New clues on understanding Down syndrome

Genetic studies at TCD on evolution have turned up some unexpected results, including completely new information about how Down syndrome arises

SOMETIMES discoveries turn up in the most unexpected of places. You might not expect a trawl through genetic evolution over the last half-billion years to open up exciting new avenues for understanding Down syndrome – but it has.

The original idea was to look at the evolutionary history of gene duplication, a process that can provide the raw material to carve out new genes, says Dr Aoife McLysaght from TCD’s Smurfit Institute of Genetics.

“Normally you get a new gene by duplicating an existing one and then tinkering with it so it has a new function. We are interested in this process.”

Of particular note are dramatic events called “whole genome duplications” where all of an organism’s DNA gets duplicated in one go. Two such duplications that took place around 500 million years ago are thought to have been important for the evolution of vertebrates, or back-boned animals including ourselves, explains McLysaght.

After such widespread duplication most of the “spare” genes are lost, but she and colleague Dr Takashi Makino were interested to see which genes stuck around over time instead. “There’s a theory that these could be genes that have a particular relationship to each other,” she says.

If such same-team genes are all duplicated together it doesn’t cause a problem, but if their relative amounts change it could adversely affect how they work together in practice.

Much like an orchestra, if all instruments are duplicated the volume just gets louder, but if the orchestra suddenly acquires three extra woodwind sections the music itself no longer sounds good.

The TCD study, which is published online this week in the Proceedings of the National Academy of Sciences, found that the genes which survived after whole genome duplication events did not undergo subsequent, smaller duplications that would mess up their dosage balance.

Lineages where the dosage was no longer in balance were probably less likely to survive, explains McLysaght.

“You see that [small-scale] gene duplication is happening a lot – but not to these genes,” she says. “So we demonstrated strong evidence for this hypothesis.”

But what’s the link with Down syndrome? “It is an example of how dosage is sometimes important, because you have an extra copy of chromosome 21,” explains McLysaght, whose work is funded under a Science Foundation Ireland President of Ireland Young Researcher Award. “None of the genes are abnormal, you just have more of them than you should.”

Down syndrome, or trisomy 21, is less severe than trisomies of other non-sex chromosomes in humans, and the new findings provide a clue why: “We saw that chromosome 21 had the smallest number of these dosage-balanced genes, which is completely consistent with having the least severe effects.”

The TCD researchers have identified 40 dosage-balanced genes on chromosome 21, and they include 12 of the 16 genes that were previously associated with Down syndrome.

McLysaght believes that the remainder of the dosage-balanced genes that their new study picked out on chromosome 21 could also include important genes involved in the condition and warrant further investigation.

“Down syndrome cannot be reversed, however there are many later life symptoms like Alzheimers disease and heart problems for which there is a therapeutic window. There is therefore great interest in discovering the particular genes on chromosome 21 that are responsible for the syndrome with the aim of developing therapies for some of the symptoms.”