Collaborative Research: Physiological and regulatory mechanisms of the attenuation of maladaptive plasticity in highland deer mice

许多生理系统通过保护生物体的内部条件不受环境变化的影响来缓冲生物体免受环境扰动的影响。然而，在新环境的殖民化过程中，在一个环境背景下进化的生理系统可能会产生错误的反应，当它们被不恰当地用来应对新的挑战时。这种现象的突出例子包括土著低地居民对高海拔环境的几种生理反应。例如，暴露在高海拔地区会导致红细胞生成过多、肺血管收缩和低地居民的其他生理变化，这些变化可能被认为是适应不良，因为它们会导致高海拔疾病（如慢性高原病、肺水肿）。在这种情况下，自然选择应该有利于这些适应不良反应的衰减。本研究的重点是了解进化、生理和遗传机制，这些机制允许这种不适应的祖先反应被钝化，而不会同时影响有益的反应。项目pi将通过对高海拔和低海拔鹿鼠种群的一系列驯化实验和实地研究，探索对高海拔应激源的生理反应的适应性改变。像当地的高海拔人群一样，高原鹿鼠对缺氧表现出迟钝的适应不良反应。这项研究的结果还将用于制定一项公共推广计划，以说明比较生理学的价值，即利用高海拔环境和栖息在高海拔环境中的动物，为人类健康提供应用问题。这些外联工作将以制作短片为中心，作为研究人员与公众之间互动讨论的跳板。许多对缺氧的生理反应在很大程度上是由一个被称为缺氧诱导因子（HIF1-3）的主转录因子家族协调的。因为像HIF这样改变转录因子功能的突变（即反调节突变）容易产生多效性效应，进化理论表明，与表型效应中更模块化的变化相比，它们在调节网络的适应性修改中应该是罕见的。尽管如此，最近对高海拔人群和其他几个物种的基因组研究表明，编码特定HIF亚型（HIF2）的基因（EPAS1）的等位基因变异是自然选择的目标，并且与对缺氧的适应不良反应的衰减有关。因此，协调缺氧反应的调节网络的适应性修改似乎在高海拔专家中通过修改跨调节因子反复进行。这提出了有趣的生理和进化问题，因为HIF2也协调了许多有益的生理变化来维持氧稳态。考虑到HIF2的改变会引起有害的多效效应，如何在维持适应性反应的同时减弱不适应反应？HIF功能的改变是否需要协调适应性反应的HIF靶点的代偿性顺式调控突变，或者代偿性修饰是否可以通过表观遗传改变来实现？本研究将通过对高原和低地鹿小鼠进行一系列生理、遗传和转录组学实验来解决这些问题。与其他高原专家一样，EPAS1的等位基因频率变异模式表明鹿鼠的局部适应性，这种变异与不适应缺氧反应的衰减有关。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Many physiological systems buffer organisms against environmental perturbations by safeguarding their internal conditions against changes in the environment. Upon colonization of new environments, however, physiological systems that evolved in one environmental context may produce misdirected responses when they are inappropriately coopted to respond to novel challenges. Prominent examples of this phenomenon include several physiological responses to high-elevation environments in native lowlanders. For example, exposure to high elevation induces excessive red blood cell production, constriction of pulmonary blood vessels, and other physiological changes in lowlanders that may be considered maladaptive because they contribute to high-altitude diseases (e.g. chronic mountain sickness, pulmonary edema). In such cases, natural selection should favor attenuation of these maladaptive responses. This research focuses on understanding the evolutionary, physiological, and genetic mechanisms that allow such maladaptive ancestral responses to blunted, without simultaneously impacting beneficial responses. The project PIs will use a series of acclimation experiments and field studies of high- and low-altitude populations of deer mice to explore the adaptive modification of physiological responses to high-altitude stressors. Like indigenous high-elevation human populations, highland deer mice exhibit blunted maladaptive responses to hypoxia. The results of this research will also be used to develop a public outreach program that illustrates the value of comparative physiology for informing applied problems in human health using high-altitude environments and the animals that inhabit them as its centerpiece. These outreach efforts will be centered on the development of short films that will serve as springboards for interactive discussions between researchers and the general public.Many physiological responses to hypoxia are largely coordinated by a family of master transcription factors, known as hypoxia-inducible factors (HIF1-3). Because mutations that alter the function of transcription factors like HIF (i.e. trans-regulatory mutations) are prone to pleiotropic effects, evolutionary theory suggests that they should be rare in the adaptive modification of regulatory networks compared to changes that are more modular in their phenotypic effects. Nonetheless, recent genomic studies of high-elevation human populations, and several other species have shown that allelic variation in a gene (EPAS1) that encodes a specific HIF isoform (HIF2) has been the target of natural selection, and is associated with the attenuation of maladaptive responses to hypoxia. Thus, adaptive modification of regulatory networks that coordinate hypoxia responses seems to have repeatedly proceeded through modification of trans-regulatory factors in high-elevation specialists. This poses interesting physiological and evolutionary questions because HIF2 also coordinates a number of beneficial physiological changes to maintain O2 homeostasis. Given that alteration of HIF2 induce deleterious pleiotropic effects, how can maladaptive responses be attenuated while adaptive responses are maintained? Does alteration of HIF function require compensatory cis-regulatory mutations in HIF targets that coordinate adaptive responses or can compensatory modifications be achieved through epigenetic changes? This research will address these questions using a series of physiological, genetic, and transcriptomic experiments on highland and lowland deer mice. Like other highland specialists, patterns of allele frequency variation at EPAS1 suggest local adaptation in deer mice, and this variation is associated with the attenuation of maladaptive hypoxia responses.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.