Accelerated cell-type-specific regulatory evolution of the human brain

The molecular basis of human brain evolution is a key piece in understanding the evolution of human-specific cognitive and behavioral traits. Comparative studies have suggested that human brain evolution was accompanied by accelerated changes of gene expression (referred to as "regulatory evolution"), especially those leading to an increase of gene products involved in energy production and metabolism. However, the signals of accelerated regulatory evolution were not always consistent across studies. One confounding factor is the diversity of distinctive cell types in the human brain. Here, we leveraged single-cell human and nonhuman primate transcriptomic data to investigate regulatory evolution at cell-type resolution. We relied on six well-established major cell types: excitatory and inhibitory neurons, astrocytes, microglia, oligodendrocytes, and oligodendrocyte precursor cells. We found pervasive signatures of accelerated regulatory evolution in the human brains compared to the chimpanzee brains in the major six cell types, as well as across multiple neuronal subtypes. Moreover, regulatory evolution is highly cell type specific rather than shared between cell types and strongly associated with cellular-level epigenomic features. Evolutionarily differentially expressed genes (DEGs) exhibit greater cell-type specificity than other genes, suggesting their role in the functional specialization of individual cell types in the human brain. As we continue to unfold the cellular complexity of the brain, the actual scope of DEGs in the human brain appears to be much broader than previously estimated. Our study supports the acceleration of cell-type-specific functional programs as an important feature of human brain evolution.