Humans may be easier to clone than sheep

HUMANS COULD be technically easier to clone than sheep, cows, pigs and mice because they possess a genetic benefit that prevents foetal overgrowth, a major obstacle encountered in cloning animals, according to new research by Duke University Medical Centre scientists.

The genetic benefit seems subtle, say researchers, but it is so important that it creates fundamental differences between humans and other animals in the way they regulate foetal growth and cancer susceptibility. The research is published in Human Molecular Genetics. The genetic benefit they found was : humans and primates have two activated copies of a gene - insulin-like growth factor II receptor (IGF2R).

Offspring receive one functional copy from each parent But sheep, pigs, mice receive only one functional copy of this gene because of a rare phenomenon known as genomic imprinting, in which the gene is literally stamped with markings that turn off its function.

With the second copy of the gene permanently imprinted, such animals are more prone to two major problems -- developing cancer and suffering from cloning complications like overly large offspring, immature lung development, enlarged hearts and reduced immunity to disease, say the scientists.

"This is a concrete genetic data showing that the cloning process could be less complicated in humans than in sheep," said Keith Killian, a Duke University Medical Center molecular evolutionist and first author of the study. "Only one in 300 sheep embryos takes hold, and up to half of these embryos have large offspring syndrome, which can kill the mother and foetus. Since humans are not imprinted at IGF2R, then foetal overgrowth would not be predicted to occur if humans were cloned."

The problems associated with cloning an imprinted animal occur when scientists manipulate the fledgling embryos in the laboratory, the Duke researchers said. While the IGF2R gene remains intact, the "epigenetic" markings -- crucial information layered on top of the gene sequence are inadvertently damaged and alter the way the gene functions, said Randy Jirtle, professor of radiation oncology at Duke. For reasons unknown, he says, the very state of being imprinted appears to make imprinted animals more susceptible to epigenetic damage.

However, many scientists have believed that up to 50 percent of people are imprinted at the IGF2R gene and are more susceptible to cancer and, potentially, cloning complications.

But scientists, found no evidence that any humans possess an imprinted IGF2R. Also, decades of successfully manipulating human embryos through in vitro fertilization have not resulted in large offspring syndrome.

While it is true that the IGF2R gene is frequently mutated in human breast, colon, head and neck, liver and lung cancers, the researchers said that is not because humans are imprinted at IGF2R. The gene, like any other involved in cancer, simply becomes mutated, or defective, for a variety of reasons unrelated to imprinting. Mutating two copies of the IGF2R gene is much more difficult and statistically unlikely than mutating a single copy, which is why mice and other imprinted animals are more susceptible to cancer than are humans, said Jirtle.

Because mice and rats comprise 90 percent of the animals used in research, scientists should take into account the rodents' genetic susceptibility to cancer when they are applying their study conclusions to humans, said Killian.

Clinical development of hundreds of potential disease-treating drugs have been abandoned after rodent studies have shown them to be potential carcinogens studies that might have had a different outcome if rodents possessed two functional copies of IGF2R. You could theoretically give new life to thousands of discarded compounds by retesting them in animals that, like humans, have both functional copies of IGF2R," said Killian.

To test for the presence of imprinting in humans and other mammals, the Duke team used six different single nucleotide polymorphisms, distinctive genetic markers called "SNIPs."

Scientists worldwide are now using SNIPs to map the entire human genome because the older method, variable number tandem repeat (VNTR), frequently produces ambiguous results. The Duke team's results definitively showed that human IGF2R is not imprinted. The gene is also not imprinted in primates or our closest non- primate relatives, including tree shrews and lemurs. In fact, the team's evolutionary research shows that all these mammals lost imprinting of the IGF2R gene approximately 70 million years ago.

sThe modern-day absence of imprinting in all primates and their closest relatives bolsters the team's genetic data showing that no humans are imprinted at IGF2R, said Jirtle.

"While there are approximately 45 imprinted genes identified in mammals, IGF2R is the only gene known to have gained imprinting at one point and later lost it during primate evolution," said Jirtle. In contrast, IGF2R is still imprinted in all other placental mammals and marsupials included in their study -- including opossums, mice, rats, sheep, cows and pigs.

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