Abstract
A 95-kb region of the mouse genome spanning the entire α-globin gene cluster was isolated as overlapping cosmid clones and characterized. In addition to the embryonic (ζ) and adult (α) genes, the cloned contig contains the complete N-methylpurine-DNA glycosylase (MPG) gene, the a-globin-positive regulatory element (mHS-26), and a previously unidentified hypervariable region (named the mouse α-HVR). In mice, the distance between the MPG gene and mHS-26 is ~18 kb; between the mHS-26 and the ζ-gene, ~26 kb; from the ζ-gene to the 5′ end of the α-gene, ~16 kb; and the two α-genes are separated by ~12 kb. In human, the corresponding distances are ~27 kb, ~40 kb, ~19 kb, and ~3 kb respectively. The ±-HVR is located ~18 kb upstream of the mouse ζ-globin gene transcription start site and contains a variable copy number tandem repeat (VNTR) array of a 35-bp sequence rich in (G+C) content. The unit sequence of the HVR shares the short core sequence with the HVRs identified in the human a-gene cluster. Thus, this HVR may be a valuable evolutionary marker, as well as a useful genetic marker for the mouse.
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References
Alter, B.P., Goff, S.C. (1980a). A murine model for the switch from fetal to adult hemoglobin during ontogeny. Blood 56, 1100–11054.
Alter, B.P., Goff, S.C. (1980b). Hemoglobin switching: a cellular model. Science 207, 647–649.
Alter, B.P., Wagner, C.K. (1987). A murine model for hemoglobin regulation: hydroxyurea increases mouse minor hemoglobin in vivo. In Developmental Control of Globin Gene Expression, G. Stamatoyannopoulos, A. Nienhuis, eds. (New York: A.R. Liss, Inc.), pp. 479–485.
Alter, B.P., Wagner, C.K., Whitney, J.B., III, Jones, R.T. (1988). Hbac3, due to a spontaneous mutation in a mouse alpha globin gene. Mouse News Lett. 81, 73.
Alter, B.P., Guillory, T., Jones, R.T., Kan, Y.W. (1994). A spontaneous point mutation or gene conversion in a mouse alpha globin gene. Blood 84 Suppl. 1, 262a.
Engelward, B.P., Boosalis, M.S., Chen, B., Deng, Z., Siciliano, M.J., Samson, L.D. (1993). Cloning and characterization of a mouse 3-methylad-enine/7-ethylguanine/3-methylguanine DNA glycosylase cDNA whose gene maps to chromosome II. Carcinogenesis 14, 175–181.
Fischel-Ghodsian, N., Nicholls, R.D., Higgs, D.R. (1987). Long range genome structure around the human a-globin complex analyzed by PFGE. Nucleic Acids Res. 15, 6197–6207.
Goodbourn, S.E.Y., Higgs, D.R., Clegg, J.B., Weatherall, D.J. (1983). Molecular basis of length polymorphism in the human ζ-globin gene complex. Proc. Natl. Acad. Sci. USA 80, 5022–5026.
Gourdon, G., Sharpe, J.A., Higgs, D.R., Wood, W.G. (1995). The mouse a-globin locus regulatory element. Blood 86, 766–775.
Hanahan, D., Meselson, M. (1980). Plasmid screening at high colony density. Gene 10, 63–67.
Hastie, N.D. (1990). Highly repeated DNA families in the genome of Mus musculus. In Genetic Variations and Strains of the Laboratory Mouse, 2nd ed., M.F. Lyon, A.G. Searle, eds. (Oxford, New York, Tokyo: Oxford University Press), pp. 559–573.
Higgs, D.R., Wainscoat, J.S., Flint, J., Hill, A.V.S., Thein, S.L., Nicholls, R.D., Teal, H., Ayyub, H., Peto, T.A., Falusi, A.G., Jarman, A.P., Clegg, J.B., Weatherall, D.J. (1986). Analysis of the human a-globin gene cluster reveals a highly informative genetic locus. Proc. Natl. Acad. Sci. USA 83, 5165–5169.
Higgs, D.R., Vickers, M.A., Wilkie, A.O.M., Pretorius, I-M., Jarman, A.P., Weatherall, D.J. (1989). A review of the molecular genetics of the human α-globin gene cluster. Blood 73, 1081–1104.
Higgs, D.R., Wood, W.G., Jarman, A.P., Sharpe, J.A., Lida, J., Pretorious, I-M., Ayyub, H. (1990). A major positive regulatory region located far upstream of the human α-globin gene locus. Genes & Dev. 4, 1588–1601.
Jarman, A.P., Higgs, D.R. (1988). A new hypervariable marker for the human α-globin gene cluster. Am. J. Hum. Genet. 43, 249–256.
Jarman, A.P., Nicholls, R.D., Weatherall, D.J., Clegg, J.B., Higgs, D.R. (1986). Molecular characterization of a hypervariable region downstream of the human α-globin gene cluster. EMBO J. 5, 1857–1863.
Jarman, A.P., Wood, W.G., Sharpe, J.A., Gourdon, G., Ayyub, H., Higgs, D.R. (1991). Characterization of the major regulatory element upstream of the human α-globin gene cluster. Mol. Cell. Biol. 11, 4679–4689.
Jeffreys, A.J., Wilson, V., Thein, S.L. (1985). Hypervariable ‘minisatellite’ regions in human DNA. Nature 314, 67–73.
Kielman, M.F., Smits, R., Devi, T.S., Fodde, R., Bernini, L.F. (1993). Homology of a 130-kb region enclosing the α-globin gene cluster, the α-locus controlling region, and two non-globin genes in human and mouse. Mamm. Genome 4, 314–323.
Kielman, M.F., Smits, R., Bernini, L.F. (1994). Localization and characterization of the mouse α-globin locus control region. Genomics 21, 431–433.
Leder, A., Weir, L., Leder, P. (1985). Characterization, expression, and evolution of the mouse embryonic ζ-globin gene. Mol. Cell. Biol. 5, 1025–1033.
Lewis, J.B., Cobb, R.R., Whitney, J.B., III (1993). Recombination and genetic polymorphism at the mouse α-globin locus. Genomics 18, 432–434.
Luo, H.Y., Alter, B.P. (1994). The mouse α-globin gene positive regulatory element functions as an enhancer in K562 cells. Blood 84 Suppl. 1, 263a.
Nakamura, Y., Leppert, M., O’Connell, P., Wolff, R., Holm, T., Culver, M., Martin, C., Fujimoto, E., Hoff, M., Kumlin, E., White, R. (1987). Variable number of tandem repeat (VNTR) markers for human gene mapping. Science 235, 1616–1622.
Nishioka, Y., Leder, P. (1979). The complete sequence of a chromosomal mouse a-globin gene reveals elements conserved throughout vertebrate evolution. Cell 8, 875–882.
Proudfoot, N.J., Gil, A., Maniatis, T. (1982). The structure of the human ζ-globin gene and a closely linked, nearly identical pseudogene. Cell 31, 553–563.
Reeders, S.T., Breuning, M.H., Davies, K.E., Nicholls, R.D., Jarman, A.P., Higgs, D.R., Pearson, P.L., Weatherall, D.J. (1985). A highly polymorphic DNA marker linked to adult polycystic kidney disease on chromosome 16. Nature 317, 542–544.
Sambrook, J., Fritsch, E.F., Maniatis, T. (1989). Molecular Cloning: A Laboratory Manual, 2nd ed. (Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press).
Stallings, R.L. (1995). Microsatellite sequences in mammalian genomes. Genomics 25, 107–113.
Stamatoyannopoulos, G., Nienhuis, A.W. (1988). Hemoglobin Switching, Part B: Cellular and Molecular Mechanisms. (New York: Alan R. Liss, Inc.).
Strand, M., Prolla, T.A., Liskay, R.M., Petes, T.D. (1993). Destablization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair. Nature 365, 274–276.
Tatsuka, M., Ibeanu, G.C., Izumi, T., Narayan, S., Ramana, C.V., Kim, N.K., Kang, W., Roy, G., Mitra, S. (1995). Structural organization of the mouse DNA repair gene, N-methylpurine-DNA glycosylase. DNA Cell Biol. 14, 7–45.
Ullrich, A., Dull, T.J., Philips, J.A., Peter, S. (1982). Variation in the sequence and modification state of the human insulin gene flanking regions. Nucleic Acids Res. 10, 225–240.
Vickers, M.A., Vyas, P., Harris, P.C., Simmons, D.L., Higgs, D.R. (1993). Structure of the 3-methyladenine-DNA glycosylase gene and localization close to the 16p telomere. Proc. Natl. Acad. Sci. USA 90, 3437–3441.
Wilkie, A.O.M., Higgs, D.R., Rack, K.A., Buckle, V.J., Spurr, N.K., Fischel-Ghodsian, N., Ceccherini, I., Brown, W.R.A., Harris, P.C. (1991). Stable length polymorphism of up to 260 kb at the tip of the short arm of human chromosome 16. Cell 64, 595–606.
Yanisch-Perron, C., Vieira, J., Messing, J. (1985). Improved M13 phage cloning vectors and host strains: nucleotide sequences of the M13mp18 and pUC-19 vectors. Gene 33, 103–119.
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Zhao, Q.Z., Liang, X.L., Mitra, S. et al. Cloning and characterization of the mouse alpha globin cluster and a new hypervariable marker. Mammalian Genome 7, 749–753 (1996). https://doi.org/10.1007/s003359900225
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DOI: https://doi.org/10.1007/s003359900225