Abstract
The vertebrate genome is a result of two rapid and successive rounds of whole genome duplication, referred to as 1R and 2R. Furthermore, teleost fish have undergone a third whole genome duplication (3R) specific to their lineage, resulting in the retention of multiple gene paralogs. The more recent 3R event in teleosts provides a unique opportunity to gain insight into how genes evolve through specific evolutionary processes. In this study we compare molecular activities of vitamin D receptors (VDR) from basal species that diverged at key points in vertebrate evolution in order to infer derived and ancestral VDR functions of teleost paralogs. Species include the sea lamprey (Petromyzon marinus), a 1R jawless fish; the little skate (Leucoraja erinacea), a cartilaginous fish that diverged after the 2R event; and the Senegal bichir (Polypterus senegalus), a primitive 2R ray-finned fish. Saturation binding assays and gel mobility shift assays demonstrate high affinity ligand binding and classic DNA binding characteristics of VDR has been conserved across vertebrate evolution. Concentration response curves in transient transfection assays reveal EC50 values in the low nanomolar range, however maximum transactivational efficacy varies significantly between receptor orthologs. Protein-protein interactions were investigated using co-transfection, mammalian 2-hybrid assays, and mutations of coregulator activation domains. We then combined these results with our previous study of VDR paralogs from 3R teleosts into a bioinformatics analysis. Our results suggest that 1, 25D3 acts as a partial agonist in basal species. Furthermore, our bioinformatics analysis suggests that functional differences between VDR orthologs and paralogs are influenced by differential protein interactions with essential coregulator proteins. We speculate that we may be observing a change in the pharmacodynamics relationship between VDR and 1, 25D3 throughout vertebrate evolution that may have been driven by changes in protein-protein interactions between VDR and essential coregulators.
Highlights
The ray-finned fishes are the largest, most successful, and most diverse group of vertebrates [1]
The data resulted in three empirical clusters of [Lamprey, Bichir], [Skate, Zebrafish β, and Medaka β] and [Zebrafish α
The cluster (C2) included Skate and the VDRβ paralogs of Zebrafish and Medaka
Summary
The ray-finned fishes (class: Actinopterygii) are the largest, most successful, and most diverse group of vertebrates [1]. Of the roughly 28,000 species in this class, fewer than 60 are not teleost fish These few species comprise the four basal Actinopterygiian lineages of Polypteriformes, Acipenseriformes, Lepisosteiformes, and Amiiformes. These lineages are collectively referred to as “ancient fish” as they are considered to be living fossils This is due to their morphology having remained unchanged over long periods of time and their lineages being relatively species poor [1, 2]. The evolution and divergence of duplicate genes may result in larger gene families and permit more complex interactions and gene networks to evolve, leading to increased morphological complexity, adaptability, and speciation [5, 6] This is consistent with the notion that larger genomes facilitate functional diversification and enable complex gene interactions. These processes in turn may facilitate morphological variation and physiological plasticity [7]
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