Lawrence Elijah S, Gu Wanjun, Kong Mitchell C, Fassardi Santiago, Anza-Ramirez Cecilia, Moya Esteban A, Heinrich Erica C, Yu James J, Orr Jeremy E, Cao Steven Y, Sanchez-Azofra Ana, Cole Amy M, Hall James E, Lin Andrew, DeYoung Pamala N, Vizcardo-Galindo Gustavo, Macarlupu Jose-Luis, Figueroa-Mujíca Rómulo, Bermudez Daniela, Corante Noemi, Cavalleri Gianpiero L, Gaio Eduardo, Evans A Mark, Powell Frank L, Malhotra Atul, Salem Rany M, Villafuerte Francisco C, Simonson Tatum S
Department of Medicine, Division of Pulmonary, Critical Care, Sleep Medicine, and Physiology University of California, San Diego, La Jolla, CA, USA.
Herbert Wertheim School of Public Health and Longevity Sciences, University of California, San Diego, La Jolla, CA, USA.
iScience. 2025 Jun 16;28(8):112911. doi: 10.1016/j.isci.2025.112911. eCollection 2025 Aug 15.
Highland groups have adapted to the extreme selective pressures of hypoxia at high altitude via alterations in the oxygen-transport cascade. , 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 in Andeans that may accentuate hypoxia-induced ventilation and provide protection from sleep-disordered breathing in both high- and lowland populations.
高原人群通过氧转运级联反应的改变，适应了高海拔地区缺氧的极端选择压力。编码AMP活化蛋白激酶（AMPK）催化亚基的基因，是安第斯人群自然选择的一个显著靶点，并且与该人群中胎儿的保护性表型有关。AMPK是一种普遍存在的细胞能量传感器，参与多种生理过程，包括动物模型中的通气和低氧通气反应（HVR）。我们定位了一个正选择信号，并鉴定出一个具有适应性意义的调控启动子变体（rs10035235，C>T），该变体与安第斯男性高原居民的通气和睡眠表型以及公开可用的低地人群队列中的睡眠表型相关。这项研究在安第斯人群中鉴定出一个功能性、适应性且可能具有多效性的调控变体，该变体可能会增强缺氧诱导的通气，并为高地和低地人群预防睡眠呼吸紊乱提供保护。
