Marco De GobbiVip ViprakasitJim R. HughesChris FisherVeronica J. BuckleHelena AyyubRichard J. GibbonsDouglas VernimmenYuko YoshinagaPieter De JongJan Fang ChengEdward M. RubinWilliam G. WoodDon BowdenDouglas R. HiggsJohn Radcliffe HospitalMahidol UniversityChildren's Hospital Oakland Research InstituteLawrence Berkeley National LaboratoryMonash University2018-08-202018-08-202006-05-26Science. Vol.312, No.5777 (2006), 1215-121710959203003680752-s2.0-33744475085https://repository.li.mahidol.ac.th/handle/20.500.14594/23950We 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.Mahidol UniversityMultidisciplinaryArticleSCOPUS10.1126/science.1126431