TY - JOUR
T1 - A MicroRNA Linking Human Positive Selection and Metabolic Disorders
AU - Wang, Lifeng
AU - Sinnott-Armstrong, Nasa
AU - Wagschal, Alexandre
AU - Wark, Abigail R.
AU - Camporez, Joao Paulo
AU - Perry, Rachel J.
AU - Ji, Fei
AU - Sohn, Yoojin
AU - Oh, Justin
AU - Wu, Su
AU - Chery, Jessica
AU - Moud, Bahareh Nemati
AU - Saadat, Alham
AU - Dankel, Simon N.
AU - Mellgren, Gunnar
AU - Tallapragada, Divya Sri Priyanka
AU - Strobel, Sophie Madlen
AU - Lee, Mi Jeong
AU - Tewhey, Ryan
AU - Sabeti, Pardis C.
AU - Schaefer, Anne
AU - Petri, Andreas
AU - Kauppinen, Sakari
AU - Chung, Raymond T.
AU - Soukas, Alexander
AU - Avruch, Joseph
AU - Fried, Susan K.
AU - Hauner, Hans
AU - Sadreyev, Ruslan I.
AU - Shulman, Gerald I.
AU - Claussnitzer, Melina
AU - Näär, Anders M.
N1 - Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/10/29
Y1 - 2020/10/29
N2 - Positive selection in Europeans at the 2q21.3 locus harboring the lactase gene has been attributed to selection for the ability of adults to digest milk to survive famine in ancient times. However, the 2q21.3 locus is also associated with obesity and type 2 diabetes in humans, raising the possibility that additional genetic elements in the locus may have contributed to evolutionary adaptation to famine by promoting energy storage, but which now confer susceptibility to metabolic diseases. We show here that the miR-128-1 microRNA, located at the center of the positively selected locus, represents a crucial metabolic regulator in mammals. Antisense targeting and genetic ablation of miR-128-1 in mouse metabolic disease models result in increased energy expenditure and amelioration of high-fat-diet-induced obesity and markedly improved glucose tolerance. A thrifty phenotype connected to miR-128-1-dependent energy storage may link ancient adaptation to famine and modern metabolic maladaptation associated with nutritional overabundance. A positively selected locus linked to ancient adaptation to milk consumption is also linked to metabolic disorders and contains a microRNA that controls energy expenditure, potentially connecting these two phenotypes and the role of selection in metabolic disease.
AB - Positive selection in Europeans at the 2q21.3 locus harboring the lactase gene has been attributed to selection for the ability of adults to digest milk to survive famine in ancient times. However, the 2q21.3 locus is also associated with obesity and type 2 diabetes in humans, raising the possibility that additional genetic elements in the locus may have contributed to evolutionary adaptation to famine by promoting energy storage, but which now confer susceptibility to metabolic diseases. We show here that the miR-128-1 microRNA, located at the center of the positively selected locus, represents a crucial metabolic regulator in mammals. Antisense targeting and genetic ablation of miR-128-1 in mouse metabolic disease models result in increased energy expenditure and amelioration of high-fat-diet-induced obesity and markedly improved glucose tolerance. A thrifty phenotype connected to miR-128-1-dependent energy storage may link ancient adaptation to famine and modern metabolic maladaptation associated with nutritional overabundance. A positively selected locus linked to ancient adaptation to milk consumption is also linked to metabolic disorders and contains a microRNA that controls energy expenditure, potentially connecting these two phenotypes and the role of selection in metabolic disease.
UR - http://www.scopus.com/inward/record.url?scp=85094173709&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2020.09.017
DO - 10.1016/j.cell.2020.09.017
M3 - Article
C2 - 33058756
AN - SCOPUS:85094173709
SN - 0092-8674
VL - 183
SP - 684-701.e14
JO - Cell
JF - Cell
IS - 3
ER -