A selective sweep on a deleterious mutation in the CPT1A gene in Arctic populations

Arctic populations live in an environment characterized by extreme cold and the absence of plant foods for much of the year, and are likely to have undergone genetic adaptations to these environmental conditions in the time they have been living there. Genome-wide selection scans based on genotype data from native Siberians have previously highlighted a 3 Mb region on chromosome 11 containing 79 protein-coding genes as the strongest candidate for positive selection in Northeast Siberians. However, it was not possible to determine which of the genes may be driving the selection signal. Here, using whole-genome high-coverage sequence data from 25 unrelated individuals from the Chukchi, Eskimo and Koryak populations, we identify the most likely causative variant as a non-synonymous G to A transition (rs80356779; p.Pro479Leu, c.1436C>T) in CPT1A, a key regulator of mitochondrial long-chain fatty acid oxidation. Remarkably, the derived allele is associated with hypoketotic hypoglycemia and high infant mortality, yet occurs at high frequency in Canadian and Greenland Inuits, and was also found at 68% frequency in our Northeast Siberian sample. We provide evidence for one of the strongest selective sweeps reported in humans, which has driven this variant to high frequency in circum-Arctic populations within the last 6 to 10 thousand years despite associated deleterious consequences, possibly due to the selective advantage it originally provided to either a high fat diet or a cold environment.