The dopamine receptor D₅ gene shows signs of independent erosion in toothed and baleen whales

To compare gene loci considering a phylogenetic framework is a promising approach to uncover the genetic basis of human diseases. Imbalance of dopaminergic systems is suspected to underlie some emerging neurological disorders. The physiological functions of dopamine are transduced via G-protein-coupled receptors, including DRD₅ which displays a relatively higher affinity toward dopamine. Importantly, DRD₅ knockout mice are hypertense, a condition emerging from an increase in sympathetic tone. We investigated the evolution of DRD₅, a high affinity receptor for dopamine, in mammals. Surprisingly, among 124 investigated mammalian genomes, we found that Cetacea lineages (Mysticeti and Odontoceti) have independently lost this gene, as well as the burrowing Chrysochloris asiatica (Cape golden mole). We suggest that DRD₅ inactivation parallels hypoxia-induced adaptations, such as peripheral vasoconstriction required for deep-diving in Cetacea, in accordance with the convergent evolution of vasoconstrictor genes in hypoxia-exposed animals. Our findings indicate that Cetacea are natural knockouts for DRD₅ and might offer valuable insights into the mechanisms of some forms of vasoconstriction responses and hypertension in humans.