Induced pluripotent stem cells (iPSCs), and cells derived from them, have become key tools for modeling biological processes, particularly in cell types that are difficult to obtain from living donors. Here we present a map of regulatory variants in iPSC-derived neurons, based on 123 differentiations of iPSCs to a sensory neuronal fate. Gene expression was more variable across cultures than in primary dorsal root ganglion, particularly for genes related to nervous system development. Using single-cell RNA-sequencing, we found that the number of neuronal versus contaminating cells was influenced by iPSC culture conditions before differentiation. Despite high differentiation-induced variability, our allele-specific method detected thousands of quantitative trait loci (QTLs) that influenced gene expression, chromatin accessibility, and RNA splicing. On the basis of these detected QTLs, we estimate that recall-by-genotype studies that use iPSC-derived cells will require cells from at least 20-80 individuals to detect the effects of regulatory variants with moderately large effect sizes.

中文翻译：

---

iPSC 衍生的感觉神经元的分子和功能变异。


诱导多能干细胞 (iPSC) 以及源自它们的细胞已成为建模生物过程的关键工具，特别是难以从活体捐赠者获得的细胞类型。在这里，我们基于 iPSC 与感觉神经元命运的 123 种分化，展示了 iPSC 衍生神经元的调控变异图。与初级背根神经节相比，不同培养物中的基因表达差异更大，特别是与神经系统发育相关的基因。使用单细胞 RNA 测序，我们发现神经元与污染细胞的数量受到分化前 iPSC 培养条件的影响。尽管分化诱导的变异性很高，但我们的等位基因特异性方法检测到了数千个影响基因表达、染色质可及性和 RNA 剪接的数量性状位点 (QTL)。根据这些检测到的 QTL，我们估计使用 iPSC 衍生细胞的基因型召回研究将需要来自至少 20-80 个个体的细胞来检测具有中等大效应大小的调节变异的影响。