Physiological and genomic evidence that selection on the transcription factor Epas1 has altered cardiovascular function in high-altitude deer mice
Physiological and genomic evidence that selection on the transcription factor Epas1 has altered cardiovascular function in high-altitude deer mice
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DOI：
10.1371/journal.pgen.1008420
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发表时间：
2019-11-01
期刊：
影响因子：
4.5
通讯作者：
Cheviron, Zachary A.
中科院分区：
文献类型：
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作者：
Schweizer, Rena M.;Velotta, Jonathan P.;Cheviron, Zachary A.
作者摘要 适应通常需要跨多个动态系统协调进化变化以维持生理功能。例如，高海拔栖息地非常重视组织氧气输送，以应对有限的氧气供应（缺氧）。循环 O-2 运输是动态调节的，以秒为单位变化，是几个相互作用的生理过程的结果。人们对这种复杂表型的适应机制知之甚少。一个有希望的候选基因是Epas1基因，它编码一种调节缺氧生理反应的转录因子。我们利用群体基因组分析和生理测定来探索高原鹿小鼠中 Epas1 遗传变异和生理功能之间的联系，这些小鼠表现出对缺氧的进化适应。我们发现了与心血管功能变化相关的 Epas1 突变：高海拔地区的主要突变与缺氧情况下心率升高的维持以及影响心率并受 Epas1 调节的基因表达差异相关。我们的群体基因组分析表明，Epas1 在高海拔地区表现出自然选择的特征，表明这些表型效应影响达尔文的适应性。我们的结果表明，复杂和动态性状的适应可能归因于相对简单的遗传变化。对极端环境的进化适应通常需要多个交叉的生理途径的协调变化，但这种多性状适应如何发生仍然悬而未决。如果诱导变化的好处超过负面多效性效应的成本，则调节许多基因表达并可以同时改变多种表型的转录因子可能是选择的常见目标。我们将北美鹿小鼠（Peromyscus maniculatus）的互补群体遗传分析和生理实验结合起来，研究协调对缺氧的生理反应（缺氧诱导因子，HIF）的转录因子的遗传变异与可能有助于高海拔适应的多种生理特征之间的联系。首先，我们对从不同海拔采集的 100 只小鼠的外显子组进行了测序，发现编码 HIF-2 α 氧敏感亚基的基因 Epas1 中的几个 SNP 在高地和低地种群之间表现出极大的等位基因频率差异。更广泛的地理采样证实，Epas1 基因型在整个美国西部随海拔高度的变化而变化。然后我们发现 Epas1 基因型影响缺氧时的心率，以及心脏和肾上腺对缺氧的转录组反应（包括 HIF 靶标和参与儿茶酚胺信号传导的基因）。最后，我们使用人口统计信息选择扫描来表明Epas1变体经历了空间变化选择的历史，这表明心血管功能和基因调控的差异有助于高海拔适应。我们的结果揭示了Epas1可能帮助高海拔鹿小鼠长期生存的机制，并为高度多效性转录因子在环境适应过程中可能发挥的作用提供了一般性见解。
Author summary Adaptation often requires coordinated evolutionary changes across multiple dynamic systems to maintain physiological function. For example, high-altitude habitats place a premium on tissue-oxygen delivery to cope with limited oxygen availability (hypoxia). Circulatory O-2 transport is regulated dynamically, changing on the order of seconds, and results from several interacting physiological processes. The mechanisms of adaptation in such complex phenotypes are poorly understood. One promising candidate is the gene Epas1, which encodes a transcription factor that regulates physiological responses to hypoxia. We used population genomic analyses and physiological assays to explore the connections between Epas1 genetic variation and physiological function in high-altitude deer mice, which exhibit evolutionary adaptations to hypoxia. We identified a mutation in Epas1 that is associated with variation in cardiovascular function: the predominant variant at high altitude is associated with the maintenance of an elevated heart rate under hypoxia and with differences in the expression of genes that influence heart rate and are regulated by Epas1. Our population genomic analyses demonstrated that Epas1 exhibits a signature of natural selection at high altitude, suggesting that these phenotypic effects influence Darwinian fitness. Our results suggest that adaptation in complex and dynamic traits may be attributable to relatively simple genetic changes.Evolutionary adaptation to extreme environments often requires coordinated changes in multiple intersecting physiological pathways, but how such multi-trait adaptation occurs remains unresolved. Transcription factors, which regulate the expression of many genes and can simultaneously alter multiple phenotypes, may be common targets of selection if the benefits of induced changes outweigh the costs of negative pleiotropic effects. We combined complimentary population genetic analyses and physiological experiments in North American deer mice (Peromyscus maniculatus) to examine links between genetic variation in transcription factors that coordinate physiological responses to hypoxia (hypoxia-inducible factors, HIFs) and multiple physiological traits that potentially contribute to high-altitude adaptation. First, we sequenced the exomes of 100 mice sampled from different elevations and discovered that several SNPs in the gene Epas1, which encodes the oxygen sensitive subunit of HIF-2 alpha, exhibited extreme allele frequency differences between highland and lowland populations. Broader geographic sampling confirmed that Epas1 genotype varied predictably with altitude throughout the western US. We then discovered that Epas1 genotype influences heart rate in hypoxia, and the transcriptomic responses to hypoxia (including HIF targets and genes involved in catecholamine signaling) in the heart and adrenal gland. Finally, we used a demographically-informed selection scan to show that Epas1 variants have experienced a history of spatially varying selection, suggesting that differences in cardiovascular function and gene regulation contribute to high-altitude adaptation. Our results suggest a mechanism by which Epas1 may aid long-term survival of high-altitude deer mice and provide general insights into the role that highly pleiotropic transcription factors may play in the process of environmental adaptation.