Skip to main content
SpringerLink
Log in

Comparative genomic analysis of the proteasome β5t subunit gene: implications for the origin and evolution of thymoproteasomes

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

Abstract

The thymoproteasome is a recently discovered, specialized form of 20S proteasomes expressed exclusively in the thymic cortex. Although the precise molecular mechanism by which the thymoproteasome exerts its function remains to be elucidated, accumulating evidence indicates that it plays a crucial role in positive selection of T cells. In the present study, we analyzed the evolution of the β5t subunit, a β-type catalytic subunit uniquely present in thymoproteasomes. The gene coding for the β5t subunit, designated PSMB11, was identified in the cartilaginous fish, the most divergent group of jawed vertebrates compared to the other jawed vertebrates, but not in jawless vertebrates or invertebrates. Interestingly, teleost fish have two copies of apparently functional PSMB11 genes, designated PSMB11a and PSMB11b, that encode β5t subunits with distinct amino acids in the S1 pocket. BLAST searches of genome databases suggest that birds such as chickens, turkey, and zebra finch lost the PSMB11 gene, and have neither thymoproteasomes nor immunoproteasomes. In mammals, reptiles, amphibians, and teleost fishes, the PSMB11 gene (the PSMB11a gene in teleost fish) is located next to the PSMB5 gene coding for the β5 subunit of the standard 20S proteasome, indicating that the PSMB11 gene arose by tandem duplication from the evolutionarily more ancient PSMB5 gene. The general absence of introns in PSMB11 and an unusual exon–intron structure of jawed vertebrate PSMB5 suggest that PSMB5 lost introns and duplicated in tandem in a common ancestor of jawed vertebrates, with PSMB5 subsequently gaining two introns and PSMB11 remaining intronless.

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

References

  • Abdulla S, Beck S, Belich M, Jackson A, Nakamura T, Trowsdale J (1996) Divergent intron arrangement in the MB1/LMP7 proteasome gene pair. Immunogenetics 44:254–258

    Article  PubMed  CAS  Google Scholar 

  • Arnold K, Bordoli L, Kopp J, Schwede T (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22:195–201

    Article  PubMed  CAS  Google Scholar 

  • Bajoghli B, Guo P, Aghaallaei N, Hirano M, Strohmeier C, McCurley N, Bockman DE, Schorpp M, Cooper MD, Boehm T (2011) A thymus candidate in lampreys. Nature 470:90–94

    Article  PubMed  CAS  Google Scholar 

  • Balakrishnan CN, Ekblom R, Volker M, Westerdahl H, Godinez R, Kotkiewicz H, Burt DW, Graves T, Griffin DK, Warren WC, Edwards SV (2010) Gene duplication and fragmentation in the zebra finch major histocompatibility complex. BMC Biol 8:29

    Article  PubMed  Google Scholar 

  • Belich MP, Trowsdale J (1995) Proteasome and class I antigen processing and presentation. Mol Biol Rep 21:53–56

    Article  PubMed  CAS  Google Scholar 

  • Chaves LD, Krueth SB, Reed KM (2009) Defining the turkey MHC: sequence and genes of the B locus. J Immunol 183:6530–6537

    Article  PubMed  CAS  Google Scholar 

  • Clark MS, Pontarotti P, Gilles A, Kelly A, Elgar G (2000) Identification and characterization of a β proteasome subunit cluster in the Japanese pufferfish (Fugu rubripes). J Immunol 165:4446–4452

    PubMed  CAS  Google Scholar 

  • Dalloul RA, Long JA, Zimin AV, Aslam L, Beal K, Le Blomberg A, Bouffard P, Burt DW, Crasta O, Crooijmans RP, Cooper K, Coulombe RA, De S, Delany ME, Dodgson JB, Dong JJ, Evans C, Frederickson KM, Flicek P, Florea L, Folkerts O, Groenen MA, Harkins TT, Herrero J, Hoffmann S, Megens HJ, Jiang A, de Jong P, Kaiser P, Kim H, Kim KW, Kim S, Langenberger D, Lee MK, Lee T, Mane S, Marcais G, Marz M, McElroy AP, Modise T, Nefedov M, Notredame C, Paton IR, Payne WS, Pertea G, Prickett D, Puiu D, Qioa D, Raineri E, Ruffier M, Salzberg SL, Schatz MC, Scheuring C, Schmidt CJ, Schroeder S, Searle SM, Smith EJ, Smith J, Sonstegard TS, Stadler PF, Tafer H, Tu ZJ, Van Tassell CP, Vilella AJ, Williams KP, Yorke JA, Zhang L, Zhang HB, Zhang X, Zhang Y, Reed KM (2010) Multi-platform next-generation sequencing of the domestic turkey (Meleagris gallopavo): genome assembly and analysis. PLoS Biol 8:e1000475

    Article  Google Scholar 

  • Danchin E, Vitiello V, Vienne A, Richard O, Gouret P, McDermott MF, Pontarotti P (2004) The major histocompatibility complex origin. Immunol Rev 198:216–232

    Article  PubMed  CAS  Google Scholar 

  • Derr LK (1998) The involvement of cellular recombination and repair genes in RNA-mediated recombination in Saccharomyces cerevisiae. Genetics 148:937–945

    PubMed  CAS  Google Scholar 

  • Fink GR (1987) Pseudogenes in yeast? Cell 49:5–6

    Article  PubMed  CAS  Google Scholar 

  • Flajnik MF, Kasahara M (2001) Comparative genomics of the MHC: glimpses into the evolution of the adaptive immune system. Immunity 15:351–362

    Article  PubMed  CAS  Google Scholar 

  • Flajnik MF, Kasahara M (2010) Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nat Rev Genet 11:47–59

    Article  PubMed  CAS  Google Scholar 

  • Goldberg AL (1995) Functions of the proteasome: the lysis at the end of the tunnel. Science 268:522–523

    Article  PubMed  CAS  Google Scholar 

  • Griffin TA, Nandi D, Cruz M, Fehling HJ, Kaer LV, Monaco JJ, Colbert RA (1998) Immunoproteasome assembly: cooperative incorporation of interferon γ (IFN-γ)-inducible subunits. J Exp Med 187:97–104

    Article  PubMed  CAS  Google Scholar 

  • Groettrup M, Kirk CJ, Basler M (2010) Proteasomes in immune cells: more than peptide producers? Nat Rev Immunol 10:73–78

    Article  PubMed  CAS  Google Scholar 

  • Groll M, Ditzel L, Loewe J, Stock D, Bochtler M, Bartunik HD, Huber R (1997) Structure of 20S proteasome from yeast at 2.4 Å resolution. Nature 386:463–471

    Article  PubMed  CAS  Google Scholar 

  • Hansen JD, Strassburger P, Thorgaard GH, Young WP, Du Pasquier L (1999) Expression, linkage, and polymorphism of MHC-related genes in rainbow trout, Oncorhynchus mykiss. J Immunol 163:774–786

    PubMed  CAS  Google Scholar 

  • Hayashi M, Ishibashi T, Tanaka K, Kasahara M (1997) The mouse genes encoding the third pair of β-type proteasome subunits regulated reciprocally by IFN-γ: structural comparison, chromosomal localization, and analysis of the promoter. J Immunol 159:2760–2770

    PubMed  CAS  Google Scholar 

  • Hillier LW, Miller W, Birney E, Warren W, Hardison RC, Ponting CP, Bork P, Burt DW, Groenen MA, Delany ME, Dodgson JB, Chinwalla AT, Cliften PF, Clifton SW, Delehaunty KD, Fronick C, Fulton RS, Graves TA, Kremitzki C, Layman D, Magrini V, McPherson JD, Miner TL, Minx P, Nash WE, Nhan MN, Nelson JO, Oddy LG, Pohl CS, Randall-Maher J, Smith SM, Wallis JW, Yang SP, Romanov MN, Rondelli CM, Paton B, Smith J, Morrice D, Daniels L, Tempest HG, Robertson L, Masabanda JS, Griffin DK, Vignal A, Fillon V, Jacobbson L, Kerje S, Andersson L, Crooijmans RP, Aerts J, van der Poel JJ, Ellegren H, Caldwell RB, Hubbard SJ, Grafham DV, Kierzek AM, McLaren SR, Overton IM, Arakawa H, Beattie KJ, Bezzubov Y, Boardman PE, Bonfield JK, Croning MD, Davies RM, Francis MD, Humphray SJ, Scott CE, Taylor RG, Tickle C, Brown WR, Rogers J, Buerstedde JM, Wilson SA, Stubbs L, Ovcharenko I, Gordon L, Lucas S, Miller MM, Inoko H, Shiina T, Kaufman J, Salomonsen J, Skjoedt K, Wong GK, Wang J, Liu B, Yu J, Yang H, Nefedov M, Koriabine M, Dejong PJ, Goodstadt L, Webber C, Dickens NJ, Letunic I, Suyama M, Torrents D, von Mering C, Zdobnov EM, Makova K, Nekrutenko A, Elnitski L, Eswara P, King DC, Yang S, Tyekucheva S, Radakrishnan A, Harris RS, Chiaromonte F, Taylor J, He J, Rijnkels M, Griffiths-Jones S, Ureta-Vidal A, Hoffman MM, Severin J, Searle SM, Law AS, Speed D, Waddington D, Cheng Z, Tuzun E, Eichler E, Bao Z, Flicek P, Shteynberg DD, Brent MR, Bye JM, Huckle EJ, Chatterji S, Dewey C, Pachter L, Kouranov A, Mourelatos Z, Hatzigeorgiou AG, Paterson AH, Ivarie R, Brandstrom M, Axelsson E, Backstrom N, Berlin S, Webster MT, Pourquie O, Reymond A, Ucla C, Antonarakis SE, Long M, Emerson JJ, Betran E, Dupanloup I, Kaessmann H, Hinrichs AS, Bejerano G, Furey TS, Harte RA, Raney B, Siepel A, Kent WJ, Haussler D, Eyras E, Castelo R, Abril JF, Castellano S, Camara F, Parra G, Guigo R, Bourque G, Tesler G, Pevzner PA, Smit A, Fulton LA, Mardis ER, Wilson RK (2004) Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. Nature 432:695–716

    Article  CAS  Google Scholar 

  • Hogquist KA, Xing Y (2010) Why CD8+ T cells need diversity when growing up. Immunity 32:5–6

    Article  PubMed  CAS  Google Scholar 

  • Kaessmann H, Vinckenbosch N, Long M (2009) RNA-based gene duplication: mechanistic and evolutionary insights. Nat Rev Genet 10:19–31

    Article  PubMed  CAS  Google Scholar 

  • Kandil E, Namikawa C, Nonaka M, Greenberg AS, Flajnik MF, Ishibashi T, Kasahara M (1996) Isolation of low molecular mass polypeptide complementary DNA clones from primitive vertebrates: implications for the origin of MHC class I-restricted antigen presentation. J Immunol 156:4245–4253

    PubMed  CAS  Google Scholar 

  • Kasahara M (2007) The 2R hypothesis: an update. Curr Opin Immunol 19:547–552

    Article  PubMed  CAS  Google Scholar 

  • Kasahara M (2010) Genome duplication and T cell immunity. Prog Mol Biol Transl Sci 92:7–36

    Article  PubMed  CAS  Google Scholar 

  • Kasahara M, Hayashi M, Tanaka K, Inoko H, Sugaya K, Ikemura T, Ishibashi T (1996) Chromosomal localization of the proteasome Z subunit gene reveals an ancient chromosomal duplication involving the major histocompatibility complex. Proc Natl Acad Sci USA 93:9096–9101

    Article  PubMed  CAS  Google Scholar 

  • Kasahara M, Nakaya J, Satta Y, Takahata N (1997) Chromosomal duplication and the emergence of the adaptive immune system. Trends Genet 13:90–92

    Article  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Kaufman J, Milne S, Gobel TW, Walker BA, Jacob JP, Auffray C, Zoorob R, Beck S (1999) The chicken B locus is a minimal essential major histocompatibility complex. Nature 401:923–925

    Article  PubMed  CAS  Google Scholar 

  • Klein L, Hinterberger M, Wirnsberger G, Kyewski B (2009) Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol 9:833–844

    Article  PubMed  CAS  Google Scholar 

  • Koch M, Camp S, Collen T, Avila D, Salomonsen J, Wallny HJ, van Hateren A, Hunt L, Jacob JP, Johnston F, Marston DA, Shaw I, Dunbar PR, Cerundolo V, Jones EY, Kaufman J (2007) Structures of an MHC class I molecule from B21 chickens illustrate promiscuous peptide binding. Immunity 27:885–899

    Article  PubMed  CAS  Google Scholar 

  • Kohda K, Matsuda Y, Ishibashi T, Tanaka K, Kasahara M (1997) Structural analysis and chromosomal localization of the Psmb5 gene coding for the constitutively expressed β-type proteasome subunit. Immunogenetics 47:77–87

    Article  PubMed  CAS  Google Scholar 

  • Kumar S, Nei M, Dudley J, Tamura K (2008) MEGA: a biologist-centric software for evolutionary analysis of DNA and protein sequences. Brief Bioinform 9:299–306

    Article  PubMed  CAS  Google Scholar 

  • Meyer A, Van de Peer Y (2005) From 2R to 3R: evidence for a fish-specific genome duplication (FSGD). Bioessays 27:937–945

    Article  PubMed  CAS  Google Scholar 

  • Michalova V, Murray BW, Sultmann H, Klein J (2000) A contig map of the Mhc class I genomic region in the zebrafish reveals ancient synteny. J Immunol 164:5296–5305

    PubMed  CAS  Google Scholar 

  • Mourier T, Jeffares DC (2003) Eukaryotic intron loss. Science 300:1393

    Article  PubMed  CAS  Google Scholar 

  • Murata S, Sasaki K, Kishimoto T, Niwa S, Hayashi H, Takahama Y, Tanaka K (2007) Regulation of CD8+ T cell development by thymus-specific proteasomes. Science 316:1349–1353

    Article  PubMed  CAS  Google Scholar 

  • Murata S, Takahama Y, Tanaka K (2008) Thymoproteasome: probable role in generating positively selecting peptides. Curr Opin Immunol 20:192–196

    Article  PubMed  CAS  Google Scholar 

  • Murray BW, Sultmann H, Klein J (1999) Analysis of a 26-kb region linked to the Mhc in zebrafish: genomic organization of the proteasome component β/tansporter associated with antigen processing-2 gene cluster and identification of five new proteasome β subunit genes. J Immunol 163:2657–2666

    PubMed  CAS  Google Scholar 

  • Nil A, Firat E, Sobek V, Eichmann K, Niedermann G (2004) Expression of housekeeping and immunoproteasome subunit genes is differentially regulated in positively and negatively selecting thymic stroma subsets. Eur J Immunol 34:2681–2689

    Article  PubMed  CAS  Google Scholar 

  • Nitta T, Murata S, Sasaki K, Fujii H, Ripen AM, Ishimaru N, Koyasu S, Tanaka K, Takahama Y (2010) Thymoproteasome shapes immunocompetent repertoire of CD8+ T cells. Immunity 32:29–40

    Article  PubMed  CAS  Google Scholar 

  • Ohno S (1970) Evolution by gene duplication. Springer, New York

    Google Scholar 

  • Pamer E, Cresswell P (1998) Mechanisms of MHC class I-restricted antigen processing. Annu Rev Immunol 16:323–358

    Article  PubMed  CAS  Google Scholar 

  • Postlethwait JH (2007) The zebrafish genome in context: ohnologs gone missing. J Exp Zool B Mol Dev Evol 308:563–577

    Article  PubMed  Google Scholar 

  • Putnam NH, Butts T, Ferrier DE, Furlong RF, Hellsten U, Kawashima T, Robinson-Rechavi M, Shoguchi E, Terry A, Yu JK, Benito-Gutierrez EL, Dubchak I, Garcia-Fernandez J, Gibson-Brown JJ, Grigoriev IV, Horton AC, de Jong PJ, Jurka J, Kapitonov VV, Kohara Y, Kuroki Y, Lindquist E, Lucas S, Osoegawa K, Pennacchio LA, Salamov AA, Satou Y, Sauka-Spengler T, Schmutz J, Shin IT, Toyoda A, Bronner-Fraser M, Fujiyama A, Holland LZ, Holland PW, Satoh N, Rokhsar DS (2008) The amphioxus genome and the evolution of the chordate karyotype. Nature 453:1064–1071

    Article  PubMed  CAS  Google Scholar 

  • Seifert U, Bialy LP, Ebstein F, Bech-Otschir D, Voigt A, Schroter F, Prozorovski T, Lange N, Steffen J, Rieger M, Kuckelkorn U, Aktas O, Kloetzel PM, Kruger E (2010) Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress. Cell 142:613–624

    Article  PubMed  CAS  Google Scholar 

  • Shiina T, Shimizu S, Hosomichi K, Kohara S, Watanabe S, Hanzawa K, Beck S, Kulski JK, Inoko H (2004) Comparative genomic analysis of two avian (quail and chicken) MHC regions. J Immunol 172:6751–6763

    PubMed  CAS  Google Scholar 

  • Takahama Y, Nitta T, Ripen AM, Nitta S, Murata S, Tanaka K (2010) Role of thymic cortex-specific self-peptides in positive selection of T cells. Semin Immunol 22:287–293

    Article  PubMed  CAS  Google Scholar 

  • Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S (2011) MEGA5: Molecular Evolutionary Genetics Analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol. doi:10.1093/molbev/msr1121

  • Tanaka K (2009) The proteasome: overview of structure and functions. Proc Jpn Acad Ser B Phys Biol Sci 85:12–36

    Article  PubMed  CAS  Google Scholar 

  • Tanaka K, Kasahara M (1998) The MHC class I ligand-generating system: roles of immunoproteasomes and the interferon-γ-inducible proteasome activator PA28. Immunol Rev 163:161–176

    Article  PubMed  CAS  Google Scholar 

  • Tomaru U, Ishizu A, Murata S, Miyatake Y, Suzuki S, Takahashi S, Kazamaki T, Ohara J, Baba T, Iwasaki S, Fugo K, Otsuka N, Tanaka K, Kasahara M (2009) Exclusive expression of proteasome subunit β5t in the human thymic cortex. Blood 113:5186–5191

    Article  PubMed  CAS  Google Scholar 

  • Unno M, Mizushima T, Morimoto Y, Tomisugi Y, Tanaka K, Yasuoka N, Tsukihara T (2002) The structure of the mammalian 20S proteasome at 2.75 Å resolution. Structure 10:609–618

    Article  PubMed  CAS  Google Scholar 

  • Van de Peer Y, Maere S, Meyer A (2009) The evolutionary significance of ancient genome duplications. Nat Rev Genet 10:725–732

    Article  PubMed  Google Scholar 

  • Venkatesh B, Kirkness EF, Loh YH, Halpern AL, Lee AP, Johnson J, Dandona N, Viswanathan LD, Tay A, Venter JC, Strausberg RL, Brenner S (2007) Survey sequencing and comparative analysis of the elephant shark (Callorhinchus milii) genome. PLoS Biol 5:e101

    Article  PubMed  Google Scholar 

  • Wallny HJ, Avila D, Hunt LG, Powell TJ, Riegert P, Salomonsen J, Skjodt K, Vainio O, Vilbois F, Wiles MV, Kaufman J (2006) Peptide motifs of the single dominantly expressed class I molecule explain the striking MHC-determined response to Rous sarcoma virus in chickens. Proc Natl Acad Sci USA 103:1434–1439

    Article  PubMed  CAS  Google Scholar 

  • Warren WC, Clayton DF, Ellegren H, Arnold AP, Hillier LW, Kunstner A, Searle S, White S, Vilella AJ, Fairley S, Heger A, Kong L, Ponting CP, Jarvis ED, Mello CV, Minx P, Lovell P, Velho TA, Ferris M, Balakrishnan CN, Sinha S, Blatti C, London SE, Li Y, Lin YC, George J, Sweedler J, Southey B, Gunaratne P, Watson M, Nam K, Backstrom N, Smeds L, Nabholz B, Itoh Y, Whitney O, Pfenning AR, Howard J, Volker M, Skinner BM, Griffin DK, Ye L, McLaren WM, Flicek P, Quesada V, Velasco G, Lopez-Otin C, Puente XS, Olender T, Lancet D, Smit AF, Hubley R, Konkel MK, Walker JA, Batzer MA, Gu W, Pollock DD, Chen L, Cheng Z, Eichler EE, Stapley J, Slate J, Ekblom R, Birkhead T, Burke T, Burt D, Scharff C, Adam I, Richard H, Sultan M, Soldatov A, Lehrach H, Edwards SV, Yang SP, Li X, Graves T, Fulton L, Nelson J, Chinwalla A, Hou S, Mardis ER, Wilson RK (2010) The genome of a songbird. Nature 464:757–762

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from The Ministry of Education, Culture, Sports, Science and Technology of Japan, and National Institutes of Health grant AI027877. Yoichi Sutoh and Mizuho Kondo are supported by the Research Fellowship of the Japan Society for the Promotion of Science.

Author information

Authors and Affiliations

  1. Department of Pathology, Hokkaido University Graduate School of Medicine, North-15 West-7, Sapporo, 060-8638, Japan

    Yoichi Sutoh, Mizuho Kondo, Utano Tomaru & Masanori Kasahara

  2. Department of Microbiology and Immunology, University of Maryland, 685 West Baltimore Street, Baltimore, MD, 21201, USA

    Yuko Ohta & Martin F. Flajnik

  3. Department of Evolutionary Studies of Biosystems, The Graduate University for Advanced Studies, Hayama, 240-0193, Japan

    Tatsuya Ota

Authors
  1. Yoichi Sutoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mizuho Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuko Ohta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tatsuya Ota
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Utano Tomaru
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Martin F. Flajnik
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Masanori Kasahara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masanori Kasahara.

Additional information

Sequence data reported in this paper have been submitted to the DDBJ/EMBL/NCBI databases under accession numbers AB624351 and AB624352.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Fig. 1S

Amino acid sequence alignment of β5i, β5, and β5t subunits from various species. H1–H5 and β1–β12 stand for helices and β-strands, respectively. The locations of secondary structures are based on the information deposited in the RCSB Protein Data Bank. This alignment was used for the construction of the tree shown in Fig. 1. (PDF 2606 kb)

Fig. 2S

Anolis Ensembl scaffold GL344036.1 encodes MHC class I, TAP1, TAP2, and PSMB8. The MHC class I gene shown here appears to be a classical class I gene as its predicted α1 and α2 domains have eight conserved residues that are involved in the anchoring of peptide termini. The draft genome sequence contains gaps upsteam of the PSMB8 gene (indicated by a broken line) and lacks the presumed exon 1 sequence of PSMB8. (PDF 186 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sutoh, Y., Kondo, M., Ohta, Y. et al. Comparative genomic analysis of the proteasome β5t subunit gene: implications for the origin and evolution of thymoproteasomes. Immunogenetics 64, 49–58 (2012). https://doi.org/10.1007/s00251-011-0558-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00251-011-0558-0

Keywords

Search

Navigation