Mechanisms of Down syndrome decrypted

Additional chromosome in trisomy 21 confuses the whole genome

04/17/2014

Down syndrome (trisomy 21) is the most common genetic mental disability. Only one chromosome is too much in the genome of those affected. As this minimal deviation leads to a disruption of the overall equilibrium in the genome, scientists from the Institute of Genetic Medicine and Development at the Faculty of Medicine of the University of Geneva have now analyzed in a hitherto unique study and their findings in the journal „Nature“ released.

Most common cause of congenital mental retardation
Just a few days ago, an online petition for disabled people with a lot of support reached 12,000 supporters. This is to allow the eleven-year-old Henri access to the high school. The boy was born with Down syndrome. About one in 750 children is born with Down syndrome. It is thus the most common cause of an innate mental disability. It is caused by the fact that the chromosome 21 is present in the cells in triplicate instead of the usual double.

For their study, the scientists around Stylianos Antonarakis from the University of Geneva offered the „very rare chance“, to study the phenomenon of trisomy 21 on two identical twins. The twins had exactly the same genome, with the exception of Trisomy 21, according to the Geneva University Communication. „To compare the levels of gene expression between the twins, researchers used the latest technology in high-throughput sequencing and bioinformatics“, the university continues to report. In this way, the scientists were able to, „eliminate interindividual variability and identify changes in gene expression attributable solely to trisomy 21.“

The researchers found that the supernumerary chromosome 21 confuses gene expression in cells on a multiple level. „In other words, the chromosome interferes with the processes by which information in the genes is stored and decoded“, reports the University of Geneva. So far, the proof of this theory has been extremely difficult, since the expression of most genes naturally varies from person to person and therefore the changes specific to trisomy 21 could be difficult to identify. As part of their study, the researchers have now been able to decipher the mechanisms by which the additional chromosome leads to the symptoms of Down's syndrome, such as congenital heart disease or chronic myeloid leukemia.

Gene expression is permanently disturbed by additional chromosome
According to the results of the additional chromosome, the expression of the genes was completely deregulated, even on sections of the genome that were supposedly unrelated to the affected chromosome pair. „ We were very surprised by this result“, said Audrey Letourneau, co-lead author of the study. This „Small supernumerary chromosome has a great impact on the entire genome of the affected people“, Letourneau continues. Some genes were significantly more activated in the affected twin than in the healthy, others much weaker. The change of nearly one percent of the genetic material have „the function of the genome as a whole and the overall balance of gene expression“ disturbed, explained Professor Antonarakis. Here the comparison with the climate is close. „When the temperature rises one or two degrees, it will rain less in the tropics and more in the temperate zones. The climate balance of the entire planet would be disturbed by a very small part“, explained the study leader. Similar is the effect of the additional chromosome on gene expression. (Fp)