Development of iPSCs for comparative genomics in primates

摘要 这是一项新的提案，是对专注于比较基因组学的资助机会的回应 研究(PAR-17-482)。FOA规定，NHGRI邀请申请，以开发新的 比较基因组学研究方法使用基因组数据类型来理解生物系统， 网络和路径。以及“将高度优先考虑那些提出创新和 进行全基因组和多物种比较的前景看好的方法。 人类和其他灵长类动物之间基因调控的差异最终可能被用来解释 人类特有特征的分子基础。虽然目前对灵长类动物的比较研究提供了 对基因调控的遗传结构的有价值的见解，但它们并没有提供一个灵活的框架来 研究同一个体多种细胞类型中基因调控的物种间差异。特别是， 冷冻的死后组织并不是许多功能性基因组分析的最佳模板；因此，我们缺乏 从相同的基因调控机制和表型的多个维度调查的数据集 样本。此外，由于从同一捐赠者身上收集大量组织样本的情况很少见，我们 从未有机会研究多个组织或细胞中基因调控的群体水平模式 类型来自相同的非人类类人猿基因(相同的捐赠者)，我们还无法研究 种群水平的基因调控动态，例如，在扰动期间。 我们建议探索另一条有希望的前进道路。最近在以下方面取得的非凡进展 分子生物学提出了一条前进的道路。现在已经可以对体细胞进行重新编程，例如 成纤维细胞和几种类型的血细胞，进入多能状态，在这种状态下，细胞有能力 两者都可以无限自我复制，并分化成体内的任何细胞类型。这些重新编程(或 诱导)多能干细胞(IPSCs)然后可以被引导分化为特定类型的细胞，这可以 然后对其进行详细研究。因此，来自多个物种的IPSC系的可用性可能会发生变化 比较灵长类遗传学和基因组学以一种深刻的方式，允许我们绕过传统的限制 在灵长类动物上的研究。

Abstract This is a new proposal submitted in response to a funding opportunity focused on comparative genomics research (PAR-17-482). The FOA states that NHGRI invites applications for the “development of new comparative genomics research approaches using genomic data types to understand biological systems, networks, and pathways.” And that “high priority will be given to applications that propose innovative and promising approaches to genome-wide and multi-species comparisons.” Differences in gene regulation between humans and other primates may ultimately be used to explain the molecular basis for human-specific traits. While current comparative studies in primates have provided valuable insight into the genetic architecture of gene regulation, they do not provide a flexible framework to study inter-species variation in gene regulation in multiple cell types from the same individuals. In particular, frozen post-mortem tissues are not optimal templates for many functional genomic assays; as a result, we lack data sets that survey multiple dimensions of gene regulatory mechanisms and phenotypes from the same samples. Moreover, because it is rare to collect a large number of tissue samples from the same donor, we have never had the opportunity to study population-level patterns of gene regulation in multiple tissues or cell types derived from the same non-human ape genotype (same donor), and we have not been able to study population-level dynamics of gene regulation, for example, during perturbation. We propose to explore an alternative promising way to move forward. Recent extraordinary advances in molecular biology suggest a way forward. It has now become possible to reprogram somatic cells, such as fibroblasts and several types of blood cells, into a pluripotent state, in which the cells have the capability to both self-replicate indefinitely and to differentiate into any cell type in the body. These reprogrammed (or induced) pluripotent stem cells (iPSCs) can then be directed to differentiate into specific cell types, which can then be studied in detail. The availability of iPSC lines from multiple species could therefore change comparative primate genetics and genomics in a profound way, by allowing us to sidestep traditional limitations on research in primates.