Trisomy 21: how one extra little chromosome throws the entire genome off balance

A study led by Stylianos Antonarakis and his team in the Department of Genetic Medicine and Development at the University of Geneva (UNIGE) Faculty of Medicine, which was published in Nature magazine, shed light on the way in which the extra chromosome 21 upsets the equilibrium of the entire genome, causing a wide variety of symptoms in affected people.

Despite much research, the exact mechanisms which cause the symptoms associated with Down syndrome, including congenital cardiopathy and chronic myeloid leukemia, remain a mystery. According to the «gene dosage disequilibrium» hypothesis, the presence of a third chromosome 21 could influence the expression of all the other genes in the body. In other words, this chromosome could disrupt the process through which information carried in the genes is decoded for the cells to function.

Based on this hypothesis, several research groups have tried, so far without success, to identify the changes to the expression of genes within trisomic cells, in order to link them with the symptoms seen in patients. It should be noted that the level of expression of most genes always varies from one person to another, and that it is therefore extremely hard to distinguish between the changes that are exclusively linked to trisomy 21 and those that are due to natural variation between individuals.

Comparing Identical Twins
However, at the UNIGE, Stylianos Antonarakis’s team has the unique opportunity to examine the genomes of two identical twins, who have the exact same genetic makeup, except for the fact the third chromosome 21 is present in only one of them. This situation is explained by the fact that the chromosome 21 distribution error takes place during the second or third cellular division, and therefore after the original egg splits in two. In order to compare the level of genetic expression between the twins, the researchers used recent, high-performing sequencing technologies, as well as other biotechnological tools developed within the Department of Genetic Medicine and Development. They were thus able to eliminate interindividual variations and identify the modifications to genetic expression that were exclusively due to trisomy 21.

Small chromosome, big consequences

The researchers noticed that the genes located next to that chromosome were disturbed in the exact same way 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 affected people’s entire genome.’

Each chromosome is generally divided into domains, which include the genes with a relatively similar level of production of RNA. 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 in comparison to the healthy twin.

By comparing their results with data previously published by other research groups, the researchers at the UNIGE noticed the correlation between this particular organisation of chromosomes and the position of DNA in the nucleus of each cell. Thus, the domains that were over-expressed in the twin with Down syndrome correspond to the portions of DNA that are known to primarily interact with the peripheral part of the nucleus. The very structure of the DNA is thus altered, which influences the expression of the genes.

This study therefore shows, for the first time, that trisomic cells undergo modifications to their internal structure, leading to changes in the genes’ expression profile. Federico Santoni, who co-authored this study, notes that, ‘These changes do not only affect chromosome 21, but the entirety of the genome. Thus, the presence of about 1% of surplus genetic material in the trisomic cells modifies the function of the entire genome, and disrupts the general equilibrium of genetic expression.’ ‘We could make an analogy with climate change,’ adds Professor Antonarakis. «Even if the temperature rises by only one or two degrees, it will rain a lot less in the tropics, and a lot more in temperate zones. The planet’s entire climatic equilibrium can thus be disrupted by a tiny element.’ This study opens the door to a new way of understanding the molecular mechanisms that explain the manifestations of trisomy 21. The UNIGE team will now continue its research in order to shed light on the molecular mechanisms that cause this generalised disruption of genetic expression, and draw a link between this disrupted genetic expression and the phenotypes that are linked with Down syndrome. The end goal of this research is to find a way to reverse this disruption, and return the genes to their normal expression, in order to correct the syndrome’s cellular anomalies. Progress in this field could also be applied to other diseases which, like trisomy 21, are caused by genetic imbalances.

This study, which lasted several years, received financial support from the Swiss National Science Foundation (FNS) and the European Research Council (ERC).

Contact: Stylianos Antonarakis, phone number: +41 22 379 57 08