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Proc Natl Acad Sci U S A. Feb 1989; 86(3): 958–962.
PMCID: PMC286598

Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection.

Abstract

To study the mechanism of maintenance of polymorphism at major histocompatibility complex (MHC) loci, synonymous and nonsynonymous (amino acid-altering) nucleotide substitutions in the putative antigen-recognition site (included in the first domain of the MHC molecule) and other regions of human and mouse class II genes were examined. In the putative antigen-recognition site, the rate of nonsynonymous substitution was found to exceed that of synonymous substitution, whereas in the second domain the former was significantly lower than the latter. In light of a previous theoretical study and parallel findings in class I MHC loci, we conclude that the unusually high degree of polymorphism at class II MHC loci is caused mainly by overdominant selection (heterozygote advantage) operating in the antigen-recognition site.

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  • Bailey DW, Kohn HI. Inherited histocompatibility changes in progeny of irradiated and unirradiated inbred mice. Genet Res. 1965 Nov;6(3):330–340. [PubMed]
  • Widera G, Flavell RA. The nucleotide sequence of the murine I-E beta b immune response gene: evidence for gene conversion events in class II genes of the major histocompatibility complex. EMBO J. 1984 Jun;3(6):1221–1225. [PMC free article] [PubMed]
  • Mengle-Gaw L, McDevitt HO. Genetics and expression of mouse Ia antigens. Annu Rev Immunol. 1985;3:367–396. [PubMed]
  • Doherty PC, Zinkernagel RM. Enhanced immunological surveillance in mice heterozygous at the H-2 gene complex. Nature. 1975 Jul 3;256(5512):50–52. [PubMed]
  • Klein J, Figueroa F. Evolution of the major histocompatibility complex. Crit Rev Immunol. 1986;6(4):295–386. [PubMed]
  • Snell GD. The H-2 locus of the mouse: observations and speculations concerning its comparative genetics and its polymorphism. Folia Biol (Praha) 1968;14(5):335–358. [PubMed]
  • Bodmer WF. Evolutionary significance of the HL-A system. Nature. 1972 May 19;237(5351):139–passim. [PubMed]
  • Hughes AL, Nei M. Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection. Nature. 1988 Sep 8;335(6186):167–170. [PubMed]
  • Maruyama T, Nei M. Genetic variability maintained by mutation and overdominant selection in finite populations. Genetics. 1981 Jun;98(2):441–459. [PMC free article] [PubMed]
  • Carson S, Trowsdale J. Molecular organization of the class II genes of the human and mouse major histocompatibility complexes. Oxf Surv Eukaryot Genes. 1986;3:63–94. [PubMed]
  • Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature. 1987 Oct 8;329(6139):512–518. [PubMed]
  • Folsom V, Gay D, Tonegawa S. The beta 1 domain of the mouse E beta chain is important for restricted antigen presentation to helper T-cell hybridomas. Proc Natl Acad Sci U S A. 1985 Mar;82(6):1678–1682. [PMC free article] [PubMed]
  • Germain RN, Ashwell JD, Lechler RI, Margulies DH, Nickerson KM, Suzuki G, Tou JY. "Exon-shuffling" maps control of antibody- and T-cell-recognition sites to the NH2-terminal domain of the class II major histocompatibility polypeptide A beta. Proc Natl Acad Sci U S A. 1985 May;82(9):2940–2944. [PMC free article] [PubMed]
  • Brown JH, Jardetzky T, Saper MA, Samraoui B, Bjorkman PJ, Wiley DC. A hypothetical model of the foreign antigen binding site of class II histocompatibility molecules. Nature. 1988 Apr 28;332(6167):845–850. [PubMed]
  • Larhammar D, Hammerling U, Rask L, Peterson PA. Sequence of gene and cDNA encoding murine major histocompatibility complex class II gene A beta 2. J Biol Chem. 1985 Nov 15;260(26):14111–14119. [PubMed]
  • Estess P, Begovich AB, Koo M, Jones PP, McDevitt HO. Sequence analysis and structure-function correlations of murine q, k, u, s, and f haplotype I-A beta cDNA clones. Proc Natl Acad Sci U S A. 1986 Jun;83(11):3594–3598. [PMC free article] [PubMed]
  • Larhammar D, Hammerling U, Denaro M, Lund T, Flavell RA, Rask L, Peterson PA. 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. [PubMed]
  • 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. [PubMed]
  • Benoist CO, Mathis DJ, Kanter MR, Williams VE, 2nd, McDevitt HO. Regions of allelic hypervariability in the murine A alpha immune response gene. Cell. 1983 Aug;34(1):169–177. [PubMed]
  • Landais D, Matthes H, Benoist C, Mathis D. A molecular basis for the Ia.2 and Ia.19 antigenic determinants. Proc Natl Acad Sci U S A. 1985 May;82(9):2930–2934. [PMC free article] [PubMed]
  • Saito H, Maki RA, Clayton LK, 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. [PMC free article] [PubMed]
  • Mengle-Gaw L, McDevitt HO. Isolation and characterization of a cDNA clone for the murine I-E beta polypeptide chain. Proc Natl Acad Sci U S A. 1983 Dec;80(24):7621–7625. [PMC free article] [PubMed]
  • Mathis DJ, Benoist CO, Williams VE, 2nd, Kanter MR, McDevitt HO. The murine E alpha immune response gene. Cell. 1983 Mar;32(3):745–754. [PubMed]
  • Lair B, Alber C, Yu WY, Watts R, Bahl M, Karr RW. A newly characterized HLA-DP beta-chain allele. Evidence for DP beta heterogeneity within the DPw4 specificity. J Immunol. 1988 Aug 15;141(4):1353–1357. [PubMed]
  • Auffray C, Lillie JW, Arnot D, Grossberger D, Kappes D, Strominger JL. Isotypic and allotypic variation of human class II histocompatibility antigen alpha-chain genes. Nature. 1984 Mar 22;308(5957):327–333. [PubMed]
  • Tonnelle C, DeMars R, Long EO. DO beta: a new beta chain gene in HLA-D with a distinct regulation of expression. EMBO J. 1985 Nov;4(11):2839–2847. [PMC free article] [PubMed]
  • Trowsdale J, Kelly A. The human HLA class II alpha chain gene DZ alpha is distinct from genes in the DP, DQ and DR subregions. EMBO J. 1985 Sep;4(9):2231–2237. [PMC free article] [PubMed]
  • Boss JM, Strominger JL. Cloning and sequence analysis of the human major histocompatibility complex gene DC-3 beta. Proc Natl Acad Sci U S A. 1984 Aug;81(16):5199–5203. [PMC free article] [PubMed]
  • Schenning L, Larhammar D, Bill P, Wiman K, Jonsson AK, Rask L, Peterson PA. 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. [PMC free article] [PubMed]
  • Schiffenbauer J, Didier DK, Klearman M, Rice K, Shuman S, Tieber VL, Kittlesen DJ, Schwartz BD. Complete sequence of the HLA DQ alpha and DQ beta cDNA from a DR5/DQw3 cell line. J Immunol. 1987 Jul 1;139(1):228–233. [PubMed]
  • So AK, Lindsay J, Bodmer J, Trowsdale J. Molecular variation of human major histocompatibility complex DQw3 beta-chains. J Immunol. 1987 Nov 15;139(10):3506–3511. [PubMed]
  • Tsukamoto K, Yasunami M, Kimura A, Inoko H, Ando A, Hirose T, Inayama S, Sasazuki T. DQw1 beta gene from HLA-DR2-Dw12 consists of six exons and expresses multiple DQw1 beta polypeptides through alternative splicing. Immunogenetics. 1987;25(5):343–346. [PubMed]
  • Turco E, Care A, Compagnone-Post P, Robinson C, Cascino I, Trucco M. Allelic forms of the alpha- and beta-chain genes encoding DQw1-positive heterodimers. Immunogenetics. 1987;26(4-5):282–290. [PubMed]
  • Lock CB, So AK, Welsh KI, Parkes JD, Trowsdale J. MHC class II sequences of an HLA-DR2 narcoleptic. Immunogenetics. 1988;27(6):449–455. [PubMed]
  • Chang HC, Moriuchi T, Silver J. The heavy chain of human B-cell alloantigen HLA-DS has a variable N-terminal region and a constant immunoglobulin-like region. Nature. 305(5937):813–815. [PubMed]
  • Bell JI, Denney D, Jr, Foster L, Belt T, Todd JA, McDevitt HO. Allelic variation in the DR subregion of the human major histocompatibility complex. Proc Natl Acad Sci U S A. 1987 Sep;84(17):6234–6238. [PMC free article] [PubMed]
  • Lee BS, Rust NA, McMichael AJ, McDevitt HO. HLA-DR2 subtypes form an additional supertypic family of DR beta alleles. Proc Natl Acad Sci U S A. 1987 Jul;84(13):4591–4595. [PMC free article] [PubMed]
  • Curtsinger JM, Hilden JM, Cairns JS, Bach FH. Evolutionary and genetic implications of sequence variation in two nonallelic HLA-DR beta-chain cDNA sequences. Proc Natl Acad Sci U S A. 1987 Jan;84(1):209–213. [PMC free article] [PubMed]
  • Young JA, Wilkinson D, Bodmer WF, Trowsdale J. Sequence and evolution of HLA-DR7- and -DRw53-associated beta-chain genes. Proc Natl Acad Sci U S A. 1987 Jul;84(14):4929–4933. [PMC free article] [PubMed]
  • Gustafsson K, Wiman K, Emmoth E, Larhammar D, Böhme J, Hyldig-Nielsen JJ, Ronne H, Peterson PA, Rask L. Mutations and selection in the generation of class II histocompatibility antigen polymorphism. EMBO J. 1984 Jul;3(7):1655–1661. [PMC free article] [PubMed]
  • Lee JS, Trowsdale J, Travers PJ, Carey J, Grosveld F, Jenkins J, Bodmer WF. 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. [PubMed]
  • Bodmer WF, Trowsdale J, Young J, Bodmer J. Gene clusters and the evolution of the major histocompatibility system. Philos Trans R Soc Lond B Biol Sci. 1986 Jan 29;312(1154):303–315. [PubMed]
  • Nei M, Gojobori T. Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol. 1986 Sep;3(5):418–426. [PubMed]
  • Nei M, Stephens JC, Saitou N. Methods for computing the standard errors of branching points in an evolutionary tree and their application to molecular data from humans and apes. Mol Biol Evol. 1985 Jan;2(1):66–85. [PubMed]
  • Mouchiroud D, Gautier C. High codon-usage changes in mammalian genes. Mol Biol Evol. 1988 Mar;5(2):192–194. [PubMed]
  • McConnell TJ, Talbot WS, McIndoe RA, Wakeland EK. The origin of MHC class II gene polymorphism within the genus Mus. Nature. 1988 Apr 14;332(6165):651–654. [PubMed]
  • Figueroa F, Günther E, Klein J. MHC polymorphism pre-dating speciation. Nature. 1988 Sep 15;335(6187):265–267. [PubMed]
  • Lawlor DA, Ward FE, Ennis PD, Jackson AP, Parham P. HLA-A and B polymorphisms predate the divergence of humans and chimpanzees. Nature. 1988 Sep 15;335(6187):268–271. [PubMed]
  • Buus S, Sette A, Colon SM, Miles C, Grey HM. The relation between major histocompatibility complex (MHC) restriction and the capacity of Ia to bind immunogenic peptides. Science. 1987 Mar 13;235(4794):1353–1358. [PubMed]
  • Sette A, Buus S, Colon S, Miles C, Grey HM. I-Ad-binding peptides derived from unrelated protein antigens share a common structural motif. J Immunol. 1988 Jul 1;141(1):45–48. [PubMed]

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