Investigating human cis-regulatory evolution with hybrid iPS cells

项目摘要 尽管进行了大量的研究，但我们对遗传基因的发现出人意料地少。 人类独特特征的基础--主要是由于伦理和实践方面的考虑 严格限制了人类和其他灵长类动物之间的比较。为了推动这一领域的发展，我们 整合了两种研究进化的有效方法：诱导多能干细胞 (IPS)细胞和种间杂交种。IPS细胞可分化为广泛的 体外细胞类型，绕过了灵长类研究的许多限制，同时测量 杂交种的等位基因特异表达允许顺式调控差异和基因 表达适应将被绘制成全基因组范围的图谱。为了将这些方法结合起来，我们 最近产生了人类/黑猩猩杂交的iPS细胞。我们建议将其描述为 这一强大的资源具有RNA-SEQ和不同细胞类型的细胞表型， 包括心肌细胞、运动神经元、肝细胞、胰腺前体细胞、骨骼肌、 视网膜色素上皮，以及皮肤器官，包括真皮/表皮，脂肪， 软骨、毛囊等等。我们的目标是发现和实验验证基因和 基因变异对我们物种的进化起源做出了贡献。

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.