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

Handle URI:
http://hdl.handle.net/10754/563835
Title:
A selective sweep on a deleterious mutation in CPT1A in Arctic populations
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 ( 0000-0003-3436-3726 ) ; 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
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.
KAUST Department:
Integrative Systems Biology Lab; Bioscience Program
Publisher:
Elsevier BV
Journal:
The American Journal of Human Genetics
Issue Date:
Nov-2014
DOI:
10.1016/j.ajhg.2014.09.016
PubMed ID:
25449608
PubMed Central ID:
PMC4225582
Type:
Article
ISSN:
00029297
Sponsors:
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.
Additional Links:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225582
Appears in Collections:
Articles; Bioscience Program

Full metadata record

DC FieldValue Language
dc.contributor.authorClemente, Florian J.en
dc.contributor.authorCardona, Alexiaen
dc.contributor.authorInchley, Charlotte E.en
dc.contributor.authorPeter, Benjamin M.en
dc.contributor.authorJacobs, Guyen
dc.contributor.authorPagani, Lucaen
dc.contributor.authorLawson, Daniel Johnen
dc.contributor.authorAntão, Tiagoen
dc.contributor.authorVicente, Márioen
dc.contributor.authorMitt, Marioen
dc.contributor.authorDegiorgio, Michaelen
dc.contributor.authorFaltyskova, Zuzanaen
dc.contributor.authorXue, Yalien
dc.contributor.authorAyub, Qasimen
dc.contributor.authorSzpak, Michalen
dc.contributor.authorMägi, Reediken
dc.contributor.authorEriksson, Andersen
dc.contributor.authorManica, Andreaen
dc.contributor.authorRaghavan, Maanasaen
dc.contributor.authorRasmussen, Morten Arendt Rendten
dc.contributor.authorRasmussen, Simon B.en
dc.contributor.authorWillerslev, Eskeen
dc.contributor.authorVidal-Puig, Antonio J.en
dc.contributor.authorTyler-Smith, Chrisen
dc.contributor.authorVillems, Richarden
dc.contributor.authorNielsen, Rasmus Wedelen
dc.contributor.authorMetspalu, Maiten
dc.contributor.authorMalyarchuk, Boris A.en
dc.contributor.authorDerenko, Miroslava V.en
dc.contributor.authorKivisild, Toomasen
dc.date.accessioned2015-08-03T12:16:13Zen
dc.date.available2015-08-03T12:16:13Zen
dc.date.issued2014-11en
dc.identifier.issn00029297en
dc.identifier.pmid25449608en
dc.identifier.doi10.1016/j.ajhg.2014.09.016en
dc.identifier.urihttp://hdl.handle.net/10754/563835en
dc.description.abstractArctic 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.en
dc.description.sponsorshipThis 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.en
dc.publisherElsevier BVen
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225582en
dc.titleA selective sweep on a deleterious mutation in CPT1A in Arctic populationsen
dc.typeArticleen
dc.contributor.departmentIntegrative Systems Biology Laben
dc.contributor.departmentBioscience Programen
dc.identifier.journalThe American Journal of Human Geneticsen
dc.identifier.pmcidPMC4225582en
dc.contributor.institutionDepartment of Archaeology and Anthropology, University of CambridgeCambridge, United Kingdomen
dc.contributor.institutionDepartment of Integrative Biology, University of California, BerkeleyBerkeley, CA, United Statesen
dc.contributor.institutionMathematical Sciences, University of SouthamptonSouthampton, United Kingdomen
dc.contributor.institutionInstitute for Complex Systems Simulation, University of SouthamptonSouthampton, United Kingdomen
dc.contributor.institutionHeilbronn Institute, School of Mathematics, University of BristolBristol, United Kingdomen
dc.contributor.institutionDepartment of Vector Biology, Liverpool School of Tropical MedicineLiverpool, United Kingdomen
dc.contributor.institutionEstonian Genome Center, University of TartuTartu, Estoniaen
dc.contributor.institutionDepartment of Biology, Pennsylvania State UniversityUniversity Park, PA, United Statesen
dc.contributor.institutionWellcome Trust Sanger InstituteHinxton, United Kingdomen
dc.contributor.institutionDepartment of Zoology, University of CambridgeCambridge, United Kingdomen
dc.contributor.institutionCentre for GeoGenetics, Natural History Museum of Denmark, University of CopenhagenCopenhagen, Denmarken
dc.contributor.institutionCenter for Biological Sequence Analysis, Department of Systems Biology, Technical University of DenmarkKongens Lyngby, Denmarken
dc.contributor.institutionMedical Research Council Metabolic Diseases Unit, Department of Clinical Biochemistry, University of Cambridge and Institute of Metabolic ScienceCambridge, United Kingdomen
dc.contributor.institutionDepartment of Evolutionary Biology, Institute of Molecular and Cell Biology, University of TartuTartu, Estoniaen
dc.contributor.institutionEstonian BiocentreTartu, Estoniaen
dc.contributor.institutionEstonian Academy of SciencesTallinn, Estoniaen
dc.contributor.institutionInstitute of Biological Problems of the North, Russian Academy of SciencesMagadan, Russian Federationen
kaust.authorEriksson, Andersen

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