Genes, physiology, and reproductive fitness in high altitude environments

这项研究解决了一个长期存在的关于基因型和表型之间的关系的问题。一种名为EPAS1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地区氧气供应不足或高氧治疗后氧气供应相对较低的情况下，会引起生物反应，以维持氧稳态。健康的人对高海拔的反应减弱，反映在高海拔地区没有典型的血红蛋白浓度上升，这为发现提供了一个天然的实验室。除了解释成功适应低氧环境的不同方式外，这一特殊情况可能有助于加深对其他条件下的基因型-表型关系的理解。例如，早产儿、伤口无法愈合的人，以及战斗机飞行员都暴露在极高的氧气水平下数小时或数天，并在恢复正常氧气水平后面临包括失明在内的病理风险的不适当的氧气稳态途径。了解研究人群中健康水平的基因产物及其相关生理特征之间的平衡，可以为设计成功的临床干预措施提供一个模型。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。遗传变异、表型变异和生殖变异之间的关系是理解人类生物变异来源的核心。这项研究旨在确定从EPAS1基因座到生物适应的路径，样本是400名生活在3000米以上的女性，她们参与了之前的一项研究。这项拟议的研究将重新访问他们，以收集新的血液、心肺和呼吸特征，并将它们整合到他们已经提供的丰富的基因组、生理和生殖数据中。将评估EPAS1基因及其目标基因及其蛋白质的变异与这些女性的适应性表型和终生生殖成功之间的关联程度。一种综合的基因组方法将选择与生理适应相关的目标基因的子集。分析将考虑社会文化影响、铁和感染状况等因素。该奖项反映了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。

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.