Publication: A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter
Issued Date
2006-05-26
Resource Type
ISSN
10959203
00368075
00368075
Other identifier(s)
2-s2.0-33744475085
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Mahidol University
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SCOPUS
Bibliographic Citation
Science. Vol.312, No.5777 (2006), 1215-1217
Suggested Citation
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 A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter. Science. Vol.312, No.5777 (2006), 1215-1217. doi:10.1126/science.1126431 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/23950
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Title
A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter
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.