Divergent Ah Receptor Ligand Selectivity during Hominin Evolution

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.

The Role of Geomagnetic Field Intensity in Late Quaternary Evolution of Humans and Large Mammals

“…Hubbard et al () showed that the AhR variant in modern humans contains Val381 residue in the ligand‐binding domain, while the AhR of Neanderthals, and a Denisovan individual, as well as nonhuman primates and other vertebrates (rodents) encode the ancestral Ala381 variant. The Val381 variant is fixed in the genome of all modern humans as well as in the genome of the oldest (45 ka) AMH individual sequenced to date (Fu et al, ).…”

Ligand activation of the Ah receptor contributes to gastrointestinal homeostasis

“…Despite the evolutionary conservation of AHR expression from invertebrates to mammals, the gene encoding AHR has undergone functionally significant divergence across and within species [55–57]. Evidence highlights a marked variability regarding the potential for a given ligand to induce AHR activity across different species e.g.…”

Human and rodent aryl hydrocarbon receptor (AHR): from mediator of dioxin toxicity to physiologic AHR functions and therapeutic options

“…In this context an interesting divergent ligand selectivity during hominin development has been discovered. Modern humans (in contrast to Neanderthals, other hominins and primates) express the AHR Val381 variant, leading to less sensitivity to aryl hydrocarbon bioactivation but retaining the sensitivity to endogenous indole AHR agonists generated through the IDO1-AHR axis (Hubbard et al, 2016). (2) AHR functions in homeostasis of stem/progenitor cells.…”

“…The AHR variant Val381 in modern humans leads to reduced AHR affinity to aryl hydrocarbons in comparison with Neanderthals, (Hubbard et al, 2016). Binding of the photoaffinity ligand 2-azido-3-([ 125 J]iodo-7,8-dibromodibenzo-p-dioxin was much lower; CYP1A1 induction by BaP was reduced in humans carrying the Val381 variant whereas CYP1A1 induction by endogenous ligands such as indirubin and indole was unimpaired.…”