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. 1980 Dec;66(6):1319–1325. doi: 10.1172/JCI109984

Two different molecular organizations account for the single alpha-globin gene of the alpha-thalassemia-2 genotype.

S H Embury, J A Miller, A M Dozy, Y W Kan, V Chan, D Todd
PMCID: PMC371617  PMID: 7440717

Abstract

The alpha-thalassemia-2 (alpha-thal-2) genotype or mild alpha-thalassemia gene consists of a single structural alpha-globin gene on the chromosome that normally bears two alpha-globin genes. We used blot hybridization to investigate variation in the molecular organization of this genotype and to determine the distributions of these variations in the world population. Two different patterns of gene organization responsible for the alpha-thal-2 genotype were found: the first was the result of a 4.2-kilobase pair deletion involving the normal 5' alpha-globin gene (leftward deletion alpha-thal-2 genotype), and the second probably the result of a crossover deletion of a DNA fragment bridging the two normal alpha-globin genes (rightward deletion alpha-thal-2- genotype). The rightward deletion was found in all 9 Black subjects, all 8 Mediterranean subjects, and 4 of 13 Chinese subjects. The leftward deletion was found in four and the nondeletion alpha-thalassemia lesion was found in five of the nine remaining Chinese subjects. It is likely that these deletions are related to specific DNA sequences that determine DNA recombinational events.

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Selected References

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

  1. Altay C., Ringelhann B., Yawson G. I., Bruce-Tagoe A. A., Konotey-Ahulu F. I., James L., Gravely M., Huisman T. H. Hemoglobin alpha chain deficiency in black children with variable quantities of hemoglobin Bart's at birth. Pediatr Res. 1977 Feb;11(2):147–152. doi: 10.1203/00006450-197702000-00017. [DOI] [PubMed] [Google Scholar]
  2. Bolivar F., Rodriguez R. L., Betlach M. C., Boyer H. W. Construction and characterization of new cloning vehicles. I. Ampicillin-resistant derivatives of the plasmid pMB9. Gene. 1977;2(2):75–93. doi: 10.1016/0378-1119(77)90074-9. [DOI] [PubMed] [Google Scholar]
  3. Brittenham G. Genetic model for observed distributions of proportions of haemoglobin in sickle-cell trait. Nature. 1977 Aug 18;268(5621):635–636. doi: 10.1038/268635a0. [DOI] [PubMed] [Google Scholar]
  4. Davis J. R., Jr, Dozy A. M., Lubin B., Koenig H. M., Pierce H. I., Stamatoyannopoulos G., Kan Y. W. Alpha-thalassemia in blacks is due to gene deletion. Am J Hum Genet. 1979 Sep;31(5):569–573. [PMC free article] [PubMed] [Google Scholar]
  5. Dozy A. M., Kan Y. W., Embury S. H., Mentzer W. C., Wang W. C., Lubin B., Davis J. R., Jr, Koenig H. M. alpha-Globin gene organisation in blacks precludes the severe form of alpha-thalassaemia. Nature. 1979 Aug 16;280(5723):605–607. doi: 10.1038/280605a0. [DOI] [PubMed] [Google Scholar]
  6. Embury S. H., Lebo R. V., Dozy A. M., Kan Y. W. Organization of the alpha-globin genes in the Chinese alpha-thalassemia syndromes. J Clin Invest. 1979 Jun;63(6):1307–1310. doi: 10.1172/JCI109426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Flavell R. A., Kooter J. M., De Boer E., Little P. F., Williamson R. Analysis of the beta-delta-globin gene loci in normal and Hb Lepore DNA: direct determination of gene linkage and intergene distance. Cell. 1978 Sep;15(1):25–41. doi: 10.1016/0092-8674(78)90080-6. [DOI] [PubMed] [Google Scholar]
  8. Friedman M. J. Oxidant damage mediates variant red cell resistance to malaria. Nature. 1979 Jul 19;280(5719):245–247. doi: 10.1038/280245a0. [DOI] [PubMed] [Google Scholar]
  9. Goossens M., Dozy A. M., Embury S. H., Zachariades Z., Hadjiminas M. G., Stamatoyannopoulos G., Kan Y. W. Triplicated alpha-globin loci in humans. Proc Natl Acad Sci U S A. 1980 Jan;77(1):518–521. doi: 10.1073/pnas.77.1.518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Higgs D. R., Old J. M., Pressley L., Clegg J. B., Weatherall D. J. A novel alpha-globin gene arrangement in man. Nature. 1980 Apr 17;284(5757):632–635. doi: 10.1038/284632a0. [DOI] [PubMed] [Google Scholar]
  11. Hood L., Campbell J. H., Elgin S. C. The organization, expression, and evolution of antibody genes and other multigene families. Annu Rev Genet. 1975;9:305–353. doi: 10.1146/annurev.ge.09.120175.001513. [DOI] [PubMed] [Google Scholar]
  12. Kan Y. W., Dozy A. M. Polymorphism of DNA sequence adjacent to human beta-globin structural gene: relationship to sickle mutation. Proc Natl Acad Sci U S A. 1978 Nov;75(11):5631–5635. doi: 10.1073/pnas.75.11.5631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kan Y. W., Dozy A. M., Stamatoyannopoulos G., Hadjiminas M. G., Zachariades Z., Furbetta M., Cao A. Molecular basis of hemoglobin-H disease in the Mediterranean population. Blood. 1979 Dec;54(6):1434–1438. [PubMed] [Google Scholar]
  14. Kan Y. W., Dozy A. M., Trecartin R., Todd D. Identification of a nondeletion defect in alpha-thalassemia. N Engl J Med. 1977 Nov 17;297(20):1081–1084. doi: 10.1056/NEJM197711172972002. [DOI] [PubMed] [Google Scholar]
  15. Lauer J., Shen C. K., Maniatis T. The chromosomal arrangement of human alpha-like globin genes: sequence homology and alpha-globin gene deletions. Cell. 1980 May;20(1):119–130. doi: 10.1016/0092-8674(80)90240-8. [DOI] [PubMed] [Google Scholar]
  16. Luzzatto L. Genetics of red cells and susceptibility to malaria. Blood. 1979 Nov;54(5):961–976. [PubMed] [Google Scholar]
  17. Mears J. G., Ramirez F., Leibowitz D., Bank A. Organization of human delta--and beta-globin genes in cellular DNA and the presence of intragenic inserts. Cell. 1978 Sep;15(1):15–23. doi: 10.1016/0092-8674(78)90079-x. [DOI] [PubMed] [Google Scholar]
  18. Mears J. G., Ramirez F., Leibowitz D., Nakamura F., Bloom A., Konotey-Ahulu F., Bank A. Changes in restricted human cellular DNA fragments containing globin gene sequences in thalassemias and related disorders. Proc Natl Acad Sci U S A. 1978 Mar;75(3):1222–1226. doi: 10.1073/pnas.75.3.1222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Orkin S. H., Old J., Lazarus H., Altay C., Gurgey A., Weatherall D. J., Nathan D. G. The molecular basis of alpha-thalassemias: frequent occurrence of dysfunctional alpha loci among non-Asians with Hb H disease. Cell. 1979 May;17(1):33–42. doi: 10.1016/0092-8674(79)90292-7. [DOI] [PubMed] [Google Scholar]
  20. Orkin S. H. Selective restriction endonuclease cleavage of human globin genes. J Biol Chem. 1978 Jan 10;253(1):12–15. [PubMed] [Google Scholar]
  21. Orkin S. H. The duplicated human alpha globin genes lie close together in cellular DNA. Proc Natl Acad Sci U S A. 1978 Dec;75(12):5950–5954. doi: 10.1073/pnas.75.12.5950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ottolenghi S., Lanyon W. G., Paul J., Williamson R., Weatherall D. J., Clegg J. B., Pritchard J., Pootrakul S., Boon W. H. The severe form of alpha thalassaemia is caused by a haemoglobin gene deletion. Nature. 1974 Oct 4;251(5474):389–392. doi: 10.1038/251389a0. [DOI] [PubMed] [Google Scholar]
  23. Robinson L. H., Landy A. HindII, HindIII, and HpaI restriction fragment maps of the left arm of bacteriophage lambda DNA. Gene. 1977 Sep;2(1):33–54. doi: 10.1016/0378-1119(77)90020-8. [DOI] [PubMed] [Google Scholar]
  24. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  25. Stahl F. W. Special sites in generalized recombination. Annu Rev Genet. 1979;13:7–24. doi: 10.1146/annurev.ge.13.120179.000255. [DOI] [PubMed] [Google Scholar]
  26. Taylor J. M., Dozy A., Kan Y. W., Varmus H. E., Lie-Injo L. E., Ganesan J., Todd D. Genetic lesion in homozygous alpha thalassaemia (hydrops fetalis). Nature. 1974 Oct 4;251(5474):392–393. doi: 10.1038/251392a0. [DOI] [PubMed] [Google Scholar]
  27. Wasi P. Is the human globin -chain locus duplicated? Br J Haematol. 1973 Mar;24(3):267–273. doi: 10.1111/j.1365-2141.1973.tb01651.x. [DOI] [PubMed] [Google Scholar]
  28. Wilson J. T., Wilson L. B., deRiel J. K., Villa-komaroff L., Efstratiadis A., Forget B. G., Weissman S. M. Insertion of synthetic copies of human globin genes into bacterial plasmids. Nucleic Acids Res. 1978 Feb;5(2):563–581. doi: 10.1093/nar/5.2.563. [DOI] [PMC free article] [PubMed] [Google Scholar]

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