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
We describe a pathogenetic mechanism underlying a variant form of the inherited blood disorder 
thalassemia. Association studies of affected individuals from Melanesia localized the disease trait to the telomeric region of human chromosome 16, which includes the -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 -globin genes and their upstream regulatory elements. The rSNP creates a new promoterlike element that interferes with normal activation of all downstream -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.
To whom correspondence should be addressed. E-mail: doug.higgs{at}imm.ox.ac.uk
