Abstract
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.
Highlights
Dopamine is a neurotransmitter essential for brain function, regulating various physiological processes including locomotion, cognition, and neuroendocrine functions (Hollon et al, 2002; Ott & Nieder, 2019)
By analyzing 124 genomes covering 16 orders, we show that independent coding-debilitating mutations occurred in the ancestors of Mysticeti, of Physeter macrocephalus and the remaining Odontoceti, strongly suggesting that DRD5 is non-coding in Cetacea
To examine the annotation tags and distribution of the DRD5 gene across mammals, 119 annotated mammalian genomes available at National Center of Biotechnology Information (NCBI) were scrutinized for the presence of DRD5 gene annotation and each respective protein product description screened for the LQ tag
Summary
Dopamine is a neurotransmitter essential for brain function, regulating various physiological processes including locomotion, cognition, and neuroendocrine functions (Hollon et al, 2002; Ott & Nieder, 2019). Dopamine molecular actions are transduced via a specific group of G-protein coupled receptors entailing two major classes: DRD1-like and DRD2-like receptors (Beaulieu & Gainetdinov, 2011; Opazo et al, 2018). While DRD1-like receptors stimulate cAMP production postsynaptically, DRD2-like receptors inhibit cAMP production both pre and postsynaptically (Beaulieu & Gainetdinov, 2011). The genomic structure of the underlying genes is distinct, with DRD1-like receptors yielding single exon coding regions (Beaulieu & Gainetdinov, 2011). DRD1-2 receptor classes have diversified in vertebrate evolution most likely as a result of genome duplications (Opazo et al, 2018).
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