LOOKING back at half a billion years of gene evolution could help uncover the genetic basis of many disorders, including Down鈥檚 syndrome.
As vertebrates evolved, the entire genome was duplicated not once but twice. In theory, excess genes are superfluous and should soon be lost, but in fact many of the duplicated genes survive to this day 鈥� around a third of our genes can be traced back to these two ancient events.
So of Trinity College Dublin, Ireland, set out to investigate why so many duplicated genes were retained. One idea concerns how duplication affects the activity of some genes. Take a process that requires balanced amounts of dozens of different proteins. If the amount of each protein produced depends on the number of copies of a gene, or gene 鈥渄osage鈥�, then duplicating an entire genome will double the amount of each protein, keeping the process balanced. If one of the genes gains or loses a copy, however, it would disrupt the process.
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To test this idea, McLysaght and her colleague Takashi Makino set out to identify dosage-sensitive genes in the human genome by searching for genes that haven鈥檛 gained or lost copies since the ancient duplication events. Because it鈥檚 common to lose or gain genes 鈥� many of us have one or three copies of some genes 鈥� dosage-sensitive genes should stand out. Sure enough, they found that 4600 of the 7000 genes left over from the genome duplications appear to be dose-sensitive (Proceedings of the National Academy of Sciences, ).
鈥淭his is where it gets even more interesting,鈥� says McLysaght. The pair also found that chromosome 21 has the fewest dosage-sensitive genes, which makes sense as people can survive with an extra copy of this chromosome, though they will have Down鈥檚 syndrome. A third copy of any other chromosome is lethal, as a person gets 1.5 times the dose of the genes on it, knocking the chemical balance out of kilter.
Of those genes on chromosome 21 that McLysaght has identified as being dosage-sensitive, many have already been linked to Down鈥檚 syndrome. But the team identified other dosage-sensitive genes, which could also contribute to the disorder. While Down鈥檚 syndrome cannot be reversed, identifying the genes involved could help treat the health problems associated with it.
鈥淚dentifying the genes involved in Down鈥檚 syndrome could help treat related health problems鈥�
The findings are not just relevant to Down鈥檚 syndrome. Dosage-sensitive genes are more likely than other genes to be involved in human disease, because it only takes a small change in their activity to cause problems.
It鈥檚 an interesting and thought-provoking study, says of Baylor College of Medicine in Houston, Texas, who studies the effect of variations in the number of gene copies. Disorders like schizophrenia and autism have recently been linked to huge chunks of missing DNA, Lupski says, and this approach might help pin down the precise genes involved.
