Master of none: GPRC6A gene loss is more widespread than previously known

Abstract GPRC6A encodes a class C GPCR that can be activated by multiple ligands and potentially acts as a central regulator of diverse metabolic processes by modulating endocrine pathways. Experimental studies have reported numerous distinct functions for GPRC6A , suggesting it may be a key drug target for several metabolic disorders. Yet, the actual function of GPRC6A has been the focus of considerable debate due to contradictory results and the prevalence of loss-of-function mutations in human populations, leading to the perception of GPRC6A as a “Master of none”. Interestingly, a genome-wide screen for gene loss events in vertebrate species identified the disruption of the GPRC6A gene in toothed whales, in contrast to widespread conservation in the closely related Bovidae family. We employ a synteny-informed comparative genomic approach to demonstrate that the loss of the GPRC6A gene among mammalian species is more widespread than previously reported, encompassing the entire Bovidae group within Artiodactyla and other fully aquatic mammals, including those belonging to Sirenia. An in-depth search of the genomes and short and long-read sequencing datasets of monotremes, hystricomorphs, rhinolophoid bats, pika, koala, and two shrews (white-toothed pygmy shrew and Asian house shrew) reveals at least nine independent GPRC6A gene loss events in vertebrates, highlighting its lineage-specific dispensability and raising questions regarding its ubiquitous functionality. The evolutionary loss of GPRC6A likely represents a lineage-specific response to specialised diets and ecological niches, reshaping metabolic regulation and taste perception and illuminating how niche specialisation influences gene retention or loss within the GPCR landscape across species.