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
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
The human α-globin gene cluster (30 kb) is embedded in a GC-rich isochore very close to the telomere of Chromosome (Chr) 16p. The α-Locus Controlling Region (α-LCR) is located upstream of the adult α-globin genes and has been shown to be essential for their expression. In this study we have been looking for expressed genes in the region upstream of the α-globin cluster to understand the role of the LCR-like element in the expression and replication timing of flanking gene clusters. We show that the upstream α-globin region is conserved over a 75-kb range and includes at least two oppositely transcribed non-globin genes, here referred to as Mid1 and Dist1. Complementary DNA sequences of 250 bp and 2.5 kb from Mid1 (coordinate-68) and Dist1 (coordinate-90 to-99), respectively, were isolated from human and mouse. The deduced partial amino acid sequences of these cDNAs are 81% and 95% identical for the Mid1 and Dist1 gene respectively. We have cloned a mouse cosmid “contig” which includes Dist1, Mid1, and the entire murine α-globin cluster. The murine homolog of the α-LCR was mapped upstream of the mouse globin genes at approximately the same position as in the human locus. Our results indicate that, in mouse and human, the α-globin loci and their flanking sequences are homologous over a range of at least 130 kb. The structural homology of this region in both mammals suggests also a functional one and indicates the mouse as a potential model for studying the role of the α-LCR controlling element in the regulation of expression and replication timing of the flanking gene clusters.
- Bernardi, G. (1989). The isochore organization of the human genome. Annu. Rev. Genet. 23, 637–661.
- Bernardi, G., Olofsson, B., Filipski, J., Zerial, M., Salinas, J., Cuny, G., Meunier-Rotival, M., and Rodier F. (1985). The mosaic genome of warm-blooded vertebrates. Science 228, 953–958.
- Blom van Assendelft, G., Hanscombe, O., Grosveld, F., and Greaves, D.R. (1989). The β-globin dominant control region activates homologous and heterologous promoters in a tissue-specific manner. Cell 56, 969–977.
- Blonden, L.A.J., den Dunnen, J.T., van Paassen, H.M.B., Wapenaar, M.C., Grootscholten, P.M., Ginjaar, H.B., Bakker, E., Pearson, P.L., and van Ommen, G.J.B. (1989). High resolution breakpoint mapping in the DMD gene by whole cosmid hybridization. Nucleic Acids Res 14, 5611–5621.
- Deininger, P.L. and Schmid, C.W. (1979). A study of the evolution of repeated DNA sequences in primates and the existence of a new class of repetitive sequences in primates. J. Mol. Biol. 127, 437–460.
- Devereax, J., Haeberli, P., and Smithies, O. (1984). A comprehensive set of sequence analysis programs for the vax. Nucleic Acids Res. 12, 387–395.
- Fodde, R., Harteveld, C.L., Losekoot, M. Giordano, P.C., Meera Kahn, P., Nayudu, N.V.S., and Bernini, L.F. (1991). Multiple recombination events and responsible for the heterogeneity of β+− haplotypes among forest tribes from Andhra Pradesh, India. Ann. Hum. Genet. 55, 43–50.
- Forrester, W.C., Epner, E., Drisscoll, M.C., Enver, T., Brice, M., Papyannopoulou, T., and Groudine, M. (1990). A deletion of the human β-globin locus activation region causes a major alteration in chromatin structure and replication across the entire β-globin locus. Genes Dev. 4, 1637–1649.
- Frohman, M.A., Dush, M.K., and Martin, G. (1988). Rapid production of full-length cDNAs from rare transcripts: amplification using a single gene-specific oligonucleotide primer. Proc. Natl. Acad. Sci. USA 85, 8998–9002.
- Giordano, P.C., Fodde, R., Losekoot, M., and Bernini, L.F. (1989). Design of a programmable automatic apparatus for the DNA polymerase chain reaction. Technique 1, 16–20.
- Goldman, M.A., Holmquist, G.P., Gray, M.C., Caston, L.A., and Nag, A. (1984). Replication timing of genes and middle repetitive sequences. Science 224, 686–692.
- Gross, D.S. and Garrard, W.T. (1988). Nuclease hypersensitive sites in chromatin. Annu. Rev. Biochem. 57, 159–197.
- Grosveld, F., Blom van Assendelft, G., Greaves, D.R., and Kollias, G. (1987). Position-independent, high-level expression of the human β-globin gene in transgenic mice. Cell 51, 975–985.
- Hanscombe, O., Vidal, M., Kaeda, J., Luzzatto, L., Greaves, D.R., and Grosveld, F. (1989). High-level, erythroid-specific expression of the human α-globin gene in transgenic mice and the production of human hemoglobin in murine erythrocytes. Genes Dev. 3, 1572–1581.
- Hatton, K.S., Dhar, V., Brown, E.H., Iqbal, M.A., Stuart, S., Didamo, V.T., and Schildkraut, C.L. (1988). Replication program of active and inactive multigene families in mammalian cells. Mol. Cell. Biol. 8, 2149–2158.
- Higgs, D.R., Vickers, M.A., Wilkie, A.O.M., Pretorius, I.M., Jarman, A.P., and Wheatherall, 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., Lida, J., Pretorius, I.M., and Ayyub, H. (1990). A major positive regulatory region located far upstream of the human α-globin gene locus. Genes Dev. 4, 1588–1601.
- Holmquist, G.P. (1987). Role of replication time in the control of tissue-specific gene expression. Am. J. Hum. Genet. 40, 151–173.
- Hozier, J., Scalzi, J., Sawyer, J., Carley, N., Applegate, M., Clive, D., and Moore, M.M. (1991). Localization of the mouse thymidine kinase gene to the distal portion of chromosome 11. Genomics 10, 827–830.
- Hultman, T., Stahl, S., Hornes, E., and Uhlén, M. (1989). Direct solid phase sequencing of genomic and plasmid DNA using magnetic beads as solid support. Nucleic Acids Res. 17, 4937–4946.
- Jarman, A.P. and 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., Wood, W.G., Sharpe, J.A., Gourdon, G., Ayyub, H., and Higgs, D.R. (1991). Characterization of the major regulatory element upstream of the human α-globin gene cluster. Mol. Cell Biol. 11, 4679–4689.
- Karlson, S. and Nienhuis, A.W. (1985). Developmental regulation of human globin genes. Annu. Rev. Biochem. 54, 1071–1108.
- Kievits, T., Dauwerse, J.G., Wiegant, J., Devilee, P., Breuning, M.H., Cornelisse, C.J., van Ommen, G.J.B., and Pearson, P.L. (1990). Rapid subchromosomal localization of cosmids by nonradioactive in situ hybridization. Cytogenet. Cell Genet. 53, 134–136.
- Kollias, G., Spanopoulou, E., Grosveld, F., Ritter, M., Beech, J., Morris, R. (1987). Differential regulation of a Thy-1 gene in transgenic mice. Proc. Natl. Acad. Sci. USA 84, 1492–1496.
- Lauer, J., Shen, C.K.J., and Maniatis, T. (1980). The chromosomal arrangement of human alpha-like globin genes: sequence homology and alpha-globin gene deletions. Cell 20, 119–130.
- Leder, A., Swan, D., Ruddle, F., D'Eustachio, P., and Leder, P. (1981). Dispersion of α-like globin genes of the mouse to three different chromosomes. Nature 293, 196–200.
- Leder, A., Weir, L., and Leder, P. (1985). Characterization, expression, and evolution of the mouse embryonic ξ-globin gene. Mol. Cell. Biol. 5, 1025–1033.
- Lin, P.F., Lieberman, H.B., Yeh, D.B., Xu, T., Zhao, T.Y., and Ruddle, F.H. (1985). Molecular cloning and structural analyses of murine thymidine kinase genomic and cDNA sequences. Mol. Cell. Biol. 5, 3149–3156.
- Mouchiroud, D., D'Onofrio, G., Aïssani, B., Macaya, G., Gautier, C., and Bernardi, G. (1991). The distribution of genes in the human genome. Gene 100, 181–187.
- Nicholls, R.D., Fishel-Ghodsian, N., and Higgs, D.R. (1987). Recombination at the human α-globin gene cluster: sequence features and topological constraints. Cell 49, 369–378.
- Orkin, S.H. (1990). Globin gene regulation and switching: circa 1990. Cell 63, 665–672.
- Saadallah, N. and Hultén, M. (1983). Chiasma distribution, genetic lengths, and recombination fractions: a comparison between chromosomes 15 and 16. J. Med. Genet. 20, 290–299.
- Saccone, S., De Sario, A., Della Valle, G., and Bernardi, G. (1992). The highest gene concentrations in the human genome are in T-bands of metaphase chromosomes. Proc. Natl. Acad. Sci. USA 89, 4913–4917.
- Sambrook, J., Fritsch, E.F., and Maniates, T. (1989) Molecular Cloning: A Laboratory Manual, 2nd ed. (Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press).
- Townes, T.M. and Behringer, R.R. (1990). Human globin locus activation region (LAR): role in temporal control. Trends Genet. 6, 9479–9490.
- Wilkie, A.O.M. and Higgs, D.R. (1992). An unusually large (CA)n repeat in the region of divergence between subtelomeric alleles of human chromosome 16p. Genomics 13, 81–88.
- Wilkie, A.O.M., Higgs, D.R., Rack, K.A., Buckle, V.J., Spurr, N.K., Fishel-Godsian, N., Ceccherini, I., Brown, W.R.A., and 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.
- 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
Volume 4, Issue 6 , pp 314-323
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- Industry Sectors