Mouse lemur cell atlas informs primate genes, physiology and disease

Abstract

Mouse lemurs (Microcebus spp.) are an emerging primate model organism, but their genetics, cellular and molecular biology remain largely unexplored. In an accompanying paper¹, we performed large-scale single-cell RNA sequencing of 27 organs from mouse lemurs. We identified more than 750 molecular cell types, characterized their transcriptomic profiles and provided insight into primate evolution of cell types. Here we use the generated atlas to characterize mouse lemur genes, physiology, disease and mutations. We uncover thousands of previously unidentified lemur genes and hundreds of thousands of new splice junctions including over 85,000 primate splice junctions missing in mice. We systematically explore the lemur immune system by comparing global expression profiles of key immune genes in health and disease, and by mapping immune cell development, trafficking and activation. We characterize primate-specific and lemur-specific physiology and disease, including molecular features of the immune program, lemur adipocytes and metastatic endometrial cancer that resembles the human malignancy. We present expression patterns of more than 400 primate genes missing in mice, many with similar expression patterns to humans and some implicated in human disease. Finally, we provide an experimental framework for reverse genetic analysis by identifying naturally occurring nonsense mutations in three primate immune genes missing in mice and by analysing their transcriptional phenotypes. This work establishes a foundation for molecular and genetic analyses of mouse lemurs and prioritizes primate genes, isoforms, physiology and disease for future study.