A MicroRNA Linking Human Positive Selection and Metabolic Disorders

Lifeng Wang, Nasa Sinnott-Armstrong, Alexandre Wagschal, Abigail R. Wark, Joao Paulo Camporez, Rachel J. Perry, Fei Ji, Yoojin Sohn, Justin Oh, Su Wu, Jessica Chery, Bahareh Nemati Moud, Alham Saadat, Simon N. Dankel, Gunnar Mellgren, Divya Sri Priyanka Tallapragada, Sophie Madlen Strobel, Mi Jeong Lee, Ryan Tewhey, Pardis C. SabetiAnne Schaefer, Andreas Petri, Sakari Kauppinen, Raymond T. Chung, Alexander Soukas, Joseph Avruch, Susan K. Fried, Hans Hauner, Ruslan I. Sadreyev, Gerald I. Shulman, Melina Claussnitzer, Anders M. Näär

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


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.

Original languageEnglish
Pages (from-to)684-701.e14
Issue number3
StatePublished - 29 Oct 2020


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