Evolution of regulatory signatures in primate cortical neurons at cell-type resolution

Alexey Kozlenkov, Marit W. Vermunt, Pasha Apontes, Junhao Li, Ke Hao, Chet C. Sherwood, Patrick R. Hof, John J. Ely, Michael Wegner, Eran A. Mukamel, Menno P. Creyghton, Eugene V. Koonin, Stella Dracheva

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


The human cerebral cortex contains many cell types that likely underwent independent functional changes during evolution. However, cell-type–specific regulatory landscapes in the cortex remain largely unexplored. Here we report epigenomic and transcriptomic analyses of the two main cortical neuronal subtypes, glutamatergic projection neurons and GABAergic interneurons, in human, chimpanzee, and rhesus macaque. Using genome-wide profiling of the H3K27ac histone modification, we identify neuron-subtype–specific regulatory elements that previously went undetected in bulk brain tissue samples. Human-specific regulatory changes are uncovered in multiple genes, including those associated with language, autism spectrum disorder, and drug addiction. We observe preferential evolutionary divergence in neuron subtype-specific regulatory elements and show that a substantial fraction of pan-neuronal regulatory elements undergoes subtype-specific evolutionary changes. This study sheds light on the interplay between regulatory evolution and cell-type–dependent gene-expression programs, and provides a resource for further exploration of human brain evolution and function.

Original languageEnglish
Pages (from-to)28422-28432
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number45
StatePublished - 10 Nov 2020


  • GABAergic neurons
  • Glutamatergic neurons
  • H3K27ac histone modification
  • Primate evolution
  • Regulatory elements


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