Abstract
The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch–seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.
Highlights
The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals[1]
Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells
Single-cell transcriptomic and epigenomic methods have been effective in elucidating the cellular makeup of complex brain tissues from patterns of gene expression and underlying regulatory mechanisms[2,3,4,5,6]
Summary
Comparative analysis is a powerful strategy with which to understand brain structure and function. Our integrated transcriptomic and epigenomic analysis of more than 450,000 nuclei in humans, non-human primates and mice has yielded a multimodal, hierarchical classification of approximately 100 cell types in each species, with distinct expression of marker genes and sites of accessible chromatin. Humans and marmosets have proportionally fewer L6 corticothalamic and L5 extratelencephalic neurons ( observed in MTG3), which may reflect dilution of these cells owing to allometric scaling of the neocortex relative to the subcortical targets of these cells in primates These results suggest evolutionary changes in local and long-range cortical circuit function, and are consistent with developmental shifts in neuronal progenitor pools and changes in the timing of neurogenesis and migration. D. et al Conserved cell types with divergent features in human versus mouse cortex. 5. Yao, Z. et al A transcriptomic and epigenomic cell atlas of the mouse primary motor cortex. Ecker[10,41], Sten Linnarsson21 &
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