Allelic polymorphism within the TAS1R3 promoter is associated with human taste sensitivity to sucrose.
Allelic polymorphism within the TAS1R3 promoter is associated with human taste sensitivity to sucrose.
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DOI：
10.1016/j.cub.2009.06.015
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发表时间：
2009-08-11
期刊：
影响因子：
--
通讯作者：
Drayna D
中科院分区：
文献类型：
--
作者：
Fushan AA;Simons CT;Slack JP;Manichaikul A;Drayna D
人类甜味感知是由TAS 1 R2和TAS 1 R3基因编码的异二聚体G蛋白偶联受体复合物介导的。这些基因的变异程度最近已被表征，但这种变异的功能后果尚不清楚。在这项研究中，我们报告了位于TAS 1 R3编码序列上游-1572（rs307355）和-1266（rs35744813）位置的两个C/T单核苷酸多态性与人类对蔗糖的味觉敏感性密切相关，并解释了16%的感知人群变异性。携带T等位基因的个体与在这些核苷酸位置携带C等位基因的个体相比，对蔗糖的敏感性降低。使用荧光素酶报告基因测定，我们证明了每个SNP的T等位基因导致启动子活性降低，与C等位基因相比，与在人类中观察到的表型一致。我们还发现，TAS 1 R3启动子区域从-1700到-1000位置延伸，包含一个新的复合顺式作用元件，对启动子活性具有强烈的沉默作用。我们的结论是rs307355和rs35744813 SNP通过改变该调控元件的功能来影响基因转录。一项全球人口调查显示，rs307355和rs35744813的T等位基因在欧洲人群中的频率最低。我们认为TAS 1 R3转录的遗传差异占人类甜味感知的全球差异的很大一部分。
Human sweet taste perception is mediated by the heterodimeric G-protein coupled receptor complex encoded by the TAS1R2 and TAS1R3 genes. The extent of variation in these genes has been recently characterized, but the functional consequences of such variation are unknown. In this study we report that two C/T single nucleotide polymorphisms 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. Individuals who carry T alleles display reduced sensitivity to sucrose compared to those who carry C alleles at these nucleotide positions. Using a luciferase reporter assay, we demonstrate 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. We also found that the TAS1R3 promoter region extending from position −1700 to −1000 harbors a novel 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.
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