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Title:
A Regulatory SNP Causes a Human Genetic Disease by Creating a New Transcriptional Promoter
Authors:
De Gobbi, Marco; Viprakasit, Vip; Hughes, Jim R.; Fisher, Chris; Buckle, Veronica J.; Ayyub, Helena; Gibbons, Richard J.; Vernimmen, Douglas; Yoshinaga, Yuko; de Jong, Pieter; Cheng, Jan-Fang; Rubin, Edward M.; Wood, William G.; Bowden, Don; Higgs, Douglas R.
Affiliation:
AA(Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, UK.), AB(Department of Pediatrics, Siriraj Hospital, Mahidol University, Bangkok, Thailand.), AC(Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, UK.), AD(Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, UK.), AE(Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, UK.), AF(Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, UK.), AG(Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, UK.), AH(Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, UK.), AI(BACPAC Resources, Oakland Research Institute Children's Hospital, Oakland, CA, USA.), AJ(BACPAC Resources, Oakland Research Institute Children's Hospital, Oakland, CA, USA.), AK(Genome Science, Genomic Division, Lawrence Berkeley National Laboratory, CA, USA.), AL(Genome Science, Genomic Division, Lawrence Berkeley National Laboratory, CA, USA.), AM(Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, UK.), AN(Department of Anatomy and Cell Biology, Monash University, Melbourne, Australia.), AO(Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, UK.)
Publication:
Science, Volume 312, Issue 5777, pp. 1215-1217 (2006).
Publication Date:
05/2006
Category:
GENETICS
Origin:
SCIENCE
Abstract Copyright:
(c) 2006: Science
DOI:
10.1126/science.1126431
Bibliographic Code:
2006Sci...312.1215D

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.
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