A selective sweep on a deleterious mutation in the CPT1A gene in Arctic populations
Clemente, Florian J
Inchley, Charlotte E
Peter, Benjamin M
Lawson, Daniel J
American Journal of Human Genetics
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Clemente, F. J., Cardona, A., Inchley, C. E., Peter, B. M., Jacobs, G. S., Pagani, L., Lawson, D. J., et al. (2014). A selective sweep on a deleterious mutation in the CPT1A gene in Arctic populations. American Journal of Human Genetics, 95 584-589. https://doi.org/10.1016/j.ajhg.2014.09.016
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 1. However, it was not possible to determine which of the genes may be driving the selection signal. Here, using whole-genome highcoverage sequence data, we identify the most likely causative variant as a non-synonymous G to A transition (rs80356779; c.1436C>T, p.Pro479Leu) 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 2–4, 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 23 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.
This research was supported by ERC Starting Investigator grant (FP7 - 261213) to T.K. http://erc.europa.eu/. CTS, YX, QA and MS were supported by the Wellcome Trust (098051). TA was supported by The Wellcome Trust (WT100066MA). M.M and R.V. were supported by EU ERDF Centre of Excellence in Genomics to EBC; T.K, M.M and R.V. by Estonian Institutional Research grant (IUT24-1), and M.M by Estonian Science Foundation (grant 8973).
European Research Council (261213)
British Heart Foundation (PG/12/53/29714)
External DOI: https://doi.org/10.1016/j.ajhg.2014.09.016
This record's URL: https://www.repository.cam.ac.uk/handle/1810/246360