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

• Published in: The American Journal of Human Genetics
• Main Authors: Clemente, Florian J., Cardona, Alexia, Inchley, Charlotte E., Peter, Benjamin M., Jacobs, Guy, Pagani, Luca, Lawson, Daniel John, Antão, Tiago, Vicente, Mário, Mitt, Mario, DeGiorgio, Michael, Faltyskova, Zuzana, Xue, Yali, Ayub, Qasim, Szpak, Michal, Mägi, Reedik, Eriksson, Anders, Manica, Andrea, Raghavan, Maanasa, Rasmussen, Morten Arendt Rendt, Rasmussen, Simon B., Willerslev, Eske, Vidal-Puig, Antonio J., Tyler-Smith, Chris, Villems, Richard, Nielsen, Rasmus Wedel, Metspalu, Mait, Malyarchuk, Boris A., Derenko, Miroslava V., Kivisild, Toomas
• Other Authors: Biological and Environmental Sciences and Engineering (BESE) Division, Bioscience Program, Integrative Systems Biology Lab, Department of Archaeology and Anthropology, University of CambridgeCambridge, United Kingdom, Department of Integrative Biology, University of California, BerkeleyBerkeley, CA, United States, Mathematical Sciences, University of SouthamptonSouthampton, United Kingdom, Institute for Complex Systems Simulation, University of SouthamptonSouthampton, United Kingdom, Heilbronn Institute, School of Mathematics, University of BristolBristol, United Kingdom, Department of Vector Biology, Liverpool School of Tropical MedicineLiverpool, United Kingdom, Estonian Genome Center, University of TartuTartu, Estonia, Department of Biology, Pennsylvania State UniversityUniversity Park, PA, United States, Wellcome Trust Sanger InstituteHinxton, United Kingdom, Department of Zoology, University of CambridgeCambridge, United Kingdom, Centre for GeoGenetics, Natural History Museum of Denmark, University of CopenhagenCopenhagen, Denmark, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of DenmarkKongens Lyngby, Denmark, Medical Research Council Metabolic Diseases Unit, Department of Clinical Biochemistry, University of Cambridge and Institute of Metabolic ScienceCambridge, United Kingdom, Department of Evolutionary Biology, Institute of Molecular and Cell Biology, University of TartuTartu, Estonia, Estonian BiocentreTartu, Estonia, Estonian Academy of SciencesTallinn, Estonia, Institute of Biological Problems of the North, Russian Academy of SciencesMagadan, Russian Federation
• Format: Article in Journal/Newspaper
• Language: unknown
• Published: Elsevier BV 2014
• Subjects: Arctic; Greenland; inuits
• Online Access: http://hdl.handle.net/10754/563835; 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 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. This research was supported by European Research Council Starting Investigator grant FP7-261213 to T.K. C.T.-S., Y.X., Q.A., and M.S. were supported by Wellcome Trust grant 098051, and T.A. was supported by Wellcome Trust grant WT100066MA. M. Metspalu and R.V. received supported from the European Union European Regional Development Fund Centre of Excellence in Genomics to the Estonian Biocentre. T.K, M. Metspalu, and R.V. were supported by Estonian Institutional Research grant IUT24-1, and M. Metspalu received Estonian Science Foundation grant 8973.