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Team Characterizes Genetic Adaptations to Diet, Cold in Greenland's Inuit Population

NEW YORK (GenomeWeb) – Genetic adaptations detected in the genomes of individuals from Greenland's Inuit population are revealing mechanisms by which humans can become adept at dealing with fatty food and extreme cold.

As they reported in today's issue of Science, researchers from the US, UK, Denmark, and Greenland scrutinized SNP patterns in almost 200 Inuit individuals from Greenland, comparing them with genotyping patterns in dozens of European or Han Chinese individuals. They then used exome sequencing to verify and further flesh out their view of genes that have been subject to selection in the Inuit.

The analysis suggests Greenland's Inuit carry versions of fatty acid desaturase (FADS) enzymes and other genes that stave off the potentially negative effects of consuming large amounts of marine mammal fat and omega-3 polyunsaturated fatty acids — including alterations that keep levels of "bad" low-density lipoprotein (LDL) cholesterol and omega-fatty acids low, and adaptations to lower obesity and insulin resistance risk.

Such findings fit with past epidemiological studies demonstrating low rates of heart disease in the Inuit, noted the study's author Rasmus Nielsen, an integrative biology and statistics researcher at the University of California at Berkeley.

But they also argue against the notion that specific components in the traditional Inuit diet — such as omega-3 fatty acids — will necessarily be protective against heart disease and other maladies across human populations, Nielsen told GenomeWeb.

The current study did not address this directly, he emphasized. Even so, the findings hint that specific human populations will likely respond differently to a given diet based on their ancestors' adaptations to varied environments and with diverse food sources.

While several epidemiological studies of Greenland's indigenous population have been done in the past, Nielsen explained, relatively little was known about the genetic patterns and adaptations present in the Inuit population.

As part of an ongoing collaboration with epidemiologists working with the Greenland Inuit population, members of the team began searching for diet and temperature-related adaptations in 191 Inuit individuals who had low levels of European ancestry in their genomes (around 0.5 percent, on average).

Using genotyping profiles generated with the Illumina MetaboChip array — a chip designed to assess variants implicated in cardiac and/or metabolism-related traits in past GWAS — the researchers searched for alleles found at dramatically different frequencies in the Inuit compared to individuals in other populations.

When they compared Inuit SNP patterns to those in 60 individuals with European ancestry and 44 individuals of Han Chinese descent, the investigators narrowed in on a chromosome 11 locus showing strong signals of selection in the Inuit.

That region is home to three FADS genes coding for enzymes involved in the production of polyunsaturated fatty acids, the team explained.

The derived version of these alleles — which are found at low frequency in European and Han Chinese individuals, but more common amongst Inuit individuals — appear to alter fatty acid network regulation in ways that curb the production of fatty acids present at high levels in marine mammal-based diets.

"The genetic network is rewired to make fewer of these [fatty acids] themselves," Nielsen said. "This clearly shows that you can't extrapolate [dietary effects] from the Inuit to other populations."

Consequently, he noted that more research is needed to understand how FADS and other genes vary depending on diet in populations from other parts of the world as well.

The search for Inuit-specific dietary and environmental adaptations led to other intriguing signals as well. Among them: FN3KRP gene alleles suspected of stemming oxidative stress in the face of elevated polyunsaturated fatty acid intake as well as variants in and around a transcription factor gene involved in the differentiation of 'brite' fat cells, which generate heat as they oxidize lipids.

Through exome sequencing on another 18 Inuit individuals, meanwhile, the researchers unearthed Inuit-specific adaptations involving the cardiomyopathy-related gene DSP and a gene called ANGPTL6 that's been linked to lower obesity and insulin-resistance levels.

And at least some of the Inuit-specific adaptations seemed to have secondary effects on other physical features, the team noted.

Most notably, the FADS gene alleles associated with altered fatty acid production in the Inuit appeared to not only diminish LDL cholesterol levels, but were also associated with shorter-than-usual stature — an effect that's apparently shared in other populations that carry the variants at low frequency.

The team speculated that the effect on height may reflect tweaks to the fatty acid network that alter growth hormone release, though it has not directly tested that assertion at this point, Nielsen explained.

Finally, he and his colleagues noted that the adaptations they detected seem to stretch back to before the Inuit population arrived in Greenland, perhaps reflecting adaptations that began in the Inuit's Siberian ancestors, who may have become adapted to coastal cold climates and/or to the consumption of other types of meat.

In an accompanying commentary, University of Pennsylvania genetics and biology researcher Sarah Tishkoff discussed the benefits of profiling indigenous groups and populations adapted to extreme environments, provided such studies are done with appropriate consent, cultural respect, and community engagement.

"[D]ialogue between researchers and indigenous communities is needed to ensure benefit sharing," Tishkoff wrote, noting that it is "critical to include diverse people in genomic studies to understand the phenotypic impact of the full range of human genetic variation and to ensure that all peoples benefit from this knowledge."