Investigating human cis-regulatory evolution with hybrid iPS cells

项目摘要 尽管进行了大量的研究，但我们对基因的发现却少得令人惊讶。 基于独特的人类特质-主要是由于道德和实际的考虑， 严重限制了人类和其他灵长类动物之间的比较。为了推进这一领域，我们 已经整合了两种研究进化的有效方法：诱导多能干细胞 (iPS)细胞和种间杂种。iPS细胞可以分化成多种类型的细胞， 细胞类型，规避了灵长类动物研究的许多限制，而测量 等位基因特异性基因表达的杂交允许顺式调节分歧和基因 表达适应被映射到全基因组。为了将这些方法联合收割机结合起来，我们 最近已经产生了人类/黑猩猩的混合iPS细胞。我们建议描述 这个强大的资源与RNA-seq和细胞表型在不同的细胞类型， 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， 遗传变异对我们物种的进化起源有贡献。

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.