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The paradox of MHC-DRB exon/intron evolution: α-helix and β-sheet encoding regions diverge while hypervariable intronic simple repeats coevolve with β-sheet codons

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Abstract

Twenty-one different caprine and 13 ovine MHC-DRB exon 2 sequences were determined including part of the adjacent introns containing simple repetitive (gt)n(ga)m elements. The positions for highly polymorphic DRB amino acids vary slightly among ungulates and other mammals. From man and mouse to ungulates the basic (gt)n(ga)m structure is fixed in evolution for 7 × 107 years whereas ample variations exist in the tandem (gt)n and (ga)m dinucleotides and especially their “degenerated” derivatives. Phylogenetic trees for the α-helices and β-pleated sheets of the ungulate DRB sequences suggest different evolutionary histories. In hoofed animals as well as in humans DRB β-sheet encoding sequences and adjacent intronic repeats can be assembled into virtually identical groups suggesting coevolution of noncoding as well as coding DNA. In contrast a-helices and C-terminal parts of the first DRB domain evolve distinctly. In the absence of a defined mechanism causing specific, site-directed mutations, double-recombination or gene-conversion-like events would readily explain this fact. The role of the intronic simple (gt)n(ga)m repeat is discussed with respect to these genetic exchange mechanisms during evolution.

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References

  • Acha-Orbea H, Scarpellino L (1991) Nonobese diabetic and nonobese nondiabetic mice have unique MHC class II haplotypes. Immunogenetics 34: 57–59

    Google Scholar 

  • Ammer H, Schwaiger F-W, Kammerbauer C, Gomolka M, Arriens A, Lazary S, Epplen JT (1992) Exonic polymorphism versus intronic simple repeat hypervariability in MHC-DRB-genes. Immunogenetics 32: 330–337

    Google Scholar 

  • Andersson L, Sigurdardottir S, Borsch C, Gustafsson K (1991) Evolution of MHC polymorphism: extensive sharing of polymorphic sequence motifs between human and bovine DRB alleles. Immunogenetics 33: 188–193

    Google Scholar 

  • Ayane M, Mengle-Gaw L, McDevitt HO, Benoist C, Mathis D (1986) E-alpha-u and E-beta-u chain association: Where lies the anomaly? J Immunol 137: 948–951

    Google Scholar 

  • Bandelt H-J, Dress AWM (1989) Weak hierarchies associated with similarity measures-an additive clustering technique. Bull Math Biol 51: 133–166

    Google Scholar 

  • Begovich AB, Vu TH, Jones PP (1990) Characterization of the molecular defects in the mouse E-beta-f and E-beta-q genes: Implications for the origin of MHC polymorphism. J Immunol 144: 1957–1964

    Google Scholar 

  • Belich MP, Madrigal JA, Hildebrand WH, Zemmour J, Williams RC, Luz R, Peztl-Erler ML, Parham P (1992) Unusual HLA-B alleles in two tribes of Brazilian Indians. Nature 357: 326–329

    Google Scholar 

  • Bodmer JG, Marsh SGE, Albert E (1990) Nomenclature for factors of the HLA system. Immunol Today 11: 3–10

    Google Scholar 

  • Braunstein NS, Germain RN (1986) The mouse E-beta-2 gene: a class II MHC beta gene with limited intraspecies polymorphism and an unusual pattern of transcription. EMBO J 5: 2469–2476

    Google Scholar 

  • Brown JH, Jardetzky T, Saper MA, Samraoui B, Bjorkman PJ, Wiley DC (1988) A hypothetical model of the foreign antigen binding site of class II histocompatibility molecules. Nature 332: 845–850

    Google Scholar 

  • Cam P, Jouvin-Marche E, LeGuern C, Marche PN (1990) Structure of class II genes in wild mouse Mus saxicola: functional and evolutionary implications. Eur J Immunol 20: 1337–1343

    Google Scholar 

  • Chao NJ, Timmerman L, McDevitt HO, Jacob CO (1989) Molecular characterization of MHC class II antigens (beta-1 domains) in the bb diabetes-prone and -resistant rat. Immunogenetics 29: 231–234

    Google Scholar 

  • Epplen JT, Ammer H, Epplen C, Kammerbauer C, Mitreiter R, Roewer L, Schwaiger W, Steimle V, Zischler H, Albert E, Andreas A, Beyermann B, Meyer W, Buitkamp J, Nanda I, Schmid M, Nürnberg P, Pena SDJ, Pöche H, Sprecher W, Schartl M, Weising K, Yassouridis A (1991) DNA fingerprinting: Approaches and applications. Birkhäuser-Verlag, Basel

    Google Scholar 

  • Erlich HA, Gyllenstein UB (1991) Shared epitopes among HLA class II alleles: gene conversion, common ancestry and balancing selection. Immunol Today 12: 411–414

    Google Scholar 

  • Falk K, Rötzschke O, Stevanovic S, Jung G, Rammensee H (1991) Allele specific motifs revealed by sequencing of selfpeptides eluted from MHC molecules. Nature 351: 290–296

    Article  CAS  PubMed  Google Scholar 

  • Felsenstein J (1988) Phylogeny from molecular sequences: inference and reliability. Ann Rev Genet 22: 521–565

    Google Scholar 

  • Figueroa F, Gutknecht J, Tichy H, Klein J (1990) Class II Mhc genes in rodent evolution. Immunol Rev 113: 207–226

    Google Scholar 

  • Fitch DHA, Mainone C, Goodman M, Slightom JL (1990) Molecular history of gene conversion in the primate fetal τ-globin genes. J Biol Chem 265: 781–793

    Google Scholar 

  • Groenen MAM, van der Poel JJ, Dijkhof RJM, Giphart RJ (1990) The nucleotide sequence of bovine MHC class 11 DQB and DRB genes. Immunogenetics 31: 37–44

    Google Scholar 

  • Gorski J, Mach B (1986) Polymorphism of human la antigens: gene conversion between two DR β loci results in a new HLA-D/DR specifity. Nature 322: 67–70

    Google Scholar 

  • Gorski J, Hayes CE (1990) The I-J-disparate mouse strains B10.A(3R) and B10.A(5R) have identical I-E beta sequences, Immunogenetics 39: 127–129

    Google Scholar 

  • Gyllenstein U, Sundvall M, Ezcurra I, Erlich HA (1991a) Genetic diversity at class II DRB Loci of the primate MHC. J Immunol 146: 4368–4376

    Google Scholar 

  • Gyllenstein U, Sundvall M, Erlich HA (1991b). Allelic diversity is generated by intraexon sequence exchange at the DRB1 locus of primates. Proc Natl Acad Sci USA 88: 3686–3690

    Google Scholar 

  • Hughes AL, Nei M (1989) Nucleotide substitution at major histocompatibility complex class II loci: Evidence for overdominant selection. Proc Natl Acad Sci USA 86: 958–962

    CAS  PubMed  Google Scholar 

  • Kasahara M, Klein D, Weimin F, Gutknecht J (1990) Evolution of the class II major histocompatibility complex alleles in higher primates. Immunol Rev 113: 65–82.

    Google Scholar 

  • Kappes D, Strominger JL (1988) Human class II major histocompatibility complex genes and proteins. Annu Rev Biochem 57: 991–1028

    Google Scholar 

  • Klein J (1980) Generation of diversity at MHC loci: implication for T cell receptor repertoires. In: Fougereau M, Dausset D (eds) Immunology 80. Academic Press, London, pp 239–253

    Google Scholar 

  • Klein J (1987) Origin of the major histocompatibility complex polymorphism: the transspecies hypothesis. Hum Immunol 19: 155–162

    Google Scholar 

  • Kuhner MK, Peterson MJ (1992) Genetic exchange in the evolution of the human MHC class II loci. Tissue Antigens 39: 209–215

    Google Scholar 

  • Legel S (1989) Nutztiere der Tropen and Subtropen (Legel S, (ed) Hirzel-Verlag, Leipzig

  • Madden DR, Gorga JC, Strominger JL, Wiley DC (1991) The structure of HLA-B27 reveals nonamer self-peptides bound in an extended conformation. Nature 353: 321–325

    Google Scholar 

  • Marsh SGE, Bodmer J (1993) HLA class II nucleotide sequences, 1992. Immunogenetics 37: 79–94

    Google Scholar 

  • Mäueler W, Muller M, Köhne AC, Epplen JT (1992) A gel retardation assay system for studying protein binding to simple repetitive DNA sequences. Electrophoresis 13: 7–10

    Google Scholar 

  • Mengle-Gaw L, Conner S, McDevitt HO, Fathman CG (1984) Gene conversion between murine class II major histocompatibility complex loci. J Exp Med 160: 1184–1194

    Google Scholar 

  • Mengle-Gaw L, McDevitt HO (1985) Predicted protein sequence of the murine I-E-S-beta polypeptide chain from cDNA and genomic clones. Proc Natl Acad Sci USA 82: 2910–2914

    Google Scholar 

  • Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16: 1215

    CAS  PubMed  Google Scholar 

  • Nei M, Gobori T (1986) Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol 3: 418–426

    CAS  PubMed  Google Scholar 

  • Ogawa S, Nishimura H, Awaji M, Nozawa S, Hirose S, Shirai T (1990) Nucleotide sequence analysis of MHC Class II genes in autoimmune disease-prone (NZB X NZW)Fl mice. Immunogenetics 32: 63–67

    Google Scholar 

  • Potts WK, Wakeland EK (1990) Evolution of diversity at the major histocompatibility complex. Tree 5(6): 181–186

    Google Scholar 

  • Rie\ O, Kammerbauer C, Roewer L, Steimle V, Andreas A, Albert E, Nagai T, Epplen JT (1990) Hypervariability of intronic simple (gt)n(ga)m repeats in HLA-DRB genes. Immunogenetics 32: 110–116

    Google Scholar 

  • Saito H, Maki RA, Clayton LK, Tonegawa S (1983) Complete primary structures of the e-beta chain and gene of the mouse major histocompatibility complex. Proc Natl Acad Sci USA 80: 5520–5524

    Google Scholar 

  • Saitou N, Nei M (1987) The neighbor joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol 4(4): 406–425

    CAS  PubMed  Google Scholar 

  • Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning. 2nd ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY

    Google Scholar 

  • Schwaiger FW, Buitkamp J, Weyers E, Epplen JT (1993) Typing of MHC-DRB genes with the help of intronic simple repeated DNA sequences. Mol Ecol 2: 55–59

    Google Scholar 

  • Scott PC, Maddox JF, Gogolin-Ewens KJ, Brandon MR (1991) The nucleotide sequence and evolution of ovine MHC class II B Genes: DQB and DRB. Immunogenetics 34: 80–87

    Google Scholar 

  • Sigurdardottir S, Borsch C, Gustafsson K, Andersson L (1992) Exon encoding the antigen-binding site of MHC class II betachains is divided into two subregions with different evolutionary histories. J Immunol 148: 968–973

    Google Scholar 

  • Sneath PHA, Sokal RR (1973) Numerical taxonomy. The principles and practice of numerical classification. Freeman and Co, San Francisco

    Google Scholar 

  • Thenius E (1979) Die Evolution der Säugetiere. Gustav Fischer Verlag, Stuttgart, New York

    Google Scholar 

  • Vu TH, Tacchini-Cottier FM, Day CE, Begovich AB, Jones PP (1988) Molecular basis for the defective expression of the mouse E-w17-Beta gene. J Immunol 141: 3654–3661

    Google Scholar 

  • Wada K, Wada Y, Doi H, Ishibashi F, Gojobori T, Ikemura T (1991) Codon usage tabulated from the GenBank genetic sequence data. Nucleic Acid Res 19 Suppl: 1981–1985

    Google Scholar 

  • Wakeland EK, Boehme S, She JX (1990) The generation and maintenance of MHC class II gene polymorphism in rodents. Immunol Rev 113: 39–46

    Google Scholar 

  • Watkins DI, McAdam SN, Liu X, Strang CR, Milford EL, Levine CG, Garber TL, Dogon AL, Lord CI, Ghim SH, Troup GM, Hughes AL, Letvin NL (1992) New recombinant HLA-B alleles in a tribe of South American Amerindians indicate rapid evolution of MHC class I loci. Nature 357: 329–333

    Google Scholar 

  • Zharkikh AA, Rzhetsky A, Morosov PS, Sitnikova TL, Krushkal JS (1991) VOSTORG: a package of microcomputer programs for sequence analysis and construction of phylogenetic trees. Gene 101: 251–254

    Google Scholar 

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Authors and Affiliations

  1. Department of Molecular Human Genetics, Ruhr-Universität Bochum, Postfach 10 21 48, W 4630 Bochum 1, Germany

    Franz-Werner Schwaiger, Eva Weyers, Cornelia Epplen, Jörg Brün & Jörg T. Epplen

  2. Department of Animal Genetics, Bremgarten Str. 109a, University of Berne, 3012, Berne, Switzerland

    Gabi Ruff

  3. Department of Biochemistry, University of Otago, P.O. Box 56, Dunedin, New Zealand

    Allan Crawford

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  1. Franz-Werner Schwaiger
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  2. Eva Weyers
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  3. Cornelia Epplen
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  4. Jörg Brün
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  5. Gabi Ruff
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  6. Allan Crawford
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  7. Jörg T. Epplen
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Schwaiger, FW., Weyers, E., Epplen, C. et al. The paradox of MHC-DRB exon/intron evolution: α-helix and β-sheet encoding regions diverge while hypervariable intronic simple repeats coevolve with β-sheet codons. J Mol Evol 37, 260–272 (1993). https://doi.org/10.1007/BF00175503

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  • DOI: https://doi.org/10.1007/BF00175503

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