Cross-species analysis across 450 million years of evolution reveals conservation and divergence of the microglia program (bulk RNA-seq)

Here we characterize microglia transcriptional program across ten species spanning more than 450 million years of evolution. We find that microglia express a conserved core gene program of orthologous genes from rodents to human, including ligands and receptors associated with interactions between glia and neurons. In most species, microglia show a single dominant transcriptional state, while humans express significant microglia heterogeneity. In addition, we observed notable differences in complement, phagocytic and several critical signaling pathways that are enriched with susceptibility genes to brain disorders, including Alzheimer’s and Parkinson’s disease in microglia of common animal models as compared to human. Our study provides an essential resource of conserved and divergent microglia pathways across evolution with important implications for future development of microglia-based therapies in humans.本研究对跨越4.5亿年进化历程的10个物种中的小胶质细胞（microglia）转录程序进行了系统表征。研究发现，从啮齿类到人类，小胶质细胞均表达一套保守的同源基因核心转录程序，其中包含与神经胶质细胞-神经元相互作用相关的配体与受体。在多数物种中，小胶质细胞仅呈现单一主导性转录状态，而人类小胶质细胞则表现出显著的异质性。此外，相较于人类，常见动物模型的小胶质细胞在补体系统、吞噬通路及若干关键信号通路中存在显著差异，这些通路富集了包括阿尔茨海默病、帕金森病在内的脑部疾病易感基因。本研究构建了一套覆盖进化历程的保守与分化小胶质细胞通路核心资源，对未来人类基于小胶质细胞的治疗手段开发具有重要指导意义。