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 (alpha-thalassemia) who has a deletion that results in a truncated, widely expressed gene (LUC7L) becoming juxtaposed to a structurally normal alpha-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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Animals, Base Sequence, Cell Line, Chromosomes, Human, Pair 16, CpG Islands, DNA, DNA Methylation, Gene Silencing, Globins, Humans, Mice, Mice, Transgenic, Models, Genetic, Promoter Regions, Genetic, RNA, Antisense, Transcription, Genetic, alpha-Thalassemia