, it is not as strong and recurrent as for BTN3. This study shows that BTN3 receptors are marked by extreme concerted evolution at the IgV domain and that BTN3A2 plays a central role in this evolution.

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
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

BTN:

Butyrophilin

IgV:

Immunoglobulin variable

NK:

Natural killer

pAg:

Phosphoantigen

NWM:

New world monkeys

OWM:

Old world monkeys

UTR:

Untranslated transcribed region

IgC:

Immunoglobulin constant

TM:

Transmembrane

References

  • Abeler-Dörner L, Swamy M, Williams G, Hayday AC, Bas A (2012) Butyrophilins: an emerging family of immune regulators. Trends Immunol 33:34–41

    Article  PubMed  Google Scholar 

  • Afrache H, Gouret P, Ainouche S, Pontarotti P, Olive D (2012) The butyrophilin (BTN) gene family: from milk fat to the regulation of the immune response. Immunogenetics 64:781–794

    Article  CAS  PubMed  Google Scholar 

  • Arnett HA, Escobar SS, Gonzalez-Suarez E, Budelsky AL, Steffen LA, Boiani N, Zhang M, Siu G, Brewer AW, Viney JL (2007) BTNL2, a butyrophilin/B7-like molecule, is a negative costimulatory molecule modulated in intestinal inflammation. Journal of immunology (Baltimore, MD: 1950) 178:1523–1533

    Article  CAS  Google Scholar 

  • Bonneville M, Fournié J-J (2005) Sensing cell stress and transformation through Vgamma9Vdelta2 T cell-mediated recognition of the isoprenoid pathway metabolites. Microbes Infect 7:503–509

    Article  CAS  PubMed  Google Scholar 

  • Carson AR, Scherer SW (2009) Identifying concerted evolution and gene conversion in mammalian gene pairs lasting over 100 million years. BMC Evol Biol 9:156

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen B, Wilkening S, Drechsel M, Hemminki K (2009) SNP_tools: a compact tool package for analysis and conversion of genotype data for MS-Excel. BMC research notes 2

  • Compte E, Pontarotti P, Collette Y, Lopez M, Olive D (2004) Frontline: characterization of BT3 molecules belonging to the B7 family expressed on immune cells. Eur J Immunol 34:2089–2099

    Article  CAS  PubMed  Google Scholar 

  • della Gaspera B, Pham-Dinh D, Roussel G, Nussbaum JL, Dautigny A (1998) Membrane topology of the myelin/oligodendrocyte glycoprotein. Eur J Biochem 258:478–484

    Article  PubMed  Google Scholar 

  • Fossum S, Saether PC, Vaage JT, Daws MR, Dissen E (2011) Paired opposing leukocyte receptors recognizing rapidly evolving ligands are subject to homogenization of their ligand binding domains. Immunogenetics 63:809–820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujimaki T, Kato K, Oguri M, Yohida T, Horibe H, Yokoi K, Watanabe S, Satoh K, Aoyagi Y, Tanaka M, Yoshida H, Shinkai S, Nozawa Y, Shin DJ, Lee JH, Jang Y, Yamada Y (2011) Association of a polymorphism of BTN2A1 with dyslipidemia in East Asian populations. Experimental and therapeutic medicine 2:745–749

    CAS  PubMed  PubMed Central  Google Scholar 

  • Genomes Project C, Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, Kang HM, Marth GT, McVean GA (2012) An integrated map of genetic variation from 1,092 human genomes. Nature 491:56–65

    Article  Google Scholar 

  • Gudys A, Deorowicz S (2014) QuickProbs—a fast multiple sequence alignment algorithm designed for graphics processors. PLoS One 9:e88901

    Article  PubMed  PubMed Central  Google Scholar 

  • Harly C, Guillaume Y, Nedellec S, Peigné C-M, Mönkkönen H, Mönkkönen J, Li J, Kuball J, Adams EJ, Netzer S, Déchanet-Merville J, Léger A, Herrmann T, Breathnach R, Olive D, Bonneville M, Scotet E (2012) Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human γδ T-cell subset. Blood 120:2269–2279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hiramatsu M, Oguri M, Kato K, Yoshida T, Fujimaki T, Horibe H, Yokoi K, Watanabe S, Satoh K, Aoyagi Y, Tanaka M, Yoshida H, Shinkai S, Nozawa Y, Murohara T, Yamada Y (2011) Association of a polymorphism of BTN2A1 with type 2 diabetes mellitus in Japanese individuals. Diabet Med 28:1381–1387

    Article  CAS  PubMed  Google Scholar 

  • Karunakaran MM, Gobel TW, Starick L, Walter L, Herrmann T (2014) Vgamma9 and Vdelta2 T cell antigen receptor genes and butyrophilin 3 (BTN3) emerged with placental mammals and are concomitantly preserved in selected species like alpaca (Vicugna pacos). Immunogenetics 66:243–254

    Article  CAS  PubMed  Google Scholar 

  • Katoh K, Misawa K, Kuma K, Miyata T (2002) MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform. Nucleic Acids Res 30:3059–3066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kennedy RB, Ovsyannikova IG, Haralambieva IH, Lambert ND, Pankratz VS, Poland GA (2014) Genetic polymorphisms associated with rubella virus-specific cellular immunity following MMR vaccination. Hum Genet

  • Lanier LL (2001) Face off—the interplay between activating and inhibitory immune receptors. Curr Opin Immunol 13:326–331

    Article  CAS  PubMed  Google Scholar 

  • Lappalainen T, Sammeth M, Friedlander MR, t Hoen PA, Monlong J, Rivas MA, Gonzalez-Porta M, Kurbatova N, Griebel T, Ferreira PG, Barann M, Wieland T, Greger L, van Iterson M, Almlof J, Ribeca P, Pulyakhina I, Esser D, Giger T, Tikhonov A, Sultan M, Bertier G, MacArthur DG, Lek M, Lizano E, Buermans HP, Padioleau I, Schwarzmayr T, Karlberg O, Ongen H, Kilpinen H, Beltran S, Gut M, Kahlem K, Amstislavskiy V, Stegle O, Pirinen M, Montgomery SB, Donnelly P, McCarthy MI, Flicek P, Strom TM, Geuvadis C, Lehrach H, Schreiber S, Sudbrak R, Carracedo A, Antonarakis SE, Hasler R, Syvanen AC, van Ommen GJ, Brazma A, Meitinger T, Rosenstiel P, Guigo R, Gut IG, Estivill X, Dermitzakis ET (2013) Transcriptome and genome sequencing uncovers functional variation in humans. Nature 501:506–511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Librado P, Rozas J (2009) DnaSP v5: a software for comprehensive analysis of DNA polymorphism data. Bioinformatics (Oxford, England) 25:1451–1452

    Article  CAS  Google Scholar 

  • Linsley PS, Peach R, Gladstone P, Bajorath J (1994) Extending the B7 (CD80) gene family. Protein science: a publication of the Protein Society 3:1341–1343

    Article  CAS  Google Scholar 

  • Messal N, Mamessier E, Sylvain A, Celis-Gutierrez J, Thibult ML, Chetaille B, Firaguay G, Pastor S, Guillaume Y, Wang Q, Hirsch I, Nunès JA, Olive D (2011) Differential role for CD277 as a co-regulator of the immune signal in T and NK cells. Eur J Immunol 41:3443–3454

    Article  CAS  PubMed  Google Scholar 

  • Naidoo K, Steenkamp ET, Coetzee MP, Wingfield MJ, Wingfield BD (2013) Concerted evolution in the ribosomal RNA cistron. PLoS One 8:e59355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nguyen T, Liu XK, Zhang Y, Dong C (2006) BTNL2, a butyrophilin-like molecule that functions to inhibit T cell activation. Journal of immunology (Baltimore, MD.: 1950) 176:7354–7360

    Article  CAS  Google Scholar 

  • Oguri M, Kato K, Yoshida T, Fujimaki T, Horibe H, Yokoi K, Watanabe S, Satoh K, Aoyagi Y, Tanaka M, Yoshida H, Shinkai S, Nozawa Y, Shin DJ, Lee JH, Jang Y, Yamada Y (2011) Association of a genetic variant of BTN2A1 with metabolic syndrome in East Asian populations. J Med Genet 48:787–792

    Article  CAS  PubMed  Google Scholar 

  • Rhodes DA, Chen HC, Price AJ, Keeble AH, Davey MS, James LC, Eberl M, Trowsdale J (2015) Activation of human gammadelta T cells by cytosolic interactions of BTN3A1 with soluble phosphoantigens and the cytoskeletal adaptor periplakin. J Immunol 194:2390–2398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rhodes DA, Reith W, Trowsdale J (2016) Regulation of immunity by Butyrophilins. Annu Rev Immunol 34:151–172

    Article  PubMed  Google Scholar 

  • Sandstrom A, Peigné C-M, Léger A, Crooks JE, Konczak F, Gesnel M-C, Breathnach R, Bonneville M, Scotet E, Adams EJ (2014) The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human Vγ9Vδ2 T cells. Immunity 40:490–500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simone R, Barbarat B, Rabellino A, Icardi G, Bagnasco M, Pesce G, Olive D, Saverino D (2010) Ligation of the BT3 molecules, members of the B7 family, enhance the proinflammatory responses of human monocytes and monocyte-derived dendritic cells. Mol Immunol 48:109–118

    Article  CAS  PubMed  Google Scholar 

  • Solovyev V (2007) Handbook of statistical genetics. In: Balding D (ed) 3rd edn. Wiley-Interscience

  • Staden R, Beal KF, Bonfield JK (2000) The Staden package, 1998. Methods in molecular biology (Clifton, NJ) 132:115–130

    CAS  Google Scholar 

  • Stamatakis A (2014) RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies. Bioinformatics (Oxford, England) 30:1312–1313

    Article  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  CAS  PubMed  PubMed Central  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  CAS  PubMed  PubMed Central  Google Scholar 

  • Swofford DL (2001) PAUP*: phylogenetic analysis using parsimony (*and other methods), version 4.0. Sinauer, Sunderland, Massachusetts

  • Tamura K, Stecher G, Peterson D, Filipski A, Kumar S (2013) MEGA6: Molecular Evolutionary Genetics Analysis version 6.0. Mol Biol Evol 30:2725–2729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tazi-Ahnini R, Henry J, Offer C, Bouissou-Bouchouata C, Mather IH, Pontarotti P (1997) Cloning, localization, and structure of new members of the butyrophilin gene family in the juxta-telomeric region of the major histocompatibility complex. Immunogenetics 47:55–63

    Article  CAS  PubMed  Google Scholar 

  • Vavassori S, Kumar A, Wan GS, Ramanjaneyulu GS, Cavallari M, El Daker S, Beddoe T, Theodossis A, Williams NK, Gostick E, Price DA, Soudamini DU, Voon KK, Olivo M, Rossjohn J, Mori L, De Libero G (2013) Butyrophilin 3A1 binds phosphorylated antigens and stimulates human γδ T cells. Nat Immunol 14:908–916

    Article  CAS  PubMed  Google Scholar 

  • Viken MK, Blomhoff A, Olsson M, Akselsen HE, Pociot F, Nerup J, Kockum I, Cambon-Thomsen A, Thorsby E, Undlien DE, Lie BA (2009) Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex. Genes Immun 10:323–333

    Article  CAS  PubMed  Google Scholar 

  • Yamada E, McVicar DW (2008) Paired receptor systems of the innate immune system. Current protocols in immunology/edited by John E. Coligan ... [et al.] Chapter 1:Appendix 1X

  • Yamada Y, Nishida T, Ichihara S, Sawabe M, Fuku N, Nishigaki Y, Aoyagi Y, Tanaka M, Fujiwara Y, Yoshida H, Shinkai S, Satoh K, Kato K, Fujimaki T, Yokoi K, Oguri M, Yoshida T, Watanabe S, Nozawa Y, Hasegawa A, Kojima T, Han BG, Ahn Y, Lee M, Shin DJ, Lee JH, Jang Y (2011) Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations. Atherosclerosis 215:145–152

    Article  CAS  PubMed  Google Scholar 

  • Yamashiro H, Yoshizaki S, Tadaki T, Egawa K, Seo N (2010) Stimulation of human butyrophilin 3 molecules results in negative regulation of cellular immunity. J Leukoc Biol 88:757–767

    Article  CAS  PubMed  Google Scholar 

  • Yoshida T, Kato K, Horibe H, Oguri M, Fukuda M, Satoh K, Aoyagi Y, Shinkai S, Nozawa Y, Yamada Y (2011a) Association of a genetic variant of BTN2A1 with chronic kidney disease in Japanese individuals. Nephrology (Carlton, Vic) 16:642–648

    CAS  Google Scholar 

  • Yoshida T, Kato K, Oguri M, Horibe H, Kawamiya T, Yokoi K, Fujimaki T, Watanabe S, Satoh K, Aoyagi Y, Tanaka M, Yoshida H, Shinkai S, Nozawa Y, Yamada Y (2011b) Association of a polymorphism of BTN2A1 with chronic kidney disease in individuals with or without hypertension or diabetes mellitus. Experimental and therapeutic medicine 2:325–331

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshida T, Kato K, Oguri M, Horibe H, Kawamiya T, Yokoi K, Fujimaki T, Watanabe S, Satoh K, Aoyagi Y, Tanaka M, Yoshida H, Shinkai S, Nozawa Y, Yamada Y (2011c) Association of polymorphisms of BTN2A1 and ILF3 with myocardial infarction in Japanese individuals with different lipid profiles. Mol Med Rep 4:511–518

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

DO laboratory is supported by Fondation pour la Recherche Médicale (Equipe FRM DEQ20140329534). DO is a senior scholar of the Institut Universitaire de France.

Author information

Authors and Affiliations

  1. Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068, F-13009, Marseille, France

    Hassnae Afrache & Daniel Olive

  2. CNRS, UMR7258, F-13009, Marseille, France

    Hassnae Afrache & Daniel Olive

  3. Institut Paoli-Calmettes, F-13009, Marseille, France

    Hassnae Afrache & Daniel Olive

  4. Aix-Marseille University, UM 105, F-13284, Marseille, France

    Hassnae Afrache & Daniel Olive

  5. Institut de Mathématiques de Marseille, UMR 7373, Marseille, France

    Pierre Pontarotti

  6. ATIP CNRS, Institut de Mathématiques de Marseille, UMR 7373, Marseille, France

    Laurent Abi-Rached

Authors
  1. Hassnae Afrache
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pierre Pontarotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laurent Abi-Rached
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniel Olive
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel Olive.

Ethics declarations

Conflict of interest

Olive D. is a founder and shareholder of Imcheck Therapeutics (Marseille, France).

Additional information

Laurent Abi-Rached and Daniel Olive are co-senior authors.

Electronic supplementary material

ESM 1

(EPS 7920 kb)

ESM 2

(EPS 2619 kb)

ESM 3

(EPS 7088 kb)

ESM 4

(EPS 107 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Afrache, H., Pontarotti, P., Abi-Rached, L. et al. Evolutionary and polymorphism analyses reveal the central role of BTN3A2 in the concerted evolution of the BTN3 gene family. Immunogenetics 69, 379–390 (2017). https://doi.org/10.1007/s00251-017-0980-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00251-017-0980-z

Keywords

Search

Navigation