,1,2, 罗瑞健1,2Research progress of the bitter taste receptor genes in primates
Ping Feng,1,2, Ruijian Luo1,2编委: 吴东东
收稿日期:2017-09-5修回日期:2017-12-18网络出版日期:2018-01-09
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Received:2017-09-5Revised:2017-12-18Online:2018-01-09
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通讯作者:冯平,博士,讲师,研究方向：动物分子进化E-mail:
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冯平, 罗瑞健. 灵长类苦味受体基因研究进展. 遗传[J], 2018, 40(2): 126-134 doi:10.16288/j.yczz.17-258
Ping Feng, Ruijian Luo.
味觉在高等生物评估食物营养成分和防止摄入有毒物质的过程中起着重要作用。它主要包括5种基本形式：鲜、甜、苦、咸、酸。咸味感受取决于促味剂浓度,浓度低引起愉悦感而浓度高则带来厌恶感,酸味和苦味令生物体产生厌恶,甜味和鲜味使生物体感到愉悦。在对生物体的生理作用方面,咸味能保证正常饮食中电解液的平衡,酸味和苦味能防止摄入有毒或有害化合物,鲜味可以识别氨基酸,甜味使得有机体能鉴别出能量丰富的营养物质[1]。
味觉可以用来评估被消化食物的质量、数量和安全性,是源于食物中的化合物刺激味蕾上的味觉受体细胞而引起的一种感觉形式[2]。味蕾分布在舌头不同部位的乳突(包括轮廓乳突、叶状乳突和菌状乳突)上[3]。每一个味蕾有着像洋葱形状的结构并且由大量味觉受体细胞组成,味觉受体在细胞的顶端表达[1],当受到刺激的时候,这些受体会引发转导级联反应,最终产生味觉信号[4]。味觉信号由大脑的味觉区域接收,通过大脑的二级或者更高级神经元来感受[5]。
目前对味觉受体基因的研究所涉及的类群包括鸟类、哺乳类、爬行类和鱼类等。研究内容包括基因的丢失[6,7,8,9]、基因数量的扩张与收缩[10,11,12]、受体的功能重塑[13]、受体基因的进化模式与食性的关系[14,15]、受体与配体的作用关系[10,16,17]和味觉受体基因的适应性进化[18,19]等。本文主要从灵长类苦味受体与配体之间的关系、苦味受体基因的进化与食性之间的关系、苦味受体基因的适应性进化等方面进行综述,以期为苦味受体基因在灵长类中的研究提供参考。
1 苦味受体作用的多样性
苦味的产生依赖于苦味物质与苦味受体相互作用,苦味受体是一类7次跨膜G蛋白偶联受体,由苦味受体基因Tas2rs编码[20,21]。Tas2rs基因在不同物种中数量变化较大[11]。在极端的情况下,有的物种甚至没有完整的Tas2rs基因,比如在某些鲸类物种中就没有发现完整的Tas2rs基因[8,14];有的物种可以多达约50个有功能的Tas2rs基因(比如蛙类)[14,15,22]。不过,苦味化合物的数量比Tas2rs基因的数量要多得多,大约存在着1000种结构多样的苦味化合物,因此几乎每一种Tas2r受体都对应着多种苦味化合物[23,24,25]。同时,Tas2rs功能基因数量少并不意味着苦味本身重要性的降低,因为它们可以通过扩大作用范围来进行补偿。例如,Meyerhof等[24]在异源表达系统中用104种天然的和人工合成的苦味化合物对人类25个Tas2rs中的20个进行了去孤儿化(deorphanization),结果表明在配体-受体对中,一些受体可以被多种配体激活,而一些配体也可以激活多种受体。表1汇总了用16种苦味物质对18个人类Tas2rs进行检测的结果,可以看出单个苦味受体对16种苦味物质的识别数量变化范围较大,从0~16个不等。因此,苦味受体与苦味物质的对应关系是一对多的关系;此外,苦味受体与苦味物质之间也存在着多对一的关系[26]。进一步研究发现,不同物种苦味受体的作用范围存在着较大的变化。Behrens等[10]对原鸡(Gallus gallus)的3个受体,火鸡(Meleagris gallopavo)的两个受体,斑胸草雀(Taeniopygia guttata)的3个受体以及热带爪蛙(Xenopus tropicalis)的6个受体用46种天然的或者人工合成的苦味化合物进行检测发现,原鸡的3个受体能够对23种化合物做出响应,其中有的化合物能激活1个以上的受体,而有的仅仅能够激活1个;火鸡2个Tas2rs可以对大量苦味化合物做出响应;与火鸡不同,斑胸草雀与原鸡Tas2r1直系同源的3个苦觉受体对应着很少的苦味化合物;而在热带爪蛙中,有的受体对应的苦味剂数量很少,
Table1
表1
表1 人类18个苦味受体对16种苦味物质的识别数量
Table1
| 苦味受体 | 16种苦味物质 被识别的数量 | 苦味物质 |
|---|---|---|
| Tas2r1 | 4 | 苦杏苷、松蒿素、氯霉素、地芬尼多 |
| Tas2r4 | 5 | 苦杏苷、松蒿素、奎宁、苦精、地芬尼多 |
| Tas2r7 | 4 | 咖啡因、奎宁、色甘酸、地芬尼多 |
| Tas2r8 | 2 | 氯霉素、苦精 |
| Tas2r10 | 7 | 松蒿素、苍术苷、咖啡因、氯霉素、奎宁、苦精、地芬尼多 |
| Tas2r13 | 2 | 苦精、地芬尼多 |
| Tas2r14 | 7 | 松蒿素、苍术苷、马兜铃酸、咖啡因、法卡林二醇、奎宁、地芬尼多 |
| Tas2r16 | 2 | 蜗牛素、地芬尼多 |
| Tas2r20 | 2 | 色甘酸、地芬尼多 |
| Tas2r30 | 3 | 苦杏苷、苦精、地芬尼多 |
| Tas2r31 | 5 | 马兜铃酸、奎宁、安赛蜜、地芬尼多、糖精 |
| Tas2r38 | 1 | 地芬尼多 |
| Tas2r39 | 5 | 苦杏苷、氯霉素、奎宁、苦精、地芬尼多 |
| Tas2r40 | 2 | 奎宁、地芬尼多 |
| Tas2r43 | 16 | 芦荟素、苦杏苷、松蒿素、苍术苷、马兜铃酸、咖啡因、氯霉素、法卡林二醇、大海米菊素、蜗牛素、奎宁、安赛蜜、色甘酸、苦精、地芬尼多、糖精 |
| Tas2r45 | 0 | - |
| Tas2r46 | 9 | 苦杏苷、松蒿素、苍术苷、咖啡因、氯霉素、大海米菊素、奎宁、苦精、地芬尼多 |
| Tas2r50 | 1 | 苦杏苷 |
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有的则很多。由此可见,火鸡Tas2rs的作用范围比较大,能对多种苦味物质产生作用,斑胸草雀Tas2rs的作用范围有限,而热带爪蛙Tas2rs的作用范围则有大有小。该研究还发现,苦味受体作用范围的可变性、促味剂范围的重叠性,以及具有交错起作用的促味剂浓度范围,是人类和其他脊椎动物Tas2rs的共同特征[10]。
2 灵长类苦味受体基因的进化
目前苦味受体基因在灵长类中的研究主要集中在苦味受体与配体之间的关系、苦味受体基因的进化与食性之间的关系、苦味受体基因的适应性进化等方面。2.1 灵长类苦味受体与配体之间的关系
为阻止被植食性动物取食,植物能分泌大量的毒素,而Tas2rs能对这些毒素做出响应[24]。例如,Tas2r7对番木鳖碱做出响应(被发现于马钱属植物)[29],Tas2r14对诺斯卡品做出响应(被发现于罂粟花属植物)[30],Tas2r16对水杨苷做出响应(被发现于柳属植物)[31]。Tas2rs对植物毒素的响应性,以及植物在大多数动物饮食中作为营养来源的重要性,预示着苦味受体的进化,由植食性动物对毒素的调节强烈地驱动[32]。目前研究出了几种灵长类苦味受体与配体之间的关系。Bufe等[31]分析了人类Tas2r16并鉴别出很多的β-吡喃葡萄糖苷作为它的配体。研究还发现,水杨苷(β-吡喃葡萄糖苷的一种)结合受体Tas2r16的第三跨膜区包含Glu86。除了在一部分旧大陆猴、猕猴和狒狒中之外,Glu86在几乎所有物种的Tas2r16序列中都是保守的[25]。猕猴中的Glu86突变成了Thr,导致水杨苷受体的敏感性急剧丢失[33],而叶猴、黑猩猩和人类Tas2r16对水杨苷的敏感性则比猕猴要高[31]。Tas2r16对水杨苷的敏感性差异存在于人类、黑猩猩和猕猴中[33,34]。即便是在亲缘关系比较近的人类和黑猩猩之间,仍然存在着Tas2r16对一些天然苦味化合物敏感程度的差异,比如对包含在熊果、小麦和梨皮中的熊果苷敏感性的差异[25]。人类Tas2r38受体能够对天然的和合成的甲状腺抑制子[如异硫
氰酸酯(ITCs,发现于十字花科的植物)、苯硫脲(PTC)和丙基硫氧嘧啶(PROP/PTU,治疗甲状腺机能亢进的药物)]做出反应[24,35],并且很多的非人类灵长类也表现出感受PTC的能力,表明Tas2r38的功能在灵长类进化过程中是保守的[36,37]。然而,PTC感受能力并非保留在所有物种中,在Tas2r38发生突变时,人类、黑猩猩和日本猕猴在敏感性方面表现出种内多态性[32,38,39]。最近的研究发现,与猕猴相比,疣猴的Tas2r38发生了4个非同义突变(V44I, Q93E, I148F, R330K),导致疣猴对PTC的敏感性降低[17]。而在群体水平,Tas2r16和Tas2r38分别在不同人类种群[19,40]和猕猴种群[41]中存在着多样性,以分别适应局部环境和取食特异性。在其他苦味受体中,夜猴(Aotus azarae)比其他新大陆猴(狨猴(Callithrix jacchus)、卷尾猴(Cebus capucinus)、黑掌蛛猴(Ateles geoffroyi)、鬃毛吼猴(Alouatta palliata))的Tas2r1对樟脑的敏感性高,而狨猴比其他新大陆猴(卷尾猴、夜猴、黑掌蛛猴、鬃毛吼猴)Tas2r4对秋水仙素的敏感性高[16]。
2.2 苦味受体基因的进化与食性之间的关系
Tas2r受体家族在食物包含不同植物毒素的物种中有着系统性的变化[26]。比如,肉食性动物需要面对的Tas2rs苦味剂相对少,因此比植食性动物有着数量更少的Tas2rs基因[8,34,41,42]。Li和Zhang[14]对包含10种灵长类在内的41种哺乳类、4种鸟类、2种爬行类、1种两栖类和6种鱼类进行Tas2rs基因数量和食性之间的相关性研究,发现Tas2rs基因数与食物中植物所占的比例相关,取食植物的物种比取食动物的物种需要更多的Tas2rs基因,并且食性类型和Tas2rs基因数量大小呈正相关。图1列出了灵长类苦味受体有功能的基因数目与食性,从图上可以看出,杂食性灵长类有功能苦味受体基因的数目比肉食性的多。行为学研究表明对于苦味化合物奎宁盐酸盐,肉食动物比杂食动物敏感,而杂食动物又比植食动物敏感[43],这可能是因为植食性动物不能承担拒绝所有苦味食物带来的后果,因为苦味物质广泛分布于它们的食物中[43]。植食动物对苦味敏感度的适度降低可以避免挨饿,更重要的是,植图1
新窗口打开|下载原图ZIP|生成PPT图1灵长类有功能的苦觉受体基因数与食性
参考文献[14]数据绘制。
Fig. 1Numbers of functional bitter taste receptor genes and diets of primates
食动物可能已经获得了解毒机制,比如在反刍动物中通过瘤胃微生物的发酵作用,来处理摄入的毒素[44]。另外,植食性动物可能对它们所取食的植物类型比较敏感,这意味着与肉食性动物相比,植食性动物能够识别数量更多的苦味化合物,同时也更能容忍(包括从行为上和从生理上)苦味化合物[14]。
基因组分析显示,具有种间和种内变异的Tas2rs基因家族在哺乳类进化过程中可能反映了食性的变化[33,45,46]。而在灵长类苦味受体与食性的关系中,研究得比较成熟的有Tas2r16和Tas2r38两种受体。β-喃葡萄糖是Tas2r16的配体[31],人类在该受体第172号的氨基酸替换(K172N)使其对有害物质—氰苷有着高度敏感性,这可能有利于避免早期人类饮食中的有毒化合物[47]。Imai等[33]对人类、黑猩猩、猕猴、叶猴和狨猴的Tas2r16进行功能分析,发现不同物种的Tas2r16对苦味化合物表现出不同的敏感性：(1)对水杨苷,猕猴比叶猴、黑猩猩和人类的敏感性要显著降低;(2)对苯基-β-喃葡萄糖,灵长类的反应模式与水杨苷的类似;(3)对熊果苷,人类和白头叶猴的Tas2r16表现出相似的敏感性,而黑猩猩和猕猴的Tas2r16表现出降低的敏感性;(4)对苦杏苷,被检测物种的Tas2r16都表现出相似的高敏感性。因为苦味是一种防御性的感觉,所以Tas2r16敏感性的不同可能与回避和亲近可接触到的食物有关。与其他灵长类不同,日本猕猴经常取食包含水杨苷的柳树皮,尤其是在冬天的时候[48],因为其他除了树皮以外的食物包含非常少的营养物质,因此,对水杨苷苦味敏感性的降低可能对它们的生存是有利的[33]。
Tas2r38是研究的比较成熟的另一个苦味受体,能感受合成的苯硫脲(PTC),丙硫氧嘧啶(PROP)和植物毒素比如甲状腺肿素、柠檬苦素和黑芥子硫苷酸钾[24,35]。Purba等[17]对4种疣猴(印尼叶猴(Presbytis femoralis)、长鼻猴(Nasalis larvatus)、银色乌叶猴(Trachypithecus cristatus)、乌叶猴(T. auratus))和1种猕猴(黑克疣猴(Macaca hecki))的Tas2r38进行行为学实验、功能测试、基因分型以及与已知东黑白疣猴(Colobus guereza))、日本猴、恒河猴、人类和黑猩猩的Tas2r38序列进行比较,发现所有疣猴均存在4个与人类、黑猩猩和猕猴不同的氨基酸位点(I44、E93、F148、K330),而这4个位点在后三者中是保守的(均为V44、Q93、I148、R330),灵长类祖先的Tas2r38被认为是对PTC高度敏感的,4个氨基酸的替换是在灵长类出现分歧产生猕猴之后,因此被认为是疣猴支系特有的减少对PTC敏感性的一种机制。疣猴大多数以叶子为食,推测对PTC敏感性的降低可能是为了适应这种叶食性[17]。
在灵长类中,除了Tas2r16和Tas2r38之外,Tas2r同源物的种间变化研究的比较少,最近,Tsutsui等[16]在新大陆猴中研究了Tas2r1和Tas2r4的敏感性变化。新大陆猴的食物比较丰富,包括果实、叶子、花、植物渗出液和昆虫等,比如夜猴主要是果食性的,补充以昆虫、花、花蜜和叶子[49];狨猴是独特的食汁液动物,并且以昆虫作为补充[49]。Tsutsui等[16]检测5种新大陆猴(狨猴、夜猴、卷尾猴、黑掌蛛猴和鬃毛吼猴)中Tas2rs的配体敏感性时,发现夜猴的Tas2r1对樟脑的敏感性显著高,而狨猴Tas2r4对秋水仙素的敏感性显著高;进一步重构Tas2r1和Tas2r4的祖先受体进行配体敏感性检测,发现第62号的氨基酸为苯丙氨酸是狨猴Tas2r4对秋水仙素有着高度敏感性的原因。该研究为新大陆猴适应物种特异的取食环境提供一种可能的适应机制—调整苦味受体的敏感性。
2.3 苦味受体基因的适应性进化
苦味受体基因的进化研究在灵长类中取得了一些进展。首先,苦味受体氨基酸的改变会导致其功能发生变化。Wang等[7]对来自不同地区22个人类的25个Tas2rs功能基因进行研究发现,在Tas2r7和Tas2r46中存在无义突变,导致提前终止密码子;有的苦味受体(比如人类Tas2r38)氨基酸改变会引起明显的功能基因缺陷[50,51];此外,Tas2r43的两处氨基酸发生改变减少了受体的活性,导致对特定苦味物质芦荟苷活性的差异[52]。人类有着25个Tas2rs功能基因和11个假基因,其中Tas2r64是假基因[53];猩猩中的Tas2r64同样也是假基因,尽管跟人类Tas2r64假基因化的位置不同[54],而该基因在东部黑猩猩、倭黑猩猩和大猩猩中均出现全基因的缺失,表明该基因的缺失是作为趋同进化的产物在不同物种中独立发生的[11,55]。苦味受体基因在不同物种中存在多种直系同源关系。Go等[53]构建了人类和小鼠所有Tas2rs基因的NJ树,发现人和小鼠Tas2rs基因的同源关系可以被分成三类：对多直系同源、多对一直系同源和一对一直系同源。在不同类型基因对中的费舍尔精确检验显示,在一对多直系同源中容易产生假基因(P<0.001)或者有着额外拷贝的基因其假基因数目要比没有额外拷贝的(多对一和一对一直系同源)显著多;然而在灵长类中,假基因化存在于没有额外拷贝的基因(一对一直系同源)中也并不是一个罕见的事件。苦味受体基因所经历的选择作用在类群之间、基因之间发生着变化。研究表明,最近复制的Tas2rs在参与配体识别结构区域中表现出快速分歧[22],该模式意味着Tas2rs作为一个家族经受了多样化的压力,使得动物能够感受到大量的苦味物质[18]。同时,选择作用在类群之间、基因之间也都发生着变化。例如,Go等[53]对人类和12种非人类灵长类Tas2rs基因复制和假基因化的速度和方式进行分析,结果显示在从共同祖先分离后,灵长类比小鼠积累更多的假基因并且支系特异性的假基因化在人类比在非人类灵长类中更加明显;虽然正选择在胞外区的一些氨基酸上起作用,但是Tas2rs基因所经历的功能限制在灵长类中比在小鼠中更加放松,这种放松导致人类苦味感受能力的快速退化。
另外,苦味受体基因不同功能区所遭受的选择压力不同[56]。Tas2rs属于GPCRs,而GPCRs作为一个家族,有着共同的保守的基底结构,包括3个初级的功能分类区域：(1)胞外区(external loops, ELs),调节胞外配体相互作用;(2)跨膜区(transmembrane regions, TMs),对受体的定位和配体的结合比较重要;(3)胞内区(internal loops, ILs),调节胞内与G蛋白的相互作用[56, 57]。这样的功能分区导致ELs 易发生变化而TMs和 ILs 则受到限制,因此,很早以前人们提出了一个假说,认为ELs、TMs和ILs经受的选择压不同[58]。Shi等[18]对人类和小鼠基因组的Tas2rs进行选择压分析发现,在Tas2rs中TMs和ILs的非同义替换率与同义替换率之比明显低于1(在人类分别为ω=0.46和0.51,而小鼠为ω=0.43和0.55),符合纯化选择;而参与配体识别的ELs其进化速率则接近1(人类ω=1.06,小鼠ω=1.002),符合中性选择;进一步分析发现,在人类ELs中存在5个特定的正选择位点(第16、177、253、254和268位氨基酸)。Wooding[32]在来源于猕猴亚科、疣猴亚科、人猿总科、卷尾猴科、狐猴下目的39个个体、以及1个作为外类群的物种中检测了Tas2r38 ELs、TMs和ILs所经受的选择压力,发现三者的ω值依次为1.16(与中性期望没有显著差异)、0.55和0.51,这个结果与Shi等[18]的结果相一致。在自然选择对单个Tas2r基因多样性的塑造作用方面,Wooding[32]对灵长类Tas2r38进行研究发现,尽管两个区域都参与配体识别,适应性过程在EL2中占主导而跨膜区TMs-3、-6、-7经历负选择;除了总体上表现正选择之外,EL2还在特定的位点表现出经受选择。总体上,在灵长类Tas2r38进化过程中,纯化选择作为主要的驱动力,这意味着在灵长类进化过程中基因的完整性被很大程度地保留着。人类Tas2r38响应着十字花科植物合成的化合物,这类化合物是高度多样(>3700种)和广泛分布于世界范围内的。这意味着通过暴露于这些植物,选择限制能被特定地发挥作用,特别是在直接参与配体识别的ELs中,大的进化速率的存在表明Tas2r38响应的化合物的范围也在随着时间的改变而发生 变化[32,57]。
动物能够通过苦味受体来防止摄入有毒有害物质,但是高度敏感性也可能会导致动物拒绝无毒的和有营养的食物,或者因为降低对有利的化合物的摄入而增加了患疾病的风险。所以在苦味受体进化过程中需要进行权衡,使得既能有效防止摄入有害物质,又不至于过分敏感而错过对有利物质的取食。
3 结语和展望
苦味受体基因具有在不同物种中数量变化大、不同受体作用范围差异大、胞外区比跨膜区和胞内区进化速率快等特点。另外,食性在苦味受体基因进化过程中起着驱动力作用,取食植物的物种比取食动物的物种需要更多的苦味受体基因。苦味受体基因的研究对于理解动物味觉受体基因与取食方式之间的关系、灵长类进化过程中基因的动态变化、以及苦味受体基因所经历的选择压力都是比较重要的。尽管灵长类苦味受体基因的数量分布、基因数量的收缩与扩张、苦味受体的进化驱动力等方面的研究进展明显,但是苦味受体基因的起源、结构与功能的关系、苦味受体的生理功能、苦味信号在大脑中的信号传输、味蕾中苦味信号的整合、以及更多的苦味受体与配体之间的识别关系等问题还需要进一步的研究。过去对灵长类苦味受体基因的研究取得了很大的进步,将来的更系统、更全面而深入的研究也同样值得期待。参考文献 原文顺序
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被引期刊影响因子
URLPMID:17108952 [本文引用: 2]
The emerging picture of taste coding at the periphery is one of elegant simplicity. Contrary to what was generally believed, it is now clear that distinct cell types expressing unique receptors are tuned to detect each of the five basic tastes: sweet, sour, bitter, salty and umami. Importantly, receptor cells for each taste quality function as dedicated sensors wired to elicit stereotypic responses.
[本文引用: 1]
URLPMID:3680351 [本文引用: 1]
The sense of taste is stimulated when nutrients or other chemical compounds activate specialized receptor cells within the oral cavity. Taste helps us decide what to eat and influences how efficiently we digest these foods. Human taste abilities have been shaped, in large part, by the ecological niches our evolutionary ancestors occupied and by the nutrients they sought. Early hominoids sought nutrition within a closed tropical forest environment, probably eating mostly fruit and leaves, and early hominids left this environment for the savannah and greatly expanded their dietary repertoire. They would have used their sense of taste to identify nutritious food items. The risks of making poor food selections when foraging not only entail wasted energy and metabolic harm from eating foods of low nutrient and energy content, but also the harmful and potentially lethal ingestion of toxins. The learned consequences of ingested foods may subsequently guide our future food choices. The evolved taste abilities of humans are still useful for the one billion humans living with very low food security by helping them identify nutrients. But for those who have easy access to tasty, energy-dense foods our sensitivities for sugary, salty and fatty foods have also helped cause over nutrition-related diseases, such as obesity and diabetes.
[本文引用: 1]
URLPMID:21885776 [本文引用: 1]
The taste system is one of our fundamental senses, responsible for detecting and responding to sweet, bitter, umami, salty, and sour stimuli. In the tongue, the five basic tastes are mediated by separate classes of taste receptor cells each finely tuned to a single taste quality. We explored the logic of taste coding in the brain by examining how sweet, bitter, umami, and salty qualities are represented in the primary taste cortex of mice. We used in vivo two-photon calcium imaging to demonstrate topographic segregation in the functional architecture of the gustatory cortex. Each taste quality is represented in its own separate cortical field, revealing the existence of a gustotopic map in the brain. These results expose the basic logic for the central representation of taste.
URLPMID:26855141 [本文引用: 1]
Despite recent advances in the knowledge of interindividual taste differences, the underlying genetic backgrounds have remained to be fully elucidated. Much of the taste variation among different mammalian species can be explained by pseudogenization of taste receptors. Here I investigated whether the most recent disruptions of taste receptor genes segregate with their intact forms in modern humans by analyzing 14 ethnically diverse populations. The results revealed an unprecedented prevalence of 25 segregating loss-of-function (LoF) taste receptor variants, identifying one of the most pronounced cases of functional population diversity in the human genome. LoF variant frequency in taste receptors (2.10%) was considerably higher than the overall LoF frequency in human genome (0.16%). In particular, molecular evolutionary rates of candidate sour (14.7%) and bitter (1.8%) receptors were far higher in humans than those of sweet (0.02%), salty (0.05%), and umami (0.17%) receptors compared with other carnivorous mammals, although not all of the taste receptors were identified. Many LoF variants are population-specific, some of which arose even after population differentiation, not before divergence of the modern and archaic human. I conclude that modern humans might have been losing some sour and bitter receptor genes because of high-frequency LoF variants.
URLPMID:15367488 [本文引用: 2]
Abstract Bitter taste perception prevents mammals from ingesting poisonous substances because many toxins taste bitter and cause aversion. We hypothesize that human bitter taste receptor (TAS2R) genes might be relaxed from selective constraints because of the change in diet, use of fire and reliance on other means of toxin avoidance that emerged in human evolution. Here, we examine the intra-specific variations of all 25 genes of the human TAS2R repertoire. Our data show hallmarks of neutral evolution, including similar rates of synonymous (d(S)) and non-synonymous (d(N)) nucleotide changes among rare polymorphisms, common polymorphisms and substitutions; no variation in d(N)/d(S) among functional domains; segregation of pseudogene alleles within species and fixation of loss-of-function mutations. These results, together with previous findings of large numbers of loss-of-function mutations in olfactory, pheromonal and visual sensory genes in humans, suggest surprisingly reduced sensory capabilities of humans in comparison with many other mammals.
URLPMID:4079202 [本文引用: 3]
Taste receptor genes are functionally important in animals, with a surprising exception in the bottlenose dolphin, which shows extensive losses of sweet, umami, and bitter taste receptor genes. To examine the generality of taste gene loss, we examined seven toothed whales and five baleen whales and sequenced the complete repertoire of three sweet/umami (T1Rs) and ten bitter (T2Rs) taste receptor genes. We found all amplified T1Rs and T2Rs to be pseudogenes in all 12 whales, with a shared premature stop codon in 10 of the 13 genes, which demonstrated massive losses of taste receptor genes in the common ancestor of whales. Furthermore, we analyzed three genome sequences from two toothed whales and one baleen whale and found that the sour taste marker gene Pkd2l1 is a pseudogene, whereas the candidate salty taste receptor genes are intact and putatively functional. Additionally, we examined three genes that are responsible for taste signal transduction and found the relaxation of functional constraints on taste signaling pathways along the ancestral branch leading to whales. Together, our results strongly suggest extensive losses of sweet, umami, bitter, and sour tastes in whales, and the relaxation of taste function most likely arose in the common ancestor of whales between 36 and 53 Ma. Therefore, whales represent the first animal group to lack four of five primary tastes, probably driven by the marine environment with high concentration of sodium, the feeding behavior of swallowing prey whole, and the dietary switch from plants to meat in the whale ancestor.<br>
URLPMID:4333347 [本文引用: 1]
Sensing its biotic and abiotic environmental cues is critical to the survival and reproduction of any organism. Of the five traditionally recognized senses of vertebrates, taste is dedicated to the differentiation between nutritious and harmful foods, triggering either appetitive or rejective behaviors. Vertebrates typically can detect five basic taste qualities: sweet, umami, bitter, sour and salty. Remarkable progress in understanding the molecular basis of taste has opened the door to inferring taste abilities from genetic data. Based on genome and relevant gene sequences, we infer that the sweet, umami, and bitter tastes have been lost in all penguins, an order of aquatic flightless birds originating and still occupying the coldest ecological niche on Earth, the Antarctic.
URLPMID:25180257 [本文引用: 4]
Bitter taste perception in vertebrates relies on a variable number of bitter taste receptor (Tas2r) genes, ranging from only three functional genes in chicken to as many as approximately 50 in frogs. Humans possess a medium-sized Tas2r repertoire encoding three broadly and several narrowly tuned receptors plus receptors with intermediate tuning properties. Such tuning information is not available for bitter taste receptors of other vertebrate species. In particular it is not known, whether a small Tas2r repertoire may be compensated for by broad tuning of these receptors, and on the other side, whether a large repertoire might entail a preponderance of narrowly tuned receptors. To elucidate this question, we cloned all three chicken Tas2rs, the two turkey Tas2rs, three zebra finch Tas2rs, and six Tas2rs of the Western clawed frog representative of major branches of the phylogenetic tree, and screened them with 46 different bitter compounds. All chicken and turkey Tas2rs were broadly tuned, the zebra finch Tas2rs were narrowly tuned, and frog Tas2rs ranged from broadly to narrowly tuned receptors. We conclude that a low number of functional Tas2r genes does not imply a reduced importance of bitter taste per se, as it can be compensated by large tuning width. A high number of functional Tas2r genes appears to allow the evolution of specialized receptors, possibly for toxins with species-specific relevance. In sum, we show that variability in tuning breadth, overlapping agonist profiles, and staggered effective agonist concentration ranges are shared features of human and other vertebrate Tas2rs.
URLPMID:24758778 [本文引用: 3]
Abstract Genome studies of mammals in the superorder Euarchontoglires (a clade that comprises the orders Primates, Dermoptera, Scandentia, Rodentia, and Lagomorpha) are important for understanding the biological features of humans, particularly studies of medical model animals such as macaques and mice. Furthermore, the dynamic ecoevolutionary signatures of Euarchontoglires genomes may be discovered because many species in this clade are characterized by their successful adaptive radiation to various ecological niches. In this study, we investigated the evolutionary trajectory of bitter taste receptor genes (TAS2Rs) in 28 Euarchontoglires species based on homology searches of 39 whole-genome assemblies. The Euarchontoglires species possessed variable numbers of intact TAS2Rs, which ranged from 16 to 40, and their last common ancestor had at least 26 intact TAS2Rs. The gene tree showed that there have been at least seven lineage-specific events involving massive gene duplications. Gene duplications were particularly evident in the ancestral branches of anthropoids (the anthropoid cluster), which may have promoted the adaptive evolution of anthropoid characteristics, such as a trade-off between olfaction and other senses and the development of herbivorous characteristics. Subsequent whole-gene deletions of anthropoid cluster TAS2Rs in hominoid species suggest ongoing ectopic homologous recombination in the anthropoid cluster. These findings provide insights into the roles of adaptive sensory evolution in various ecological niches and important clues related to the molecular mechanisms that underlie taste diversity in Euarchontoglires mammalian species, including humans. 漏 The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
URLPMID:5564386 [本文引用: 1]
As nontraditional model organisms with extreme physiological and morphological phenotypes, snakes are believed to possess an inferior taste system. However, the bitter taste sensation is essential to distinguish the nutritious and poisonous food resources and the genomic evidence of bitter taste in snakes is largely scarce. To explore the genetic basis of the bitter taste of snakes and characterize the evolution of bitter taste receptor genes (Tas2rs) in reptiles, we identifiedTas2rgenes in 19 genomes (species) corresponding to three orders of non-avian reptiles. Our results indicated contractions ofTas2rgene repertoires in snakes, however dramatic gene expansions have occurred in lizards. Phylogenetic analysis of theTas2rs with NJ and BI methods revealed thatTas2rgenes of snake species formed two clades, whereas in lizards theTas2rgenes clustered into two monophyletic clades and four large clades. Evolutionary changes (birth and death) of intactTas2rgenes in reptiles were determined by reconciliation analysis. Additionally, the taste signaling pathway calcium homeostasis modulator 1 (Calhm1) gene of snakes was putatively functional, suggesting that snakes still possess bitter taste sensation. Furthermore, Phylogenetically Independent Contrasts (PIC) analyses reviewed a significant correlation between the number ofTas2rgenes and the amount of potential toxins in reptilian diets, suggesting that insectivores such as some lizards may require moreTas2rs genes than omnivorous and carnivorous reptiles.
URLPMID:25146290 [本文引用: 1]
Abstract Sensory systems define an animal's capacity for perception and can evolve to promote survival in new environmental niches. We have uncovered a noncanonical mechanism for sweet taste perception that evolved in hummingbirds since their divergence from insectivorous swifts, their closest relatives. We observed the widespread absence in birds of an essential subunit (T1R2) of the only known vertebrate sweet receptor, raising questions about how specialized nectar feeders such as hummingbirds sense sugars. Receptor expression studies revealed that the ancestral umami receptor (the T1R1-T1R3 heterodimer) was repurposed in hummingbirds to function as a carbohydrate receptor. Furthermore, the molecular recognition properties of T1R1-T1R3 guided taste behavior in captive and wild hummingbirds. We propose that changing taste receptor function enabled hummingbirds to perceive and use nectar, facilitating the massive radiation of hummingbird species. Copyright 漏 2014, American Association for the Advancement of Science.
URLPMID:24202612 [本文引用: 6]
Abstract Vertebrate Tas2r taste receptors bind to bitter compounds, which are typically poisonous, to elicit bitter sensation to prevent the ingestion of toxins. Previous studies noted a marked variation in the number of Tas2r genes among species, but the underlying cause is unclear. To address this question, we compile the Tas2r gene repertoires from 41 mammals, 4 birds, 2 reptiles, 1 amphibian, and 6 fishes. The number of intact Tas2r genes varies from 0 in the bottlenose dolphin to 51 in the Western clawed frog, with numerous expansions and contractions of the gene family throughout vertebrates, especially among tetrapods. The Tas2r gene number in a species correlates with the fraction of plants in its diet. Because plant tissues contain more toxic compounds than animal tissues do, our observation supports the hypothesis that dietary toxins are a major selective force shaping the diversity of the Tas2r repertoire.
URLPMID:19144204 [本文引用: 2]
Background Sensing bitter tastes is crucial for many animals because it can prevent them from ingesting harmful foods. This process is mainly mediated by the bitter taste receptors (T2R), which are largely expressed in the taste buds. Previous studies have identified some T2R gene repertoires, and marked variation in repertoire size has been noted among species. However, the mechanisms underlying the evolution of vertebrate T2R genes remain poorly understood. Results To better understand the evolutionary pattern of these genes, we identified 16 T2R gene repertoires based on the high coverage genome sequences of vertebrates and studied the evolutionary changes in the number of T2R genes during birth-and-death evolution using the reconciled-tree method. We found that the number of T2R genes and the fraction of pseudogenes vary extensively among species. Based on the results of phylogenetic analysis, we showed that T2R gene families in teleost fishes are more diverse than those in tetrapods. In addition to the independent gene expansions in teleost fishes, frogs and mammals, lineage-specific gene duplications were also detected in lizards. Furthermore, extensive gains and losses of T2R genes were detected in each lineage during their evolution, resulting in widely differing T2R gene repertoires. Conclusion These results further support the hypotheses that T2R gene repertoires are closely related to the dietary habits of different species and that birth-and-death evolution is associated with adaptations to dietary changes.
PMID:5062938 [本文引用: 4]
New World monkeys (NWMs) are unique in that they exhibit remarkable interspecific variation in color vision and feeding behavior, making them an excellent model for studying sensory ecology. However, it is largely unknown whether non-visual senses co-vary with feeding ecology, especially gustation, which is expected to be indispensable in food selection. Bitter taste, which is mediated by bitter taste receptors (TAS2Rs) in the tongue, helps organisms avoid ingesting potentially toxic substances in food. In this study, we compared the ligand sensitivities of the TAS2Rs of five species of NWMs by heterologous expression in HEK293T cells and calcium imaging. We found that TAS2R1 and TAS2R4 orthologs differ in sensitivity among the NWM species for colchicine and camphor, respectively. We then reconstructed the ancestral receptors of NWM TAS2R1 and TAS2R4, measured the evolutionary shift in ligand sensitivity, and identified the amino acid replacement at residue 62 as responsible for the high sensitivity of marmoset TAS2R4 to colchicine. Our results provide a basis for understanding the differences in feeding ecology among NWMs with respect to bitter taste. The online version of this article (doi:10.1186/s12862-016-0783-0) contains supplementary material, which is available to authorized users.
URLPMID:28123110 [本文引用: 4]
Bitterness perception in mammals is mostly directed at natural toxins that induce innate avoidance behaviours. Bitter taste is mediated by the G protein-coupled receptor TAS2R, which is located in taste cell membranes. One of the best-studied bitter taste receptors is TAS2R38, which recognizes phenylthiocarbamide (PTC). Here we investigate the sensitivities of TAS2R38 receptors to PTC in four species of leaf-eating monkeys (subfamily Colobinae). Compared with macaque monkeys (subfamily Cercopithecinae), colobines have lower sensitivities to PTC in behavioural and in vitro functional analyses. We identified four non-synonymous mutations in colobine TAS2R38 that are responsible for the decreased sensitivity of the TAS2R38 receptor to PTC observed in colobines compared with macaques. These results suggest that tolerance to bitterness in colobines evolved from an ancestor that was sensitive to bitterness as an adaptation to eating leaves.
URLPMID:12679530 [本文引用: 4]
The diversity and evolution of bitter taste perception in mammals is not well understood. Recent discoveries of bitter taste receptor (T2R) genes provide an opportunity for a genetic approach to this question. We here report the identification of 10 and 30 putative T2R genes from the draft human and mouse genome sequences, respectively, in addition to the 23 and 6 previously known T2R genes from the two species. A phylogenetic analysis of the T2R genes suggests that they can be classified into three main groups, which are designated A, B, and C. Interestingly, while the one-to-one gene orthology between the human and mouse is common to group B and C genes, group A genes show a pattern of species- or lineage-specific duplication. It is possible that group B and C genes are necessary for detecting bitter tastants common to both humans and mice, whereas group A genes are used for species-specific bitter tastants. The analysis also reveals that phylogenetically closely related T2R genes are close in their chromosomal locations, demonstrating tandem gene duplication as the primary source of new T2Rs. For closely related paralogous genes, a rate of nonsynonymous nucleotide substitution significantly higher than the rate of synonymous substitution was observed in the extracellular regions of T2Rs, which are presumably involved in tastant-binding. This suggests the role of positive selection in the diversification of newly duplicated T2R genes. Because many natural poisonous substances are bitter, we conjecture that the mammalian T2R genes are under diversifying selection for the ability to recognize a diverse array of poisons that the organisms may encounter in exploring new habitats and diets.
PMID:24785689 [本文引用: 2]
Bitter taste perception, mediated by receptors encoded by the TAS2R loci, has important roles in human health and nutrition. Prior studies have demonstrated that nonsynonymous variation at site 516 in the coding exon of TAS2R16, a bitter taste receptor gene on chromosome 7, has been subject to positive selection and is strongly correlated with differences in sensitivity to salicin, a bitter anti-inflammatory compound, in human populations. However, a recent study suggested that the derived G-allele at rs702424 in the TAS2R16 promoter has also been the target of recent selection and may have an additional effect on the levels of salicin bitter taste perception. Here, we examined alleles at rs702424 for signatures of selection using Extended Haplotype Homozygosity (EHH) and FST statistics in diverse populations from West Central, Central and East Africa. We also performed a genotype-phenotype analysis of salicin sensitivity in a subset of 135 individuals from East Africa. Based on our data, we did not find evidence for positive selection at rs702424 in African populations, suggesting that nucleotide position 516 is likely the site under selection at TAS2R16. Moreover, we did not detect a significant association between rs702424 alleles and salicin bitter taste recognition, implying that this site does not contribute to salicin phenotypic variance. Overall, this study of African diversity provides further information regarding the genetic architecture and evolutionary history of a biologically-relevant trait in humans.
URLPMID:4172856 [本文引用: 1]
Abstract BACKGROUND: Human bitter taste receptors are encoded by a gene family consisting of 25 functional TAS2R loci. In addition, humans carry 11 TAS2R pseudogenes, some of which display evidence for substantial diversification among species, showing lineage-specific loss of function. Since bitter taste is thought to help prevent the intake of toxic substances, diversity at TAS2R genes could reflect the action of natural selection on the ability to recognize some bitter compounds rather than others. Whether species-specific variation in TAS2R pseudogenes is solely the result of genetic drift or whether it may have been influenced by selection due to different feeding behaviors has been an open question. RESULTS: In this study, we analyzed patterns of variation at human TAS2R pseudogenes in both African and non-African populations, and compared them to those observable in nonhuman primates and archaic human species. Our results showed a similar worldwide distribution of allelic variation for most of the pseudogenes, with the exception of the TAS2R6P and TAS2R18P loci, both of which presented an unexpected higher frequency of derived alleles outside Africa. At the TAS2R6P locus, two SNPs were found in strong linkage disequilibrium (r2鈥>鈥0.9) with variants in the functional TAS2R5 gene, which showed signatures of selection. The human TAS2R18P carried a species-specific stop-codon upstream of four polymorphic insertions in the reading frame. SNPs at this locus showed significant positive values in a number of neutrality statistics, and age estimates indicated that they arose after the homo-chimp divergence. CONCLUSIONS: The similar distribution of variation of many human bitter receptor pseudogenes among human populations suggests that they arose from the ancestral forms by a unidirectional loss of function. However we explain the higher frequency of TAS2R6P derived alleles outside Africa as the effect of the balancing selection acting on the closely linked TAS2R5 gene. In contrast, TAS2R18P displayed a more complex history, suggesting an acquired function followed by a recent pseudogenization that predated the divergence of human modern and archaic species, which we hypothesize was associated with adaptions to dietary changes.
URL [本文引用: 1]
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PMID:16207936 [本文引用: 2]
Taste reception is fundamental to diet selection in many animals. The genetic basis underlying the evolution and diversity of taste reception, however, is not well understood. Recent discoveries of T1R sweet/umami receptor genes and T2R bitter receptor genes in humans and mice provided an opportunity to address this question. Here, we report the identification of 20 putatively functional T1R genes and 167 T2R genes from the genome sequences of nine vertebrates, including three fishes, one amphibian, one bird, and four mammals. Our comparative genomic analysis shows that orthologous T1R sequences are relatively conserved in evolution and that the T1R gene repertoire remains virtually constant in size across most vertebrates, except for the loss of the T1R2 sweet receptor gene in the sweet-insensitive chicken and the absence of all T1R genes in the tongueless western clawed frog. In contrast, orthologous T2R sequences are more variable, and the T2R repertoire diverges tremendously among species, from only three functional genes in the chicken to 49 in the frog. These evolutionary patterns suggest the relative constancy in the number and type of sweet and umami tastants encountered by various vertebrates or low binding specificities of T1Rs but a large variation in the number and type of bitter compounds detected by different species. Although the rate of gene duplication is much lower in T1Rs than in T2Rs, signals of positive selection are detected during the functional divergences of paralogous T1Rs, as was previously found among paralogous T2Rs. Thus, functional divergence and specialization of taste receptors generally occurred via adaptive evolution.
URLPMID:17595105 [本文引用: 1]
Abstract Sesquiterpene lactones are a major class of natural bitter compounds occurring in vegetables and culinary herbs as well as in aromatic and medicinal plants, where they often represent the main gustatory and pharmacologically active component. Investigations on sesquiterpene lactones have mainly focused on their bioactive potential rather than on their sensory properties. In the present study, we report about the stimulation of heterologously expressed human bitter taste receptors, hTAS2Rs, by the bitter sesquiterpene lactone herbolide D. A specific response to herbolide D was observed i.a. for hTAS2R46, a so far orphan bitter taste receptor without any known ligand. By further investigation of its agonist pattern, we characterized hTAS2R46 as a bitter receptor broadly tuned to sesquiterpene lactones and to clerodane and labdane diterpenoids as well as to the unrelated bitter substances strychnine and denatonium.
PMID:20022913 [本文引用: 6]
Abstract Humans perceive thousands of compounds as bitter. In sharp contrast, only approximately 25 taste 2 receptors (TAS2R) bitter taste receptors have been identified, raising the question as to how the vast array of bitter compounds can be detected by such a limited number of sensors. To address this issue, we have challenged 25 human taste 2 receptors (hTAS2Rs) with 104 natural or synthetic bitter chemicals in a heterologous expression system. Thirteen cognate bitter compounds for 5 orphan receptors and 64 new compounds for previously identified receptors were discovered. Whereas some receptors recognized only few agonists, others displayed moderate or extreme tuning broadness. Thus, 3 hTAS2Rs together were able to detect approximately 50% of the substances used. Conversely, though 63 bitter substances activated only 1-3 receptors, 19 compounds stimulated up to 15 hTAS2Rs. Our data suggest that the detection of the numerous bitter chemicals is related to the molecular receptive ranges of hTAS2Rs.
[本文引用: 3]
URLPMID:27340135 [本文引用: 3]
Abstract Bitter taste receptor genes (TAS2Rs) harbor extensive diversity, which is broadly distributed across human populations and strongly associated with taste response phenotypes. The majority of TAS2R variation is composed of single-nucleotide polymorphisms. However, 2 closely positioned loci at 12p13, TAS2R43 and -45, harbor high-frequency deletion (Δ) alleles in which genomic segments are absent, resulting in copy number variation (CNV). To resolve their chromosomal structure and organization, we generated maps using long-range contig alignments and local sequencing across the TAS2R43–45 region. These revealed that the deletion alleles (43Δ and 45Δ) are 37.8 and 32.2kb in length, respectively and span the complete coding region of each gene (~1kb) along with extensive up- and downstream flanking sequence, producing separate CNVs at the 2 loci. Comparisons with a chimpanzee genome, which contained intact homologs of TAS2R43, -45, and nearby TAS2Rs, indicated that the deletions evolved recently, through unequal recombination in a cluster of closely related loci. Population genetic analyses in 946 subjects from 52 worldwide populations revealed that copy number ranged from 0 to 2 at both TAS2R43 and TAS2R45, with 43Δ and 45Δ occurring at high global frequencies (0.33 and 0.18). Estimated recombination rates between the loci were low (ρ = 2.7×10614; r = 6.6×10619) and linkage disequilibrium was high (D′ = 1.0), consistent with their adjacent genomic positioning and recent origin. Geographic variation pointed to an African origin for the deletions. However, no signatures of natural selection were found in population structure or integrated haplotype scores spanning the region, suggesting that patterns of diversity at TAS2R43 and -45 are primarily due to genetic drift.
URLPMID:23632330 [本文引用: 1]
A complete understanding of bitterness perception requires identification of cognate bitter substances for all human bitter taste receptors (TAS2Rs). However, so far, no agonists have been identified for five of the 25 TAS2Rs, i.e., TAS2R41, TAS2R42, TAS2R45, TAS2R48 and TAS2R60. Due to substantial genetic variability several haplotypes exist for most bitter receptor genes. For some of the deorphaned TAS2Rs, haplotypes have been identified coding for proteins with severely impaired or even lacking receptor function, proposing that the use of non-functional receptor variants in previous investigations accounted for the failure to identify cognate bitter agonists for the orphan TAS2Rs. In the present report we reasoned that at least one out of the major genetically encoded TAS2R variants is functional. Therefore, we expressed the major haplotypes of the five orphan TAS2Rs in our functional assay and challenged the cells with 106 bitter compounds. Chloramphenicol was identified as agonist for TAS2R41. Further studies revealed that TAS2R41 is a 'specialist' receptor highly selective for this antibiotic. None of the other TAS2R variants responded to any of the 106 compounds, suggesting that the use of non-functional variants does not explain the failure to identify cognate agonists for the other four TAS2Rs. Probably, these TAS2Rs are highly selective for bitter substances absent in our compound library.
URLMagsci [本文引用: 1]
苦味的识别作为一种防御机制, 能帮助动物避免摄入有毒物质, 它在动物的长期进化过程中起着至关重要的作用. 由于不同动物具有不同的生存环境和取食偏好, 使苦味识别能力在动物的长期进化中产生了分化. 苦味的识别源于苦味物质和苦味受体的结合, 所以对编码苦味受体基因的研究成为研究苦味识别的分子基础. 近年来, 随着体外功能实验体系的建立, 越来越多苦味受体的配体被发现. 另一方面, 随着许多脊椎动物基因组的测序完成, 人们对苦味受体基因家族的演化研究也取得了很大的进展. 对演化驱动力的研究, 能够使我们了解不同物种中苦味受体功能的变化趋势, 从而帮助我们发现更多的苦味配体. 本文主要介绍了苦味受体基因家族的功能及其在脊椎动物中演化的最新进展, 并对苦味受体基因家族今后的研究提出了展望.
URLMagsci [本文引用: 1]
苦味的识别作为一种防御机制, 能帮助动物避免摄入有毒物质, 它在动物的长期进化过程中起着至关重要的作用. 由于不同动物具有不同的生存环境和取食偏好, 使苦味识别能力在动物的长期进化中产生了分化. 苦味的识别源于苦味物质和苦味受体的结合, 所以对编码苦味受体基因的研究成为研究苦味识别的分子基础. 近年来, 随着体外功能实验体系的建立, 越来越多苦味受体的配体被发现. 另一方面, 随着许多脊椎动物基因组的测序完成, 人们对苦味受体基因家族的演化研究也取得了很大的进展. 对演化驱动力的研究, 能够使我们了解不同物种中苦味受体功能的变化趋势, 从而帮助我们发现更多的苦味配体. 本文主要介绍了苦味受体基因家族的功能及其在脊椎动物中演化的最新进展, 并对苦味受体基因家族今后的研究提出了展望.
URL [本文引用: 1]
The T2Rs belong to a multi-gene family of G-protein-coupled receptors responsible for the detection of ingested bitter-tasting compounds. The T2Rs are conserved among mammals with the human and mouse gene families consisting of about 25 members. In the present study we address the signalling properties of human and mouse T2Rs using an in vitro reconstitution system in which both the ligands and G-proteins being assayed can be manipulated independently and quantitatively assessed. We confirm that the mT2R5, hT2R43 and hT2R47 receptors respond selectively to micromolar concentrations of cycloheximide, aristolochic acid and denatonium respectively. We also demonstrate that hT2R 14 is a receptor for aristolochic acid and report the first characterization of the ligand specificities of hT2R7, which is a broadly tuned receptor responding to strychnine, quinacrine, chloroquine and papaverine. Using these defined ligand-receptor interactions, we assayed the ability of the ligand-activated T2Rs to catalyse GTP binding on divergent members of the G(alpha) family including three members of the G(alpha i) subfamily (transducin, G(alpha i1) and G(alpha o))as well as G(alpha s) and G(alpha q). The T2Rs coupled with each of the three G(alpha i) members tested. However, none of the T2Rs coupled to either G(alpha s) or G(alpha q) suggesting the T2Rs signal primarily through G(alpha i) mediated signal transduction pathways. Furthermore, we observed different G-protein selectivities among the T2Rs with respect to both G(alpha i) subunits and G(beta y) dimers, suggesting that bitter taste is transduced by multiple G-proteins that may differ among the T2Rs.
URLPMID:15178431 [本文引用: 1]
The recent advances in the functional expression of TAS2Rs in heterologous systems resulted in the identification of bitter tastants that specifically activate receptors of this family. All bitter taste receptors reported to date exhibit a pronounced selectivity for single substances or structurally related bitter compounds. In the present study we demonstrate the expression of the hTAS2R14 gene by RT-PCR analyses and in situ hybridisation in human circumvallate papillae. By functional expression in HEK-293T cells we show that hTAS2R14 displays a, so far, unique broad tuning towards a variety of structurally diverse bitter compounds, including the potent neurotoxins, (-)-alpha-thujone, the pharmacologically active component of absinthe, and picrotoxinin, a poisonous substance of fishberries. The observed activation of heterologously expressed hTAS2R14 by low concentrations of (-)-alpha-thujone and picrotoxinin suggests that the receptor is sufficiently sensitive to caution us against the ingestion of toxic amounts of these substances.
[本文引用: 4]
URLPMID:22218679 [本文引用: 5]
Abstract Bitter taste receptors (TAS2Rs) enable animals to detect and avoid toxins in the environment, including noxious defense compounds produced by plants. This suggests that TAS2Rs are under complex pressures from natural selection. To investigate these pressures, we examined signatures of selection in the primate TAS2R38 gene. Whole-gene (1,002 bp) sequences from 40 species representing all major primate taxa uncovered extensive variation. Nucleotide substitutions occurred at 448 positions, resulting in 201 amino acid changes. Two single-nucleotide deletions, one three-nucleotide in-frame deletion, and one premature stop codon were also observed. The rate of non-synonymous substitution (ω = dN/dS), was high in TAS2R38 (ω = 0.60) compared to other genes, but significantly lower than expected under neutrality (P = 4.0 × 10(-9)), indicating that purifying selection has maintained the basic structure of the receptor. However, differences were present among receptor subregions. Non-synonymous rates were significantly lower than expected in transmembrane domains (ω = 0.55, P = 1.18 × 10(-12)) and internal loops (ω = 0.51, P = 7.04 × 10(-5)), but not external loops (ω = 1.16, P = 0.53), and evidence of positive selection was found in external loop 2, which exhibited a high rate (ω = 2.53) consistent with rapid shifts in ligand targeting. These patterns point to a history of rapid yet constrained change in bitter taste responses in the course of primate evolution.
URLPMID:3391450 [本文引用: 5]
Abstract In mammals, bitter taste is mediated by TAS2R genes, which belong to the large family of seven transmembrane G protein-coupled receptors. Because TAS2Rs are directly involved in the interaction between mammals and their dietary sources, it is likely that these genes evolved to reflect species-specific diets during mammalian evolution. Here, we investigated the sensitivities of TAS2R16s of various primates by using a cultured cell expression system, and found that the sensitivity of each primate species varied according to the ligand. Especially, the sensitivity of TAS2R16 of Japanese macaques to salicin was much lower than that of human TAS2R16, which was supported by behavioural tests. These results suggest the possibility that bitter-taste sensitivities evolved independently by replacing specific amino acid residues of TAS2Rs in different primate species to adapt to food items they use.
URLPMID:26037485 [本文引用: 2]
Background Domestic cats (felis catus) have a reputation for being rather unpredictable in their dietary choices. While their appetite for protein or savory flavors is consistent with their nutritional needs, their preference among protein-sufficient dietary options may relate to differences in the response to other flavor characteristics. Studies of domestic cat taste perception are limited, in part, due to the lack of receptor sequence information. Several studies have described the phylogenetic relationship of specific cat taste receptor sequences as compared with other carnivores. For example, domestic cats are obligate carnivores and their receptor Tas1r2, associated with the human perception of sweet, is present only as a pseudogene. Similarly, the cat perception of bitter may differ from that of other mammals due to variations in their repertoire of bitter receptor (Tas2r) genes. This report includes the first functional characterization of domestic cat taste receptors. Results We functionally expressed two uncharacterized domestic sequences Tas2r38 and Tas2r43 and deorphanized the receptors using a cellular functional assay. Statistical significance was determined using an unpaired, two-tailed t-test. The cat sequence for Tas2r38 contains 3 major amino acid residues known to confer the taster phenotype (PAI), which is associated with sensitivity to the bitter compounds PROP and PTC. However, in contrast to human TAS2R38, cat Tas2r38 is activated by PTC but not by PROP. Furthermore, like its human counterpart, cat Tas2r43 is activated by aloin and denatonium, but differs from the human TAS2R43 by insensitivity to saccharin. The responses of both cat receptors to the bitter ligands were concentration-dependent and were inhibited by the human bitter blocker probenecid. Conclusions These data demonstrate that the response profiles of the cat bitter receptors Tas2r38 and Tas2r43 are distinct from those of their orthologous human receptors. Results with cat Tas2r38 also demonstrate that additional residues beyond those classically associated with PROP sensitivity in humans influence the sensitivity to PROP and PTC. Functional studies of the human bitter receptor family are being applied to the development of food and medicinal products with more appealing flavor profiles. Our work lays the foundation for similar work applied to felines.
URLPMID:20551074 [本文引用: 2]
The perceived bitterness of cruciferous vegetables such as broccoli varies from person to person, but the functional underpinnings of this variation are not known. Some evidence suggests that it arises, in part, from variation in ability to perceive goitrin (5-vinyloxazolidine-2-thione), a potent antithyroid compound found naturally in crucifers. Individuals vary in ability to perceive synthetic compounds similar to goitrin, such as 6-propyl-2-thiouracil (PROP) and phenylthiocarbamide (PTC), as the result of mutations in the TAS2R38 gene, which encodes a bitter taste receptor. This suggests that taste responses to goitrin itself may be mediated by TAS2R38. To test this hypothesis, we examined the relationships between genetic variation in TAS2R38, functional variation in the encoded receptor, and threshold taste responses to goitrin, PROP, and PTC in 50 subjects. We found that threshold responses to goitrin were associated with responses to both PROP (P = 8.9 x 10(-4); r(s) = 0.46) and PTC (P = 7.5 x 10(-4); r(s) = 0.46). However, functional assays revealed that goitrin elicits a weaker response from the sensitive (PAV) allele of TAS2R38 (EC(50) = 65.0 渭M) than do either PROP (EC(50) = 2.1 渭M) or PTC (EC(50) = 1.1 渭M) and no response at all from the insensitive (AVI) allele. Furthermore, goitrin responses were significantly associated with mutations in TAS2R38 (P = 9.3 $\times$ 10(-3)), but the same mutations accounted for a smaller proportion of variance in goitrin response (r(2) = 0.16) than for PROP (r(2) = 0.50) and PTC (r(2) = 0.57). These findings suggest that mutations in TAS2R38 play a role in shaping goitrin perception, but the majority of variance must be explained by other factors.
URL [本文引用: 1]
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URLPMID:4161000 [本文引用: 1]
Abstract The taste threshold of 228 subjects from 17 species of non-human primates was determined with graded solutions of P-T-C. Among species for which the sample size was sufficiently large, only the chimpanzee definitely showed a bimodal distribution. Experiments with tyrosine and cabbage indicate that the concentration of the former, in saliva, influences the individual's threshold and that the amount of cabbage, or other goitrogens, in the diet probably also has an influence. These results, in addition to information in the literature, indicate that sensitivity to P-T-C is not selectively neutral and, in man, may be another example of balance polymorphism.
URLPMID:16612383 [本文引用: 1]
Abstract It was reported over 65 years ago that chimpanzees, like humans, vary in taste sensitivity to the bitter compound phenylthiocarbamide (PTC). This was suggested to be the result of a shared balanced polymorphism, defining the first, and now classic, example of the effects of balancing selection in great apes. In humans, variable PTC sensitivity is largely controlled by the segregation of two common alleles at the TAS2R38 locus, which encode receptor variants with different ligand affinities. Here we show that PTC taste sensitivity in chimpanzees is also controlled by two common alleles of TAS2R38; however, neither of these alleles is shared with humans. Instead, a mutation of the initiation codon results in the use of an alternative downstream start codon and production of a truncated receptor variant that fails to respond to PTC in vitro. Association testing of PTC sensitivity in a cohort of captive chimpanzees confirmed that chimpanzee TAS2R38 genotype accurately predicts taster status in vivo. Therefore, although Fisher et al.'s observations were accurate, their explanation was wrong. Humans and chimpanzees share variable taste sensitivity to bitter compounds mediated by PTC receptor variants, but the molecular basis of this variation has arisen twice, independently, in the two species.
URLPMID:20665225 [本文引用: 1]
Bitter taste perception evolved as a key detection mechanism against the ingestion of bioactive substances, and is mediated by TAS2R gene family members in vertebrates. The most widely known and best studied bitter substance is phenylthiocarbamide (PTC), which is recognized by TAS2R38 and has a molecular structure similar to that of glucosinolates contained in Brassica plants. The “non-taster” phenotypic polymorphism (i.e., not sensitive to PTC-containing foods) has been identified in many primates, including humans. Here, we report genetic and behavioral evidence for the existence of “non-taster” Japanese macaques, which originated from a restricted region of Japan. Comparison of the sequences of the TAS2R38 gene of 333 Japanese and 55 rhesus macaques suggested that this genotype appeared after the divergence of these two species, independently of the appearance of human and chimpanzee “non-tasters”. This finding might give a clue for elucidating the ecological, evolutionary, and neurobiological aspects of bitter taste perception of primates, as related to the plants that they sometimes use as foods in their habitats.
URLPMID:24177185 [本文引用: 1]
Abstract Bitter taste perception influences human nutrition and health, and the genetic variation underlying this trait may play a role in disease susceptibility. To better understand the genetic architecture and patterns of phenotypic variability of bitter taste perception, we sequenced a 996 bp region, encompassing the coding exon of TAS2R16, a bitter taste receptor gene, in 595 individuals from 74 African populations and in 94 non-Africans from 11 populations. We also performed genotype-phenotype association analyses of threshold levels of sensitivity to salicin, a bitter anti-inflammatory compound, in 296 individuals from Central and East Africa. In addition, we characterized TAS2R16 mutants in vitro to investigate the effects of polymorphic loci identified at this locus on receptor function. Here, we report striking signatures of positive selection, including significant Fay and Wu's H statistics predominantly in East Africa, indicating strong local adaptation and greater genetic structure among African populations than expected under neutrality. Furthermore, we observed a "star-like" phylogeny for haplotypes with the derived allele at polymorphic site 516 associated with increased bitter taste perception that is consistent with a model of selection for "high-sensitivity" variation. In contrast, haplotypes carrying the "low-sensitivity" ancestral allele at site 516 showed evidence of strong purifying selection. We also demonstrated, for the first time, the functional effect of nonsynonymous variation at site 516 on salicin phenotypic variance in vivo in diverse Africans and showed that most other nonsynonymous substitutions have weak or no effect on cell surface expression in vitro, suggesting that one main polymorphism at TAS2R16 influences salicin recognition. Additionally, we detected geographic differences in levels of bitter taste perception in Africa not previously reported and infer an East African origin for high salicin sensitivity in human populations.
URLPMID:26201026 [本文引用: 2]
Abstract Bitter taste receptors (TAS2R proteins) allow mammals to detect and avoid ingestion of toxins in food. Thus, TAS2Rs play an important role in food choice and are subject to complex natural selection pressures. In our previous study, we examined nucleotide variation in TAS2R38, a gene expressing bitter taste receptor for phenylthiocarbamide (PTC), in 333 Japanese macaques (Macaca fuscata) from 9 local populations in Japan. We identified a PTC "non-taster" TAS2R38 allele in Japanese macaques that was caused by a loss of the start codon. This PTC non-taster allele was only found in a limited local population (the Kii area), at a frequency of 29%. In this study, we confirmed that this allele was present in only the Kii population by analyzing an additional 264 individuals from eight new populations. Using cellular and behavioral experiments, we found that this allele lost its receptor function for perceiving PTC. The nucleotide sequences of the allele including flanking regions (of about 10 kb) from 23 chromosomes were identical, suggesting that a non-taster allele arose and expanded in the Kii population during the last 13,000 years. Genetic analyses of non-coding regions in Kii individuals and neighboring populations indicated that the high allele frequency in the Kii population could not be explained by demographic history, suggesting that positive selection resulted in a rapid increase in PTC non-tasters in the Kii population. The loss-of-function that occurred at the TAS2R38 locus presumably provided a fitness advantage to Japanese macaques in the Kii population. Because TAS2R38 ligands are often found in plants, this functional change in fitness is perhaps related to feeding habit specificity. These findings should provide valuable insights for elucidating adaptive evolutionary changes with respect to various environments in wild mammals.
URLPMID:4619199 [本文引用: 1]
Cats are obligate carnivores and under most circumstances eat only animal products. Owing to the pseudogenization of one of two subunits of the sweet receptor gene, they are indifferent to sweeteners, presumably having no need to detect plant-based sugars in their diet. Following this reasoning and a recent report of a positive correlation between the proportion of dietary plants and the number ofTas2r(bitter receptor) genes in vertebrate species, we tested the hypothesis that if bitter perception exists primarily to protect animals from poisonous plant compounds, the genome of the domestic cat (Felis catus) should have lost functional bitter receptors and they should also have reduced bitter receptor function. To test functionality of cat bitter receptors, we expressed cat Tas2R receptors in cell-based assays. We found that they have at least 7 functional receptors with distinct receptive ranges, showing many similarities, along with some differences, with human bitter receptors. To provide a comparative perspective, we compared the cat repertoire of intact receptors with those of a restricted number of members of the order Carnivora, with a range of dietary habits as reported in the literature. The numbers of functional bitter receptors in the terrestrial Carnivora we examined, including omnivorous and herbivorous species, were roughly comparable to that of cats thereby providing no strong support for the hypothesis that a strict meat diet influences bitter receptor number or function. Maintenance of bitter receptor function in terrestrial obligate carnivores may be due to the presence of bitter compounds in vertebrate and invertebrate prey, to the necessary role these receptors play in non-oral perception, or to other unknown factors. We also found that the two aquatic Carnivora species examined had fewer intact bitter receptors. Further comparative studies of factors driving numbers and functions of bitter taste receptors will aid in understanding the forces shaping their repertoire.
URLPMID:7878094 [本文引用: 2]
Abstract The bitter rejection response consists of a suite of withdrawal reflexes and negative affective responses. It is generally assumed to have evolved as a way to facilitate avoidance of foods that are poisonous because they usually taste bitter to humans. Using previously published studies, the present paper examines the relationship between bitterness and toxicity in mammals, and then assesses the ecological costs and benefits of the bitter rejection response in carnivorous, omnivorous, and herbivorous (grazing and browsing) mammals. If the bitter rejection response accurately predicts the potential toxicity of foods, then one would expect the threshold for the response to be lower for highly toxic compounds than for nontoxic compounds. The data revealed no such relationship. Bitter taste thresholds varied independently of toxicity thresholds, indicating that the bitter rejection response is just as likely to be elicited by a harmless bitter food as it is by a harmful one. Thus, it is not necessarily in an animal's best interest to have an extremely high or low bitter threshold. Based on this observation, it was hypothesized that the adaptiveness of the bitter rejection response depends upon the relative occurrence of bitter and potentially toxic compounds in an animal's diet. Animals with a relatively high occurrence of bitter and potentially toxic compounds in their diet (e.g., browsing herbivores) were predicted to have evolved a high bitter taste threshold and tolerance to dietary poisons. Such an adaptation would be necessary because a browser cannot "afford" to reject all foods that are bitter and potentially toxic without unduly restricting its dietary options. At the other extreme, animals that rarely encounter bitter and potentially toxic compounds in their diet (e.g., carnivores) were predicted to have evolved a low bitter threshold. Carnivores could "afford" to utilize such a stringent rejection mechanism because foods containing bitter and potentially toxic compounds constitute a small portion of their diet. Since the low bitter threshold would reduce substantially the risk of ingesting anything poisonous, carnivores were also expected to have a relatively low tolerance to dietary poisons. This hypothesis was supported by a comparison involving 30 mammal species, in which a suggestive relationship was found between quinine hydrochloride sensitivity and trophic group, with carnivores > omnivores > grazers > browsers. Further support for the hypothesis was provided by a comparison across browsers and grazers in terms of the production of tannin-binding salivary proteins, which probably represent an adaptation for reducing the bitterness and astringency of tannins.(ABSTRACT TRUNCATED AT 400 WORDS)
URL [本文引用: 1]
Large herbivores must select food from a wide variety of plant parts, species, and strains. These differ in nutritional value (protein, carbohydrate, etc.), toughness, spinosity, etc. Even greater differences are found in types and concentrations of secondary compounds. Every plant produces its own set of secondary chemical compounds, which to a great extent are unique to it or its species. Ingestion of natural concentrations of these compounds can lead to either death or severe physiological impairment. The ubiquitous nature of these compounds would make herbivory impossible unless animals had mechanisms for degrading and excreting them. An animal displaying no obvious symptoms of poisoning is not free of the problem of ridding itself of toxic compounds; if it is eating plants, it almost certainly has this problem. Herbivores are capable of detoxifying and eliminating secondary compounds. Limitations of these mechanisms force mammalian herbivores to consume a variety of plant foods at any one time, to treat new foods with caution, to ingest small amounts on the first encounter, and to sample food continuously. Selection of foods is based on learning in response to adverse internal physiological effects, and herbivores probably cannot predict these from the smell or taste of new foods. Herbivores prefer to eat familiar foods and can seek out and consume foods that rectify specific nutritional deficiencies induced by detoxification. They should prefer to feed on foods that contain small amounts of secondary compounds, and their body size and searching strategies should be adapted to optimize the number of types of foods available with respect to the total amount of food that can be eaten and will be present in the future. Natural selection can increase the efficiency of degrading particular secondary compounds. Specialist herbivores, like koala and mountain viscacha, are expected where a large amount of several related toxic foods is present in a year-round supply. However, few large herbivores are specialized on such a restricted range of foods.
[本文引用: 1]
URLPMID:20961961 [本文引用: 1]
Abstract In mammals, bitter taste is mediated by T2R genes, which belong to the large family of seven transmembrane G protein-coupled receptors. Because T2Rs are directly involved in the interaction between mammals and their dietary sources, it is likely that these genes evolved to reflect species' specific diets during mammalian evolution. Here, we investigated the sequences of all 28 putative functional chimpanzee T2R genes (cT2Rs) in 46 western chimpanzees to compare the intraspecies variations in chimpanzees to those already known for all 25 human functional T2R genes (hT2Rs). The numbers of functional genes varied among individuals in western chimpanzees, and most chimpanzees had two or three more functional genes than humans. Similarly to hT2Rs, cT2Rs showed high nucleotide diversity along with a large number of amino acid substitutions. Comparison of the nucleotide substitution patterns in cT2Rs with those in five cT2R pseudogenes and 14 autosomal intergenic noncoding regions among the same individuals revealed that the evolution of cT2R genes was almost identical to that of putative neutral regions with slight but significantly positive Tajima's D values, suggesting that selective constraint on these genes was relaxed with weak balancing selection. These trends have resulted in the occurrence of various divergent alleles of T2Rs within the western chimpanzee populations and in heterozygous individuals who might have the ability to taste a broader range of substances.
URLPMID:16051168 [本文引用: 1]
Abstract BACKGROUND: During periods of human expansion into new environments, recognition of bitter natural toxins through taste may have conferred an important selective advantage. The G protein-coupled receptor encoded by TAS2R16 mediates response to salicin, amygdalin, and many bitter beta-glucopyranosides. beta-glucopyranosides are ubiquitous in nature, with many having a highly toxic cyanogenic activity. RESULTS: We examined evidence for natural selection on the human receptor TAS2R16 by sequencing the entire coding region, as well as part of the 5' and 3' UTRs, in 997 individuals from 60 human populations. We detected signatures of positive selection, indicated by an excess of evolutionarily derived alleles at the nonsynonymous site K172N and two linked sites and significant values of Fay and Wu's H statistics in 19 populations. The estimated age range for the common ancestor of the derived N172 variant is 78,700-791,000 years, placing it in the Middle Pleistocene and before the expansion of early humans out of Africa. Using calcium imaging in cells expressing different receptor variants, we showed that N172 is associated with an increased sensitivity to salicin, arbutin, and five different cyanogenic glycosides. CONCLUSION: We have detected a clear signal of positive selection at the bitter-taste receptor gene TAS2R16. We speculate that the increased sensitivity that is shown toward harmful cyanogenic glycosides and conferred by the N172 allele may have driven the signal of selection at an early stage of human evolution.
URL [本文引用: 1]
Ecological Study of Wild Japanese Monkeys in Snowy Areas A great difference in vegetationis that, while in the former evergreen leaves grow even in winter, in organized at Kyoto Universityhave on the one hand made intensive ecological and sociological studies of Japanese
URL [本文引用: 2]
"Most of the papers in the first part of this book were presented in a symposium, 'Anthropological Perspectives on New World Primates,' on Nov. 19, 1988 at the annual meeting of the American Anthropological Association in Phoenix, Arizona"--Intrd. Includes bibliographical references (p. 325-429) and index.
URLPMID:12595690 [本文引用: 1]
Abstract The ability to taste the substance phenylthiocarbamide (PTC) has been widely used for genetic and anthropological studies, but genetic studies have produced conflicting results and demonstrated complex inheritance for this trait. We have identified a small region on chromosome 7q that shows strong linkage disequilibrium between single-nucleotide polymorphism (SNP) markers and PTC taste sensitivity in unrelated subjects. This region contains a single gene that encodes a member of the TAS2R bitter taste receptor family. We identified three coding SNPs giving rise to five haplotypes in this gene worldwide. These haplotypes completely explain the bimodal distribution of PTC taste sensitivity, thus accounting for the inheritance of the classically defined taste insensitivity and for 55 to 85% of the variance in PTC sensitivity. Distinct phenotypes were associated with specific haplotypes, which demonstrates that this gene has a direct influence on PTC taste sensitivity and that sequence variants at different sites interact with each other within the encoded gene product.
URLPMID:15723792 [本文引用: 1]
Abstract Individual differences in perception are ubiquitous within the chemical senses: taste, smell, and chemical somesthesis . A hypothesis of this fact states that polymorphisms in human sensory receptor genes could alter perception by coding for functionally distinct receptor types . We have previously reported evidence that sequence variants in a presumptive bitter receptor gene (hTAS2R38) correlate with differences in bitterness recognition of phenylthiocarbamide (PTC) . Here, we map individual psychogenomic pathways for bitter taste by testing people with a variety of psychophysical tasks and linking their individual perceptions of the compounds PTC and propylthiouracil (PROP) to the in vitro responses of their TAS2R38 receptor variants. Functional expression studies demonstrate that five different haplotypes from the hTAS2R38 gene code for operatively distinct receptors. The responses of the three haplotypes we also tested in vivo correlate strongly with individuals' psychophysical bitter sensitivities to a family of compounds. These data provide a direct molecular link between heritable variability in bitter taste perception to functional variations of a single G protein coupled receptor that responds to compounds such as PTC and PROP that contain the N-C=S moiety. The molecular mechanisms of perceived bitterness variability have therapeutic implications, such as helping patients to consume beneficial bitter-tasting compounds-for example, pharmaceuticals and selected phytochemicals.
URLPMID:17702579 [本文引用: 1]
Abstract Variation in human taste is a well-known phenomenon. However, little is known about the molecular basis for it. Bitter taste in humans is believed to be mediated by a family of 25 G protein-coupled receptors (hT2Rs, or TAS2Rs). Despite recent progress in the functional expression of hT2Rs in vitro, up until now, hT2R38, a receptor for phenylthiocarbamide (PTC), was the only gene directly linked to variations in human bitter taste. Here we report that polymorphism in two hT2R genes results in different receptor activities and different taste sensitivities to three bitter molecules. The hT2R43 gene allele, which encodes a protein with tryptophan in position 35, makes people very sensitive to the bitterness of the natural plant compounds aloin and aristolochic acid. People who do not possess this allele do not taste these compounds at low concentrations. The same hT2R43 gene allele makes people more sensitive to the bitterness of an artificial sweetener, saccharin. In addition, a closely related gene's (hT2R44's) allele also makes people more sensitive to the bitterness of saccharin. We also demonstrated that some people do not possess certain hT2R genes, contributing to taste variation between individuals. Our findings thus reveal new examples of variations in human taste and provide a molecular basis for them.
URLPMID:15744053 [本文引用: 3]
Abstract Since the process of becoming dead genes or pseudogenes (pseudogenization) is irreversible and can occur rather rapidly under certain environmental circumstances, it is one plausible determinant for characterizing species specificity. To test this evolutionary hypothesis, we analyzed the tempo and mode of duplication and pseudogenization of bitter taste receptor (T2R) genes in humans as well as in 12 nonhuman primates. The results show that primates have accumulated more pseudogenes than mice after their separation from the common ancestor and that lineage-specific pseudogenization becomes more conspicuous in humans than in nonhuman primates. Although positive selection has operated on some amino acids in extracellular domains, functional constraints against T2R genes are more relaxed in primates than in mice and this trend has culminated in the rapid deterioration of the bitter-tasting capability in humans. Since T2R molecules play an important role in avoiding generally bitter toxic and harmful substances, substantial modification of the T2R gene repertoire is likely to reflect different responses to changes in the environment and to result from species-specific food preference during primate evolution.
URLPMID:28333344 [本文引用: 1]
Abstract Lineage-specific gene losses can be driven by selection or environmental adaptations. However, a lack of studies on the original function of species-specific pseudogenes leaves a gap in our understanding of their role in evolutionary histories. Pseudogenes are of particular relevance for taste perception genes, which encode for receptors that confer the ability to both identify nutritionally valuable substances and avoid potentially harmful substances. To explore the role of bitter taste pseudogenization events in human origins, we restored the open reading frames of the three human-specific pseudogenes and synthesized the reconstructed functional hTAS2R2, hTAS2R62 and hTAS2R64 receptors. We have identified ligands that differentially activate the human and chimpanzee forms of these receptors and several other human functional TAS2Rs. We show that these receptors are narrowly tuned, suggesting that bitter-taste sensitivities evolved independently in different species, and that these pseudogenization events occurred because of functional redundancy. The restoration of function of lineage-specific pseudogenes can aid in the reconstruction of their evolutionary history, and in understanding the forces that led to their pseudogenization.
URLPMID:3420883 [本文引用: 1]
Chimpanzees (Pan troglodytes) have region-specific difference in dietary repertoires from East to West across tropical Africa. Such differences may result from different genetic backgrounds in addition to cultural variations. We analyzed the sequences of all bitter taste receptor genes (cTAS2Rs) in a total of 59 chimpanzees, including 4 putative subspecies. We identified genetic variations including single-nucleotide variations (SNVs), insertions and deletions (indels), gene-conversion variations, and copy-number variations (CNVs) in cTAS2Rs. Approximately two-thirds of all cTAS2R haplotypes in the amino acid sequence were unique to each subspecies. We analyzed the evolutionary backgrounds of natural selection behind such diversification. Our previous study concluded that diversification of cTAS2Rs in western chimpanzees (P. t. verus) may have resulted from balancing selection. In contrast, the present study found that purifying selection dominates as the evolutionary form of diversification of the so-called human cluster of cTAS2Rs in eastern chimpanzees (P. t. schweinfurthii) and that the other cTAS2Rs were under no obvious selection as a whole. Such marked diversification of cTAS2Rs with different evolutionary backgrounds among subspecies of chimpanzees probably reflects their subspecies-specific dietary repertoires.
Magsci [本文引用: 2]
苦味的感知是机体有效的自我保护机制之一。文章采用PCR和克隆测序方法首次从猪獾基因组中获得一全长为1 169 bp的苦味受体T2R2基因DNA序列(GenBank登录号: FJ812727)。该序列含有完整的1个外显子(无内含子), 大小为915 bp, 编码304个氨基酸残基。其蛋白质等电点为9.76, 分子量为34.74 kDa。拓扑结构预测显示猪獾T2R2蛋白上含有N-糖基化位点、N-肉豆蔻酰化位点各1个, 蛋白激酶C磷酸化位点2个。整个蛋白质多肽链含有7个跨膜螺旋区, 4个细胞外区和4个细胞内区。亲水性/疏水性分析表明, 猪獾<EM>T2R2</EM>蛋白质为一疏水性蛋白, 其亲水性区段所占比例较小。种间相似性比较显示, 猪獾T2R2基因与犬、猫、牛、马、黑猩猩和小鼠的T2R2基因cDNA序列相似性分别为91.4%、90.6%、84.4%、85.4%、83.8%、72.1%, 氨基酸序列相似性分别为85.5%、85.8%、74.0%、77.6%、75.3%、61.5%。核苷酸替换计算和选择性检验结果表明, 猪獾T2R2基因与犬、猫、牛、马、黑猩猩和小鼠间存在着强烈的纯净化选择(Purifying selection), 即强烈的功能束缚(Functional constraint), 进一步分析发现该选择作用实际上主要存在于跨膜区。猪獾、犬、猫、牛、马、黑猩猩和小鼠的T2R2基因外显子核苷酸序列构建的基因树与其物种树的拓扑结构是相一致的, 表明<EM>T2R2</EM>基因适合于构建不同物种间的系统进化树。
Magsci [本文引用: 2]
苦味的感知是机体有效的自我保护机制之一。文章采用PCR和克隆测序方法首次从猪獾基因组中获得一全长为1 169 bp的苦味受体T2R2基因DNA序列(GenBank登录号: FJ812727)。该序列含有完整的1个外显子(无内含子), 大小为915 bp, 编码304个氨基酸残基。其蛋白质等电点为9.76, 分子量为34.74 kDa。拓扑结构预测显示猪獾T2R2蛋白上含有N-糖基化位点、N-肉豆蔻酰化位点各1个, 蛋白激酶C磷酸化位点2个。整个蛋白质多肽链含有7个跨膜螺旋区, 4个细胞外区和4个细胞内区。亲水性/疏水性分析表明, 猪獾<EM>T2R2</EM>蛋白质为一疏水性蛋白, 其亲水性区段所占比例较小。种间相似性比较显示, 猪獾T2R2基因与犬、猫、牛、马、黑猩猩和小鼠的T2R2基因cDNA序列相似性分别为91.4%、90.6%、84.4%、85.4%、83.8%、72.1%, 氨基酸序列相似性分别为85.5%、85.8%、74.0%、77.6%、75.3%、61.5%。核苷酸替换计算和选择性检验结果表明, 猪獾T2R2基因与犬、猫、牛、马、黑猩猩和小鼠间存在着强烈的纯净化选择(Purifying selection), 即强烈的功能束缚(Functional constraint), 进一步分析发现该选择作用实际上主要存在于跨膜区。猪獾、犬、猫、牛、马、黑猩猩和小鼠的T2R2基因外显子核苷酸序列构建的基因树与其物种树的拓扑结构是相一致的, 表明<EM>T2R2</EM>基因适合于构建不同物种间的系统进化树。
[本文引用: 2]
URLPMID:20708652 [本文引用: 1]
Once introduced into the very early eukaryotic blueprint, seven-transmembrane receptors soon became the central and versatile components of the evolutionary highly successful G protein-coupled transmembrane signaling mechanism. In contrast to all other components of this signal transduction pathway, G protein-coupled receptors (GPCR) evolved in various structural families, eventually comprising hundreds of members in vertebrate genomes. Their functional diversity is in contrast to the conserved transmembrane core and the invariant set of intracellular signaling mechanisms, and it may be the interplay of these properties that is the key to the evolutionary success of GPCR. The GPCR repertoires retrieved from extant vertebrate genomes are the recent endpoints of this long evolutionary process. But the shaping of the fine structure and the repertoire of GPCR is still ongoing, and signatures of recent selection acting on GPCR genes can be made visible by modern population genetic methods. The very dynamic evolution of GPCR can be analyzed from different perspectives: at the levels of sequence comparisons between species from different families, orders and classes, and at the level of populations within a species. Here, we summarize the main conclusions from studies at these different levels with a specific focus on the more recent evolutionary dynamics of GPCR.
