Nature Genetics34, 157 - 165 (2003)
Published online: 5 May 2003; | doi:10.1038/ng1157
Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease
Cristina Tufarelli, Jackie A Sloane Stanley, David Garrick, Jackie A Sharpe, Helena Ayyub, William G Wood
& Douglas R Higgs
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
Nearly all human genetic disorders result from a limited repertoire of mutations in an associated gene or its regulatory elements. We recently described an individual with an inherited form of anemia (-thalassemia) who has a deletion that results in a truncated, widely expressed gene (LUC7L) becoming juxtaposed to a structurally normal -globin gene (HBA2). Although it retains all of its local and remote cis-regulatory elements, expression of HBA2 is silenced and its CpG island becomes completely methylated early during development. Here we show that in the affected individual, in a transgenic model and in differentiating embryonic stem cells, transcription of antisense RNA mediates silencing and methylation of the associated CpG island. These findings identify a new mechanism underlying human genetic disease.
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-thalassemia) who has a deletion that results in a truncated, widely expressed gene (LUC7L) becoming juxtaposed to a structurally normal 
- and 
-globin genes occurs within different nuclear domains in haemopoietic cells
