Diversity as Opportunity: Insights from 600 Million Years of AHR Evolution

Abstract

The aryl hydrocarbon receptor (AHR) was for many years of interest only to pharmacologists and toxicologists. However, this protein has fundamental roles in biology that are being revealed through studies in diverse animal species. The AHR is an ancient protein. AHR homologs exist in most major groups of modern bilaterian animals, including deuterostomes (chordates, hemichordates, echinoderms) and the two major clades of protostome invertebrates [ecdysozoans (e.g. arthropods and nematodes) and lophotrochozoans (e.g. molluscs and annelids)]. AHR homologs also have been identified in cnidarians such as the sea anemone Nematostella and in the genome of Trichoplax, a placozoan. Bilaterians, cnidarians, and placozoans form the clade Eumetazoa, whose last common ancestor lived approximately 600 million years ago (MYA). The presence of AHR homologs in modern representatives of all these groups indicates that the original eumetazoan animal possessed an AHR homolog. Studies in invertebrates and vertebrates reveal parallel functions of AHR in the development and function of sensory neural systems, suggesting that these may be ancestral roles. Vertebrate animals are characterized by the expansion and diversification of AHRs, via gene and genome duplications, from the ancestral protoAHR into at least five classes of AHR-like proteins: AHR, AHR1, AHR2, AHR3, and AHRR. The evolution of multiple AHRs in vertebrates coincided with the acquisition of high-affinity binding of halogenated and polynuclear aromatic hydrocarbons and the emergence of adaptive functions involving regulation of xenobiotic-metabolizing enzymes and roles in adaptive immunity. The existence of multiple AHRs may have facilitated subfunction partitioning and specialization of specific AHR types in some taxa. Additional research in diverse model and non-model species will continue to enrich our understanding of AHR and its pleiotropic roles in biology and toxicology.

Keywords: Ah receptor; aryl hydrocarbon receptor; bHLH-PAS; development; dioxin; evolution; fish; gene expression; genome duplication; metazoan; vertebrate.

Figure 1. Presence of AHR homologs in holozoans

The tree shows the relationships of selected metazoan (animal) taxa and related unicellular eukaryotes and whether they possess AHR homologs. Ecdysozoa and Lophotrochozoa together comprise the protostomes. Protostomes and deuterostomes are bilaterian animals (green-shaded box). Solid boxes represent groups containing species from which AHR homologs have been confirmed by cloning. Dashed boxes occur around groups with AHR homologs predicted from sequenced genomes. The large yellow-shaded box encompasses the eumetazoans, a group that includes all the taxa in which AHR has been identified to date. See text for additional information. Phylogenetic relationships of choanoflagellates and filastereans after Torruella [149].

Figure 2. Analysis of shared synteny supports AHR classification

(A) Zebrafish AHR1a and related AHR genes in earlier-diverging fishes may be orthologous to human AHR and related AHR genes. (B) Predicted AHR2 genes found in several mammals exhibit shared synteny with AHR2 genes from fish and birds. Analysis of syntenic relationships was performed using Genomicus [150] and manual scanning of sequenced genomes.