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Human Molecular Genetics, 2001, Vol. 10, No. 4 371-382
© 2001 Oxford University Press

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

Jonathan Flint1, Cristina Tufarelli1, John Peden1, Kevin Clark1, Rachael J. Daniels1, Ross Hardison2, Webb Miller2, Sjaak Philipsen3, Kian Chen Tan-Un4, Tara McMorrow3, Jonathan Frampton1, Blanche P. Alter5,+, Anna-Marie Frischauf6 and Douglas R. Higgs1,§

1MRC Molecular Haematology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK, 2Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, USA, 3Faculteit der Geneeskunde en Gezondheids-Wetenschappen, Erasmus Universiteit, dr. Molewaterplein 50, Rotterdam, The Netherlands, 4School of Professional and Continuing Education, University of Hong Kong, Pokfulam Road, Hong Kong, 5Division of Pediatric Hematology/Oncology, Children’s Hospital, University of Texas Medical Branch, Galveston, TX, USA and 6Institut fuer Genetik und Allgemeine Biologie, Universitaet Salzburg, Austria

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 (~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.

+ Present address: Clinical Genetics, NCI, Rockville, MD 20852, USA

§ To whom correspondence should be addressed. Tel: +44 1865 222393; Fax: +44 1865 222500; Email: drhiggs@molbiol.ox.ac.uk


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