Abstract
A comparison of seven human DR and DC class II histocompatibility antigen beta-chain amino acid sequences indicates that the allelic variation is of comparable magnitude within the DR and DC beta-chain genes. Silent and replacement nucleotide substitutions in six DR and DC beta-chain sequences, as well as in seven murine class II sequences (three I-A beta and four I-A alpha alleles) were analyzed. The results suggest that the mutation rates are of a comparable magnitude in the nucleotide sequences encoding the first and second external domains of the class II molecules. Nevertheless, the allelic amino acid replacements are predominantly located in the first domains. We conclude that a conservative selective pressure acts on the second domains, whereas in many positions in the first domains replacement substitutions are selectively neutral or maybe even favoured. Thus, the difference between the first and second domains as regards the number of amino acid replacements is mainly due to selection.
Full text
PDF






Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Auffray C., Ben-Nun A., Roux-Dosseto M., Germain R. N., Seidman J. G., Strominger J. L. Polymorphism and complexity of the human DC and murine I-A alpha chain genes. EMBO J. 1983;2(1):121–124. doi: 10.1002/j.1460-2075.1983.tb01392.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Auffray C., Korman A. J., Roux-Dosseto M., Bono R., Strominger J. L. cDNA clone for the heavy chain of the human B cell alloantigen DC1: strong sequence homology to the HLA-DR heavy chain. Proc Natl Acad Sci U S A. 1982 Oct;79(20):6337–6341. doi: 10.1073/pnas.79.20.6337. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Auffray C., Kuo J., DeMars R., Strominger J. L. A minimum of four human class II alpha-chain genes are encoded in the HLA region of chromosome 6. Nature. 1983 Jul 14;304(5922):174–177. doi: 10.1038/304174a0. [DOI] [PubMed] [Google Scholar]
- 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]
- Benacerraf B. Role of MHC gene products in immune regulation. Science. 1981 Jun 12;212(4500):1229–1238. doi: 10.1126/science.6165083. [DOI] [PubMed] [Google Scholar]
- Benoist C. O., Mathis D. J., Kanter M. R., Williams V. E., 2nd, McDevitt H. O. Regions of allelic hypervariability in the murine A alpha immune response gene. Cell. 1983 Aug;34(1):169–177. doi: 10.1016/0092-8674(83)90147-2. [DOI] [PubMed] [Google Scholar]
- Benoist C. O., Mathis D. J., Kanter M. R., Williams V. E., 2nd, McDevitt H. O. The murine Ia alpha chains, E alpha and A alpha, show a surprising degree of sequence homology. Proc Natl Acad Sci U S A. 1983 Jan;80(2):534–538. doi: 10.1073/pnas.80.2.534. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bothwell A. L., Paskind M., Reth M., Imanishi-Kari T., Rajewsky K., Baltimore D. Heavy chain variable region contribution to the NPb family of antibodies: somatic mutation evident in a gamma 2a variable region. Cell. 1981 Jun;24(3):625–637. doi: 10.1016/0092-8674(81)90089-1. [DOI] [PubMed] [Google Scholar]
- Brack C., Hirama M., Lenhard-Schuller R., Tonegawa S. A complete immunoglobulin gene is created by somatic recombination. Cell. 1978 Sep;15(1):1–14. doi: 10.1016/0092-8674(78)90078-8. [DOI] [PubMed] [Google Scholar]
- Charron D. J., McDevitt H. O. Analysis of HLA-D region-associated molecules with monoclonal antibody. Proc Natl Acad Sci U S A. 1979 Dec;76(12):6567–6571. doi: 10.1073/pnas.76.12.6567. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Choi E., McIntyre K., Germain R. N., Seidman J. G. Murine I-A beta chain polymorphism: nucleotide sequences of three allelic I-A beta genes. Science. 1983 Jul 15;221(4607):283–286. doi: 10.1126/science.6407114. [DOI] [PubMed] [Google Scholar]
- Cook R. G., Siegelman M. H., Capra J. D., Uhr J. W., Vitetta E. S. Structural studies on the murine Ia alloantigens. IV. NH2-terminal sequence analysis of allelic products of the I-A and I-E/C subregions. J Immunol. 1979 Jun;122(6):2232–2237. [PubMed] [Google Scholar]
- Crews S., Griffin J., Huang H., Calame K., Hood L. A single VH gene segment encodes the immune response to phosphorylcholine: somatic mutation is correlated with the class of the antibody. Cell. 1981 Jul;25(1):59–66. doi: 10.1016/0092-8674(81)90231-2. [DOI] [PubMed] [Google Scholar]
- Efstratiadis A., Posakony J. W., Maniatis T., Lawn R. M., O'Connell C., Spritz R. A., DeRiel J. K., Forget B. G., Weissman S. M., Slightom J. L. The structure and evolution of the human beta-globin gene family. Cell. 1980 Oct;21(3):653–668. doi: 10.1016/0092-8674(80)90429-8. [DOI] [PubMed] [Google Scholar]
- 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]
- Gergen J. P., Stern R. H., Wensink P. C. Filter replicas and permanent collections of recombinant DNA plasmids. Nucleic Acids Res. 1979 Dec 20;7(8):2115–2136. doi: 10.1093/nar/7.8.2115. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Hyldig-Nielsen J. J., Schenning L., Hammerling U., Widmark E., Heldin E., Lind P., Servenius B., Lund T., Flavell R., Lee J. S. The complete nucleotide sequence of the I-E alpha d immune response gene. Nucleic Acids Res. 1983 Aug 11;11(15):5055–5071. doi: 10.1093/nar/11.15.5055. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Korman A. J., Auffray C., Schamboeck A., Strominger J. L. The amino acid sequence and gene organization of the heavy chain of the HLA-DR antigen: homology to immunoglobulins. Proc Natl Acad Sci U S A. 1982 Oct;79(19):6013–6017. doi: 10.1073/pnas.79.19.6013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kratzin H., Yang C. Y., Götz H., Pauly E., Kölbel S., Egert G., Thinnes F. P., Wernet P., Altevogt P., Hilschmann N. Primärstruktur menschlicher Histokompatibilitätsantigene der Klasse II. 1. Mitteilung: Aminosäuresequenz der N-terminalen 198 Reste der beta-Kette des HLA-Dw2,2;DR2,2-Alloantigens. Hoppe Seylers Z Physiol Chem. 1981 Dec;362(12):1665–1669. [PubMed] [Google Scholar]
- Larhammar D., Gustafsson K., Claesson L., Bill P., Wiman K., Schenning L., Sundelin J., Widmark E., Peterson P. A., Rask L. Alpha chain of HLA-DR transplantation antigens is a member of the same protein superfamily as the immunoglobulins. Cell. 1982 Aug;30(1):153–161. doi: 10.1016/0092-8674(82)90021-6. [DOI] [PubMed] [Google Scholar]
- Larhammar D., Hammerling U., Denaro M., Lund T., Flavell R. A., Rask L., Peterson P. A. Structure of the murine immune response I-A beta locus: sequence of the I-A beta gene and an adjacent beta-chain second domain exon. Cell. 1983 Aug;34(1):179–188. doi: 10.1016/0092-8674(83)90148-4. [DOI] [PubMed] [Google Scholar]
- 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]
- Larhammar D., Schenning L., Gustafsson K., Wiman K., Claesson L., Rask L., Peterson P. A. Complete amino acid sequence of an HLA-DR antigen-like beta chain as predicted from the nucleotide sequence: similarities with immunoglobulins and HLA-A, -B, and -C antigens. Proc Natl Acad Sci U S A. 1982 Jun;79(12):3687–3691. doi: 10.1073/pnas.79.12.3687. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee J. S., Trowsdale J., Travers P. J., Carey J., Grosveld F., Jenkins J., Bodmer W. F. Sequence of an HLA-DR alpha-chain cDNA clone and intron-exon organization of the corresponding gene. Nature. 1982 Oct 21;299(5885):750–752. doi: 10.1038/299750a0. [DOI] [PubMed] [Google Scholar]
- Long E. O., Wake C. T., Gorski J., Mach B. Complete sequence of an HLA-dR beta chain deduced from a cDNA clone and identification of multiple non-allelic DR beta chain genes. EMBO J. 1983;2(3):389–394. doi: 10.1002/j.1460-2075.1983.tb01435.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Malissen M., Hunkapiller T., Hood L. Nucleotide sequence of a light chain gene of the mouse I-A subregion: A beta d. Science. 1983 Aug 19;221(4612):750–754. doi: 10.1126/science.6410508. [DOI] [PubMed] [Google Scholar]
- Maloy W. L., Coligan J. E. Primary structure of the H-2Db alloantigen. II. Additional amino acid sequence information, localization of a third site of glycosylation and evidence for K and D region specific sequences. Immunogenetics. 1982;16(1):11–22. doi: 10.1007/BF00364438. [DOI] [PubMed] [Google Scholar]
- Mathis D. J., Benoist C. O., Williams V. E., 2nd, Kanter M. R., McDevitt H. O. The murine E alpha immune response gene. Cell. 1983 Mar;32(3):745–754. doi: 10.1016/0092-8674(83)90060-0. [DOI] [PubMed] [Google Scholar]
- 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]
- McNicholas J., Steinmetz M., Hunkapiller T., Jones P., Hood L. DNA sequence of the gene encoding the E alpha Ia polypeptide of the BALB/c mouse. Science. 1982 Dec 17;218(4578):1229–1232. doi: 10.1126/science.6815800. [DOI] [PubMed] [Google Scholar]
- Miyata T., Yasunaga T., Nishida T. Nucleotide sequence divergence and functional constraint in mRNA evolution. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7328–7332. doi: 10.1073/pnas.77.12.7328. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Perler F., Efstratiadis A., Lomedico P., Gilbert W., Kolodner R., Dodgson J. The evolution of genes: the chicken preproinsulin gene. Cell. 1980 Jun;20(2):555–566. doi: 10.1016/0092-8674(80)90641-8. [DOI] [PubMed] [Google Scholar]
- Saito H., Maki R. A., Clayton L. K., Tonegawa S. Complete primary structures of the E beta chain and gene of the mouse major histocompatibility complex. Proc Natl Acad Sci U S A. 1983 Sep;80(18):5520–5524. doi: 10.1073/pnas.80.18.5520. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schenning L., Larhammar D., Bill P., Wiman K., Jonsson A. K., Rask L., Peterson P. A. Both alpha and beta chains of HLA-DC class II histocompatibility antigens display extensive polymorphism in their amino-terminal domains. EMBO J. 1984 Feb;3(2):447–452. doi: 10.1002/j.1460-2075.1984.tb01826.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shaw S., Johnson A. H., Shearer G. M. Evidence for a new segregant series of B cell antigens that are encoded in the HLA-D region and that stimulate secondary allogenic proliferative and cytotoxic responses. J Exp Med. 1980 Sep 1;152(3):565–580. doi: 10.1084/jem.152.3.565. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shevach E. M., Rosenthal A. S. Function of macrophages in antigen recognition by guinea pig T lymphocytes. II. Role of the macrophage in the regulation of genetic control of the immune response. J Exp Med. 1973 Nov 1;138(5):1213–1229. doi: 10.1084/jem.138.5.1213. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Steinmetz M., Minard K., Horvath S., McNicholas J., Srelinger J., Wake C., Long E., Mach B., Hood L. A molecular map of the immune response region from the major histocompatibility complex of the mouse. Nature. 1982 Nov 4;300(5887):35–42. doi: 10.1038/300035a0. [DOI] [PubMed] [Google Scholar]
- Tanigaki N., Tosi R. The genetic control of human Ia alloantigens: a three-loci model derived from the immunochemical analysis of 'supertypic' specificities. Immunol Rev. 1982;66:5–37. doi: 10.1111/j.1600-065x.1982.tb00432.x. [DOI] [PubMed] [Google Scholar]
- Thorsby E., Berle E., Nousiainen H. HLA-D region molecules restrict proliferative T cell responses to antigen. Immunol Rev. 1982;66:39–56. doi: 10.1111/j.1600-065x.1982.tb00433.x. [DOI] [PubMed] [Google Scholar]
- Tosi R., Tanigaki N., Centis D., Ferrara G. B., Pressman D. Immunological dissection of human Ia molecules. J Exp Med. 1978 Dec 1;148(6):1592–1611. doi: 10.1084/jem.148.6.1592. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Trowsdale J., Lee J., Carey J., Grosveld F., Bodmer J., Bodmer W. Sequences related to HLA-DR alpha chain on human chromosome 6: restriction enzyme polymorphism detected with DC alpha chain probes. Proc Natl Acad Sci U S A. 1983 Apr;80(7):1972–1976. doi: 10.1073/pnas.80.7.1972. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tu C. P., Cohen S. N. 3'-end labeling of DNA with [alpha-32P]cordycepin-5'-triphosphate. Gene. 1980 Jul;10(2):177–183. doi: 10.1016/0378-1119(80)90135-3. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Yang C., Kratzin H., Götz H., Thinnes F. P., Kruse T., Egert G., Pauly E., Kölbel S., Wernet P., Hilschmann N. Primärstruktur menschlicher Histokompatibilitätsantigene der Klasse II. 2. Mitteilung: Aminosäuresequenz der N-terminalen 179 Reste der alpha-Kette des HLA-Dw2/DR2-Alloantigens. Hoppe Seylers Z Physiol Chem. 1982 Jun;363(6):671–676. [PubMed] [Google Scholar]
- Zinkernagel R. M., Doherty P. C. MHC-restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness. Adv Immunol. 1979;27:51–177. doi: 10.1016/s0065-2776(08)60262-x. [DOI] [PubMed] [Google Scholar]