Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1984 Apr;3(4):887–894. doi: 10.1002/j.1460-2075.1984.tb01901.x

Complete nucleotide sequence of a functional class I HLA gene, HLA-A3: implications for the evolution of HLA genes.

T Strachan, R Sodoyer, M Damotte, B R Jordan
PMCID: PMC557443  PMID: 6609814

Abstract

The complete nucleotide sequence of an active class I HLA gene, HLA-A3, has been determined. This sequence, together with that obtained for the HLA-CW3 gene, represents the first complete nucleotide sequence to be determined for functional class I HLA genes. The gene organisation of HLA-A3 closely resembles that of class I H-2 genes in mouse: it shows a signal exon, three exons encoding the three extracellular domains, one exon encoding the transmembrane region and three exons encoding the cytoplasmic domain. The complete nucleotide sequences of the active HLA genes, HLA-A3 and HLA-CW3, now permit a meaningful comparison of the nucleotide sequences of class I HLA genes by alignment with the sequence established for a HLA-B7-specific cDNA clone and the sequences of two HLA class I pseudogenes HLA 12.4 and LN- 11A . The comparisons show that there is a non-random pattern of nucleotide differences in both exonic and intronic regions featuring segmental homologies over short regions, which is indicative of a gene conversion mechanism. In addition, analysis of the frequency of nucleotide substitution at the three base positions within the codons of the functional genes HLA-A3, HLA-B7 and HLA-CW3 shows that the pattern of nucleotide substitution in the exon coding for the 3rd extracellular domain is consistent with strong selection pressure to conserve the sequence. The distribution of nucleotide variation in the other exons specifying the mature protein is nearly random with respect to the frequencies of substitution at the three nucleotide positions of their codons. The evolutionary implications of these findings are discussed.

Full text

PDF
887

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baltimore D. Gene conversion: some implications for immunoglobulin genes. Cell. 1981 Jun;24(3):592–594. doi: 10.1016/0092-8674(81)90082-9. [DOI] [PubMed] [Google Scholar]
  2. Barbosa J. A., Kamarck M. E., Biro P. A., Weissman S. M., Ruddle F. H. Identification of human genomic clones coding the major histocompatibility antigens HLA-a2 and HLA-B7 by DNA-mediated gene transfer. Proc Natl Acad Sci U S A. 1982 Oct;79(20):6327–6331. doi: 10.1073/pnas.79.20.6327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Breathnach R., Chambon P. Organization and expression of eucaryotic split genes coding for proteins. Annu Rev Biochem. 1981;50:349–383. doi: 10.1146/annurev.bi.50.070181.002025. [DOI] [PubMed] [Google Scholar]
  4. Brégégère F. A directional process of gene conversion is expected to yield dynamic polymorphism associated with stability of alternative alleles in class I histocompatibility antigens gene family. Biochimie. 1983 Apr-May;65(4-5):229–237. doi: 10.1016/s0300-9084(83)80274-0. [DOI] [PubMed] [Google Scholar]
  5. Coen E., Strachan T., Dover G. Dynamics of concerted evolution of ribosomal DNA and histone gene families in the melanogaster species subgroup of Drosophila. J Mol Biol. 1982 Jun 15;158(1):17–35. doi: 10.1016/0022-2836(82)90448-x. [DOI] [PubMed] [Google Scholar]
  6. Dover G. Molecular drive: a cohesive mode of species evolution. Nature. 1982 Sep 9;299(5879):111–117. doi: 10.1038/299111a0. [DOI] [PubMed] [Google Scholar]
  7. Evans G. A., Margulies D. H., Camerini-Otero R. D., Ozato K., Seidman J. G. Structure and expression of a mouse major histocompatibility antigen gene, H-2Ld. Proc Natl Acad Sci U S A. 1982 Mar;79(6):1994–1998. doi: 10.1073/pnas.79.6.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fukumaki Y., Collins F., Kole R., Stoeckert C. J., Jr, Jagadeeswaran P., Duncan C. H., Weissman S. M., Jagadeeswaran P., Pan J., Forget B. G. Sequences of human repetitive DNA, non-alpha-globin genes, and major histocompatibility locus genes. Cold Spring Harb Symp Quant Biol. 1983;47(Pt 2):1079–1086. [PubMed] [Google Scholar]
  9. Hayashida H., Miyata T. Unusual evolutionary conservation and frequent DNA segment exchange in class I genes of the major histocompatibility complex. Proc Natl Acad Sci U S A. 1983 May;80(9):2671–2675. doi: 10.1073/pnas.80.9.2671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hood L., Steinmetz M., Malissen B. Genes of the major histocompatibility complex of the mouse. Annu Rev Immunol. 1983;1:529–568. doi: 10.1146/annurev.iy.01.040183.002525. [DOI] [PubMed] [Google Scholar]
  11. Jordan B. R., Lemonnier F. A., Caillol D. H., Trucy J. Transformation of murine LMTK- cells with purified HLA class I genes. III. Human HLA class I antigens coded by hybrid genes constructed in vitro indicate association of serologic reactivities with the first two domains of the molecule. Immunogenetics. 1983;18(2):165–171. doi: 10.1007/BF00368546. [DOI] [PubMed] [Google Scholar]
  12. Kvist S., Roberts L., Dobberstein B. Mouse histocompatibility genes: structure and organisation of a Kd gene. EMBO J. 1983;2(2):245–254. doi: 10.1002/j.1460-2075.1983.tb01413.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lalanne J. L., Bregegere F., Delarbre C., Abastado J. P., Gachelin G., Kourilsky P. Comparison of nucleotide sequences of mRNAs belonging to the mouse H-2 multigene family. Nucleic Acids Res. 1982 Feb 11;10(3):1039–1049. doi: 10.1093/nar/10.3.1039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Larhammar D., Hyldig-Nielsen J. J., Servenius B., Andersson G., Rask L., Peterson P. A. Exon-intron organization and complete nucleotide sequence of a human major histocompatibility antigen DC beta gene. Proc Natl Acad Sci U S A. 1983 Dec;80(23):7313–7317. doi: 10.1073/pnas.80.23.7313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lemonnier F. A., Dubreuil P. C., Layet C., Malissen M., Bourel D., Mercier P., Jakobsen B. K., Caillol D. H., Svejgaard A., Kourilsky F. M. Transformation of LMTK- cells with purified HLA class I genes. II. Serologic characterization of HLA-A3 and CW3 molecules. Immunogenetics. 1983;18(1):65–77. doi: 10.1007/BF00401357. [DOI] [PubMed] [Google Scholar]
  16. Lemonnier F. A., Malissen M., Golstein P., Le Bouteiller P., Rebai N., Damotte M., Birnbaum D., Caillol D., Trucy J., Jordan B. R. Expression of human class I histocompatibility antigens at the surface of DNA-transformed mouse L cells. Immunogenetics. 1982;16(4):355–361. doi: 10.1007/BF00372307. [DOI] [PubMed] [Google Scholar]
  17. López de Castro J. A., Strominger J. L., Strong D. M., Orr H. T. Structure of crossreactive human histocompatibility antigens HLA-A28 and HLA-A2: possible implications for the generation of HLA polymorphism. Proc Natl Acad Sci U S A. 1982 Jun;79(12):3813–3817. doi: 10.1073/pnas.79.12.3813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Malissen M., Damotte M., Birnbaum D., Trucy J., Jordan B. R. HLA cosmid clones show complete, widely spaced human class I genes with occasional clusters. Gene. 1982 Dec;20(3):485–489. doi: 10.1016/0378-1119(82)90219-0. [DOI] [PubMed] [Google Scholar]
  19. Malissen M., Malissen B., Jordan B. R. Exon/intron organization and complete nucleotide sequence of an HLA gene. Proc Natl Acad Sci U S A. 1982 Feb;79(3):893–897. doi: 10.1073/pnas.79.3.893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Maxam A. M., Gilbert W. Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol. 1980;65(1):499–560. doi: 10.1016/s0076-6879(80)65059-9. [DOI] [PubMed] [Google Scholar]
  21. Mellor A. L., Weiss E. H., Ramachandran K., Flavell R. A. A potential donor gene for the bm1 gene conversion event in the C57BL mouse. Nature. 1983 Dec 22;306(5945):792–795. doi: 10.1038/306792a0. [DOI] [PubMed] [Google Scholar]
  22. Moore K. W., Sher B. T., Sun Y. H., Eakle K. A., Hood L. DNA sequence of a gene encoding a BALB/c mouse Ld transplantation antigen. Science. 1982 Feb 5;215(4533):679–682. doi: 10.1126/science.7058332. [DOI] [PubMed] [Google Scholar]
  23. Ohta T. Allelic and nonallelic homology of a supergene family. Proc Natl Acad Sci U S A. 1982 May;79(10):3251–3254. doi: 10.1073/pnas.79.10.3251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Orr H. T., DeMars R. Class I-like HLA genes map telomeric to the HLA-A2 locus in human cells. Nature. 1983 Apr 7;302(5908):534–536. doi: 10.1038/302534a0. [DOI] [PubMed] [Google Scholar]
  25. Pease L. R., Schulze D. H., Pfaffenbach G. M., Nathenson S. G. Spontaneous H-2 mutants provide evidence that a copy mechanism analogous to gene conversion generates polymorphism in the major histocompatibility complex. Proc Natl Acad Sci U S A. 1983 Jan;80(1):242–246. doi: 10.1073/pnas.80.1.242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ploegh H. L., Cannon L. E., Strominger J. L. Cell-free translation of the mRNAs for the heavy and light chains of HLA-A and HLA-B antigens. Proc Natl Acad Sci U S A. 1979 May;76(5):2273–2277. doi: 10.1073/pnas.76.5.2273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Rechavi G., Bienz B., Ram D., Ben-Neriah Y., Cohen J. B., Zakut R., Givol D. Organization and evolution of immunoglobulin VH gene subgroups. Proc Natl Acad Sci U S A. 1982 Jul;79(14):4405–4409. doi: 10.1073/pnas.79.14.4405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sanger F., Coulson A. R., Barrell B. G., Smith A. J., Roe B. A. Cloning in single-stranded bacteriophage as an aid to rapid DNA sequencing. J Mol Biol. 1980 Oct 25;143(2):161–178. doi: 10.1016/0022-2836(80)90196-5. [DOI] [PubMed] [Google Scholar]
  29. Selsing E., Miller J., Wilson R., Storb U. Evolution of mouse immunoglobulin lambda genes. Proc Natl Acad Sci U S A. 1982 Aug;79(15):4681–4685. doi: 10.1073/pnas.79.15.4681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Steinmetz M., Hood L. Genes of the major histocompatibility complex in mouse and man. Science. 1983 Nov 18;222(4625):727–733. doi: 10.1126/science.6356354. [DOI] [PubMed] [Google Scholar]
  31. Steinmetz M., Moore K. W., Frelinger J. G., Sher B. T., Shen F. W., Boyse E. A., Hood L. A pseudogene homologous to mouse transplantation antigens: transplantation antigens are encoded by eight exons that correlate with protein domains. Cell. 1981 Sep;25(3):683–692. doi: 10.1016/0092-8674(81)90175-6. [DOI] [PubMed] [Google Scholar]
  32. Strachan T., Coen E., Webb D., Dover G. Modes and rates of change of complex DNA families of Drosophila. J Mol Biol. 1982 Jun 15;158(1):37–54. doi: 10.1016/0022-2836(82)90449-1. [DOI] [PubMed] [Google Scholar]
  33. Weiss E. H., Mellor A., Golden L., Fahrner K., Simpson E., Hurst J., Flavell R. A. The structure of a mutant H-2 gene suggests that the generation of polymorphism in H-2 genes may occur by gene conversion-like events. Nature. 1983 Feb 24;301(5902):671–674. doi: 10.1038/301671a0. [DOI] [PubMed] [Google Scholar]
  34. Weiss E., Golden L., Zakut R., Mellor A., Fahrner K., Kvist S., Flavell R. A. The DNA sequence of the H-2kb gene: evidence for gene conversion as a mechanism for the generation of polymorphism in histocompatibilty antigens. EMBO J. 1983;2(3):453–462. doi: 10.1002/j.1460-2075.1983.tb01444.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Winoto A., Steinmetz M., Hood L. Genetic mapping in the major histocompatibility complex by restriction enzyme site polymorphisms: most mouse class I genes map to the Tla complex. Proc Natl Acad Sci U S A. 1983 Jun;80(11):3425–3429. doi: 10.1073/pnas.80.11.3425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Yokoyama K., Nathenson S. G. Intramolecular organization of Class I H-2 MHC antigens; localization of the alloantigenic determinants and the beta 2 m binding site to different regions of the H-2 Kb glycoprotein. J Immunol. 1983 Mar;130(3):1419–1425. [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES