Thiourea Tasting

A number sign (#) is used with this entry because 5 haplotypes arising from 3 coding SNPs in the TAS2R38 gene (607751) are associated with distinct phenotypes of phenylthiocarbamide (PTC) taste sensitivity.

Description

The sense of bitter taste is mediated by a group of bitter taste receptor proteins that reside on the surface of taste cells within the taste buds of the tongue. These proteins are 7-transmembrane domain, G protein-coupled receptors that are encoded by the TAS2R gene family (see TAS2R10; 604791), which contains at least 25 functional genes (Kim et al., 2005).

Humans worldwide display a bimodality in sensitivity to the bitter taste of PTC, with approximately 75% of individuals perceiving it as intensely bitter, whereas the rest perceive it as tasteless. This difference has been the basis of study of taste perception in humans for over 70 years. Kim and Drayna (2004) provided an historical review of the subject.

Propylthiouracil (PROP) and PTC are members of a class of compounds known as thioureas. The compounds carry the chemical group N-C=S, which is responsible for their characteristic bitter taste (Bartoshuk et al., 1994; Drewnowski and Rock, 1995).

Clinical Features

Variation in the ability to taste PTC was discovered by Fox (1931). Supplementation of the standard test using quinine in the intermediate cases was suggested by Kalmus (1958). There has been a suggestion that PTC tasting in man is related to a component of saliva: Cohen and Ogdon (1949) claimed that PTC tasters can taste PTC only if it is dissolved in their own saliva. If the tongue is dried and then presented with PTC dissolved in someone else's saliva, it is tasteless. Jones and McLachlan (1991) described a technique for fitting mixture distributions to data on PTC sensitivity.

It has long been proposed that there is a relationship between athyreotic hypothyroidism (218700; formerly called athyreotic cretinism) and PTC nontasting (e.g., Shepard, 1961). Both PTC and PROP are structurally similar to the naturally occurring antithyroid substance l-goitrin; all members of this class of chemicals have antithyroidal activity and are not tasted by PTC nontasters (Shepard, 1961). Nearly all individuals with athyreotic hypothyroidism are nontasters.

Tepper (1998) reviewed the literature for the ability to taste PTC and PROP and the implications for food preference and dietary habits. Tepper (1998) discussed the classic explanation for the persistence of the PROP polymorphism, i.e., a selective advantage for avoidance of harmful compounds in the environment that are often bitter tasting (Drewnowski and Rock, 1995). This taste aversion may have special relevance for the avoidance of certain bitter-tasting vegetables. PROP and PTC are chemically related to the isothiocyanates and goitrin, bitter-tasting compounds that are present in cruciferous vegetables such as cabbage, broccoli, brussels sprouts, turnips, and kale. When eaten in large quantities, these compounds interfere with iodine metabolism, producing thyroid enlargement and goiterlike symptoms. Tepper (1998) noted that the incidence of thyroid deficiency disease is relatively rare among PTC tasters. In modern society, however, avoidance of bitter-tasting foods may have health disadvantages, since epidemiologic studies indicate that diets low in fruits and vegetables and high in fat may be associated with increased risk of heart disease and cancer.

Kinnamon (2000) reviewed the role of taste receptors in taste transduction.

Inheritance

Reddy and Rao (1989) examined the genetics of PTC taste thresholds by studying 100 nuclear families. They concluded that variability in thresholds is controlled by a major locus with incomplete dominance, as well as by a multifactorial component. Olson et al. (1989) studied 120 families and concluded that the data fitted best a 2-locus model in which one locus controls PTC tasting and the other locus controls a more general taste ability.

Mapping

Chautard-Freire-Maia (1974) found evidence for linkage of PTC to blood group Kell (KEL; 110900). Crandall and Spence (1974) tested linkage of PTC with 18 autosomal loci. None was found, although linkage of Gm (147100) and PTC was suggested by analysis of recombination in the male parent. A number of small scores, when combined, hinted that KEL and PTC may be linked to Colton, Km, and Kidd (Jk), which were thought to be on chromosome 7 (Keats et al., 1978).

Conneally et al. (1976) found close linkage of PTC and KEL, with a lod score of 10.78 at theta = 0.045. Spence et al. (1984) analyzed 2 new sets of data on the PTC-KEL linkage. The new data gave a theta of 0.28 (sexes combined); male theta was estimated as 0.29 and female as 0.23. The estimate of theta for all published data was 0.14 (lod = 8.94), with statistically significant evidence of heterogeneity among the published studies.

Reed et al. (1999) identified a locus on chromosome 5p15 as giving the strongest evidence for linkage to PROP tasting, with the peak score near D5S2505. In addition to chromosome 5, there was a suggestion of linkage on chromosome 7, about 35 to 40 cM centromeric to the KEL locus, with a maximum t-score of 2.34 (P = 0.008) near D7S1789 and D7S796. The results of the study by Reed et al. (1999) suggested that the region on chromosome 7 may also influence the taster phenotype.

Prodi et al. (2002) reported linkage to 7q35 in a Sardinian genetic isolate.

Kim et al. (2003) identified a small region on chromosome 7q that showed strong linkage disequilibrium between SNP markers and PTC taste sensitivity in unrelated subjects. This region was narrowed to a 2.6-Mb interval using the Utah CEPH families and further narrowed to a 150-kb interval of linkage disequilibrium extending from about 139,835,000 to 139,981,000 basepairs on the chromosome 7 sequence.

Drayna et al. (2003) undertook a genetic analysis of the ability to taste PTC. They obtained a quantitative measure of PTC tasting ability in 267 members of 26 large 3-generation Utah CEPH families that had been used for genetic mapping. Significant bimodality was found for the distribution of age and gender adjusted scores (P less than 0.001). They performed a genome screen by using 1,324 markers with an average spacing of 4 cM. Analyses were first carried out with a recessive genetic model that had traditionally been assumed for the trait, and a threshold score of 8.0 delineating tasters from nontasters. In this qualitative analysis, the maximum genomewide lod score was 4.74 at 246 cM on chromosome 7; 17 families showed segregation of the dichotomous PTC phenotype. No other lod scores were significant; the next highest score was on chromosome 10 (lod = 1.64 at 85 cM), followed by chromosome 3 (lod = 1.29 at 267 cM). Treating PTC taste ability as a quantitative variable, they found a maximum quantitative genomewide lod score of 8.85 at 246 cM on chromosome 7. Drayna (2003) stated that position 246 cM resides in the region 7q35-q36, and is probably at or near the boundary of these 2 cytogenetic bands.

Drayna et al. (2003) found evidence for other possible quantitative loci on chromosomes 1 (lod = 2.31 at 344 cM) and 16 (lod = 2.01 at 14 cM). A subsequent 2-locus whole genome scan conditional on the chromosome 7 quantitative trait locus identified the chromosome 16 locus (2-locus lod = 3.33 at 14 cM). Drayna et al. (2003) replicated the original linkage findings with KEL on 7q.

Molecular Genetics

Kim et al. (2003) cloned the TAS2R38 gene (607751) and identified 3 coding SNPs giving rise to 5 haplotypes worldwide that completely explained the bimodal distribution of PTC taste sensitivity. Distinct phenotypes were associated with specific haplotypes, which demonstrated that the TAS2R38 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.

Fisher et al. (1939) hypothesized that the pervasive phenotypic variation in PTC perception is due to balancing natural selection, which may have favored heterozygotes. Wooding et al. (2004) examined patterns of DNA sequence variation to test the PTC gene for evidence of long-term selected pressures. They analyzed the entire coding region of PTC (1,002 bp) in a sample of 330 chromosomes from different populations (62 African, 138 Asian, 110 European, and 20 North American) by use of statistical tests for natural selection that take into account the potentially confounding effects of human population growth. Two haplotypes of intermediate frequency corresponding to 'taster' and 'nontaster' phenotypes were found. These haplotypes had similar frequencies across Africa, Asia, and Europe. Genetic differentiation between the continental population samples was low in comparison with estimates based on other genes. In addition, a significant deviation from neutrality was found because of an excess of variants of intermediate frequency when human population growth was taken into account. These results supported the hypothesis of Fisher et al. (1939) and suggested that balancing natural selection has acted to maintain 'taster' and 'nontaster' alleles at the PTC locus.

Kim et al. (2005) sequenced 24 human TAS2R genes in 55 unrelated individuals of African, Asian, European, and North American Native ancestry, and found a high degree of nucleotide variation. A total of 144 SNPs were identified with an average of 4.2 variant amino acids per gene. In aggregate, the 24 genes analyzed specified 151 different protein-coding haplotypes. Data analysis showed that the observed excess of nonsynonymous nucleotide substitutions was much higher than expected given observations in other genes. Kim et al. (2005) hypothesized that natural selection may have been relaxed on these genes and that local adaptation in human bitter taste receptor genes is common, driven by the fitness advantages of avoiding toxins found in plants. The findings were consistent with the view that different alleles of the TAS2R genes encode receptors that recognize different ligands.

Population Genetics

Kim and Drayna (2004) stated that the frequency of PTC nontasters in Caucasians is approximately 28%.

Henkin and Gillis (1977) observed that 2 of 8 people served a pie made from berries of the tree Antidesma bunius, a popular fruit in southeast Asia and Florida, found their dessert bitter and inedible, whereas the remainder found it edible and sweet. They studied 170 predominantly Caucasian American male and female volunteers aged 7 to 89 years and found that 15% found antidesma berries bitter and 68% found PTC bitter. The results were independent of age, sex, race, national origin, color blindness, and ichthyosis. The antidesma nonresponders deemed it slightly sour, sweet, salty, or tasteless. None of those who found antidesma bitter tasted PTC, and no PTC responders found antidesma bitter. Analysis of 3 families in which the father, but not the mother, was an antidesma responder identified only 1 son who shared the antidesma response. The substance responsible for the antidesma taste response was unknown, but it was found to be water soluble and heat stable.

History

Nebert (1997) suggested that the first example of pharmacogenetics was the phenylthiourea nontaster trait first described by Snyder (1932). Nebert (1997) used the occasion of the sixty-fifth anniversary of that discovery to review other discoveries in chronologic sequence: G6PD deficiency (300908) in 1956; N-acetylation polymorphism (243400) in 1959; genetic variation in ethanol metabolism by alcohol dehydrogenase and aldehyde dehydrogenase in 1964; debrisoquine/sparteine oxidation polymorphism, found in 1977 and subsequently shown to be due to polymorphism of the CYP2D6 gene (124030); and thiopurine methyltransferase polymorphism (TPMT; 187680), first found in 1980.

Animal Model

Azen et al. (1986) found close linkage between genes for proline-rich proteins of saliva (PRPs; see 168730, etc.) and taste for some bitter substances in mice. This suggested that PTC and genes for salivary proline-rich proteins, which are clustered on chromosome 12, might be linked in man; however, O'Hanlon et al. (1988) demonstrated that they are not linked.