title: A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations.
abstract: 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.
authors.affiliation: Department of Archaeology and Anthropology, University of Cambridge, Cambridge CB2 3QG, UK.
authors.forename: Florian J
authors.initials: FJ
authors.lastname: Clemente
authors.affiliation: Department of Archaeology and Anthropology, University of Cambridge, Cambridge CB2 3QG, UK. Electronic address: ac812@cam.ac.uk.
authors.forename: Alexia
authors.initials: A
authors.lastname: Cardona
authors.affiliation: Department of Archaeology and Anthropology, University of Cambridge, Cambridge CB2 3QG, UK.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Inchley
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720-3140, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Peter
authors.affiliation: Mathematical Sciences, University of Southampton, Southampton SO17 1BJ, UK; Institute for Complex Systems Simulation, University of Southampton, Southampton SO17 1BJ, UK.
authors.forename: Guy
authors.initials: G
authors.lastname: Jacobs
authors.affiliation: Department of Archaeology and Anthropology, University of Cambridge, Cambridge CB2 3QG, UK.
authors.forename: Luca
authors.initials: L
authors.lastname: Pagani
authors.affiliation: Heilbronn Institute, School of Mathematics, University of Bristol, Bristol BS8 1TH, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lawson
authors.affiliation: Department of Vector Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK.
authors.forename: Tiago
authors.initials: T
authors.lastname: Antão
authors.affiliation: Department of Archaeology and Anthropology, University of Cambridge, Cambridge CB2 3QG, UK.
authors.forename: Mário
authors.initials: M
authors.lastname: Vicente
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
authors.forename: Mario
authors.initials: M
authors.lastname: Mitt
authors.affiliation: Department of Biology, Pennsylvania State University, University Park, PA 16802-5301, USA.
authors.forename: Michael
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authors.lastname: DeGiorgio
authors.affiliation: Department of Archaeology and Anthropology, University of Cambridge, Cambridge CB2 3QG, UK.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Faltyskova
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Yali
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Qasim
authors.initials: Q
authors.lastname: Ayub
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Michal
authors.initials: M
authors.lastname: Szpak
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
authors.forename: Reedik
authors.initials: R
authors.lastname: Mägi
authors.affiliation: Department of Zoology, University of Cambridge, Cambridge CB2 3EJ, UK; Integrative Systems Biology Laboratory, King Abdullah University of Science and Technology, Thuwal 23955-6900, Kingdom of Saudi Arabia.
authors.forename: Anders
authors.initials: A
authors.lastname: Eriksson
authors.affiliation: Department of Zoology, University of Cambridge, Cambridge CB2 3EJ, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Manica
authors.affiliation: Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Copenhagen 1350, Denmark.
authors.forename: Maanasa
authors.initials: M
authors.lastname: Raghavan
authors.affiliation: Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Copenhagen 1350, Denmark.
authors.forename: Morten
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authors.lastname: Rasmussen
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kongens Lyngby 2800, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Rasmussen
authors.affiliation: Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Copenhagen 1350, Denmark.
authors.forename: Eske
authors.initials: E
authors.lastname: Willerslev
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Medical Research Council Metabolic Diseases Unit, Department of Clinical Biochemistry, University of Cambridge and Institute of Metabolic Science, Cambridge CB2 2QR, UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Tyler-Smith
authors.affiliation: Department of Evolutionary Biology, Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia; Estonian Biocentre, Tartu 51010, Estonia; Estonian Academy of Sciences, Tallinn 10130, Estonia.
authors.forename: Richard
authors.initials: R
authors.lastname: Villems
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720-3140, USA.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Nielsen
authors.affiliation: Department of Evolutionary Biology, Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia; Estonian Biocentre, Tartu 51010, Estonia.
authors.forename: Mait
authors.initials: M
authors.lastname: Metspalu
authors.affiliation: Institute of Biological Problems of the North, Russian Academy of Sciences, Magadan 685000, Russia.
authors.forename: Boris
authors.initials: B
authors.lastname: Malyarchuk
authors.affiliation: Institute of Biological Problems of the North, Russian Academy of Sciences, Magadan 685000, Russia.
authors.forename: Miroslava
authors.initials: M
authors.lastname: Derenko
authors.affiliation: Department of Archaeology and Anthropology, University of Cambridge, Cambridge CB2 3QG, UK; Estonian Biocentre, Tartu 51010, Estonia. Electronic address: tk331@cam.ac.uk.
authors.forename: Toomas
authors.initials: T
authors.lastname: Kivisild