NEW YORK – A team of investigators in Canada has identified distinct genetic features in a Canadian Inuit population, including parts of the genome that appear to have been under selection and variants that seem to be linked to increased risk of intracranial aneurysm, a cerebrovascular disorder that is more common in Inuit in the region.
"Future research will build on the findings to determine if these unique genetic traits increase risk of aneurysm, and if so, what interventions can be designed to reduce this risk," senior and corresponding author Guy Rouleau, a neurology researcher at McGill University, said in a statement.
In collaboration with the Nunavik Nutrition and Health Committee and local community members, Rouleau and colleagues generated exome sequences and genotyping profiles for 170 individuals from an Inuit population in Nunavik, Quebec, comparing them to one another and to thousands more modern and ancient genome sequences. Their findings, scheduled to appear online this week in the Proceedings of the National Academy of Sciences, uncovered sequences that offered clues to Nunavik Inuit population history, relationships, and adaptation signatures.
"We identified genetic differentiations in Nunavik Inuit villages that correlate with their migration route and placed Nunavik Inuit in a population tree in relation to Siberian and Native Americans," Rouleau and his co-authors wrote. "Nunavik Inuit also had genetic footprints that reflect high levels of natural selection in functionally relevant genes, from which may arise the genetic risk responsible for their predisposition toward diseases such as intracranial aneurysm."
In addition to identifying missense variants or SNPs with apparent ties to intracranial aneurysm risk in the OR4C3 or SHANK3 genes, respectively, the team identified potential signatures of selection in the Inuit exomes and went on to evaluate the expression of such genes using real-time quantitative PCR.
The authors noted that the Nunavik Inuit "have distinct genetic signatures in pathways involving lipid metabolism and cell adhesion, which suggests differential adaptation to extreme environments in regions under selection that may be associated with risk of [intracranial aneurysms]."
The team's analysis included exome sequences and Illumina array-based genotypes for 155 Inuit individuals from 10 villages in Nunavik, along with 15 more Inuit individuals whose villages of origin were not known.
By comparing these profiles to SNP or sequence profiles from 5,252 individuals from present-day or ancient populations, including Siberian, Native American, North American, and other individuals, the researchers started untangling Inuit relationships. For example, they uncovered genetic ties between the Nunavik Inuit and ancient Paleo-Eskimo, Greenlandic Inuit, and Siberian populations, though most individuals carried little or no ancestry from Europeans or Native Americans from other parts of the continent.
"Aside from a few individuals with recent admixture from Europeans, the Nunavik Inuit have nearly no ancestry from other present-day populations and are distinct from other Arctic Indigenous populations including Greenlandic Inuit," the authors explained, "making the present data a valuable addition for the construction of a genomic reference panel for Arctic Indigenous peoples."
The team did see potential signs of past admixture with Native American populations in Inuit populations from the Ungava Bay village of Kangiqsualujjuaq, on the other hand, and the Ungava Bay Inuit individuals appeared to be genetically distinct from Inuit in the Hudson Bay area.
Based on the data on hand, the researchers estimated that the Nunavik Inuit likely split from Inuit populations in Greenland some 10,500 years ago, subsequently going through a population bottleneck and, potentially, mixing with individuals descended from Paleo-Eskimos, landing at a present-day effective population size of around 3,000 individuals.
"The Nunavik Inuit is a unique population with small [effective population size]," the authors concluded, "and have a substantial ancestry component that had previously been observed primarily in ancient samples."