Functional Genomics of Tibetan Adaptations

西藏适应的功能基因组学

基本信息

批准号：
10569514
负责人：
Anna Di Rienzo
金额：
$ 74.45万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10569514
关键词：
ATAC-seq Acclimatization Alleles Altitude Andean Biology Cardiac Myocytes Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Chicago Chinese Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Data Endothelial Cells Endothelium Enhancers Environment Frequencies Gene set enrichment analysis Genes Genetic Genetic Enhancer Element Genetic Transcription Genome Genotype Hemoglobin Hemoglobin concentration result Human Hypoxemia Hypoxia Maps Mediator Molecular Mus Natural Selections Oxygen Pathway interactions Phenotype Physiologic pulse Physiological Physiology Population Quantitative Trait Loci Research Research Design Resolution Resources Respiratory Disease Signal Transduction Stress System Technology Testing Time Transgenic Mice Variant Work base editing cell type coping environmental stressor experience experimental study functional genomics genetic testing genome wide association study heart function humanized mouse in vitro Assay indexing induced pluripotent stem cell insight lymphoblastoid cell line multidisciplinary normoxia precise genome editing pressure reproductive outcome response single-cell RNA sequencing trait transcriptome sequencing

项目摘要

ABSTRACT Although hypoxia is a major stress on human physiology, several populations have adapted to high altitude (HA) hypoxic environments. Among them, Tibetans have been studied most extensively and they have been shown to have relatively low hemoglobin (Hb) levels. As a result, they are severely hypoxemic and how their physiology copes with hypoxia remains poorly understood. Through a unique combination of genome-wide association studies, tests for polygenic adaptation and functional in vitro assays, the Di Rienzo lab has made two major observations: 1) the strongest association signals for Hb and the strongest selective sweep signals in the genome, found at the EPAS1 locus, influence enhancer activity in endothelial cells (ECs), and 2) lower pulse was favored by natural selection in Tibetans. These findings raise the questions of whether and how cardiovascular functions changed in Tibetans as a result of adaptations to HA hypoxia. To answer them, we propose the following specific aims: Aim 1. Develop a unique resource for the functional characterization of Tibetan adaptations. We will generate and genotype lymphoblastoid cell lines for 24 Tibetans (TBC) and will purchase 24 LCLs from Han Chinese (CHB) from the 1000 genome project. These LCLs will be reprogrammed to induced pluripotent stem cells (iPSCs) and then differentiated in parallel into cardiomyocytes (CMs) and ECs. Aim 2. Test the hypothesis that cardiovascular functions were targets of adaptation to hypoxia in Tibetans. All the CMs and ECs will be cultured in normoxia and hypoxia; RNA-seq data will be collected and analyzed to identify genes and co-expression modules that differ in the transcriptional response to hypoxia between TBC and CHB. Cis-regulatory variants that may account for between-population differences in response to hypoxia will be identified using the RNA-seq data and, in turn, will be tested for evidence of polygenic adaptations in Tibetans. Aim 3. Investigate the effects of adaptive alleles by editing iPSCs. We will use editing technologies to delete 10 enhancers including those at the EPAS1 locus and others identified in Aim 2. We will replace alleles by precise genome editing. We will also generate transgenic mice with deletion of EPAS1 enhancer and with the corresponding enhancer alleles in humans. In summary, we will characterize the mechanisms of cardiovascular adaptations to HA hypoxia through a unique combination of approaches to elucidate the causal basis of a polygenic adaptation to an important environmental stressor, in a non-European population.

抽象的尽管缺氧是对人类生理学的主要压力，但有几个人口已适应高海拔（HA）低氧环境。其中，藏人研究了最多广泛的，它们的血红蛋白（Hb）水平相对较低。作为结果，它们严重低氧，其生理学如何与缺氧保持较差理解。通过全基因组关联研究的独特组合，测试多基因适应和在体外测定中功能性，Di Rienzo实验室已成为两个主要的观察：1）HB的最强关联信号和最强的选择性扫描在EPAS1基因座中发现的基因组中的信号会影响内皮细胞中增强子活性（EC）和2）藏在藏族中的自然选择有利于较低的脉冲。这些发现提出了由于藏族功能是否以及如何在藏族中发生变化的问题适应HA缺氧。为了回答它们，我们提出以下具体目的：目标1。为藏族适应的功能表征开发独特的资源。我们将生成24个藏族（TBC）的基因型淋巴细胞细胞系，并将购买24 来自1000基因组项目的Han Chinese（CHB）的LCL。这些LCL将是重新编程为诱导的多能干细胞（IPSC），然后并行分化为心肌细胞（CMS）和ECS。 AIM 2。测试心血管功能是适应缺氧的靶标的假设藏人。所有CMS和EC将在常规氧和缺氧中培养； RNA-seq数据将是收集和分析以鉴定基因和共表达模块在对TBC和CHB之间缺氧的转录反应。顺式调节变体可能考虑到对缺氧的响应中人口间差异的解释 RNA-seq数据又将测试藏族中多基因适应的证据。 AIM 3。通过编辑IPSC来研究自适应等位基因的影响。我们将使用编辑删除10个增强剂的技术，包括EPAS1基因座和其他确定的技术目标2。我们将通过精确的基因组编辑代替等位基因。我们还将生成转基因小鼠随着EPAS1增强子的删除以及人类中相应的增强等位基因。总而言之，我们将表征心血管适应HA缺氧的机制通过独特的方法组合，以阐明多基因的因果关系在非欧洲人口中适应重要的环境压力源。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regulatory Landscapes of Nppa and Nppb.

DOI：
10.1161/circresaha.120.318495
发表时间：
2021-01-08
期刊：
Circulation research
影响因子：
20.1
作者：
Sobreira DR;Nóbrega MA
通讯作者：
Nóbrega MA

Ancient genomes from the Himalayas illuminate the genetic history of Tibetans and their Tibeto-Burman speaking neighbors.

DOI：
10.1038/s41467-022-28827-2
发表时间：
2022-03-08
期刊：
Nature communications
影响因子：
16.6
作者：
Liu CC;Witonsky D;Gosling A;Lee JH;Ringbauer H;Hagan R;Patel N;Stahl R;Novembre J;Aldenderfer M;Warinner C;Di Rienzo A;Jeong C
通讯作者：
Jeong C

Adaptations to local environments in modern human populations.

DOI：
10.1016/j.gde.2014.06.011
发表时间：
2014-12
期刊：
CURRENT OPINION IN GENETICS & DEVELOPMENT
影响因子：
4
作者：
Jeong, Choongwon;Di Rienzo, Anna
通讯作者：
Di Rienzo, Anna

Evidence of Polygenic Adaptation to High Altitude from Tibetan and Sherpa Genomes.

藏族和夏尔巴人基因组多基因适应高海拔的证据。

DOI：
10.1093/gbe/evy233
发表时间：
2018-11-01
期刊：
Genome biology and evolution
影响因子：
3.3
作者：
Gnecchi-Ruscone GA;Abondio P;De Fanti S;Sarno S;Sherpa MG;Sherpa PT;Marinelli G;Natali L;Di Marcello M;Peluzzi D;Luiselli D;Pettener D;Sazzini M
通讯作者：
Sazzini M

Admixture facilitates genetic adaptations to high altitude in Tibet.

DOI：
10.1038/ncomms4281
发表时间：
2014
期刊：
Nature communications
影响因子：
16.6
作者：
Jeong C;Alkorta-Aranburu G;Basnyat B;Neupane M;Witonsky DB;Pritchard JK;Beall CM;Di Rienzo A
通讯作者：
Di Rienzo A