Human Molecular Genetics Advance Access published online on July 15, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn205
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A large deletion in the human 
-globin cluster caused by a replication error is associated with an unexpectedly mild phenotype
1 Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, UK 2 National Haemoglobinopathy Reference Laboratory, Oxford Haemophilia Centre, Churchill Hospital, Oxford, OX3 7LJ, UK
* To whom correspondence should be addressed at: Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS,UK. Tel: +441865 222392; Fax: +441865 222500; Email: david.garrick{at}imm.ox.ac.uk
Received June 6, 2008; Revised July 11, 2008; Accepted July 11, 2008
We have characterized a newly identified 16.6 kb deletion which removes a significant proportion of the human 
-globin cluster including the 
1, D, 1 and 2 globin genes but leaves the duplicated 1 gene intact. This complicated rearrangement results from a combination of slippage and strand switching at sites of microhomology during replication. Functional analysis shows that expression of the remaining 1 gene is increased, rather than down regulated by this deletion. This could be related to its proximity to the remote upstream -globin regulatory elements or reduced competition for these elements in the absence of the dominant 2 globin gene. The finding of a very mild phenotype associated with such an extensive deletion in the -globin cluster implies that much of the DNA removed by the deletion is likely to be functionally unimportant. These findings suggest that other than the upstream regulatory elements and promoter proximal elements there are unlikely to be additional positive cis-acting sequences in the -globin cluster.