resurrected: woolly mammoth blood protein
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8 May 2010 | NewScientist | 9
LOOKING back at half a billion years of gene evolution could help uncover the genetic basis of many disorders, including Downs 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 around a third of our genes can be traced back to these two ancient events.
So Aoife McLysaght 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 dosage, 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.
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 havent gained or lost copies since the ancient duplication events. Because its common to lose or gain genes many of us have one or three copies of some genes
dosage-sensitive genes should stand out by having two copies. 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, DOI: 10.1073/pnas.0914697107).
This is where it gets even more interesting, 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 Downs 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 Downs syndrome. But the team identified other dosage-sensitive genes, which could also contribute to the disorder. While Downs syndrome cannot be reversed, identifying the genes involved could help treat the health problems associated with it.
The findings are not just relevant to Downs 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. Michael Le Page n
Identifying the genes involved in Downs syndrome could help treat related health problems
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The deep roots of genetic disorders
Back from the dead?
FLOATING in a test tube in a lab in Winnipeg, Canada, is a tiny speck of woolly mammoth a blood protein which may explain how the animals coped with the cold of an ice age.
It is one of the first proteins from a long-dead organism to be resurrected in a living cell. Other extinct animals, including Neanderthals, are sure to follow suit. Such techniques will make it possible to explore exactly how extinct animals lived, rather than making educated guesses based on reconstructed gene sequences.
Woolly mammoths died out about 3500 years ago. They shared an African ancestor with elephants around 7 million years ago, before moving north between 1 and 2 million years ago.
To cope with the cold, they evolved smaller ears and fur coats. Kevin Campbell of the University of Manitoba in Winnipeg, was curious to see if their proteins had changed too. The only way was to resurrect them, he says.
His team began with DNA from
a 43,000-year-old mammoth from Siberia. Its haemoglobin, the blood protein that ferries oxygen around the body, contains three genetic sequences not found in Asian elephants its closest living relative. Campbells team engineered these sequences into an Asian elephants haemoglobin gene, then used Eschicheria coli to
Woolly mammoth blood protein resurrected
produce millions of copies of the resurrected protein.
Haemoglobin is designed to load up on oxygen in the lungs and release the gas when it gets to warmer, exercised muscles. This posed a challenge for mammoths because their muscles probably werent warm enough to coax oxygen away from haemoglobin. The animals solved this problem by evolving a less heat-hungry haemoglobin protein that offloaded oxygen at lower temperatures, the team discovered.
Campbell says his team is resurrecting other mammoth proteins, and he suspects that teams studying other ancient organisms are doing the same. Neanderthals are a prime candidate. A draft of their complete genome will be published shortly, allowing researchers to identify proteins that are different from human versions.
Experiments like Campbells may not explain subtler differences between humans and Neanderthals, says Carles LaLueza-Fox of Pompeu Fabra University in Barcelona, Spain, so an alternative may be to engineer a mouse with Neanderthal genes.
There is good reason to believe this would work. Last year, the team sequencing the Neanderthal genome inserted a human gene linked to language and speech, into mice. The mice with this FOXP2 gene produced different squeaks to normal mice and their brains were wired differently. Neanderthals have the same version of FOXP2 as humans but other genes involved in cognition may vary. Could we soon see mice with Neanderthal intelligence? Watch this space. Ewen Callaway n
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