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免受环境干扰的影响。然而，在新环境的殖民后，在一个环境背景下进化的生理系统在被不适当地拉拢以应对新的挑战时，可能会产生错误的反应。这种现象的突出例子包括原住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低海拔地区的人产生过量的红细胞，肺血管收缩，以及其他可能被认为是不适应的生理变化，因为它们会导致高原疾病(如慢性高原病、肺水肿)。在这种情况下，自然选择应该有利于减弱这些不适应的反应。这项研究的重点是了解进化、生理和遗传机制，使这种不适应的祖先对钝化的反应，而不同时影响有益的反应。PIS项目将利用一系列驯化实验和对高海拔和低海拔鹿鼠种群的实地研究，探索对高海拔应激源的生理反应的适应性修改。与当地高海拔人类种群一样，高原鹿小鼠对低氧表现出迟钝的适应不良反应。这项研究的结果还将被用来开发一个公共推广计划，说明比较生理学的价值，以高海拔环境和生活在高海拔环境中的动物为中心，向人类健康中的应用问题提供信息。这些推广工作将集中在短片的开发上，这些短片将作为研究人员和公众之间互动讨论的跳板。许多对低氧的生理反应在很大程度上是由一个被称为低氧诱导因子(HIF1-3)的主要转录因子家族协调的。由于改变HIF等转录因子功能的突变(即反式调节突变)容易产生多效性效应，进化理论认为，与表型效应更模块化的变化相比，它们在调节网络的适应性修饰中应该是罕见的。然而，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)的等位基因变异已经成为自然选择的目标，并与对低氧的不良适应反应的减弱有关。因此，协调低氧反应的调节网络的适应性修改似乎反复地通过修改高海拔专家的跨调节因子进行。这提出了有趣的生理和进化问题，因为HIF2还协调一些有益的生理变化来维持O2的动态平衡。鉴于HIF2的改变导致有害的多效性效应，如何在保持适应性反应的同时减弱不良适应反应？HIF功能的改变是否需要HIF靶标中的补偿性顺式调控突变来协调适应性反应，或者补偿性修改是否可以通过表观遗传变化来实现？这项研究将通过在高原和低地鹿小鼠身上进行一系列生理、遗传和转录实验来解决这些问题。与其他高原专家一样，EPAS1的等位基因频率变化模式表明鹿小鼠的局部适应，这种变化与适应不良的低氧反应的减弱有关。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.