Adaptive PRKAA1 variant in Andeans is associated with improved ventilation and sleep phenotypes

Adaptive PRKAA1 variant in Andeans is associated with improved ventilation and sleep phenotypes

Summary: Highland groups have adapted to the extreme selective pressures of hypoxia at high altitude via alterations in the oxygen-transport cascade. PRKAA1, which encodes the catalytic subunit of the AMP-activated protein kinase (AMPK), is a notable target of natural selection in Andeans and has be...

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Main Authors: Elijah S. Lawrence, Wanjun Gu, Mitchell C. Kong, Santiago Fassardi, Cecilia Anza-Ramirez, Esteban A. Moya, Erica C. Heinrich, James J. Yu, Jeremy E. Orr, Steven Y. Cao, Ana Sanchez-Azofra, Amy M. Cole, James E. Hall, Andrew Lin, Pamala N. DeYoung, Gustavo Vizcardo-Galindo, Jose-Luis Macarlupu, Rómulo Figueroa-Mujíca, Daniela Bermudez, Noemi Corante, Gianpiero L. Cavalleri, Eduardo Gaio, A. Mark Evans, Frank L. Powell, Atul Malhotra, Rany M. Salem, Francisco C. Villafuerte, Tatum S. Simonson
Format: Article
Language:English
Published: Elsevier 2025-08-01
Series:iScience
Subjects:
Health sciences
Medicine
Medical specialty
Precision medicine
atural sciences
Biological sciences
Online Access:http://www.sciencedirect.com/science/article/pii/S2589004225011721
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Summary:Summary: Highland groups have adapted to the extreme selective pressures of hypoxia at high altitude via alterations in the oxygen-transport cascade. PRKAA1, which encodes the catalytic subunit of the AMP-activated protein kinase (AMPK), is a notable target of natural selection in Andeans and has been associated with protective fetal phenotypes in this population. AMPK is a universal cellular energy sensor involved in a multitude of physiological processes, including ventilation and the hypoxic ventilatory response (HVR) in animal models. We localized a signal of positive selection and identified a regulatory promoter variant (rs10035235, C>T) of adaptive significance that is associated with ventilatory and sleep phenotypes in male Andean highlanders as well as sleep phenotypes in publicly available lowland cohorts. This work identifies a functional, adaptive, and likely pleiotropic regulatory variant in PRKAA1 in Andeans that may accentuate hypoxia-induced ventilation and provide protection from sleep-disordered breathing in both high- and lowland populations.
ISSN:2589-0042

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