Investigating human cis-regulatory evolution with hybrid iPS cells

用混合 iPS 细胞研究人类顺式调控进化

• 批准号: 10342219
• 负责人: Hunter B Fraser
• 金额: $ 76.06万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-25 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10342219
• 关键词: 3-Dimensional; ATAC-seq; Acne; Adipose tissue; Affect; Alleles; Alzheimer' s Disease; CRISPR/Cas technology; Candidate Disease Gene; Carcinoma; Cardiac Myocytes; Cartilage; Cell Differentiation process; Cell Line; Cell fusion; Cells; Chromatin; Data; Dermis; Disease; Environment; Epidermis; Ethics; Etiology; Evolution; Exposure to; Ganglia; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomic Imprinting; Goals; Hair follicle structure; Hamsters; Hepatocyte; High-Throughput RNA Sequencing; Human; Hybrid Cells; Hybrids; In Vitro; Knowledge; Lead; Maps; Measurement; Methods; Modeling; Motor Neurons; Mus; Muscle Fibers; Natural Selections; Organism; Organoids; Pan Genus; Pancreas; Pathway interactions; Phenotype; Play; Primates; Radiation Hybrid Map; Rana; Regulation; Research; Resources; Rodent; Role; Salmo trutta; Sampling; Schizophrenia; Skeletal Muscle; Skin; Structure of retinal pigment epithelium; Sum; System; Testing; Trans-Activators; X Inactivation; autism spectrum disorder; cell type; enzyme activity; experience; fetal; genetic variant; genome-wide; hybrid gene; improved; in vitro Model; induced pluripotent stem cell; interest; progenitor; three dimensional cell culture; trait; transcription factor; transcriptome sequencing; unethical

Project Summary Despite a great deal of research, we have discovered surprisingly little about the genetic basis of uniquely human traits—largely due to the ethical and practical considerations that severely limit comparisons between humans and other primates. To advance this field, we have integrated two effective approaches for studying evolution: induced pluripotent stem (iPS) cells, and interspecific hybrids. iPS cells can be differentiated into a wide range of cell types in vitro, circumventing many limitations of primate research, while measurement of allele-specific gene expression in hybrids allows cis-regulatory divergence and gene expression adaptations to be mapped genome-wide. To combine these approaches, we have recently generated human/chimpanzee hybrid iPS cells. We propose to characterize this powerful resource with RNA-seq and cellular phenotyping in diverse cell types, including cardiomyocytes, motor neurons, hepatocytes, pancreatic progenitors, skeletal muscle, retinal pigmented epithelium, and skin organoids that include dermis/epidermis, adipose, cartilage, hair follicles, and more. Our goal is to discover and experimentally validate genes and genetic variants that have contributed to the evolutionary origin of our species.

项目概要 尽管进行了大量的研究，但令人惊讶的是，我们对基因的发现却很少。 人类独特特征的基础——很大程度上是出于伦理和实践的考虑 为了推进这一领域，我们对人类和其他灵长类动物进行严格的极限比较。 整合了两种研究进化的有效方法：诱导多能干 (iPS) 细胞和种间杂种 iPS 细胞可以分化为多种细胞。 体外细胞类型，规避了灵长类动物研究的许多限制，同时测量 杂种中等位基因特异性基因表达的变化允许顺式调控分歧和基因 为了结合这些方法，我们将表达适应映射到全基因组。 我们最近生成了人类/黑猩猩杂交 iPS 细胞。 这种强大的资源，具有多种细胞类型的 RNA 测序和细胞表型分析功能， 包括心肌细胞、运动神经元、肝细胞、胰腺祖细胞、骨​​骼肌、 视网膜色素上皮和皮肤类器官，包括真皮/表皮、脂肪、 我们的目标是发现并通过实验验证基因等。 促成我们物种进化起源的遗传变异。