Genomic and physiological mechanisms of hypoxia adaptation in high-altitude mice

项目摘要 高海拔动物已经进化出在缺氧条件下生存和发挥功能的能力 （缺氧）模拟人类的疾病状态。确定缺氧适应的进化机制， 因此，长期生活在高海拔地区的哺乳动物可以产生生物医学相关的发现， 也为复杂性状的进化提供了一般性的见解。许多野生啮齿动物栖息在 比西藏人和安第斯人更极端的海拔，也代表了更容易处理的主题， 涉及遗传杂交和侵入性生理操作的实验方法。这个项目 整合了基因组学和实验生理学，剖析了适应性增强的机制基础， 极端高海拔啮齿动物在缺氧条件下的整体表现。实验比较了高和低- 两个物种的海拔种群：鹿鼠（Peromyscus maniculatus），其分布范围最广 任何北美哺乳动物的海拔范围（海平面至4350米），和安第斯叶耳鼠 （Phyllotis vaccarum），一种极端嗜物物种，拥有世界上最高居住的哺乳动物的记录， 它也有最广泛的海拔范围（海平面到>6700米[> 22，000 ']）。为了检验适应性的假设 调节反应缺氧，我们将使用一个共同的花园实验设计，整合措施， 整体动物生理性能（缺氧条件下的有氧运动能力）和各种从属性状 （呼吸、心血管和代谢）与组织特异性转录组学和代谢组学特征。 实验将涉及高度侵入性的操作（例如，动静脉外科器械 在运动试验和重要器官的终末采样期间测量血气的导管）， 在人类受试者中可行。在这两个物种中，机械实验将通过人口补充 基因组实验，以产生关于特定基因和途径的假设， 缺氧适应。这些假设将通过后续实验进行测试，以测量表型 基因功能和/或基因表达变化的影响，正如我们正在进行的鹿鼠研究所示。 本研究的具体目的是：（1）阐明有氧运动适应性增强的机制基础 （2）确定基因表达的调控变化如何转化为 在生物组织的不同等级水平上的表型变化;以及（3）识别和 实验测试新的候选基因和缺氧适应途径。纳入人口 基因组学、功能基因组学和实验生理学将通过阐明 复杂性能性状适应性进化的机制基础。

PROJECT SUMMARY High-altitude animals have evolved the ability to survive and function under conditions of oxygen deprivation (hypoxia) that mimic disease states in humans. Identifying evolved mechanisms of hypoxia adaptation in mammals that are long-term high-altitude natives can therefore yield discoveries of biomedical relevance while also providing general insights into the evolution of complex traits. A number of wild rodent species inhabit far more extreme altitudes than Tibetan and Andean humans and also represent far more tractable subjects for experimental approaches that involve genetic crosses and invasive physiological manipulations. This project integrates genomics and experimental physiology to dissect the mechanistic basis of adaptive enhancements of whole-animal performance in hypoxia in extreme high-altitude rodents. The experiments compare high- and low- altitude populations of two species: the deer mouse (Peromyscus maniculatus), which has the broadest altitudinal range of any North American mammal (sea level to 4350 m), and the Andean leaf-eared mouse (Phyllotis vaccarum), an extremophile species that holds the record as the world’s highest dwelling mammal and that also has the broadest altitudinal range (sea level to >6700 m [>22,000’]). To test hypotheses about adaptive regulatory responses to hypoxia, we will use a common-garden experimental design to integrate measures of whole-animal physiological performance (aerobic exercise capacity in hypoxia) and various subordinate traits (respiratory, cardiovascular, and metabolic) with tissue-specific transcriptomic and metabolomic profiles. Experiments will involve highly invasive manipulations (e.g., surgical instrumentation of arterial and venous catheters to measure blood gases during exercise trials and terminal sampling of vital organs) that are not feasible in human subjects. In both species, mechanistic experiments will be complemented by population genomic experiments to generate hypotheses about the specific genes and pathways that may have contributed to hypoxia adaptation. Such hypotheses will then be tested using follow-up experiments to measure phenotypic effects of changes in gene function and/or gene expression, as illustrated by our ongoing work on deer mice. The specific aims of the research are (1) to elucidate the mechanistic basis of adaptive enhancements of aerobic performance capacity in hypoxia; (2) to determine how regulatory changes in gene expression translate into changes in phenotype at different hierarchical levels of biological organization; and (3) to identify and experimentally test new candidate genes and pathways for hypoxia adaptation. The integration of population genomics, functional genomics, and experimental physiology will advance the field by elucidating the mechanistic basis of adaptive evolutionary change in complex performance traits.