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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.

Original publication




Journal article


Nat Genet

Publication Date





157 - 165


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