Comparative transcriptomics reveals human-specific cortical features

Abstract

Humans have unique cognitive abilities among primates, including language, but their molecular, cellular, and circuit substrates are poorly understood. We used comparative single nucleus transcriptomics in adult humans, chimpanzees, gorillas, rhesus macaques, and common marmosets from the middle temporal gyrus (MTG) to understand human-specific features of cellular and molecular organization. Human, chimpanzee, and gorilla MTG showed highly similar cell type composition and laminar organization, and a large shift in proportions of deep layer intratelencephalic-projecting neurons compared to macaque and marmoset. Species differences in gene expression generally mirrored evolutionary distance and were seen in all cell types, although chimpanzees were more similar to gorillas than humans, consistent with faster divergence along the human lineage. Microglia, astrocytes, and oligodendrocytes showed accelerated gene expression changes compared to neurons or oligodendrocyte precursor cells, indicating either relaxed evolutionary constraints or positive selection in these cell types. Only a few hundred genes showed human-specific patterning in all or specific cell types, and were significantly enriched near human accelerated regions (HARs) and conserved deletions (hCONDELS) and in cell adhesion and intercellular signaling pathways. These results suggest that relatively few cellular and molecular changes uniquely define adult human cortical structure, particularly by affecting circuit connectivity and glial cell function.

Transcriptomic cytoarchitecture reveals principles of human neocortex organization

“…Of note, there were more layer 5 intratelencephalic projecting (L5 IT) and L4 IT types in V1, the latter expected based on the known expansion and specialization of the thalamorecipient layer 4. L6 IT Car3 neurons were more diverse in MTG, A1, and AnG compared to other areas reflecting a balanced population of CUX2 -expressing and non-expressing neurons specifically in these cortical areas that we reported as an evolutionary specialization of great apes compared to monkeys ( 29 ). L5 ET neurons were least diverse in the most rostral area ACC and the most caudal area V1, while layer 6 corticothalamic-projecting (L6 CT) neurons were most diverse in M1, S1, MTG and V1.…”

Inter-individual variation in human cortical cell type abundance and expression

“…S2e ). Variable genes in glial types were significantly enriched for “glutamatergic synapse” genes (FDR<=1.1E-6 for oligodendrocytes, OPCs, and astrocytes), which capture known genes involved in neuron-glia and glia-glia signaling and which are also the most variable genes when comparing human to non-human primate ( 36 ). Inflammatory response genes were overrepresented among highly variable genes selectively in microglia (FDR = 3.9E-14), suggesting an increase in reactive microglia in a subset of individuals.…”

Delineating the Effective Use of Self-Supervised Learning in Single-Cell Genomics

“…50 IV: Circulating Immune cells after CV19 infection, vaccination, and HC. 51 V: Human: Great apes study 52 ) measuring the macro F1 Score of a random baseline, a Zero-Shot SSL model, the supervised model, and an SSL model.…”