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Title: A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter
Authors: Marco De Gobbi
Vip Viprakasit
Jim R. Hughes
Chris Fisher
Veronica J. Buckle
Helena Ayyub
Richard J. Gibbons
Douglas Vernimmen
Yuko Yoshinaga
Pieter De Jong
Jan Fang Cheng
Edward M. Rubin
William G. Wood
Don Bowden
Douglas R. Higgs
John Radcliffe Hospital
Mahidol University
Children's Hospital Oakland Research Institute
Lawrence Berkeley National Laboratory
Monash University
Keywords: Multidisciplinary
Issue Date: 26-May-2006
Citation: Science. Vol.312, No.5777 (2006), 1215-1217
Abstract: We describe a pathogenetic mechanism underlying a variant form of the inherited blood disorder α thalassemia. Association studies of affected individuals from Melanesia localized the disease trait to the telomeric region of human chromosome 16, which includes the α-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 non-genic region between the α-globin genes and their upstream regulatory elements. The rSNP creates a new promoterlike element that interferes with normal activation of all downstream α-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.
ISSN: 10959203
Appears in Collections:Scopus 2006-2010

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