Genetic architecture and adaptations of Nunavik Inuit

Abstract

The Canadian Inuit have a distinct population background that may entail particular implications for the health of its individuals. However, the number of genetic studies examining this Inuit population is limited, and much remains to be discovered in regard to its genetic characteristics. In this study, we generated whole-exome sequences and genomewide genotypes for 170 Nunavik Inuit, a small and isolated founder population of Canadian Arctic indigenous people. Our study revealed the genetic background of Nunavik Inuit to be distinct from any known present-day population. The majority of Nunavik Inuit show little evidence of gene flow from European or present-day Native American peoples, and Inuit living around Hudson Bay are genetically distinct from those around Ungava Bay. We also inferred that Nunavik Inuit have a small effective population size of 3,000 and likely split from Greenlandic Inuit ∼10.5 kya. Nunavik Inuit went through a bottleneck at approximately the same time and might have admixed with a population related to the Paleo-Eskimos. Our study highlights population-specific genomic signatures in coding regions that show adaptations unique to Nunavik Inuit, particularly in pathways involving fatty acid metabolism and cellular adhesion (CPNE7, ICAM5, STAT2, and RAF1). Subsequent analyses in selection footprints and the risk of intracranial aneurysms (IAs) in Nunavik Inuit revealed an exonic variant under weak negative selection to be significantly associated with IA (rs77470587; P = 4.6 × 10^-8).

Keywords: Nunavik Inuit; demographic history; genetic architecture; intracranial aneurysm; natural selection.

Fig. 1.

Genetic structure of Nunavik Inuit and affinities between Nunavik Inuit and worldwide populations. (A) PCA of Nunavik Inuit and out-of-Africa populations. Red cluster represents Nunavik Inuit, with notable populations identified on the figure in their respective colors. (B) Nunavik Inuit by villages per exome data. Orange colors represent Ungava Bay Inuit; blue colors represent Hudson Bay Inuit. (C) Admixture proportions estimated by ADMIXTURE software assuming K = 8 ancestral components of Nunavik Inuit and present-day populations. Populations are arranged by their geographical distance with Nunavik Inuit, and colors represent the admixture proportions from each ancestral component. The Native American admixture observed in Nunavik Inuit is displayed in dark purple. (D) Maximum-likelihood genetic-drift tree topology relating people from villages of Nunavik Inuit and other Arctic indigenous populations (estimated by Treemix; three migration events displayed). (Scale bar: 10-unit SE of entries in the covariance matrix.) Yoruba is set as outgroup in rooting the tree. Nunavik_NA, Nunavik Inuit recruitment location unknown.

Fig. 2.

Demographic history of Nunavik Inuit in the context of arctic indigenous populations. (A) D-statistics in the form of D (Nunavik, Greenlandic Inuit; X, CHB). X represents each arctic indigenous population. CHB is the outgroup. Dashed line represents D = 0. Error bars show 95% CIs estimated from Z values. D < 0 suggests Nunavik Inuit is closer to population X; D > 0 suggests Greenlandic Inuit is closer to population X. (B) SMC++-inferred historical Ne values in respect to times for Nunavik Inuit and other populations. (C) momi2-fitted demographic history of Nunavik Inuit, Altai, and Saqqaq using single pulse model. Estimates with the highest likelihood from 50 bootstraps resampling data are displayed. “Greenlander” represents a ghost population in Greenland.

Fig. 3.

Manhattan plot depicting PBS of Nunavik Inuit. Variants with PBS > 0.1 in Nunavik Inuit using CHB as a sister population and CEU as an outgroup. Red and pink dots represent exonic variants. Genes included in the subsequent expression analysis are labeled. The y axis is folded at PBS > 2.