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

TY - JOUR

T1 - A selective sweep on a deleterious mutation in CPT1A in Arctic populations

AU - Clemente, Florian J.

AU - Cardona, Alexia

AU - Inchly, Charlotte E.

AU - Peters, Benjamin M.

AU - Jacobs, Guy

AU - Pagani, Luca

AU - Lawson, Daniel J.

AU - Añtao, Tiago

AU - Vicente, Mário

AU - Mitt, Mario

AU - DiGiorgio, Michael

AU - Faltyskova, Zuzana

AU - Xue, Yali

AU - Ayub, Qasim

AU - Szpak, Michal

AU - Mägi, Reedik

AU - Eriksson, Anders

AU - Manica, Andrea

AU - Raghavan, Maanasa

AU - Rasmussen, Morten

AU - Rasmussen, Simon

AU - Willerslev, Eske

AU - Vidal-Puig, Antonio

AU - Tyler-Smith, Chris

AU - Willems, Richard

AU - Nielsen, Rasmus

AU - Metspalu, Mait

AU - Malyarchuk, Boris

AU - Derenko, Miroslava

AU - Kivisild, Toomas

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

U2 - 10.1016/j.ajhg.2014.09.016

DO - 10.1016/j.ajhg.2014.09.016

M3 - Journal article

SN - 0002-9297

VL - 95

SP - 584

EP - 589

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 5

ER -