Down syndrome, also known as trisomy 21, is one of the most common cause of intellectual disability and occurs in one in every eight hundred births.

Comparing Identical Twins
At UNIGE, Stylianos Antonarakis's team has the unique opportunity to examine the genomes of two identical twins with the exact same genetic makeup, except for an extra chromosome 21 present in one of them. Indeed, the chromosome 21 distribution error can take place during an early cellular division, after the original fertilized egg splits in two. To compare gene expression levels between the twins, UNIGE researchers used recent, high-throughput sequencing technologies and other biotechnological tools developed within the Department of Genetic Medicine and Development, or in collaboration with scientists in Strasbourg, Barcelona, Amsterdam, and Seattle. They were thus able to eliminate interindividual variations and identify the changes in gene expression exclusively due to trisomy 21.
Small chromosome, big consequences
The researchers noticed that the expression of genes located on all the other chromosomes (outside of chromosome 21) were disturbed in trisomic cells. "We were very surprised by this result", explains Audrey Letourneau, who co-authored this study. "It does seem that this extra little chromosome has a huge influence on the entire genome."
Generally speaking, chromosomes are divided into domains that contain genes with rather similar levels of RNA production. RNA is the molecule which transmits the information contained in DNA, before this information is translated into proteins with precise functions. In the twin with Down syndrome, the domains are sometimes over-expressed, and sometimes under-expressed when compared with the healthy twin. By comparing their results with data previously published by other research groups, UNIGE researchers noticed that this specific chromosomes organization correlates with DNA position in the cell nucleus. Therefore, domains over-expressed in the twin with Down syndrome correspond to portions of DNA known to primarily interact with the nucleus periphery.
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This study opens the door to a new way of understanding the molecular mechanisms that explain the symptoms of Down syndrome. The UNIGE team will now continue its research to understand molecular mechanisms at stake, and link this disrupted gene expression with the phenotypes associated with Down syndrome. The end goal of this research is to find ways to revert the dysregulation of cellular gene expression back to normal, with the objective to correct the cellular abnormalities in this disease. Progress in this field could also be applied to other diseases with genome imbalance.
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Source-Eurekalert