Comparative genome analysis delimits a chromosomal domain and identifies key regulatory elements in the α globin cluster

• Published in: Human molecular genetics Vol. 10; no. 4; pp. 371 - 382
• Main Authors: FLINT, Jonathan, TUFARELLI, Cristina, FRAMPTON, Jonathan, ALTER, Blanche P, FRISCHAUF, Anna-Marie, HIGGS, Douglas R, PEDEN, John, CLARK, Kevin, DANIELS, Rachael J, HARDISON, Ross, MILLER, Webb, PHILIPSEN, Sjaak, KIAN CHEN TAN-UN, MCMORROW, Tara
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.02.2001
• Subjects: Animals; Base Sequence; Biological and medical sciences; Chickens; Chromosomes - chemistry; Chromosomes - genetics; Conserved Sequence - genetics; CpG Islands - genetics; Evolution, Molecular; Fishes; Fundamental and applied biological sciences. Psychology; Genes. Genome; Globins - chemistry; Globins - genetics; Humans; Mice; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; Multigene Family - genetics; Nucleic Acid Hybridization - methods; Protein Structure, Tertiary - genetics; Regulatory Sequences, Nucleic Acid - physiology; Human; Nucleotide sequence; Chromosome; Homology; Gene organization; Gene expression; Globin; Vertebrata; Regulation(control); Mammalia; Contig; Gene; Transcription factor
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/10.4.371

We have cloned, sequenced and annotated segments of DNA spanning the mouse, chicken and pufferfish alpha globin gene clusters and compared them with the corresponding region in man. This has defined a small segment ( approximately 135-155 kb) of synteny and conserved gene order, which may contain all of the elements required to fully regulate alpha globin gene expression from its natural chromosomal environment. Comparing human and mouse sequences using previously described methods failed to identify the known regulatory elements. However, refining these methods by ranking identity scores of non-coding sequences, we found conserved sequences including the previously characterized alpha globin major regulatory element. In chicken and pufferfish, regions that may correspond to this element were found by analysing the distribution of transcription factor binding sites. Regions identified in this way act as strong enhancer elements in expression assays. In addition to delimiting the alpha globin chromosomal domain, this study has enabled us to develop a more sensitive and accurate routine for identifying regulatory elements in the human genome.