Genes, physiology, and reproductive fitness in high altitude environments

这项研究解决了一个长期存在的问题，即基因型和表型之间的关系。 一种名为EPAS 1的基因通过改变数百个靶基因的表达来说明这种复杂的关系，这些靶基因在高海拔氧气供应较低或高氧治疗后相对较低时引起生物反应以维持氧气稳态。 健康人对高海拔的反应减弱，反映在没有典型的高海拔血红蛋白浓度增加，这为发现提供了天然的实验室。 除了解释成功适应低氧环境的不同方法外，这种特殊情况可能会提高对其他条件下基因型-表型关系的理解。 例如，早产儿、伤口无法愈合的人以及战斗机飞行员不适当地参与氧气稳态途径，这些人都暴露在极高的氧气水平下数小时或数天，并且在恢复正常氧气水平后有发生包括失明在内的病理学风险。 了解研究人群中基因产物的健康水平及其相关生理特征的平衡可以为设计成功的临床干预提供模型。 该项目还将支持国际研究合作，社区科学推广以及本科生培训和指导。遗传、表型和生殖变异之间的关系是理解人类生物学变异来源的核心目标。本研究旨在确定从EPAS 1基因座到生物适应的途径，这些途径来自参与先前研究的400名生活在3000米以上的妇女。拟议的研究将重新审视它们，以收集新的血液学、心肺和呼吸特征，并将它们整合到它们已经提供的丰富的基因组、生理和生殖数据中。 将评估EPAS 1基因座及其靶基因和蛋白质的变异与这些妇女的适应性表型和终生生殖成功的相关程度。 一个综合的基因组方法将选择一个子集的靶基因假设与生理适应。 该奖项反映了NSF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。

This research tackles a long-standing question about the relationship between genotype and phenotype. A gene called EPAS1 illustrates that complex relationship by modifying the expression of hundreds of target genes that cause biological responses to maintain oxygen homeostasis when oxygen supplies are low at high-altitude or relatively low after high-oxygen therapy. Healthy people with a dampened response to high-altitude, reflected by an absence of the typical increase in hemoglobin concentration at high altitudes, provide a natural laboratory for discovery. In addition to explaining the different ways to adapt successfully to low oxygen environments, this special case may improve understanding of genotype-phenotype relationships under other conditions. Examples include inappropriately engaging oxygen homeostasis pathways by premature infants, people with wounds that will not heal, and fighter pilots who are all exposed for hours or days to extremely high oxygen levels and are at risk of pathologies including blindness upon return to normal oxygen levels. Learning the balance of healthy levels of gene products and their associated physiological traits in the study population can provide a model for designing successful clinical interventions. This project will also support international research collaborations, community science outreach, and undergraduate student training and mentoring. The relationship between genetic, phenotypic and reproductive variation is central to the goal of understanding the sources of human biological variation. This research is designed to determine pathways from the EPAS1 locus to biological adaptations in a sample of 400 women living above 3000m who participated in a previous study. The proposed research will revisit them to collect new hematological, cardiopulmonary, and respiratory traits and integrate them into the rich body of genomic, physiological, and reproductive data they have already provided. Variation at the EPAS1 locus and its target genes and their proteins will be assessed for the extent to which they associate with the adaptive phenotypes and the lifetime reproductive success of these women. An integrated genomic approach will choose a subset of target genes hypothesized to associate with physiological adaptations. Analyses will consider factors such as sociocultural influences, iron, and infection status.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.