Abstract
A functional immune system requires a tight control over major histocompatibility complex (MHC) gene transcription, as the abnormal MHC expression patterns of severe immunodeficiency and autoimmune diseases demonstrate. Although the regulation of MHC expression has been well documented in humans and mice, little is known in other species. In this study, we detail the level of polymorphism in wolf and dog MHC gene promoters. The promoter regions of the DRB, DQA and DQB locus were sequenced in 90 wolves and 90 dogs. The level of polymorphism was high in the DQB promoters, with variation found within functionally relevant regions, including binding sites for transcription factors. Clear associations between DQB promoters and exon 2 alleles were noted in wolves, indicating strong linkage disequilibrium in this region. Low levels of polymorphism were found within the DRB and DQA promoter regions. However, a variable site was identified within the T box, a TNF-α response element, of the DQA promoter. Furthermore, we identified a previously unrecognised 18-base-pair deletion within exon 1 of the DQB locus.
Similar content being viewed by others
References
Andersen LC, Beaty JS, Nettles JW, Seyfried CE, Nepom GT, Nepom BS (1991) Allelic polymorphism in transcriptional regulatory regions of HLA–DQB genes. J Exp Med 173:181–192
Benoist C, Mathis D (1990) Regulation of major histocompatibility complex class-II genes: X, Y and other letters of the alphabet. Annu Rev Immunol 8:681–715
Cowell LG, Kepler TB, Janitz M, Lauster R, Mitchison NA (1998) The distribution of variation in regulatory gene segments, as present in MHC class II promoters. Genome Res 8:124–134
Emery P, Mach B, Reith W (1993) The different level of expression of HLA–DRB1 and –DRB3 genes is controlled by conserved isotypic differences in promoter sequence. Hum Immunol 38:137–147
Glimcher LH, Kara CJ (1992) Sequences and factors: a guide to MHC class-II transcription. Hum Immunol 10:13–49
Guardiola J, Maffei A, Lauster R, Mitchison NA, Accolla RS, Sartoris S (1996) Functional significance of polymorphism among MHC class II gene promoters. Tissue Antigens 48:615–625
Janitz M, Mitchison A, Reiners-Schramm L, Lauster R (1997) Polymorphic MHC class II promoters exhibit distinct expression pattern in various antigen-presenting cell lines. Tissue Antigens 49:99–106
Kirkness EF, Bafna V, Halpern AL, Levy S, Remington K, Rusch DB, Delcher AL, Pop M, Wang W, Fraser CM, Venter JC (2003) The dog genome: survey sequencing and comparative analysis. Science 301:1898–1903
Kruger A, Quack P, Schneider PM, Rittner C, Hohler T (2001) Sequence analysis of the DRB1 promoter reveals limited polymorphism with no influence on gene expression. Genes Immun 2:211–215
Louis P, Vincent R, Cavadore P, Clot J, Eliaou JF (1994) Differential transcriptional activities of HLA–DR genes in the various haplotypes. J Immunol 153:5059–5067
Mach B, Steimle V, Martinez-Soria E, Reith W (1996) Regulation of MHC class II genes: lessons from a disease. Annu Rev Immunol 14:301–331
Meyer D, Thomson G (2001) How selection shapes variation of the human major histocompatibility complex: a review. Ann Hum Genet 65:1–26
Mitchison NA, Roes J (2002) Patterned variation in murine MHC promoters. Proc Natl Acad Sci USA 99:10561–10566
Morzycka-Wroblewska E, Harwood JI, Smith JR, Kagnoff MF (1993) Structure and evolution of the promoter regions of the DQA genes. Immunogenetics 37:364–372
Morzycka-Wroblewska E, Munshi A, Ostermayer M, Harwood JI, Kagnoff MF (1997) Differential expression of HLA–DQA1 alleles associated with promoter polymorphism. Immunogenetics 45:163–170
Orita M, Suzuki Y, Sekiya T, Hayashi K (1989) Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5:874–879
Perfetto C, Zacheis M, McDaid D, Meador III JW, Schwartz BD (1993) Polymorphism in the promoter region of HLA–DRB genes. Hum Immunol 36:27–33
Radosevich M, Ono SJ (2003) Novel mechanisms of class II major histocompatibility complex gene regulation. Immunol Res 27:85–105
Reichstetter S, Krellner PH, Meenzen CM, Kalden JR, Wassmuth R (1994) Comparative analysis of sequence variability in the upstream regulatory region of the HLA–DQB1 gene. Immunogenetics 39:207–212
Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, New York
Seddon JM, Ellegren H (2002) MHC class II genes in European wolves: a comparison with dogs. Immunogenetics 54:490-500
Singal DP, Qiu X (1995) Polymorphism in both X and Y box motifs controls level of expression of HLA–DRB1 genes. Immunogenetics 43:50–56
Ting JP-Y, Trowsdale J (2002) Genetic control of MHC class II expression. Cell 109 (Suppl):S21–S33
van den Elsen PJ, Holling TM, Kuipers HF, van der Stoep N (2004) Transcriptional regulation of antigen presentation. Curr Opin Immunol 16:67–75
Wagner JL (2003) Molecular organization of the canine major histocompatibility complex. J Hered 94:23-26
Wagner JL, Burnett RC, DeRose SA, Storb R (1996a) Molecular analysis and polymorphism of the DLA–DQA gene. Tissue Antigens 48:199–204
Wagner JL, Burnett RC, Storb R (1996b) Molecular analysis of the DLA DR region. Tissue Antigens 48:549–553
Wagner JL, Hayes-Lattin B, Works JD, Storb R (1998) Molecular analysis and polymorphism of the DLA–DQB genes. Tissue Antigens 52:242–250
Woolfrey AE, Nepom GT (1995) Differential transcription elements direct expression of HLA–DQ genes. Clin Immunol Immunopathol 74:119–126
Acknowledgements
We would like to thank Ilpo Kojola, Adriano Casulli, Carles Vilá, Åke Hedhammar and Anna-Karin Sundqvist for providing samples for this study. Financial support was obtained from the Swedish and Norwegian Environmental Protection Agencies (to Hans Ellegren, Uppsala University). The experiments comply with the relevant current laws of Sweden.
Author information
Authors and Affiliations
Corresponding author
Electronic Supplementary Material
Rights and permissions
About this article
Cite this article
Berggren, K.T., Seddon, J.M. MHC promoter polymorphism in grey wolves and domestic dogs. Immunogenetics 57, 267–272 (2005). https://doi.org/10.1007/s00251-005-0776-4
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00251-005-0776-4