Humans vs. Neanderthals: What One Gene May Reveal About Our Past

The Aryl Hydrocarbon Receptor (AHR) is deeply woven into our evolution. It has been present in the animal kingdom since the earliest metazoans, serving very different functions at different points in time. During vertebrate evolution, AHR became a receptor that recognises exogenous particles in the organism (xenobiotics) and activates a cellular response.

The AHR activation pathway works as follows: AHR is bound in the cytoplasm within a complex that stabilises its structure and keeps it inactive. Upon ligand binding, the proteins that were part of the complex with AHR are released, and AHR translocates into the nucleus where it binds with the aryl hydrocarbon receptor nuclear translocator. This complex then attaches to DNA, specifically to Xenobiotic Response Elements (XRE). Some examples of enzymes expressed during AHR activation include CYP1A1, CYP1A2, and CYP1B1. The role of these enzymes is to catalyse the biotransformation of lipophilic compounds into more soluble, excretable metabolites.

This biochemical pathway is not unique to humans but is shared by many other mammals. However, due to differences in this protein among species, some functional variations may exist. Building on this idea, research was carried out to compare functional roles between to compare the functional roles between humans and our closest extinct relatives whose genomes can be examined – Homo sapiens neanderthalensis. This work was further developed into a Master’s thesis, which was partly funded by the EDIAQI project. 

By comparing the genomes of Neanderthals and modern humans (Homo sapiens sapiens), four differences were found in the UTR regions of the human and Neanderthal AHR, as well as two differences in the coding region of AHR. One of these lies within the PAS domain of AHR – the part of the protein responsible for ligand binding. This difference is especially interesting, not only because it potentially has the greatest impact on AHR functionality. In fact, all known species, including Neanderthals, are fixed for alanine at position 381, whereas humans are fixed for valine. This raises the question: what happened in human evolution that exerted selective pressure on AHR, driving the fixation of this mutation? Did it occur randomly? Was it genetic drift, or natural selection?

One factor specific to humans is the everyday use and manufacture of fire, which led to frequent exposure to novel xenobiotics in smoky environments. Could Val381 be an adaptation to fire use and smoke exposure?

It may be overly ambitious to think we will ever fully answer that question. However, the question we can answer is what functional differences exist between Neanderthal and human AHR. Using information from Neanderthal genome databases, we modelled the Neanderthal AHR with Pymol software. With RxDock software, we performed molecular docking analyses on both the human and Neanderthal AHR with over 46,000 ligands, under the same conditions. 

Although both the human and Neanderthal forms of the protein react similarly when binding different ligands, statistically significant differences were observed in the docking of molecules with relatively larger molecular weights and volumes. These findings suggest that the change in the amino acid sequence may introduce steric hindrances upon binding large ligands in the active site. As a result, humans would be less responsive to large ligands due to potential interference at the binding site. 

That leaves us to explain why Val381 is a characteristically human trait, if it conferred us with an evolutionary advantage, and whether it has contributed to our unique adaptation to environmental challenges.

Note: This article has been published on behalf of Lana Žoldoš, Master student, University of Rijeka, Faculty of Biotechnology and Drug Development.