Microglia Genealogy: Microglia through the lens of evolution

Abstract: Microglia, the brain-resident immune cells, are critically involved in many physiological and pathological processes, including neurodegeneration. We have charted microglia morphology and transcriptional program across ten species spanning more than 450 million years of evolutionary divergence to find human-specific genes or gene-sets that can provide insight into the human susceptibility neurodegenerative diseases. We find that microglia express a conserved core gene program of orthologous genes from rodents to humans, including ligands and receptors associated with interactions between glia and neurons. Microglia shows a single dominant transcriptional state in most species, while human microglia display significant heterogeneity. Additionally, we observed notable differences in rodents' gene modules compared to primate microglia, including complement, phagocytic, and susceptibility genes to neurodegeneration, such as Alzheimer's and Parkinson's disease. Ultimately, gene atlases will not be sufficient if we wish to truly forward predictive modeling of brain tissue function in health and disease. To that end, I will share my preliminary results of our human brain organoids experimental model, which represent a remarkable opportunity, mainly when developed in the context of human cell atlases.