Among primates, humans display a unique trajectory of development that is responsible for the many traits specific to our species. However, the inaccessibility of primary human and chimpanzee tissues has limited our ability to study human evolution. Comparative in vitro approaches using primate-derived induced pluripotent stem cells have begun to reveal species differences on the cellular and molecular levels^1,2. In particular, brain organoids have emerged as a promising platform to study primate neural development in vitro^3,4,5, although cross-species comparisons of organoids are complicated by differences in developmental timing and variability of differentiation^6,7. Here we develop a new platform to address these limitations by fusing human and chimpanzee induced pluripotent stem cells to generate a panel of tetraploid hybrid stem cells. We applied this approach to study species divergence in cerebral cortical development by differentiating these cells into neural organoids. We found that hybrid organoids provide a controlled system for disentangling cis- and trans-acting gene-expression divergence across cell types and developmental stages, revealing a signature of selection on astrocyte-related genes. In addition, we identified an upregulation of the human somatostatin receptor 2 gene (SSTR2), which regulates neuronal calcium signalling and is associated with neuropsychiatric disorders^8,9. We reveal a human-specific response to modulation of SSTR2 function in cortical neurons, underscoring the potential of this platform for elucidating the molecular basis of human evolution.

在灵长类动物中，人类表现出独特的发展轨迹，这导致了我们物种特有的许多特征。然而，原始人类和黑猩猩组织的不可获取性限制了我们研究人类进化的能力。使用灵长类衍生的诱导多能干细胞的体外比较方法已开始揭示细胞和分子水平上的物种差异^1,2。特别是，脑类器官已成为体外研究灵长类神经发育的有前途的平台^3,4,5，尽管类器官的跨物种比较由于发育时间的差异和分化的变异性而变得复杂^6,7。在这里，我们开发了一个新平台，通过融合人类和黑猩猩诱导的多能干细胞产生一组四倍体杂交干细胞来解决这些限制。我们应用这种方法通过将这些细胞分化为神经类器官来研究大脑皮层发育中的物种差异。我们发现，混合类器官提供了一个受控系统，可以消除不同细胞类型和发育阶段的顺式和反式基因表达差异，揭示星形胶质细胞相关基因的选择特征。此外，我们还发现人类生长抑素受体 2 基因 ( SSTR2 ) 的上调，该基因调节神经元钙信号传导并与神经精神疾病相关^8,9。我们揭示了人类对皮质神经元中 SSTR2 功能调节的特异性反应，强调了该平台在阐明人类进化的分子基础方面的潜力。