Comparative landscape of genetic dependencies in human and chimpanzee stem cells

Comparative studies of great apes provide a window into our evolutionary past, but the extent and identity of cellular differences that emerged during hominin evolution remain largely unexplored. We established a comparative loss-of-function approach to evaluate whether changes in human cells alter requirements for essential genes. By performing genome-wide CRISPR interference screens in human and chimpanzee pluripotent stem cells, we identified 75 genes with species-specific effects on cellular proliferation. These genes comprised coherent processes, including cell cycle progression and lysosomal signaling, which we determined to be human-derived by comparison with orangutan cells. Human-specific robustness to CDK2 and CCNE1 depletion persisted in neural progenitor cells and cerebral organoids, supporting the G1-phase length hypothesis as a potential evolutionary mechanism in human brain expansion. This GEO submission contains comparative gene expression profiling of the six human and six chimpanzee CRISPRi engineered cell lines used in this study.

类人猿比较研究为我们洞悉人类演化历程提供了关键视角，但人族（hominin）演化过程中出现的细胞差异的范围与具体类型，目前仍未得到充分探索。我们建立了比较性功能缺失研究范式，用以评估人类细胞的演化改变是否会影响其对必需基因的依赖需求。通过在人类与黑猩猩多能干细胞中开展全基因组CRISPR干扰（CRISPR interference, CRISPRi）筛选实验，我们共鉴定出75个对细胞增殖具有物种特异性调控作用的基因。这些基因所参与的生物学过程具有高度协同性，涵盖细胞周期进程与溶酶体信号通路；通过与红毛猩猩细胞的比对分析，我们确认这些特征源自人类演化特异性改变。人类细胞对CDK2与CCNE1敲低所特有的耐受性，在神经前体细胞与大脑类器官中同样得以保留；这一结果支持"G1期长度假说"，该假说或为人类大脑扩张的潜在演化机制。本次提交至基因表达综合数据库（Gene Expression Omnibus, GEO）的数据集，包含本研究中使用的6株人类与6株黑猩猩CRISPRi工程化细胞系的比较性基因表达谱信息。