Investigating Targets of Natural Selection for Hypoxic Adaptation at High Altitudes

研究高海拔低氧适应自然选择的目标

• 批准号: 1638642
• 负责人: Abigail Bigham
• 金额: $ 40.8万
• 依托单位: Regents of the University of Michigan - Ann Arbor
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1638642&HistoricalAwards=false
• 关键词: Investigating; Targets; Natural; Selection; Hypoxic

Around 11,000 years ago, modern humans adapted to high altitude locations where the oxygen concentration is only 65% of that at sea level. This project seeks to identify the specific genetic changes that have allowed populations to survive at high elevations on the Andean Plateau. Findings from this research will advance our understanding of the ways in which modern human populations have been able to adapt to extreme environments through evolution by natural selection, and will also help to distinguish between natural selection and individual-level developmental adaptability. Improving our understanding of how the human body responds to low oxygen could inform the development of treatments for widespread diseases characterized by low oxygen, such as cancer and heart disease. The project will support student training and mentoring, and results of this study will be shared with the larger research community and integrated into public outreach programs aimed to encourage and financially support participation by underserved public middle school students. Andeans exhibit a unique suite of physiologic adaptations to high altitude including a blunted hypoxic ventilatory response, elevated arterial oxygen saturation, and elevated hemoglobin concentration. Their ability to live in chronic hypoxia provides an unprecedented opportunity to examine the underlying mechanisms of their adaptation. Recent genomic studies have identified the gene EGLN1 as a high priority candidate locus for natural selection among Andean highlanders. However, the functionally important SNP/mutation(s) has not been identified. To address this gap in our knowledge, the investigators will study how genetic changes mechanistically translate into the dramatic Andean phenotype. They will rigorously characterize the strength of natural selection for two candidate functional SNPs using next generation sequencing technologies; link genotype to phenotype through association testing and mRNA expression analysis; and characterize their functional importance using a combination of Crispr technology and chromatin immunoprecipitation assays. By integrating evolutionary and functional approaches to the study of human high altitude adaptation, this research will provide critical insight into the molecular mechanisms governing functional, adaptive change. Additionally, project results will reveal how genetic changes translate into adaptive, fitness-related phenotypes. In so doing, the outcomes of this research will lead to a major change in our understanding of Andean adaptation for which developmental adaptation, as opposed to genetic adaptation, is often considered to be the main adaptive strategy. Furthermore, by contrasting these results to emerging data on the functional consequence of Tibetan EGLN1 genetic changes, this research is uniquely poised to definitively establish convergent evolution between Andeans and Tibetans.

大约11000年前，现代人类适应了高海拔地区，那里的氧气浓度仅为海平面的65%。该项目旨在确定使人们能够在安第斯高原高海拔地区生存的特定基因变化。 这项研究的结果将增进我们对现代人类如何通过自然选择的进化来适应极端环境的方式的理解，也将有助于区分自然选择和个体水平的发展适应性。提高我们对人体对低氧反应的了解，可以为癌症和心脏病等以低氧为特征的广泛疾病的治疗方法的开发提供信息。该项目将支持学生培训和指导，这项研究的结果将与更大的研究界分享，并纳入公共外展计划，旨在鼓励和财政支持服务不足的公立中学生的参与。安第斯山脉对高海拔表现出一套独特的生理适应能力，包括缺氧通气反应迟钝、动脉氧饱和度升高和血红蛋白浓度升高。它们在慢性缺氧中生活的能力为研究其适应的潜在机制提供了前所未有的机会。最近的基因组研究已确定基因 EGLN1 是安第斯高地人自然选择的高度优先候选基因座。然而，功能上重要的 SNP/突变尚未确定。为了弥补我们知识上的这一空白，研究人员将研究基因变化如何机械地转化为戏剧性的安第斯表型。他们将使用下一代测序技术严格表征两个候选功能性 SNP 的自然选择强度；通过关联测试和 mRNA 表达分析将基因型与表型联系起来；并结合 Crispr 技术和染色质免疫沉淀测定来表征其功能重要性。通过将进化和功能方法整合到人类高海拔适应的研究中，这项研究将为控制功能、适应性变化的分子机制提供重要的见解。此外，项目结果将揭示遗传变化如何转化为适应性、与健康相关的表型。这样一来，这项研究的结果将导致我们对安第斯适应的理解发生重大变化，对于安第斯适应，发展适应（而不是遗传适应）通常被认为是主要的适应策略。此外，通过将这些结果与西藏 EGLN1 基因变化的功能后果的新数据进行对比，这项研究具有独特的优势，可以明确建立安第斯人和西藏人之间的趋同进化。

项目成果

Association of EGLN1 gene with high aerobic capacity of Peruvian Quechua at high altitude

• DOI: 10.1073/pnas.1906171116
• 发表时间: 2019-11-26
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Brutsaert, Tom D.;Kiyamu, Melisa;Bigham, Abigail W.
• 通讯作者: Bigham, Abigail W.