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dc.contributor.authorClemente, Florian Jen
dc.contributor.authorCardona, Alexiaen
dc.contributor.authorInchley, Charlotte Een
dc.contributor.authorPeter, Benjamin Men
dc.contributor.authorJacobs, Guy Sherwinen
dc.contributor.authorPagani, Lucaen
dc.contributor.authorLawson, Daniel Jen
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, Mortenen
dc.contributor.authorRasmussen, Simonen
dc.contributor.authorWillerslev, Eskeen
dc.contributor.authorVidal‐Puig, Antonioen
dc.contributor.authorTyler‐Smith, Chrisen
dc.contributor.authorVillems, Richarden
dc.contributor.authorNielsen, Rasmusen
dc.contributor.authorMetspalu, Maiten
dc.contributor.authorMalyarchuk, Borisen
dc.contributor.authorDerenko, Miroslavaen
dc.contributor.authorKivisild, Toomasen
dc.date.accessioned2014-11-12T15:04:13Z
dc.date.available2014-11-12T15:04:13Z
dc.date.issued2014-10-23en
dc.identifier.citationAmerican Journal of Human Genetics Volume 95, Issue 5, p584–589, 6 November 2014. DOI: 10.1016/j.ajhg.2014.09.016en
dc.identifier.issn0002-9297
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/246360
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 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.
dc.description.sponsorshipThis 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).
dc.languageEnglishen
dc.language.isoenen
dc.publisherElsevier
dc.titleA selective sweep on a deleterious mutation in the CPT1A gene in Arctic populationsen
dc.typeArticle
dc.description.versionThis is the accepted manuscript. The final version is available from Cell/Elsevier at http://www.cell.com/ajhg/abstract/S0002-9297%2814%2900422-4.en
prism.endingPage589
prism.publicationDate2014en
prism.publicationNameAmerican Journal of Human Geneticsen
prism.startingPage584
prism.volume95en
dc.rioxxterms.funderERC
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.projectid098051
dc.rioxxterms.projectidWT100066MA
dcterms.dateAccepted2014-09-29en
rioxxterms.versionofrecord10.1016/j.ajhg.2014.09.016en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2014-10-23en
dc.contributor.orcidCardona, Alexia [0000-0002-7877-5565]
dc.contributor.orcidJacobs, Guy Sherwin [0000-0002-4698-7758]
dc.contributor.orcidEriksson, Anders [0000-0003-3436-3726]
dc.contributor.orcidManica, Andrea [0000-0003-1895-450X]
dc.contributor.orcidRaghavan, Maanasa [0000-0003-1997-0739]
dc.contributor.orcidWillerslev, Eske [0000-0002-7081-6748]
dc.contributor.orcidKivisild, Toomas [0000-0002-6297-7808]
dc.identifier.eissn1537-6605
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idBBSRC (BB/H005854/1)
pubs.funder-project-idMRC (MC_UU_12012/2)
pubs.funder-project-idMRC (MC_G0802535)
pubs.funder-project-idBBSRC (BB/J009865/1)
pubs.funder-project-idBBSRC (BB/H002731/1)
pubs.funder-project-idMRC (G0600717B)
pubs.funder-project-idEuropean Research Council (261213)
pubs.funder-project-idBritish Heart Foundation (PG/12/53/29714)
rioxxterms.freetoread.startdate2015-10-23


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