Bitter taste perception is critical to prevent animals from ingesting potentially harmful substances. The aim of this study was to characterize the evolution of T2R4 and test the hypothesis that different regions of the T2R gene are subject to disparate selective pressures, with extracellular regions (ECs) being erratic while transmembrane (TMs) and intracellular regions (ICs) being constrained. Thus, we examined the selective pressures acting on T2R4 and its different regions in 37 primates, and discovered that T2R4 and ECs were subject to neutral evolution and purifying selection, respectively, whereas both TMs and ICs showed purifying selection, as suggested by the hypothesis. We attribute this result to the relatively conservative property of T2R4 gene and the limited number of bitter tastants that T2R4 can respond to. Furthermore, we found that positive selection had acted on the first loop of extracellular regions (EL1). In contrast, the second loop (EL2) and transmembrane region-3, -6, -7 (TM367) were subject to purifying selection, and the third loop (EL3) was subject to neutral evolution. This discovery is probably because EL2, EL3, and TMs play a crucial role in the ligand-binding process, and EL1 is involved in the tastant recognition process. We further tested whether the ω of T2R4 differs among species with different diets and found that a specialized diet affected the evolution of T2R4. Feeding habits, fewer T2Rs, and a dietary shift may account for the results. This study can help to uncover the evolution of T2Rs during the primate evolutionary course.

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