A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations.
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 da...
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ftunivcam:oai:www.repository.cam.ac.uk:1810/246360 2024-05-12T07:59:30+00:00 A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations. Clemente, Florian J Cardona, Alexia Inchley, Charlotte E Peter, Benjamin M Jacobs, Guy Pagani, Luca Lawson, Daniel J 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 Rasmussen, Simon Willerslev, Eske Vidal-Puig, Antonio Tyler-Smith, Chris Villems, Richard Nielsen, Rasmus Metspalu, Mait Malyarchuk, Boris Derenko, Miroslava Kivisild, Toomas 2014-11-06 application/pdf https://www.repository.cam.ac.uk/handle/1810/246360 English eng eng Elsevier BV http://dx.doi.org/10.1016/j.ajhg.2014.09.016 Am J Hum Genet https://www.repository.cam.ac.uk/handle/1810/246360 0604 Genetics Genetics Human Genome Article 2014 ftunivcam 2024-04-17T23:31:20Z 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 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). This is the accepted manuscript. The final version is available from Cell/Elsevier at http://www.cell.com/ajhg/abstract/S0002-9297%2814%2900422-4. Article in Journal/Newspaper Arctic Greenland inuits Apollo - University of Cambridge Repository Arctic Greenland |
institution |
Open Polar |
collection |
Apollo - University of Cambridge Repository |
op_collection_id |
ftunivcam |
language |
English |
topic |
0604 Genetics Genetics Human Genome |
spellingShingle |
0604 Genetics Genetics Human Genome Clemente, Florian J Cardona, Alexia Inchley, Charlotte E Peter, Benjamin M Jacobs, Guy Pagani, Luca Lawson, Daniel J 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 Rasmussen, Simon Willerslev, Eske Vidal-Puig, Antonio Tyler-Smith, Chris Villems, Richard Nielsen, Rasmus Metspalu, Mait Malyarchuk, Boris Derenko, Miroslava Kivisild, Toomas A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations. |
topic_facet |
0604 Genetics Genetics Human Genome |
description |
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 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). This is the accepted manuscript. The final version is available from Cell/Elsevier at http://www.cell.com/ajhg/abstract/S0002-9297%2814%2900422-4. |
format |
Article in Journal/Newspaper |
author |
Clemente, Florian J Cardona, Alexia Inchley, Charlotte E Peter, Benjamin M Jacobs, Guy Pagani, Luca Lawson, Daniel J 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 Rasmussen, Simon Willerslev, Eske Vidal-Puig, Antonio Tyler-Smith, Chris Villems, Richard Nielsen, Rasmus Metspalu, Mait Malyarchuk, Boris Derenko, Miroslava Kivisild, Toomas |
author_facet |
Clemente, Florian J Cardona, Alexia Inchley, Charlotte E Peter, Benjamin M Jacobs, Guy Pagani, Luca Lawson, Daniel J 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 Rasmussen, Simon Willerslev, Eske Vidal-Puig, Antonio Tyler-Smith, Chris Villems, Richard Nielsen, Rasmus Metspalu, Mait Malyarchuk, Boris Derenko, Miroslava Kivisild, Toomas |
author_sort |
Clemente, Florian J |
title |
A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations. |
title_short |
A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations. |
title_full |
A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations. |
title_fullStr |
A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations. |
title_full_unstemmed |
A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations. |
title_sort |
selective sweep on a deleterious mutation in cpt1a in arctic populations. |
publisher |
Elsevier BV |
publishDate |
2014 |
url |
https://www.repository.cam.ac.uk/handle/1810/246360 |
geographic |
Arctic Greenland |
geographic_facet |
Arctic Greenland |
genre |
Arctic Greenland inuits |
genre_facet |
Arctic Greenland inuits |
op_relation |
https://www.repository.cam.ac.uk/handle/1810/246360 |
_version_ |
1798840871467089920 |