Functional genomics of growth hormone response in a natural human model for short stature with comparisons to other populations and species

项目总结/摘要 身体大小是生物学和健康的一个基本方面。然而，尽管最近在了解方面取得了许多进展， 根据其遗传变异的基础，种群内和种群间变异的近细胞原因 身体的大小基本上是未知的。在一个极端，小的身体尺寸，或“侏儒”的表型，是一个特征， 热带雨林狩猎采集者（RHG）在世界范围内，这种遗传介导的特征可能是一种适应 热带雨林对人类居住的严酷生态条件。RHG与 因此，非RHG人群为研究遗传、功能和进化提供了一个自然的人类模型。 生长和身体大小的基础。我建议研究全基因组对胰岛素样受体的调节反应。 生长因子1（IGF 1）和成纤维细胞生长因子（FGF-9）在用源自于 乌干达巴特瓦RHG群体样本的诱导多能干细胞（iPSC）（N=20）及其 农学家邻居Bakiga（N=20）。我将评估IGF 1的全基因组基因表达反应， 和FGF-9，并通过治疗（基线与激发）鉴定差异表达（DE）的基因， 群体和群体x治疗相互作用-即对IGF 1或FGF-9具有Batwa特异性反应的基因。我 还将同时表征黑猩猩和狒狒iPSC衍生的IGF 1和FGF-9反应， 软骨细胞，从而允许将生长因子反应的变化划分为人类谱系特异性， 人类特有的，共享的组件。Batwa和Bakiga特异性DE反应基因集 将与来自同一人群的SNP基因型数据的人群基因组分析结果进行比较， 检测DE基因是否在含有阳性特征的基因组区域内显著富集 选择.与其他数据集的比较将有助于识别具有潜在表型和临床特征的基因座。 的重要性。这项功能强大的、相关的体外系统的比较功能基因组学研究， 一个自然的人类模型将促进我们对关键的人类成长和发展途径的理解。的 拟议的研究将是第一个全基因组功能基因组研究的相关细胞类型的增长 在以侏儒表型为特征的人群中的因子反应。作为最早的iPSC研究之一， 该项目是非洲人和第一个RHG，将人类细胞模型与群体基因组方法相结合， 提供了人类基因组和功能多样性的扩展视图。与以往的研究不同， 将有必要的范围，相关的细胞类型和权力，以探索生长因子途径中断， 在RHG的侏儒表型中起作用。作为我的NRSA奖学金的一部分， 我将推进我的职业目标，整合人口基因组学和功能基因组学方法，以了解 生物医学相关的适应，将是我过渡到一个独立的研究人员探索的理想选择。 过去进化适应的生物医学相关性。

PROJECT SUMMARY / ABSTRACT Body size is a fundamental aspect of biology and health. However, despite many recent gains in understand- ing its genetic variation underpinnings, the proximate cellular causes of variation in intra- and inter-population body size are largely unknown. At one extreme, small body size, or the “pygmy” phenotype, is a characteris- tic of rainforest hunter-gatherers (RHGs) worldwide, and this genetically-mediated trait is likely an adaptation to the harsh ecological conditions of tropical rainforests for human inhabitants. Comparisons between RHG and non-RHG populations thus present a natural human model for studying the genetic, functional, and evolutionary bases of growth and body size. I propose to investigate the genome-wide regulatory response to Insulin-like Growth Factor 1 (IGF1) and a Fibroblast Growth Factor (FGF-9) in experiments with chondrocytes derived from induced pluripotent stem cells (iPSCs) for population samples of the Batwa RHGs of Uganda (N=20) and their agriculturalist neighbors the Bakiga (N=20). I will estimate genome-wide gene expression responses to IGF1 and FGF-9 via RNAseq and identify differentially expressed (DE) genes by treatment (baseline vs. challenge), population, and population x treatment interaction–i.e. genes with Batwa-specific response to IGF1 or FGF-9. I will also simultaneously characterize the IGF1 and FGF-9 responses in chimpanzee and baboon iPSC-derived chondrocytes, thus allowing the partitioning of variation in growth factor response into human lineage-specific, human population-specific, and shared components. The sets of Batwa- and Bakiga-specific DE response genes will be intersected with results from population genomic analyses of SNP genotype data from the same popula- tions to test whether DE genes are significantly enriched within genome regions containing signatures of positive selection. Comparisons to other datasets will facilitate the identification of loci with potential phenotypic and clin- ical significance. This comparative functional genomics investigation of a powerful, relevant in vitro system from a natural human model will advance our understanding of critical human growth and development pathways. The proposed study will be the first genome-wide functional genomic investigation in a relevant cell type of the growth factor response in a human population characterized by the pygmy phenotype. As one of the first iPSC studies of Africans and the first of RHGs, the project integrates human cellular models with population genomic methods to afford an expanded view of human genomic and functional diversity. Unlike previous studies, the proposed project will have the scope, relevant cell type, and power necessary to explore the growth factor pathway disruptions that play a role in the pygmy phenotype in RHGs. The project and training proposed as part of my NRSA fellowship will advance my career goal of integrating population genomic and functional genomic approaches to understand biomedically relevant adaptations and will be ideal for my transition to an independent researcher exploring the biomedical relevance of past evolutionary adaptations.