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

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

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A genomic analysis of RNA polymerase II modification and chromatin architecture related to 3' end RNA polyadenylation.

Z. Lian, A. Karpikov, J. Lian, M. C. Mahajan, S. Hartman, M. Gerstein, M. Snyder, and S. M. Weissman (2008)
Genome Res. 18, 1224-1237
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Chromatin profiling across the human tumour necrosis factor gene locus reveals a complex, cell type-specific landscape with novel regulatory elements.

J. M. Taylor, K. Wicks, C. Vandiedonck, and J. C. Knight (2008)
Nucleic Acids Res.
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Qualifying the relationship between sequence conservation and molecular function.

G. M. Cooper and C. D. Brown (2008)
Genome Res. 18, 201-205
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Allelic Imbalance at rs6983267 Suggests Selection of the Risk Allele in Somatic Colorectal Tumor Evolution.

S. Tuupanen, I. Niittymaki, K. Nousiainen, S. Vanharanta, J.-P. Mecklin, K. Nuorva, H. Jarvinen, S. Hautaniemi, A. Karhu, and L. A. Aaltonen (2008)
Cancer Res. 68, 14-17
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Molecular Cloning of a Brain-specific, Developmentally Regulated Neuregulin 1 (NRG1) Isoform and Identification of a Functional Promoter Variant Associated with Schizophrenia.

W. Tan, Y. Wang, B. Gold, J. Chen, M. Dean, P. J. Harrison, D. R. Weinberger, and A. J. Law (2007)
J. Biol. Chem. 282, 24343-24351
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Breast cancer prognostication and prediction in the postgenomic era.

P. Lonning, S Knappskog, V Staalesen, R Chrisanthar, and J. Lillehaug (2007)
Ann. Onc. 18, 1293-1306
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Identification of polymorphic antioxidant response elements in the human genome.

X. Wang, D. J. Tomso, B. N. Chorley, H.-Y. Cho, V. G. Cheung, S. R. Kleeberger, and D. A. Bell (2007)
Hum. Mol. Genet. 16, 1188-1200
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