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Adaptation to high-fat diet, cold had profound effect on Inuit, including shorter height

The traditional diet of Greenland natives - the Inuit - is held up as an example of how high levels of omega-3 fatty acids can counterbalance the bad health effects of a high-fat diet, but a new study hints that what's true for the Inuit may not be true for everyone else.

The study, which appears in the journal Science, shows that the Inuit and their Siberian ancestors have special mutations in genes involved in fat metabolism that help them partly counteract the effects of a diet high in marine mammal fat, mostly from seals and whales that eat fish with high levels of omega-3 polyunsaturated fatty acids.

Those genetic mutations, found in nearly 100 percent of the Inuit, are found in a mere 2 percent of Europeans and 15 percent of Han Chinese, which means they would synthesize omega-3 polyunsaturated fatty acids differently from the Inuit.

"The original focus on fish oil and omega-3s came from studies of Inuit: on their traditional diet, rich in fat from marine mammals, Inuit seemed quite healthy with a low incidence of cardiovascular disease, so fish oil must be protective," said project leader Rasmus Nielsen, a UC Berkeley professor of integrative biology. "We've now found that they have unique genetic adaptations to this diet, so you cannot extrapolate from them to other populations. It could be very good for the Inuit to eat all these omega-3 fatty acids, but not for the rest of us."

These genetic mutations in the Inuit have more widespread effects. They lower "bad" LDL cholesterol and fasting insulin levels, presumably protecting against cardiovascular disease and diabetes. They also have a significant effect on height, because growth is in part regulated by a person's fatty acid profile. The researchers found that the mutations causing shorter height in the Inuit are also associated with shorter height in Europeans.

"The mutations we found in the Inuit have profound physiological effects, changing the whole profile of fatty acids in the body, plus it reduces their height by 2 centimeters: nearly an inch," said Ida Moltke, a University of Copenhagen associate professor of bioinformatics who is joint first author on the study. "Height is controlled by many genes, but this mutation has one of the strongest effects on height ever found by geneticists."

Personalized diets

Nielsen noted that this is the first evidence that human populations are actually adapted to particular diets; that is, they differ in the way they physiologically respond to diets. Just as genome sequencing can lead to personalized medicine tailored to an individual's specific set of genes, so too may a person's genome dictate a personalized diet.

"People ask themselves whether they should be on a stone-age diet, for example. The response may well depend on their genome," Nielsen said.

Nielsen and his colleagues at UC Berkeley and in Greenland and Denmark came to their conclusions after analyzing the genomes of 191 Greenlanders with a low admixture of European genes (less than 5 percent) and comparing them to the genomes of 60 Europeans and 44 Han Chinese. They looked for mutations occurring in a large percentage of Inuit individuals but in few or no other groups, which indicates that the mutation spread throughout the Inuit because it was somehow useful to their survival while not essential in other groups.

One cluster of mutations - in genes that code for enzymes that desaturate carbon-carbon bonds in fatty acids - stood out strongly, said Anders Albrechtsen, an associate professor of bioinformatics at the University of Copenhagen and a joint project leader. Fatty acids are the fat in our diet, and occur in saturated or monounsaturated and polyunsaturated forms depending on whether the molecules' carbon atoms are linked together with no, one, or more than one double bonds. Saturated fats are considered bad because they raise levels of cholesterol and low density lipoproteins (LDL) in the blood, which leads to plaque formation and clogged arteries. Diets rich in monounsaturated and polyunsaturated fats are linked to lower heart disease. Desaturase enzymes convert dietary fatty acids into fatty acids stored and metabolized by the body.

The mutations common in the Inuit, once known as Eskimos, downregulate the production of both omega-3 and omega-6 polyunsaturated fatty acids, presumably to account for the high amount of these fatty acids coming from the diet. Changing production of one fatty acid affects all fatty acids, however, since they regulate one another in a complex way, Albrechtsen said.

Thus, while it's not clear which specific gene or genes within the cluster is responsible for the alteration in fatty acid metabolism, he said that "when you change the genes that are involved in fatty acid synthesis, you change the whole conversation among fatty acids, and that has a lot of downstream effects."

Adaptation to Ice Age living

The mutations seem to be at least 20,000 years old, and may have helped many groups of humans adapt to high-meat, high-fat, hunter-gatherer diets from large land and marine mammals high in certain types of omega-3 and omega-6 fatty acids, says Matteo Fumagalli, a researcher at University College - London, who is joint first author of the study. They may have arisen among the original Siberians, who have lived in the Arctic for more than 20,000 years, and arrived in Greenland when Inuit settled there about 1,000 years ago.

"We think it is a quite old selection that may have helped humans adapt to the environment during the last Ice Age, but the selection is far stronger in the Inuit than anywhere else," said Fumagalli. "It's fascinating that Greenlanders have a unique genetic makeup that lets them better use their traditional food sources."

The researchers discovered another common mutation in a gene that is involved in the differentiation of brown, subcutaneous fat cells and brite fat cells, the latter of which generate heat. This may also have helped the Inuit adapt to a cold environment.

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