Membrane Environment Imposes Unique Selection Pressures on Transmembrane Domains of G Protein-Coupled Receptors

G protein-coupled receptors (GPCRs) represent one of the largest families of membrane proteins in eukaryotes. In Metazoa, GPCRs play significant roles in a wide variety of cri6cal physiological func6ons, including percep6on and metabolism, and over 40% of pharmaceu6cals target GPCRs [1]. Despite their clear func6onal importance, few studies have examined their evolu6on, or indeed the evolu6on of membrane proteins, which account for up to 35% of an organism’s proteome. Here, we present a large-scale computa6onal study of the molecular evolu6on of over 350 mammalian GPCRs, including up to 27 species per gene [2]. We calculated an evolu6onary rate, dN/dS, or ω, using the HyPhy batch language [4] as well as rela6ve solvent accessibility (RSA) for receptors with available structures at each residue.