title: Homology of a 130-kb region enclosing the alpha-globin gene cluster, the alpha-locus controlling region, and two non-globin genes in human and mouse.
abstract: The human alpha-globin gene cluster (30 kb) is embedded in a GC-rich isochore very close to the telomere of Chromosome (Chr) 16p. The alpha-Locus Controlling Region (alpha-LCR) is located upstream of the adult alpha-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 alpha-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 alpha-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 alpha-globin cluster. The murine homolog of the alpha-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 alpha-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 alpha-LCR controlling element in the regulation of expression and replication timing of the flanking gene clusters.
authors.affiliation: Department of Human Genetics, Leiden University, The Netherlands.
authors.forename: M F
authors.initials: MF
authors.lastname: Kielman
authors.forename: R
authors.initials: R
authors.lastname: Smits
authors.forename: T S
authors.initials: TS
authors.lastname: Devi
authors.forename: R
authors.initials: R
authors.lastname: Fodde
authors.forename: L F
authors.initials: LF
authors.lastname: Bernini
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D017124:Conserved Sequence; D004247:DNA / Q000235:genetics; D004277:DNA, Single-Stranded; D066246:ErbB Receptors; D015870:Gene Expression; D005914:Globins / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D005810:Multigene Family; D011506:Proteins / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D015183:Restriction Mapping; D012689:Sequence Homology, Nucleic Acid
chemical_list: D004277:DNA, Single-Stranded; D008565:Membrane Proteins; D011506:Proteins; C081962:RHBDF1 protein, human; C484141:Rhbdf1 protein, mouse; D005914:Globins; D004247:DNA; D066246:ErbB Receptors