Human sweet taste perception is mediated by the heterodimeric G protein-coupled receptor encoded by the TAS1R2 and TAS1R3 genes 1, 2, 3, 4, 5, 6, 7. Variation in these genes has been characterized [8], but the functional consequences of such variation for sweet perception are unknown. We found that two C/T single-nucleotide polymorphisms (SNPs) located at positions −1572 (rs307355) and −1266 (rs35744813) upstream of the TAS1R3 coding sequence strongly correlate with human taste sensitivity to sucrose and explain 16% of population variability in perception. By using a luciferase reporter assay, we demonstrated that the T allele of each SNP results in reduced promoter activity in comparison to the C alleles, consistent with the phenotype observed in humans carrying T alleles. We also found that the distal region of the TAS1R3 promoter harbors a composite cis-acting element that has a strong silencing effect on promoter activity. We conclude that the rs307355 and rs35744813 SNPs affect gene transcription by altering the function of this regulatory element. A worldwide population survey reveals that the T alleles of rs307355 and rs35744813 occur at lowest frequencies in European populations. We propose that inherited differences in TAS1R3 transcription account for a substantial fraction of worldwide differences in human sweet taste perception.
