Cell
Volume 183, Issue 3, 29 October 2020, Pages 684-701.e14
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Article
A MicroRNA Linking Human Positive Selection and Metabolic Disorders

https://doi.org/10.1016/j.cell.2020.09.017Get rights and content
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Highlights

  • The long haplotype at 2q21.3 is linked to positive selection and metabolic disorders

  • The miR-128-1 microRNA is located at the center of the 2q21.3 locus

  • miR-128-1 controls energy expenditure and contributes to metabolic disease

  • Ancient adaptation to famine and metabolic diseases may be linked through miR-128-1

Summary

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.

Cited by (0)

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These authors contributed equally

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Present address: Cardiovascular & Metabolism, Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, PA 19477, USA

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Present address: Vertex Pharmaceuticals, Watertown, MA 02472, USA

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Present address: Ribeirao Preto School of Medicine, University of Sao Paulo, Sao Paulo 14049-90, Brazil

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Present address: Vanderbilt University, Nashville, TN 37235, USA

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Present address: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA

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Present address: Dana-Farber Cancer Institute, Boston, MA 02215, USA

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Present address: Department of Human Nutrition, Food and Animal Sciences, University of Hawaii, Honolulu, HI 96822, USA

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Present address: The Jackson Laboratory, Bar Harbor, ME 04609, USA

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Present address: Diabetes, Obesity and Metabolism Institute, Mt. Sinai School of Medicine, New York, NY 10029, USA

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Present address: Department of Nutritional Sciences & Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA

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