Comparative single-cell multiome reveals evolutionary innovations in neural progenitor cells during primate corticogenesis

The cellular and genetic mechanism underlying the human-specific features of cortex development remains unclear. We generated a cell-type resolved atlas of transcriptome and chromatin accessibility of the developing macaque and mouse prefrontal cortex, and conducted evolutionary analyses with the published complementary human data. The cortex cell type composition shows an overall conservation across species. We found the human neural progenitors show extensive transcriptional rewiring in the growth factor and extracellular matrix pathways. Expression of the human-specific progenitor marker ITGA2 in the cortex of fetal mouse promotes progenitor proliferation and an increased upper-layer neuron proportion. We demonstrate that these transcriptional divergences are primarily driven by the activity changes of the distal regulatory elements in the genome. Markedly, the chromatin regions with human-gained accessibility enrich the human-fixed sequence changes, as well as sequence polymorphisms associated with intelligence and neuropsychiatric disorders. Our results uncover evolutionary innovations in neural progenitors and gene regulatory mechanism during primate cortex evolution. To investigate the cellular and genetic mechanism of the human specifications in cortex development, We generated a comprehensive cell atlas of transcriptome and regulatome for macaque and mouse prefrontal cortex (PFC) during mid-digestion using snRNA-seq, scATAC-seq and scMultiome.目前，解析大脑皮层发育的人类特异性特征背后的细胞与遗传机制仍不明确。我们构建了发育中猕猴与小鼠前额叶皮层的细胞类型分辨率转录组与染色质可及性图谱，并结合已发表的配套人类数据开展进化分析。不同物种的大脑皮层细胞类型组成整体上较为保守。我们发现人类神经祖细胞在生长因子与细胞外基质通路中存在广泛的转录重编程现象。在胎鼠大脑皮层中表达人类特异性祖细胞标志物ITGA2，可促进祖细胞增殖并提升上层神经元比例。我们证实，此类转录差异主要由基因组中远端调控元件的活性变化所驱动。值得注意的是，携带人类获得性染色质可及性的区域，富集了人类固定序列变异，以及与智力和神经精神疾病相关的序列多态性位点。本研究结果揭示了灵长类大脑皮层进化过程中神经祖细胞与基因调控机制的进化创新。为解析大脑皮层发育中人类特异性特征的细胞与遗传机制，我们利用单细胞核RNA测序（snRNA-seq）、单细胞转座酶可及性测序（scATAC-seq）及单细胞多组学测序（scMultiome）技术，构建了妊娠中期猕猴与小鼠前额叶皮层（PFC）的全面转录组与调控组细胞图谱。