EPAS1基因适应性遗传变异与世居高原藏族脑结构和功能网络的关系

Correlating EPAS1 gene variations to hypoxic environments with structural and functional brain network adaptations of Tibetans in the Qinghai-Xizang Plateau

世居高原藏族已形成独特的适应低氧环境的机制,低氧诱导因子(hypoxia-inducible factor,HIF)通路基因内皮PAS结构域蛋白1(endothelial PAS domain protein 1,EPAS1)的遗传变异已被阐明与其低氧适应密切相关.脑耗氧量高,因此最容易受到高原低氧的影响.本研究旨在探讨HIF通路基因遗传变异与世居高原藏族脑结构和功能网络的关系.本研究招募了135名世居高原藏族人(19.9±1.1岁)作为研究对象,匹配的65名平原汉族人作为基因遗传变异的对照人群.首先,根据文献选择EPAS1基因中12个单核苷酸多态性(single nucleotide polymorphism,SNP)位点进行基因分型.其次,通过脑磁共振成像(magnetic resonance imaging,MRI)扫描获得藏族脑T1结构像和静息态功能MRI(functional MRI,fMRI).藏族人群中单倍型GA和CAAA的频率显著高于平原汉族,具有这些高频率单倍型的适应较好藏族人群的脑皮层表面积在左中央后回、右距状旁回、右额中回和右后扣带回显著增加,皮层体积在左距状旁回和右颞上回显著增加,脑功能连接主要在躯体运动、腹侧注意、视觉和默认模式网络上显著增加.总之,本研究揭示了EPAS1基因适应性遗传变异与世居高原藏族脑结构和功能网络的关系,发现基因上适应较好的藏族人群脑的变化集中在功能活跃的视觉感知和运动控制脑区及其相关功能神经网络以及默认模式网络.脑的这些变化有助于调节藏族的高原活动.

Indigenous Tibetans have developed adaptive physiological mechanisms to cope with the hypoxic environment of the Qinghai-Xizang Plateau.Genetic variation within the hypoxia-inducible factor pathway-related endothelial PAS domain protein 1 gene(EPAS1)has been reported to be associated with hypoxic adaptations among Tibetans.The brain,which exhibits the highest oxygen consumption in the body,is particularly susceptible to high-altitude hypoxia.We investigated the genetic influence of EPAS1 on the structural and functional brain networks of Tibetans in the Qinghai-Xizang Plateau.In this study,135 young indigenous Tibetans(62 males and 73 females)were recruited as an experimental group;and 65 lowland Han Chinese individuals who matched for relevant characteristics were recruited as a control group for genetic variation analyses.Based on previous reports,12 single nucleotide polymorphism loci in EPAS1 were selected for genotyping.Subsequently,T1 structural and resting-state functional images of the brain were obtained using magnetic resonance imaging(MRI).Haplotype analysis revealed that the frequencies of the GA and CAAA haplotypes were significantly higher in Tibetans than in lowland Han Chinese individuals.Tibetans with higher frequencies of GA and CAAA haplotypes were considered higher-adapted.Accordingly,Tibetans were categorized as genetically higher-adapted Tibetans(GHA-Tibetans)and genetically lower-adapted Tibetans(GLA-Tibetans).Compared to GLA-Tibetans,GHATibetans exhibited a significantly larger cortical surface area in the left postcentral gyrus,right pericalcarine gyrus,right middle frontal gyrus,and right posterior cingulate gyrus,and a significantly larger cortical volume in the left pericalcarine gyrus and right superior temporal gyrus.Significantly increased functional connectivity was observed in multiple networks,including the somatomotor network,ventral attention network,visual network,and default mode network.This study reveals the relationship between EPAS1 genetic variation and the adaptation of brain structural and functional networks in indigenous Tibetans,revealing that the adaptive changes in the brain are primarily focused on regions associated with visual perception,motor control,and related functional networks.Adaptive brain changes are also involved in a network of spontaneous resting-state activities.These brain changes may help indigenous populations to better regulate their body activities in extreme environments.