ArticleMolecular biology and evolution2016
Divergent Ah Receptor Ligand Selectivity during Hominin Evolution.
Article in Molecular biology and evolution, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 73 citations in OpenAlex.
- Mitochondrial vulnerability to aldehydic load and the role mitochondrial aldehyde dehydrogenases.Pharmacological research · 2026Review
- Investigating human lung resilience, its evolutionary history and its relation to COPD.American journal of physiology. Lung cellular and molecular physiology · 2026Review
- Burn Selection: How Fire Injury Shaped Human Evolution.BioEssays : news and reviews in molecular, cellular and developmental biology · 2026Review
- Benefits of equilibrium between microbiota- and host-derived ligands of the aryl hydrocarbon receptor after stroke in aged male mice.Nature communications · 2025Article
- The modern human aryl hydrocarbon receptor is more active when ancestralized by genome editing.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Comparative physiological anthropogeny: exploring molecular underpinnings of distinctly human phenotypes.Physiological reviews · 2023Review
- The role of intestinal microbes on intestinal barrier function and host immunity from a metabolite perspective.Frontiers in immunology · 2023Review
- Evolutionary Implications of Environmental Toxicant Exposure.Biomedicines · 2022Review
- Food Security and Nutrition as the Neglected Missing Links in Cultural Evolution: The Role of the Sociotype.Rambam Maimonides medical journal · 2022Review
- Evidence for reduced BRCA2 functional activity in Homo sapiens after divergence from the chimpanzee-human last common ancestor.Cell reports · 2022Article
- What If Not All Metabolites from the Uremic Toxin Generating Pathways Are Toxic? A Hypothesis.Toxins · 2022Review
- The aryl hydrocarbon receptor as a model PAS sensor.Toxicology reports · 2022Review
- Diverse roles of microbial indole compounds in eukaryotic systems.Biological reviews of the Cambridge Philosophical Society · 2021Review
- The aryl hydrocarbon receptor suppresses immunity to oral squamous cell carcinoma through immune checkpoint regulation.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Evolution of Hominin Detoxification: Neanderthal and Modern Human Ah Receptor Respond Similarly to TCDD.Molecular biology and evolution · 2021Article
- Trajectory Shifts in Interdisciplinary Research of the Aryl Hydrocarbon Receptor-A Personal Perspective on Thymus and Skin.International journal of molecular sciences · 2021Review
- How the AHR Became Important in Cancer: The Role of Chronically Active AHR in Cancer Aggression.International journal of molecular sciences · 2020Review
- How Ah Receptor Ligand Specificity Became Important in Understanding Its Physiological Function.International journal of molecular sciences · 2020Review
- Intestinal microbiota-derived tryptophan metabolites are predictive of Ah receptor activity.Gut microbes · 2020Article
- The aryl hydrocarbon receptor as a mediator of host-microbiota interplay.Gut microbes · 2020Review
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8 authors at 2 institutions in 1 country.
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Abstract
We have identified a fixed nonsynonymous sequence difference between humans (Val381; derived variant) and Neandertals (Ala381; ancestral variant) in the ligand-binding domain of the aryl hydrocarbon receptor (AHR) gene. In an exome sequence analysis of four Neandertal and Denisovan individuals compared with nine modern humans, there are only 90 total nucleotide sites genome-wide for which archaic hominins are fixed for the ancestral nonsynonymous variant and the modern humans are fixed for the derived variant. Of those sites, only 27, including Val381 in the AHR, also have no reported variability in the human dbSNP database, further suggesting that this highly conserved functional variant is a rare event. Functional analysis of the amino acid variant Ala381 within the AHR carried by Neandertals and nonhuman primates indicate enhanced polycyclic aromatic hydrocarbon (PAH) binding, DNA binding capacity, and AHR mediated transcriptional activity compared with the human AHR. Also relative to human AHR, the Neandertal AHR exhibited 150-1000 times greater sensitivity to induction of Cyp1a1 and Cyp1b1 expression by PAHs (e.g., benzo(a)pyrene). The resulting CYP1A1/CYP1B1 enzymes are responsible for PAH first pass metabolism, which can result in the generation of toxic intermediates and perhaps AHR-associated toxicities. In contrast, the human AHR retains the ancestral sensitivity observed in primates to nontoxic endogenous AHR ligands (e.g., indole, indoxyl sulfate). Our findings reveal that a functionally significant change in the AHR occurred uniquely in humans, relative to other primates, that would attenuate the response to many environmental pollutants, including chemicals present in smoke from fire use during cooking.
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