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Genetics of Human Taste Perception

¹ National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 5 Research Court, Room 2B46, Rockville, MD 20850; and
² Monell Chemical Senses Center, 3500 Market Street, Philadelphia, PA 19104;

^* corresponding author, drayna{at}nidcd.nih.gov

	ABSTRACT

TOP ABSTRACT INTRODUCTION TASTE MODALITIES BITTER PTC SWEET AND UMAMI SOUR SALT SUMMARY REFERENCES

 
Genetic approaches are rapidly yielding new information about our sense of taste. This information comes from both molecular studies of genes encoding taste receptors and other taste-signaling components, and from studies of inherited variation in taste abilities. Our understanding of bitter taste has advanced by combined information from discovery and study of the TAS2R family of taste receptor genes, hand in hand with genetic linkage and positional cloning studies, notably on the ability to taste phenylthiocarbamide (PTC). Sweet and umami tastes, mediated by TAS1R receptors, are becoming well-characterized at the molecular genetic level, and these taste classes are now targets for linkage, positional cloning, and genetic association strategies. Salty and sour tastes are still poorly characterized in genetic terms, and represent opportunities for the future.

KEY WORDS: taste • genetics • variation • gene identification

	INTRODUCTION

TOP ABSTRACT INTRODUCTION TASTE MODALITIES BITTER PTC SWEET AND UMAMI SOUR SALT SUMMARY REFERENCES

 
Genetic studies rely on variation, and substantial variation has been found in normal human taste abilities (Kahn, 1951), opening the possibility of using genetic methods to improve our understanding of our sense of taste. Although sensitivity to some compounds spans a narrow range of variability, there are many substances for which different individuals show great differences in their taste thresholds (Blakeslee and Salmon, 1935). Much of this variation remains poorly characterized, but this area of study is seeing increased attention, and our understanding of many aspects of taste variation is now expanding. In contrast to this broad new area before us, a small number of specific differences in taste ability have long been known and are well-studied (Guo and Reed, 2001). Recent advances in our understanding of the genetic and molecular basis of these classic differences may provide important lessons as this field expands to pursue the many other differences that await detailed analysis.

	TASTE MODALITIES

TOP ABSTRACT INTRODUCTION TASTE MODALITIES BITTER PTC SWEET AND UMAMI SOUR SALT SUMMARY REFERENCES

 
Humans experience 5 well-characterized taste qualities: sweet, sour, bitter, salty, and umami, a savory flavor exemplified by the amino acid glutamate. These tastes are mediated by taste receptor proteins that reside on the surfaces of taste receptor cells within the taste buds of the tongue. Studies of the various signal transduction pathways in taste receptor cells (TRCs) indicate that sour and salty tastes depolarize TRCs by directly interacting with ion channels (Herness and Gilbertson, 1999). In contrast, amino acids, sugars and other compounds perceived as sweet, and most compounds perceived as bitter activate G-protein-coupled receptors (GPCRs). While sensory physiologists and molecular biologists have elucidated much about these 5 taste modalities, little is known about variation in these taste senses, and still less is known about the heritability of this variation. However, several suggestive observations have been made for all taste classes.

	BITTER

TOP ABSTRACT INTRODUCTION TASTE MODALITIES BITTER PTC SWEET AND UMAMI SOUR SALT SUMMARY REFERENCES

 
Bitter taste appears to be the most complex taste quality in humans, based on both the wide variety of chemical structures that elicit bitterness and on the apparently large number of genes encoding receptors for this taste modality. Bitter taste is believed to have evolved to allow organisms to detect and avoid toxins from the environment. Since the discovery of bitter taste receptor genes (alternatively designated T2R or TAS2R genes) in humans and mice (Adler et al., 2000; Chandrashekar et al., 2000), 24 potentially functional T2R genes and several T2R psuedogenes have been reported in humans, and some 33 functional T2R genes have been reported in mice (Shi et al., 2003). T2R proteins within each species display 25% to 80% amino acid sequence identity. In the human genome, the genes encoding these proteins reside in three locations. Fourteen genes reside in a cluster on chromosome 12p13, 9 genes are in a cluster on chromosome 7q31, and a single member of the gene family resides on chromosome 5p15. These genes all contain a single coding exon that encodes a 7-transmembrane-domain G-protein-coupled receptor averaging 335 amino acids in length. These receptors have a short amino-terminal extracellular domain, and, despite substantial sequence diversity, they contain conserved sequence motifs in the first, second, third, and seventh transmembrane domains, and in the second intracellular loop. It has been argued that the significant sequence variation between different members of the T2R gene family has served an adaptive function during evolution (Shi et al., 2003).

Little is currently known about ligand specificities for most of these taste receptors. In humans, in vitro studies have shown that TAS2R16 responds to salicin and other beta-glucopyranosides, and hT2R10 displays activity upon exposure to strychnine (Bufe et al., 2002). Chandrashekar et al. demonstrated that the mouse T2R5 (mT2R5) receptor responds to the bitter tastant cyclohexamide in a heterologous expression system, and that the ability to taste cyclohexamide is correlated with amino acid substitutions in this protein (Chandrashekar et al., 2000). It is unclear whether TAS2R receptors in humans will respond to the same bitter tastant compounds as the orthologous mT2R receptors in the mouse, due to the low sequence identity between them. Nevertheless, selected mouse and human bitter receptors show sufficient homology to indicate that the gene duplication events that gave rise to the multiple members of the T2R family pre-dated the separation of rodents and primates (Shi et al., 2003).

Given our limited knowledge of receptor-ligand specificity, genetic studies are likely to be important for the understanding of taste biology in humans. Genetic methods provide information that is complementary to in vitro and cell-based assays of receptor function. All ex vivo assays involve several artificial components, such as chimeric G proteins and taste receptor molecules that have been engineered to improve expression. Thus, receptor-ligand relationships defined by such methods will likely provide important insights, but studies in vivo will ultimately be required to confirm authentic biological function. Human studies of bitter taste in vivo have a long history that provides an example of the power of this approach.

	PTC

TOP ABSTRACT INTRODUCTION TASTE MODALITIES BITTER PTC SWEET AND UMAMI SOUR SALT SUMMARY REFERENCES

 
Responses of humans to some bitter compounds show a bimodal distribution that distinguishes two phenotypes, tasters and non-tasters. The best-studied example of these is the ability to taste phenylthiocarbamide (PTC) and structurally related compounds (Guo and Reed, 2001). A large fraction of the population was initially reported to be "taste blind" to PTC (Fox, 1932), and subsequent studies demonstrated that taste thresholds exhibit a strong bimodal distribution in the population, with the most sensitive individuals capable of perceiving a concentration of PTC 10,000-fold lower than that perceived by the least sensitive individuals (Harris and Kalmus, 1949a). Subsequent studies showed that many other compounds, typically sharing the N-C=S chemical moiety with PTC, also show the same bimodal threshold distribution (Barnicot et al., 1951), including the compound propyl-thiouracil (PROP). Taste thresholds for these substances are strongly correlated in the same individual (Harris and Kalmus, 1949b), and thus, it is generally believed that the bimodal sensitivity distribution to all these compounds is caused by a common mechanism.

After the discovery of this sensory variation, several investigators reported that PTC-insensitive parents tended to produce PTC-insensitive children, and in many families where both parents were sensitive, 25% of their children were not (Blakeslee, 1932). This observation led scientists to suggest that the ability to detect PTC was inherited as a two-allele trait, with a recessive insensitive allele. Because the mode of inheritance appeared to be Mendelian, and because the trait is easy to measure in the classroom, PTC insensitivity has come to be a textbook example of a recessive trait in humans.

Some subsequent family and twin studies were consistent with this interpretation of PTC genetics (Harris and Kalmus, 1951; Merton, 1958). However, other investigators found that the Mendelian model of inheritance did not adequately explain their data, and suggested other models that invoked multiple alleles (Rychkov and Borodina, 1969; Ramana and Naidu, 1992), multiple loci (Olson et al., 1989), and incomplete dominance (Bartoshuk et al., 1994; Reed et al., 1995). In addition, genetic background and environmental modifiers also may have an influence on the phenotype (Morton et al., 1981; Olson et al., 1989; Bartoshuk et al., 1996; Drayna et al., 2003).

This situation has been clarified by two recent discoveries. A gene with a major effect on PTC sensitivity was located on chromosome 7 by a large linkage study, although a second gene, possibly on chromosome 16, appears to have an effect and is likely responsible for this trait in a subset of families (Drayna et al., 2003). In a second study, the major gene on chromosome 7 responsible for this trait was identified as a member of the TAS2R bitter taste receptor gene family, TAS2R38 (Kim et al., 2003). The Fig. shows a schematic diagram of this protein. Two major forms of this bitter receptor gene were identified in most of the world’s populations, designated the ‘major taster’ form and the ‘major non-taster’ form. These two forms differ at 3 amino acid positions, numbers 49, 262, and 296. The major taster form contains a proline at position 49, an alanine at position 262, and a valine at position 296 (constituting the PAV form), while the non-taster form contains an alanine, a valine, and an isoleucine at these 3 positions, respectively (constituting the AVI form). These two forms, called alleles, account for the bimodal distribution of taste thresholds and the classic recessive inheritance pattern observed.

View larger version (34K): [in this window] [in a new window]   Figure. Schematic protein structure of the PTC receptor. Horizontal lines denote the inner and outer surfaces of the cell membrane. Sequences above the lines are extracellular domains of the protein, those between the lines are transmembrane helical domains, and those below the lines are intracellular domains. The variant amino acid positions are marked with circles.

Recent studies have demonstrated that both the taster and non-taster forms of the PTC receptor have been maintained at high frequency in the population by balancing natural selection. This raised the question of the nature of the selective advantage provided by the non-taster allele. We have hypothesized that the non-taster allele may encode a molecule that serves as a functional receptor for another toxic bitter substance not yet identified (Wooding et al., 2004).

Based on the example of PTC perception, it appears likely that inter-individual differences in taste response to other bitter compounds come from allelic or haplotype variations between individuals. Individual differences in bitterness sensitivities are reliable (Yokomukai et al., 1993; Delwiche et al., 2001; Sugino et al., 2002) and heritable in many instances (Smith and Davies, 1973). For example, a family segregating taste blindness to a broad range of bitter substances independent of PTC/PROP has been described (Breslin et al., unpublished observation).

As a first step to investigating this area, we looked for genetic variation in all of the potentially functional TAS2R genes in numerous populations worldwide, as well as in primates. The results of this survey demonstrated that these genes showed a broad range of variation, including a substantial number of coding single nucleotide polymorphisms (cSNPs) (Kim et al., 2004). Many of these cSNPs are non-synonymous polymorphisms, and thus change the amino acid encoded in the protein. This information will provide an essential resource for investigating phenotypic variations among individuals and populations in taste sensitivity to a variety of bitter compounds. In addition, comparative sequence analysis of TAS2R genes in mammals should help define conserved regions in TAS2R proteins, and may help us elucidate important sites for bitter transduction within these proteins.

Additional sources of possible genetic variation in our sense of bitter taste are the genes encoding the G proteins that couple to the TAS2R receptors. These genes encode G , ß, and proteins that act as a heterotrimer to initiate downstream cellular signaling events in response to ligand activation of the GPCR. Humans carry multiple genes encoding numerous members of each class of G protein, and some of these, such as human G 13, are known to participate in bitter taste signaling (Huang et al., 1999). The extent of DNA sequence variation in these human G protein genes is currently not well-characterized.

	SWEET AND UMAMI

TOP ABSTRACT INTRODUCTION TASTE MODALITIES BITTER PTC SWEET AND UMAMI SOUR SALT SUMMARY REFERENCES

 
These two taste qualities indicate the presence of calorically rich and essential nutrients. In humans, the two taste qualities are very different perceptually, but are closely related phylogenetically. The chemical structure of substances that taste sweet is almost as broad as the set of compounds that taste bitter. Many polyalcohols, such as sugars and glycerol, taste sweet, as do some amino acids, peptides such as the dipeptide aspartame, and proteins such as thaumatin and monellin. In addition, there are many artificial sweeteners of widely varying and unrelated structures that taste sweet, such as Na saccharin, Na Cyclamate, dulcin, as well as inorganic sweeteners such as Pb and Be salts. There are modest individual differences in the detection and recognition thresholds for sweeteners (Blakeslee and Salmon, 1935; Kahn, 1951), and the responses to sugars tend to be unimodally distributed among the population. There has been one observation of a subject who did not perceive a sweet taste from sucrose (Richter, 1943). Inter-individual differences in response to sweet compounds are not yet fully characterized, and to date there have been no comprehensive family or twin studies published regarding threshold and perceived intensity measures of sweet perception. One difficulty has been that inter-subject differences are relatively modest in magnitude, and detection thresholds for sweeteners demonstrate relatively weak test-retest reliability.

Assessment of umami taste is usually performed with monosodium glutamate (MSG), which requires exacting tests to discriminate the flavor of glutamate from the salty component imparted by the sodium it contains. A recent report suggests that variation in umami perception is common in the population (Lugaz et al., 2002). In this study, approximately 6% of individuals showed no ability to distinguish 29 mM MSG from 29 mM NaCl, and demonstrated greatly reduced MSG taste intensity, suggesting a severe impairment in their ability to perceive umami. This MSG insensitivity has not, however, been shown to segregate in families or to show higher correlation in identical twins, so there is not yet evidence that it is a genetic trait.

Similar to bitter taste, the taste receptor proteins that participate in sweet and umami taste transduction are 7-transmembrane-domain G-protein-coupled receptors. Two proteins, labeled T1R2 and T1R3 for taste receptor family 1, receptors 2 and 3, interact to create a dimer that is sensitive to sweeteners (Li et al., 2002). The names of the associated genes for these proteins in mice are Tas1r2 and Tas1r3. When T1R3 pairs with the first member of this family, T1R1, the resulting receptor dimer is sensitive to MSG.

These sweet and glutamate receptor genes were discovered through gene-mapping experiments in mice. Inbred mouse strains differ in their preference for saccharin, and the results of breeding experiments suggested that an allele of a single gene was partially responsible for these differences. Through positional cloning approaches, this gene was identified and found to be the gene Tas1r3 (McDaniel and Reed, 2004). More generally, it now appears that several small changes in the DNA sequence of the mouse Tas1r3 gene lead to large differences in the consumption of sweetener (Reed et al., 2004). This reduction of sweetener preference by mice with different Tas1r3 alleles is probably due to their reduced ability to perceive the intensity of the sweeteners. Recordings of their peripheral taste nerves suggest that mice with the low-preference Tas1r3 alleles exhibit lower nerve firing in response to saccharin (Bachmanov et al., 1997). Furthermore, when the Tas1r3 gene is knocked out in mice, the peripheral nerve firing is reduced in response to sweeteners (Damak et al., 2003).

The T1R2/T1R3 dimer is not the only receptor for all sweeteners, however. When the Tas1r3 gene is knocked out in mice, their ability to detect glucose and maltose is little affected compared with mice with a normal Tas1r3 gene (Damak et al., 2003). Furthermore, the ability to detect other sugars and high-intensity sweeteners is reduced, but not absent, in Tas1r3 knockout mice. Therefore, other receptors or mechanisms exist that signal sweetness in mice. For instance, the remaining partner (T1R2) could act as a taste receptor by itself (Zhao et al., 2003).

If DNA sequence variants have a large effect on the intake of saccharin and other sweeteners in mice, then this may also be true in humans. Like mice, humans have three sweet receptor genes, designated TAS1R1, TAS1R2, and TAS1R3 (Liao and Schultz, 2003) that show substantial sequence similarity to their counterparts in mice. [The protein name for each of the 3 receptors has the same name in mice and humans (T1R1, T1R2, and T1R3). However, the gene names in the mice (Tas1r1, Tas1r2, and Tas1r3) are lower-case and italic, whereas the human gene symbols are upper-case and italic: TAS1R1, TAS1R2, TAS1R3.] Because the peripheral neural responses of humans to sugars predict their verbal reports about the taste of sugars (Diamant et al., 1965), peripheral differences in taste sensitivity may be an important component of the human sweet preference. There may be more variation than appreciated in human perception of sweeteners, and one investigator has even suggested that there is a "different receptor site for each subject" (Faurion, 1987). Although the differences in human ability to perceive sweet stimuli has been thought to be of little consequence in human sweet intake and preference, the clear relationship in mice may stimulate further study of this topic.

The number of sweet and umami receptor genes is small, and little genetic variation has been reported. Breslin et al. (unpublished observation) reported that the common polymorphism in T1R3 (A5T) was not correlated with umami taste sensitivity, according to the phenotyping procedure developed by Lugaz et al.(2002). Studies are also under way to look for correlation between taste phenotype and genetic variation, and the known splice variants of hT1R1 (Makalowska et al., 2002). These approaches show promise for the understanding of these taste modalities in humans.

	SOUR

TOP ABSTRACT INTRODUCTION TASTE MODALITIES BITTER PTC SWEET AND UMAMI SOUR SALT SUMMARY REFERENCES

 
The sour taste is a basic taste quality that evokes an innate rejection response in adult humans and many other animals at high concentrations. Interestingly, acids appear attractive to many animals at low concentrations. Acidic stimuli are the unique sources of sour taste, so a rejection response may serve to discourage ingestion of foods spoiled by acid-producing micro-organisms or serve as an inverse indicator of fruit ripeness and hence sugar content. Since each stimulus evoking a sour sensation also produces dissociable hydrogen ions, the perception of sour taste would be expected to be a graded function of stimulus pH. However, only a low correlation exists between the perception of sour taste and stimulus pH. This finding has been repeatedly confirmed in both human psychophysical studies (Ganzevles and Kroeze, 1987) and in human studies, where the rate of acid-induced salivary secretion has been used as the index of sour taste (Makhlouf and Blum, 1972). Recordings from gustatory afferent nerves in rats failed to show a strong correlation between stimulus pH and the neural response to organic acidic stimuli (Beidler and Gross, 1971; Ogiso et al., 2000). However, responses are highly correlated with pH for strong inorganic stimuli such as HCl and HNO₃.

A variety of potential transduction mechanisms for these compounds has been described. In general, these mechanisms involve the actions of protons, affecting a variety of pH-sensitive cellular targets, coupled with their high permeability through many types of ion channels and inter-cellular junctions. The proposed cellular mechanisms proposed for acid sensing include: (1) the direct blockage of apical K⁺ channels by protons; (2) an H⁺-gated Ca²⁺ channel; (3) proton conduction through apical amiloride-blockable Na⁺ channels; (4) a Cl^– conductance blocked by 5-nitro 2-(3-phenylpropylamine) benzoic acid (NPPB); (5) the activation of the proton-gated channel, BNC-1, a member of the Na⁺ channel/degenerin super family; (6) activation of HCN channels by stimulus-evoked changes in extracellular pH; and (7) direct passage of protons into cells via acid-sensing ion channels (ASICs). In addition, specific sour-sensing activity in the rat has been recently proposed for the products of the ASIC2a and ASIC2b gene products (Ugawa, 2003).

Only a few studies have examined variation in sour sensitivity. The studies that have been done have found that human sour sensitivity exhibits a unimodal distribution of detection thresholds, with the mean values ranging from 7 X 10^–5 M for citric acid to 1.07 X 10^–4 M for acetic acid. The detection thresholds of these and other acids are summarized in Breslin (2000). Inter-individual variation in sour perception and the relative contributions of genes and environment have received little experimental attention. In one study of human twins, the threshold at which subjects could detect hydrochloric acid was determined, and the between-twin differences in taste threshold were compared. The investigators concluded there was little evidence of heritabilty for sour threshold, while at the same time, using similar methods, they found substantial evidence for heritability for the bitter compound propylthiouracil (Kaplan et al., 1967). Absolute detection thresholds, however, may not be the best measure for phenotyping subjects, since acids may act on other sensory modalities at concentrations for which the taste system is not responsive.

	SALT

TOP ABSTRACT INTRODUCTION TASTE MODALITIES BITTER PTC SWEET AND UMAMI SOUR SALT SUMMARY REFERENCES

 
Salt taste guides the consumption of NaCl and possibly other required minerals, thus serving an essential function in ion and water homeostasis. Salt consumption shows variations across animal species, depending on the ion content of the characteristic diet (Lindemann, 1996). The transduction of sodium salts is composed of a sodium-specific and a non-specific mechanism. It was long suspected that a sodium channel sensitive to the channel-blocker amiloride serves as a salt receptor (Schiffman et al., 1983; Heck et al., 1984). In rodents, the amiloride-sensitive epithelial sodium channel ENaC acts as a salt-taste receptor by providing a specific pathway for sodium current into the taste cell, provided that Na⁺ ions are present in the oral space in sufficient concentration (Lindemann et al., 1998; Kretz et al., 1999; Lin et al., 1999). However, Ossebaard and Smith, (1995) provided evidence that the amiloride sensitivity of NaCl taste in humans is specific to the very minor sour component and not to the salty taste itself. This suggests that the presumed ion channel responsible for salty taste in humans is structurally different. The human salty taste response to NaCl can be blocked by the addition of the compound chlorhexidine (Breslin and Tharp, 2001), supporting this view.

In an African population, the taste sensitivity thresholds for sodium chloride are bimodal (Odeigah, 1994), but in European populations the same phenotype is unimodal (Blakeslee and Salmon, 1935). One twin study that examined the heritability of sodium chloride preferences over a range of concentrations found no evidence for genetic effects (Beauchamp et al., 1985).

	SUMMARY

TOP ABSTRACT INTRODUCTION TASTE MODALITIES BITTER PTC SWEET AND UMAMI SOUR SALT SUMMARY REFERENCES

 
The strategy of exploiting natural variation in taste sensitivity to identify the genes that underlie this variation has produced a number of recent successes. This approach is likely to help us in a broader understanding of the human sense of taste in the future.

	ACKNOWLEDGMENTS

 
We thank R. Morell, T. Friedman, and S. Sullivan for helpful comments on the manuscript. This work was supported by the Division of Intramural Research, National Institute on Deafness and Other Communication Disorders (grant Z01-000046-04 to DD) and by the National Institutes of Health (DC02995 to PB, and DC004698 to DRR).

Received January 6, 2004; Last revision April 8, 2004; Accepted April 19, 2004

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