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. 1982 Feb;79(4):1235–1239. doi: 10.1073/pnas.79.4.1235

Gene dosage and gene expression in the HLA region: Evidence from deletion variants

Paul Gladstone *, Lucy Fueresz *, Donald Pious *,†
PMCID: PMC345936  PMID: 6951171

Abstract

Among variants selected in a human cell line for nonexpression of a single gene product in the HLA complex, most are single-gene variants, but several have been isolated that are cis-acting and abolish expression of a series of closely linked genes. The two most plausible mechanisms by which such variants could arise are mitotic crossing-over and chromosome deletion. In two HLA variants the presence of a visible chromosome deletion, a 50% reduction in activity of glyoxalase I (a closely linked marker), or both provided evidence for deletional origins. In a third variant these changes were not demonstrable. All three variants showed reductions in amount of cell surface HLA antigens: 40% for the Ia antigens (HLA-DR) and 20-25% for HLA-ABC antigens. The reductions in cell surface antigen in deletion variants have an important implication: in the case of the HLA-A, -B, and -C heterodimer, which consists of a subunit coded for within the major histocompatibility complex and another subunit (β2-microglobulin) coded for on a different chromosome, it is the gene of the major histocompatibility complex that is limiting. The nonmutant haplotype includes A2; binding of an A2 monoclonal antibody in two of the mutants was found to be approximately equal to that in the wild-type cells. Thus, loss of one copy of HLA-ABC genes does not lead to gene dosage compensation—i.e., increased activity by the remaining ABC alleles. The results with the two types of antibodies support a deletional mechanism and are inconsistent with mitotic crossing-over. Of interest with respect to the potential use of deletion variants for purposes of mapping is the fact that each of these variants has distinctive breakpoints. The absence of mitotic crossing-over in 1.2 × 107 cells selected suggests that the event is rare in this autosomal region, if it occurs at all.

Keywords: regulation of HLA, mitotic crossing-over, monoclonal antibodies, dosage compensation

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Selected References

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

  1. Bach F. H. Genetics of transplantation: the major histocompatibility complex. Annu Rev Genet. 1976;10:319–339. doi: 10.1146/annurev.ge.10.120176.001535. [DOI] [PubMed] [Google Scholar]
  2. Berger R., Bernheim A., Sasportes M., Hauptmann G., Hors J., Legrand L., Fellous M. Regional mapping of the HLA on the short arm of chromosome 6. Clin Genet. 1979 Mar;15(3):245–251. doi: 10.1111/j.1399-0004.1979.tb00975.x. [DOI] [PubMed] [Google Scholar]
  3. Brodsky F. M., Parham P., Barnstable C. J., Crumpton M. J., Bodmer W. F. Monoclonal antibodies for analysis of the HLA system. Immunol Rev. 1979;47:3–61. doi: 10.1111/j.1600-065x.1979.tb00288.x. [DOI] [PubMed] [Google Scholar]
  4. Brown J. P., Klitzman J. M., Hellström K. E. A microassay for antibody binding to tumor cell surface antigens using 125I-labelled protein a from Staphylococcus aureus. J Immunol Methods. 1977;15(1):57–66. doi: 10.1016/0022-1759(77)90017-5. [DOI] [PubMed] [Google Scholar]
  5. Brégégère F., Abastado J. P., Kvist S., Rask L., Lalanne J. L., Garoff H., Cami B., Wiman K., Larhammar D., Peterson P. A. Structure of C-terminal half of two H-2 antigens from cloned mRNA. Nature. 1981 Jul 2;292(5818):78–81. doi: 10.1038/292078a0. [DOI] [PubMed] [Google Scholar]
  6. Campbell C. E., Worton R. G. Segregation of recessive phenotypes in somatic cell hybrids: role of mitotic recombination, gene inactivation, and chromosome nondisjunction. Mol Cell Biol. 1981 Apr;1(4):336–346. doi: 10.1128/mcb.1.4.336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cook R. G., Vitetta E. S., Uhr J. W., Capra J. D. Structural studies on the murine Ia alloantigens--III. Tryptic peptide comparisons of allelic products of the I-E/C sub-region. Mol Immunol. 1979 Jan;16(1):29–35. doi: 10.1016/0161-5890(79)90024-5. [DOI] [PubMed] [Google Scholar]
  8. Davis K. A., Williams G. R. Cation activation of glyoxalase I. Biochim Biophys Acta. 1966 Feb 14;113(2):393–395. doi: 10.1016/s0926-6593(66)80078-4. [DOI] [PubMed] [Google Scholar]
  9. Francke U., Pellegrino M. A. Assignment of the major histocompatibility complex to a region of the short arm of human chromosome 6. Proc Natl Acad Sci U S A. 1977 Mar;74(3):1147–1151. doi: 10.1073/pnas.74.3.1147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Francke U., Weitkamp L. R. Report of the committee on the genetic constitution of chromosome 6. Cytogenet Cell Genet. 1979;25(1-4):32–38. doi: 10.1159/000131397. [DOI] [PubMed] [Google Scholar]
  11. Gladstone P., Pious D. Identification of a trans-acting function regulation HLA-DR expression in a DR-negative B cell variant. Somatic Cell Genet. 1980 Mar;6(2):285–298. doi: 10.1007/BF01538802. [DOI] [PubMed] [Google Scholar]
  12. Gladstone, Pious D. Stable variants affecting B cell alloantigens in human lymphoid cells. Nature. 1978 Feb 2;271(5644):459–461. doi: 10.1038/271459a0. [DOI] [PubMed] [Google Scholar]
  13. Holtkamp B., Cramer M., Lemke H., Rajewsky K. Isolation of a cloned cell line expressing variant H-2Kk using fluorescence-activated cell sorting. Nature. 1981 Jan 1;289(5793):66–68. doi: 10.1038/289066a0. [DOI] [PubMed] [Google Scholar]
  14. Kavathas P., Bach F. H., DeMars R. Gamma ray-induced loss of expression of HLA and glyoxalase I alleles in lymphoblastoid cells. Proc Natl Acad Sci U S A. 1980 Jul;77(7):4251–4255. doi: 10.1073/pnas.77.7.4251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Klinger H. P. Rapid processing of primary embryonic tissues for chromosome banding pattern analysis. Cytogenetics. 1972;11(5):424–435. doi: 10.1159/000130208. [DOI] [PubMed] [Google Scholar]
  16. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  17. Old L. J., Stockert E., Boyse E. A., Kim J. H. Antigenic modulation. Loss of TL antigen from cells exposed to TL antibody. Study of the phenomenon in vitro. J Exp Med. 1968 Mar 1;127(3):523–539. doi: 10.1084/jem.127.3.523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pious D., Hawley P., Forrest G. Isolation and characterization of HL-A variants in cultured human lymphoid cells. Proc Natl Acad Sci U S A. 1973 May;70(5):1397–1400. doi: 10.1073/pnas.70.5.1397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Pious D., Martin S., Gladstone P., Soderland C. Linked marker analysis of spontaneous HLA variants of somatic cells. Somatic Cell Genet. 1980 Jul;6(4):529–541. doi: 10.1007/BF01539154. [DOI] [PubMed] [Google Scholar]
  20. Rosenstraus M. J., Chasin L. A. Separation of linked markers in Chinese hamster cell hybrids: mitotic recombination is not involved. Genetics. 1978 Dec;90(4):735–760. doi: 10.1093/genetics/90.4.735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sato K., Slesinski R. S., Littlefield J. W. Chemical mutagenesis at the phosphoribosyltransferase locus in cultured human lymphoblasts. Proc Natl Acad Sci U S A. 1972 May;69(5):1244–1248. doi: 10.1073/pnas.69.5.1244. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Seabright M. A rapid banding technique for human chromosomes. Lancet. 1971 Oct 30;2(7731):971–972. doi: 10.1016/s0140-6736(71)90287-x. [DOI] [PubMed] [Google Scholar]
  23. Tarrant G. M., Holliday R. A search for allelic recombination in Chinese hamster cell hybrids. Mol Gen Genet. 1977 Nov 18;156(3):273–279. doi: 10.1007/BF00267182. [DOI] [PubMed] [Google Scholar]

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