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

合作研究：高原鹿小鼠适应不良可塑性减弱的生理和调节机制

基本信息

批准号：
1755411
负责人：
Zac Cheviron
金额：
$ 58.25万
依托单位：
University of Montana
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1755411&HistoricalAwards=false
关键词：
Collaborative Research Physiological regulatory mechanisms

项目摘要

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.

许多生理系统通过保护其内部条件免受环境变化的影响来缓冲生物体对环境扰动的影响。然而，在新环境的殖民化后，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，当它们被不适当地挑选来应对新的挑战时。这种现象的突出例子包括当地低地人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，以及低地人的其他生理变化，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（例如慢性高山病，肺水肿）。在这种情况下，自然选择应该有利于减弱这些适应不良的反应。这项研究的重点是了解进化，生理和遗传机制，使这种适应不良的祖先反应钝化，而不同时影响有益的反应。项目研究员将利用一系列适应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调整。像土著高海拔人群一样，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开发一个公共宣传计划，该计划说明了比较生理学的价值，用于利用高海拔环境和居住在其中的动物作为其核心来告知人类健康中的应用问题。这些外展工作将集中在短片的发展，将作为研究人员和公众之间的互动讨论的跳板。许多生理反应，缺氧在很大程度上是由一个家庭的主转录因子，称为缺氧诱导因子（HIF 1 -3）协调。由于改变转录因子如HIF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饰中应该是罕见的。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（HIF 2）的基因（EPAS 1）的等位基因变异一直是自然选择的目标，并与缺氧适应不良反应的减弱有关。因此，适应性修改的调节网络，协调缺氧反应似乎已经多次进行通过修改的反式调节因子在高海拔的专家。这提出了有趣的生理和进化问题，因为HIF 2还协调许多有益的生理变化以维持O2稳态。考虑到HIF 2的改变会诱导有害的多效性效应，如何在维持适应性反应的同时减弱适应不良反应？HIF功能的改变是否需要HIF靶点的补偿性顺式调节突变来协调适应性反应，或者补偿性修饰可以通过表观遗传变化来实现？本研究将通过一系列对高地和低地鹿鼠进行的生理学、遗传学和转录组学实验来解决这些问题。与其他高原专家一样，EPAS 1的等位基因频率变化模式表明鹿鼠的局部适应性，这种变化与适应不良缺氧反应的减弱有关。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Botfly infections impair the aerobic performance and survival of montane populations of deer mice, Peromyscus maniculatus rufinus

马蝇感染会损害山区鹿鼠 Peromyscus maniculatus rufinus 的有氧性能和生存能力

DOI：
10.1111/1365-2435.13276
发表时间：
2019
期刊：
Functional Ecology
影响因子：
5.2
作者：
Wilde, Luke R.;Wolf, Cole J.;Porter, Stephanie M.;Stager, Maria;Cheviron, Zachary A.;Senner, Nathan R.;White, ed., Craig
通讯作者：
White, ed., Craig

Physiological and genomic evidence that selection on the transcription factor Epas1 has altered cardiovascular function in high-altitude deer mice