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Science 26 May 2006:
Vol. 312. no. 5777, pp. 1215 - 1217
DOI: 10.1126/science.1126431
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Reports

A Regulatory SNP Causes a Human Genetic Disease by Creating a New Transcriptional Promoter

Marco De Gobbi,1* Vip Viprakasit,2* Jim R. Hughes,1 Chris Fisher,1 Veronica J. Buckle,1 Helena Ayyub,1 Richard J. Gibbons,1 Douglas Vernimmen,1 Yuko Yoshinaga,3 Pieter de Jong,3 Jan-Fang Cheng,4 Edward M. Rubin,4 William G. Wood,1 Don Bowden,5 Douglas R. Higgs1{ddagger}

We describe a pathogenetic mechanism underlying a variant form of the inherited blood disorder {alpha} thalassemia. Association studies of affected individuals from Melanesia localized the disease trait to the telomeric region of human chromosome 16, which includes the {alpha}-globin gene cluster, but no molecular defects were detected by conventional approaches. After resequencing and using a combination of chromatin immunoprecipitation and expression analysis on a tiled oligonucleotide array, we identified a gain-of-function regulatory single-nucleotide polymorphism (rSNP) in a nongenic region between the {alpha}-globin genes and their upstream regulatory elements. The rSNP creates a new promoterlike element that interferes with normal activation of all downstream {alpha}-like globin genes. Thus, our work illustrates a strategy for distinguishing between neutral and functionally important rSNPs, and it also identifies a pathogenetic mechanism that could potentially underlie other genetic diseases.

1 Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
2 Department of Pediatrics, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
3 BACPAC Resources, Oakland Research Institute Children's Hospital, Oakland, CA, USA.
4 Genome Science, Genomic Division, Lawrence Berkeley National Laboratory, CA, USA.
5 Department of Anatomy and Cell Biology, Monash University, Melbourne, Australia.

* These authors contributed equally to this work.

{ddagger} To whom correspondence should be addressed. E-mail: doug.higgs{at}imm.ox.ac.uk

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