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Remarkable Twin Study Widens View of Down’s Syndrome

A large coalition of European and American researchers this week published a new gene expression study of trisomy 21, better known as Down’s syndrome, using a novel cellular model of the disorder. Induced pluripotent stem cells were derived from a set of identical twins, only one of which possessed the third copy of chromosome 21 that causes the symptoms of Down’s syndrome. Because identical twins are genetically identical, twin studies are frequently used to control for the effects of genetic variation when studying variables affected by both genetic and environmental factors. However, a resource like this has never previously been available for research in Down’s syndrome.

This study, coordinated by senior author Stylianos E. Antonarakis of the University of Geneva Medical School in Switzerland, conducted whole transcriptome sequencing of the twin cell lines, looking for differences in the expression levels of genes between the two samples. While a prevailing theory of Down’s syndrome has held that symptoms are caused primarily by overexpression of genes on chromosome 21, the researchers’ analysis showed significant upregulation and downregulation of diverse genes across the entire genome in the cells with trisomy 21. The regions where gene expression was dysregulated were consistent across multiple cell samples. Moreover, these domains tended to cluster around regions of the genome involved in DNA replication, and in the nuclear lamina, a structural component of the nucleus that plays roles in cell division. These findings give new insights into the cellular activities that may be involved in Down’s syndrome, and suggest that future research into genes implicated in Down’s syndrome should not be restricted to chromosome 21.

These effects of trisomy 21 on gene expression had not been detected in previous studies, because genetic differences between individuals masked the specific gene expression changes caused by the presence of a third copy of chromosome 21. The study was published in Nature along with a commentary by two experts in DNA replication from Florida State University.

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