A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations

Florian J Clemente, Alexia Cardona, Charlotte E Inchley, Benjamin M Peter, Guy Jacobs, Luca Pagani, Daniel J Lawson, Tiago Antão, Mário Vicente, Mario Mitt, Michael DeGiorgio, Zuzana Faltyskova, Yali Xue, Qasim Ayub, Michal Szpak, Reedik Mägi, Anders Eriksson, Andrea Manica, Maanasa Raghavan, Morten RasmussenSimon Rasmussen, Eske Willerslev, Antonio Vidal-Puig, Chris Tyler-Smith, Richard Villems, Rasmus Nielsen, Mait Metspalu, Boris Malyarchuk, Miroslava Derenko, Toomas Kivisild

Research output: Contribution to journalArticle (Academic Journal)peer-review

108 Citations (Scopus)


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 chromosome 11 region containing 79 protein-coding genes as the strongest candidates for positive selection in Northeast Siberians. However, it was not possible to determine which of the genes might be driving the selection signal. Here, using whole-genome high-coverage sequence data, we identified the most likely causative variant as a nonsynonymous G>A transition (rs80356779; c.1436C>T [p.Pro479Leu] on the reverse strand) 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 of one of the strongest selective sweeps reported in humans; this sweep has driven this variant to high frequency in circum-Arctic populations within the last 6-23 ka despite associated deleterious consequences, possibly as a result of the selective advantage it originally provided to either a high-fat diet or a cold environment.

Original languageEnglish
Pages (from-to)584-589
Number of pages6
JournalAmerican Journal of Human Genetics
Issue number5
Publication statusPublished - 23 Oct 2014

Bibliographical note

Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.


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