The modern human aryl hydrocarbon receptor is more active when ancestralized by genome editing

• Published in: Proceedings of the National Academy of Sciences Vol. 121; no. 22; p. e2402159121
• Main Authors: Helmbrecht, Nelly, Lackner, Martin, Maricic, Tomislav, Pääbo, Svante
• Format: Journal Article
• Language: English
• Published: United States Proceedings of the National Academy of Sciences 28.05.2024; National Academy of Sciences
• Subjects: AhR gene; Amino acid substitution; Amino acids; Animals; Aromatic compounds; Aromatic hydrocarbons; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological Sciences; Cytochrome P450; Cytochromes P450; Divergence; Editing; Evolution, Molecular; Expression vectors; Gene Editing - methods; Gene expression; Genes; Genomes; Hominids; Humans; Hydrocarbons; Ligands; Neanderthals - genetics; Pan troglodytes - genetics; Receptors; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; Substrates; anthropology; genetics; evolution
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2402159121

The aryl hydrocarbon receptor (AHR) is a transcription factor that has many functions in mammals. Its best known function is that it binds aromatic hydrocarbons and induces the expression of cytochrome P450 genes, which encode enzymes that metabolize aromatic hydrocarbons and other substrates. All present-day humans carry an amino acid substitution at position 381 in the AHR that occurred after the divergence of modern humans from Neandertals and Denisovans. Previous studies that have expressed the ancestral and modern versions of AHR from expression vectors have yielded conflicting results with regard to their activities. Here, we use genome editing to modify the endogenous AHR gene so that it encodes to the ancestral, Neandertal-like AHR protein in human cells. In the absence of exogenous ligands, the expression of AHR target genes is higher in cells expressing the ancestral AHR than in cells expressing the modern AHR, and similar to the expression in chimpanzee cells. Furthermore, the modern human AHR needs higher doses of three ligands than the ancestral AHR to induce the expression of target genes. Thus, the ability of AHR to induce the expression of many of its target genes is reduced in modern humans.