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 alpha thalassemia. Association studies of affected individuals from Melanesia localized the disease trait to the telomeric region of human chromosome 16, which includes the alpha-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 alpha-globin genes and their upstream regulatory elements. The rSNP creates a new promoterlike element that interferes with normal activation of all downstream alpha-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.
authors.affiliation: Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: De Gobbi
authors.forename: Vip
authors.initials: V
authors.lastname: Viprakasit
authors.forename: Jim R
authors.initials: JR
authors.lastname: Hughes
authors.forename: Chris
authors.initials: C
authors.lastname: Fisher
authors.forename: Veronica J
authors.initials: VJ
authors.lastname: Buckle
authors.forename: Helena
authors.initials: H
authors.lastname: Ayyub
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gibbons
authors.forename: Douglas
authors.initials: D
authors.lastname: Vernimmen
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yoshinaga
authors.forename: Pieter
authors.initials: P
authors.lastname: de Jong
authors.forename: Jan-Fang
authors.initials: JF
authors.lastname: Cheng
authors.forename: Edward M
authors.initials: EM
authors.lastname: Rubin
authors.forename: William G
authors.initials: WG
authors.lastname: Wood
authors.forename: Don
authors.initials: D
authors.lastname: Bowden
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Higgs
mesh_terms: D001665:Binding Sites; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D004900:Erythroblasts; D050982:GATA1 Transcription Factor / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D005914:Globins / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008542:Melanesia; D018598:Minisatellite Repeats; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D050436:Regulatory Elements, Transcriptional; D014158:Transcription, Genetic; D017085:alpha-Thalassemia / Q000235:genetics*
chemical_list: D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D005914:Globins