The ability to taste bitterness evolved to safeguard most animals, including humans, against potentially toxic substances, thereby leading to food rejection. Nonetheless, bitter perception is subject to individual variations due to the presence of genetic functional polymorphisms in bitter taste receptor (TAS2R) genes, such as the long-known association between genetic polymorphisms in TAS2R38 and bitter taste perception of phenylthiocarbamide. Yet, due to overlaps in specificities across receptors, such associations with a single TAS2R locus are uncommon. Therefore, to investigate more complex associations, we examined taste responses to six structurally diverse compounds (absinthin, amarogentin, cascarillin, grosheimin, quassin, and quinine) in a sample of the Caucasian population. By sequencing all bitter receptor loci, inferring long-range haplotypes, mapping their effects on phenotype variation, and characterizing functionally causal allelic variants, we deciphered at the molecular level how a subjects’ genotype for the whole-family of TAS2R genes shapes variation in bitter taste perception. Within each haplotype block implicated in phenotypic variation, we provided evidence for at least one locus harboring functional polymorphic alleles, e.g. one locus for sensitivity to amarogentin, one of the most bitter natural compounds known, and two loci for sensitivity to grosheimin, one of the bitter compounds of artichoke. Our analyses revealed also, besides simple associations, complex associations of bitterness sensitivity across TAS2R loci. Indeed, even if several putative loci harbored both high- and low-sensitivity alleles, phenotypic variation depended on linkage between these alleles. When sensitive alleles for bitter compounds were maintained in the same linkage phase, genetically driven perceptual differences were obvious, e.g. for grosheimin. On the contrary, when sensitive alleles were in opposite phase, only weak genotype-phenotype associations were seen, e.g. for absinthin, the bitter principle of the beverage absinth. These findings illustrate the extent to which genetic influences on taste are complex, yet arise from both receptor activation patterns and linkage structure among receptor genes.
References
[1]
Berridge KC. Measuring hedonic impact in animals and infants: microstructure of affective taste reactivity patterns. Neurosci Biobehav Rev. 2000; 24(2): 173–98. pmid:10714382 doi: 10.1016/s0149-7634(99)00072-x
[2]
Pfaffmann C, Norgren R. Sensory affect and motivation. Ann N Y Acad Sci. 1977; 290(1): 18–34. doi: 10.1111/j.1749-6632.1977.tb39713.x
[3]
Rosenstein D, Oster H. Differential facial responses to four basic tastes in newborns. Child Dev. 1988; 59: 1555–68. pmid:3208567 doi: 10.2307/1130670
[4]
Schwartz C, Issanchou S, Nicklaus S. Developmental changes in the acceptance of the five basic tastes in the first year of life. Br J Nutr. 2009; 102(9): 1375–85. doi: 10.1017/S0007114509990286. pmid:19505346
[5]
Steiner JE. Facial expressions of the neonate infant indicating the hedonics of foodrelated chemical stimuli. In: Weiffenbach JM, editor. Taste and Development: the genesis of sweet preference. Washington DC, USA: Government Printing Office; 1977. p. 173–89.
[6]
Brown PD, Morra MJ. Control of Soil-Borne Plant Pests Using Glucosinolate-Containing Plants. In: Donald LS, editor. Advances in Agronomy. Volume 61. New York, USA: Academic Press; 1997. p. 167–231.
[7]
Garcia J, Hankins WG. The evolution of bitter and the acquisition of toxiphobia. In: Denton DA, Coghlan JP, editors. Proceedings of the 5th International Symposium on Olfaction and Taste. Melbourne, Australia: Academic Press; 1975. p. 39.
[8]
Mauricio R, Rausher MD. Experimental manipulation of putative selective agents provides evidence for the role of natural enemies in the evolution of plant defense. Evolution. 1997; 51(5): 1435–44. doi: 10.2307/2411196
[9]
Whittaker RH, Feeny PP. Allelochemics: Chemical Interactions between Species. Science. 1971; 171(3973): 757–70. pmid:5541160 doi: 10.1126/science.171.3973.757
[10]
Glendinning JI. Is the bitter rejection response always adaptive? Physiol Behav. 1994; 56(6): 1217–27. pmid:7878094 doi: 10.1016/0031-9384(94)90369-7
[11]
Koshimizu K, Ohigashi H, Huffman MA. Use of Veronia-amygdalina by wild chimpanzee—possible roles of its bitter and related constituents. Physiol Behav. 1994; 56(6): 1209–16. pmid:7878093 doi: 10.1016/0031-9384(94)90368-9
[12]
Faiz MA, Bin Yunus E, Rahman MR, Islam F, Hoque MG, et al.; South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005; 366(9487): 717–25. doi: 10.1016/s0140-6736(05)67176-0
[13]
Drewnowski A, Gomez-Carneros C. Bitter taste, phytonutrients, and the consumer: a review. Am J Clin Nutr. 2000; 72(6): 1424–35. pmid:11101467
[14]
Tepper BJ. Nutritional Implications of Genetic Taste Variation: The Role of PROP Sensitivity and Other Taste Phenotypes. Annu Rev Nutr. 2008; 28(1): 367–88. doi: 10.1146/annurev.nutr.28.061807.155458
[15]
Ventura AK, Worobey J. Early Influences on the Development of Food Preferences. Curr Biol. 2013; 23(9): R401–R8. doi: 10.1016/j.cub.2013.02.037. pmid:23660363
[16]
Adler E, Hoon MA, Mueller KL, Chandrashekar J, Ryba NJP, Zuker CS. A novel family of mammalian taste receptors. Cell. 2000; 100(6): 693–702. pmid:10761934 doi: 10.1016/s0092-8674(00)80705-9
[17]
Bufe B, Breslin PAS, Kuhn C, Reed DR, Tharp CD, Slack JP, et al. The molecular basis of individual differences in phenylthiocarbamide and propylthiouracil bitterness perception. Curr Biol. 2005; 15(4): 322–7. pmid:15723792 doi: 10.1016/j.cub.2005.01.047
[18]
Chandrashekar J, Mueller KL, Hoon MA, Adler E, Feng LX, Guo W, et al. T2Rs function as bitter taste receptors. Cell. 2000; 100(6): 703–11. pmid:10761935 doi: 10.1016/s0092-8674(00)80706-0
[19]
Matsunami H, Montmayeur JP, Buck LB. A family of candidate taste receptors in human and mouse. Nature. 2000; 404(6778): 601–6. pmid:10766242 doi: 10.1038/35007072
[20]
Shi P, Zhang JZ, Yang H, Zhang YP. Adaptive diversification of bitter taste receptor genes in mammalian evolution. Mol Biol Evol. 2003; 20(5): 805–14. pmid:12679530 doi: 10.1093/molbev/msg083
[21]
Kim UK, Jorgenson E, Coon H, Leppert M, Risch N, Drayna D. Positional cloning of the human quantitative trait locus underlying taste sensitivity to phenylthiocarbamide. Science. 2003; 299(5610): 1221–5. pmid:12595690 doi: 10.1126/science.1080190
[22]
Kim U, Wooding S, Ricci D, Jorde LB, Drayna D. Worldwide haplotype diversity and coding sequence variation at human bitter taste receptor loci. Hum Mutat. 2005; 26(3): 199–204. pmid:16086309 doi: 10.1002/humu.20203
[23]
Bufe B, Hofmann T, Krautwurst D, Raguse JD, Meyerhof W. The human TAS2R16 receptor mediates bitter taste in response to beta-glucopyranosides. Nat Genet. 2002; 32(3): 397–401. pmid:12379855 doi: 10.1038/ng1014
Pronin AN, Xu H, Tang H, Zhang L, Li Q, Li X. Specific Alleles of Bitter Receptor Genes Influence Human Sensitivity to the Bitterness of Aloin and Saccharin. Curr Biol. 2007; 17(16): 1403–8. pmid:17702579 doi: 10.1016/j.cub.2007.07.046
[26]
Roudnitzky N, Bufe B, Thalmann S, Kuhn C, Gunn HC, Xing C, et al. Genomic, genetic and functional dissection of bitter taste responses to artificial sweeteners. Hum Mol Genet. 2011; 20(17): 3437–49. doi: 10.1093/hmg/ddr252. pmid:21672920
[27]
Soranzo N, Bufe B, Sabeti PC, Wilson JF, Weale ME, Marguerie R, et al. Positive selection on a high-sensitivity allele of the human bitter-taste receptor TAS2R16. Curr Biol. 2005; 15(14): 1257–65. pmid:16051168 doi: 10.1016/j.cub.2005.06.042
[28]
Allen AL, McGeary JE, Hayes JE. Polymorphisms in TRPV1 and TAS2Rs Associate with Sensations from Sampled Ethanol. Alcohol Clin Exp Res. 2014; 38(10): 2550–60. doi: 10.1111/acer.12527. pmid:25257701
[29]
Dotson CD, Wallace MR, Bartoshuk LM, Logan HL. Variation in the Gene TAS2R13 is Associated with Differences in Alcohol Consumption in Patients with Head and Neck Cancer. Chem Senses. 2012; 37(8): 737–44. doi: 10.1093/chemse/bjs063. pmid:22824251
[30]
Risso D, Morini G, Pagani L, Quagliariello A, Giuliani C, De Fanti S, et al. Genetic signature of differential sensitivity to stevioside in the Italian population. Genes and Nutrition. 2014; 9(3). doi: 10.1007/s12263-014-0401-y
[31]
Meyerhof W, Batram C, Kuhn C, Brockhoff A, Chudoba E, Bufe B, et al. The Molecular Receptive Ranges of Human TAS2R Bitter Taste Receptors. Chem Senses. 2010; 35(2): 157–70. doi: 10.1093/chemse/bjp092. pmid:20022913
[32]
Ledda M, Kutalik Z, Souza Destito MC, Souza MM, Cirillo CA, Zamboni A, et al. GWAS of human bitter taste perception identifies new loci and reveals additional complexity of bitter taste genetics. Hum Mol Genet. 2014; 23(1): 259–67. doi: 10.1093/hmg/ddt404. pmid:23966204
[33]
Reed DR, Zhu G, Breslin PAS, Duke FF, Henders AK, Campbell MJ, et al. The perception of quinine taste intensity is associated with common genetic variants in a bitter receptor cluster on chromosome 12 Hum Mol Genet. 2010; 19(21): 4278–85. doi: 10.1093/hmg/ddq324. pmid:20675712
[34]
Hayes JE, Wallace MR, Knopik VS, Herbstman DM, Bartoshuk LM, Duffy VB. Allelic Variation in TAS2R Bitter Receptor Genes Associates with Variation in Sensations from and Ingestive Behaviors toward Common Bitter Beverages in Adults. Chem Senses. 2011; 36(3): 311–9. doi: 10.1093/chemse/bjq132. pmid:21163912
[35]
International Standing Committee on Human Cytogenetic Nomenclature. ISCN 2009: An International System for Human Cytogenetic Nomenclature. 1st ed. Shaffer LG, Slovak ML, Campbell LJ, editors. Basel, Switzerland: Karger; 2009. 138 p.
[36]
Altshuler DM, Durbin RM, Abecasis GR, Bentley DR, Chakravarti A, Clark AG et al.; 1000 Genomes Project Consortium. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012; 491(7422): 56–65. doi: 10.1038/nature11632. pmid:23128226
[37]
Campbell MC, Ranciaro A, Zinshteyn D, Rawlings-Goss R, Hirbo J, Thompson S, et al. Origin and Differential Selection of Allelic Variation at TAS2R16 Associated with Salicin Bitter Taste Sensitivity in Africa. Mol Biol Evol. 2013; 31(2): 288–302. doi: 10.1093/molbev/mst211. pmid:24177185
[38]
Altshuler D, Brooks LD, Chakravarti A, Collins FS, Daly MJ, Donnelly P et al.; International Haplotype Map (HapMap) Consortium. A haplotype map of the human genome. Nature. 2005; 437(7063): 1299–320. pmid:16255080 doi: 10.1038/nature04226
[39]
Thalmann S, Behrens M, Meyerhof W. Major haplotypes of the human bitter taste receptor TAS2R41 encode functional receptors for chloramphenicol. Biochem Biophys Res Commun. 2013; 435(2): 267–73. doi: 10.1016/j.bbrc.2013.04.066. pmid:23632330
[40]
Wooding S, Kim UK, Bamshad MJ, Larsen J, Jorde LB, Drayna D. Natural selection and molecular evolution in PTC, a bitter-taste receptor gene. Am J Hum Genet. 2004; 74(4): 637–46. pmid:14997422 doi: 10.1086/383092
[41]
Born S, Levit A, Niv MY, Meyerhof W, Behrens M. The Human Bitter Taste Receptor TAS2R10 Is Tailored to Accommodate Numerous Diverse Ligands. J Neurosci. 2013; 33(1): 201–13. doi: 10.1523/JNEUROSCI.3248-12.2013. pmid:23283334
[42]
Brockhoff A, Behrens M, Niv MY, Meyerhof W. Structural requirements of bitter taste receptor activation. Proc Natl Acad Sci USA. 2010; 107(24): 11110–5. doi: 10.1073/pnas.0913862107. pmid:20534469
[43]
Campa D, De Rango F, Carrai M, Crocco P, Montesanto A, Canzian F, et al. Bitter Taste Receptor Polymorphisms and Human Aging. PLoS One. 2012; 7(11): e45232. doi: 10.1371/journal.pone.0045232. pmid:23133589
[44]
Wall JD, Pritchard JK. Haplotype blocks and linkage disequilibrium in the human genome. Nat Rev Genet. 2003; 4(8): 587–97. pmid:12897771 doi: 10.1038/nrg1123
[45]
Altshuler D, Brooks LD, Chakravarti A, Collins FS, Daly MJ, Donnelly P et al.; International Haplotype Map (HapMap) Consortium. A second generation human haplotype map of over 3.1 million SNPs. Nature. 2007; 449(7164): 851–61. pmid:17943122
[46]
Wooding S, Gunn H, Ramos P, Thalmann S, Xing C, Meyerhof W. Genetics and Bitter Taste Responses to Goitrin, a Plant Toxin Found in Vegetables. Chem Senses. 2010; 35(8): 685–92. doi: 10.1093/chemse/bjq061. pmid:20551074
[47]
Wooding S. Phenylthiocarbamide: A 75-Year Adventure in Genetics and Natural Selection. Genetics. 2006; 172(4): 2015–23. pmid:16636110
[48]
Hayes JE, Feeney EL, Allen AL. Do polymorphisms in chemosensory genes matter for human ingestive behavior? Food Quality and Preference. 2013; 30(2): 202–16. pmid:23878414 doi: 10.1016/j.foodqual.2013.05.013
[49]
Stephens JC, Schneider JA, Tanguay DA, Choi J, Acharya T, Stanley SE, et al. Haplotype Variation and Linkage Disequilibrium in 313 Human Genes. Science. 2001; 293(5529): 489–93. pmid:11452081 doi: 10.1126/science.1059431
[50]
Witherspoon DJ, Wooding S, Rogers AR, Marchani EE, Watkins WS, Batzer MA, et al. Genetic Similarities Within and Between Human Populations. Genetics. 2007; 176(1): 351–9. pmid:17339205 doi: 10.1534/genetics.106.067355
[51]
Fushan AA, Simons CT, Slack JP, Manichaikul A, Drayna D. Allelic Polymorphism within the TAS1R3 Promoter Is Associated with Human Taste Sensitivity to Sucrose. Curr Biol. 2009; 19(15): 1288–93. doi: 10.1016/j.cub.2009.06.015. pmid:19559618
[52]
Lipchock SV, Mennella JA, Spielman AI, Reed DR. Human bitter perception correlates with bitter receptor messenger RNA expression in taste cells. Am J Clin Nutr. 2013; 98(4): 1136–43. doi: 10.3945/ajcn.113.066688. pmid:24025627
[53]
Fushan A, Simons C, Slack J, Drayna D. Association between common variation in genes encoding sweet taste signaling components and human sucrose perception. Chem Senses. 2010; 35(7): 579–92. doi: 10.1093/chemse/bjq063. pmid:20660057
[54]
Loper HB, La Sala M, Dotson C, Steinle N. Taste perception, associated hormonal modulation, and nutrient intake. Nutr Rev. 2015; 73(2): 83–91. doi: 10.1093/nutrit/nuu009. pmid:26024495
[55]
Faas MM, Melgert BN, de Vos P. A Brief Review on How Pregnancy and Sex Hormones Interfere with Taste and Food Intake. Chemosens Percept. 2010; 3(1): 51–6. pmid:20352054 doi: 10.1007/s12078-009-9061-5
[56]
Brockhoff A, Behrens M, Massarotti A, Appendino G, Meyerhof W. Broad tuning of the human bitter taste receptor hTAS2R46 to various sesquiterpene lactones, clerodane and labdane diterpenoids, strychnine, and denatonium. J Agric Food Chem. 2007; 55(15): 6236–43. pmid:17595105 doi: 10.1021/jf070503p
[57]
Levy S, Sutton G, Ng PC, Feuk L, Halpern AL, Walenz BP, et al. The Diploid Genome Sequence of an Individual Human. PLoS Biol. 2007; 5(10): 2113–44. doi: 10.1371/journal.pbio.0050254
Reichling C, Meyerhof W, Behrens M. Functions of human bitter taste receptors depend on N-glycosylation. J Neurochem. 2008; 106(3): 1138–48. doi: 10.1111/j.1471-4159.2008.05453.x. pmid:18466324
[60]
Jeanmougin F, Thompson JD, Gouy M, Higgins DG, Gibson TJ. Multiple sequence alignment with Clustal X. Trends Biochem Sci. 1998; 23(10): 403–5. pmid:9810230 doi: 10.1016/s0968-0004(98)01285-7
[61]
Ye J, Coulouris G, Zaretskaya I, Cutcutache I, Rozen S, Madden T. Primer-BLAST: A tool to design target-specific primers for polymerase chain reaction. BMC Bioinform. 2012; 13(1): 134–44. doi: 10.1186/1471-2105-13-134
[62]
Stephens M, Donnelly P. A Comparison of Bayesian Methods for Haplotype Reconstruction from Population Genotype Data. Am J Hum Genet. 2003; 73(5): 1162–9. pmid:14574645 doi: 10.1086/379378
[63]
Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001; 68(4): 978–89. pmid:11254454 doi: 10.1086/319501
[64]
Weir BS, Cockerham CC. Testing hypotheses about linkage disequilibrium with multiple alleles. Genetics. 1978; 88(3): 633–42. pmid:17248813
[65]
Zaykin DV, Pudovkin A, Weir BS. Correlation-Based Inference for Linkage Disequilibrium With Multiple Alleles. Genetics. 2008; 180(1): 533–45. doi: 10.1534/genetics.108.089409. pmid:18757931
[66]
Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005; 21(2): 263–5. pmid:15297300 doi: 10.1093/bioinformatics/bth457
[67]
Wang N, Akey JM, Zhang K, Chakraborty R, Jin L. Distribution of Recombination Crossovers and the Origin of Haplotype Blocks: The Interplay of Population History, Recombination, and Mutation. Am J Hum Genet. 2002; 71(5): 1227–34. pmid:12384857 doi: 10.1086/344398
[68]
Cai JJ. PGEToolbox: A Matlab Toolbox for Population Genetics and Evolution. J Hered. 2008; 99(4): 438–40. doi: 10.1093/jhered/esm127. pmid:18310616
[69]
ISO 6658:2005. Sensory analysis—Methodology—General guidance. Vernier, Geneva (Switzerland): International Organization for Standardization; 2005. p. 1–20.
[70]
Lawless HT, Heymann H. Sensory Evaluation of Food: Principles and Practices: Springer US; 1999. 819 p.
[71]
ISO 13301:2002. Sensory analysis—Methodology—General guidance for measuring odour, flavour and taste detection thresholds by a three-alternative forced-choice (3-AFC) procedure. Vernier, Geneva (Switzerland): International Organization for Standardization; 2005. p. 1–27.
[72]
Green BG, Dalton P, Cowart B, Shaffer G, Rankin K, Higgins J. Evaluating the ‘Labeled Magnitude Scale’ for Measuring Sensations of Taste and Smell. Chem Senses. 1996; 21(3): 323–34. pmid:8670711 doi: 10.1093/chemse/21.3.323
[73]
Green BG, Shaffer GS, Gilmore MM. Derivation and evaluation of a semantic scale of oral sensation magnitude with apparent ratio properties. Chem Senses. 1993; 18(6): 683–702. doi: 10.1093/chemse/18.6.683
[74]
Bartoshuk LM, Duffy VB, Green BG, Hoffman HJ, Ko CW, Lucchina LA, et al. Valid across-group comparisons with labeled scales: the gLMS versus magnitude matching. Physiol Behav. 2004; 82(1): 109–14. pmid:15234598 doi: 10.1016/j.physbeh.2004.02.033
[75]
Gould BA. On Peirce's Criterion for the Rejection of Doubtful Observations, with tables for facilitating its application. Astron J. 1855; 4(83): 81–7. doi: 10.1086/100480
[76]
Peirce B. Criterion for the rejection of doubtful observations. Astron J. 1852; 2(45): 161–3. doi: 10.1086/100259
[77]
Nyholt DR. A Simple Correction for Multiple Testing for Single-Nucleotide Polymorphisms in Linkage Disequilibrium with Each Other. Am J Hum Genet. 2004; 74(4): 765–9. pmid:14997420 doi: 10.1086/383251
[78]
Ueda T, Ugawa S, Yamamura H, Imaizumi Y, Shimada S. Functional Interaction between T2R Taste Receptors and G-Protein α Subunits Expressed in Taste Receptor Cells. J Neurosci. 2003; 23(19): 7376–80. pmid:12917372
[79]
Hill AV. The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. J Physiol. 1910; 40(Suppl): iv–vii.
