Evolution of Functionally Diverse Alleles Associated with PTC Bitter Taste Sensitivity in Africa

Department of Genetics, University of Pennsylvania, PA, USA.
Molecular Biology and Evolution (Impact Factor: 9.11). 11/2011; 29(4):1141-53. DOI: 10.1093/molbev/msr293
Source: PubMed


Although human bitter taste perception is hypothesized to be a dietary adaptation, little is known about genetic signatures of selection and patterns of bitter taste perception variability in ethnically diverse populations with different diets, particularly from Africa. To better understand the genetic basis and evolutionary history of bitter taste sensitivity, we sequenced a 2,975 bp region encompassing TAS2R38, a bitter taste receptor gene, in 611 Africans from 57 populations in West Central and East Africa with diverse subsistence patterns, as well as in a comparative sample of 132 non-Africans. We also examined the association between genetic variability at this locus and threshold levels of phenylthiocarbamide (PTC) bitterness in 463 Africans from the above populations to determine how variation influences bitter taste perception. Here, we report striking patterns of variation at TAS2R38, including a significant excess of novel rare nonsynonymous polymorphisms that recently arose only in Africa, high frequencies of haplotypes in Africa associated with intermediate bitter taste sensitivity, a remarkably similar frequency of common haplotypes across genetically and culturally distinct Africans, and an ancient coalescence time of common variation in global populations. Additionally, several of the rare nonsynonymous substitutions significantly modified levels of PTC bitter taste sensitivity in diverse Africans. While ancient balancing selection likely maintained common haplotype variation across global populations, we suggest that recent selection pressures may have also resulted in the unusually high level of rare nonsynonymous variants in Africa, implying a complex model of selection at the TAS2R38 locus in African populations. Furthermore, the distribution of common haplotypes in Africa is not correlated with diet, raising the possibility that common variation may be under selection due to their role in nondietary biological processes. In addition, our data indicate that novel rare mutations contribute to the phenotypic variance of PTC sensitivity, illustrating the influence of rare variation on a common trait, as well as the relatively recent evolution of functionally diverse alleles at this locus.

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Available from: Paul Breslin, Oct 01, 2015
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    • "Individual variability in sensitivity to the bitter taste of phenythiocarbamide was first recognized by Fox more than eight decades ago [1]. Since that time, steady progress has been made in elucidating the psychophysical features [2–5], population genetics [6,7] and molecular basis of this trait [8,9]. PTC/PROP tasting has also gained considerable attention as an oral marker for food preferences and eating habits that ultimately impacts nutritional status and health [10]. "
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    ABSTRACT: Taste sensitivity to PROP varies greatly among individuals and is associated with polymorphisms in the bitter receptor gene TAS2R38, and with differences in fungiform papilla density on the anterior tongue surface. Recently we showed that the PROP non-taster phenotype is strongly associated with the G variant of polymorphism rs2274333 (A/G) of the gene that controls the salivary trophic factor, gustin. The aims of this study were 1) to investigate the role of gustin gene polymorphism rs2274333 (A/G), in PROP sensitivity and fungiform papilla density and morphology, and 2) to investigate the effect of this gustin gene polymorphism on cell proliferation and metabolic activity. Sixty-four subjects were genotyped for both genes by PCR techniques, their PROP sensitivity was assessed by scaling and threshold methods, and their fungiform papilla density, diameter and morphology were determined. In vitro experiments examined cell proliferation and metabolic activity, following treatment with saliva of individuals with and without the gustin gene mutation, and with isolated protein, in the two iso-forms. Gustin and TAS2R38 genotypes were associated with PROP threshold (p=0.0001 and p=0.0042), but bitterness intensity was mostly determined by TAS2R38 genotypes (p<0.000001). Fungiform papillae densities were associated with both genotypes (p<0.014) (with a stronger effect for gustin; p=0.0006), but papilla morphology was a function of gustin alone (p<0.0012). Treatment of isolated cells with saliva from individuals with the AA form of gustin or direct application of the active iso-form of gustin protein increased cell proliferation and metabolic activity (p<0.0135). These novel findings suggest that the rs2274333 polymorphism of the gustin gene affects PROP sensitivity by acting on fungiform papilla development and maintenance, and could provide the first mechanistic explanation for why PROP super-tasters are more responsive to a broad range of oral stimuli.
    PLoS ONE 09/2013; 8(9):e74151. DOI:10.1371/journal.pone.0074151 · 3.23 Impact Factor
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    • "Indications that susceptibility to BEN arises, in part, from inherited mutations also has epidemiological implications. In particular, it is well established that mutations in TAS2R genes vary substantially in frequency among populations [27-29]. For this reason, variation in TAS2R-mediated traits, and therefore susceptibility, could differ among groups. "
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    ABSTRACT: Background Balkan Endemic Nephropathy (BEN) is late-onset kidney disease thought to arise from chronic exposure to aristolochic acid, a phytotoxin that contaminates wheat supplies in rural areas of Eastern Europe. It has recently been demonstrated that humans are capable of perceiving aristolochic acid at concentrations below 40 nM as the result of high-affinity interactions with the TAS2R43 bitter taste receptor. Further, TAS2R43 harbors high-frequency loss-of-function mutations resulting in 50-fold variability in perception. This suggests that genetic variation in TAS2R43 might affect susceptibility to BEN, with individuals carrying functional forms of the receptor being protected by an ability to detect tainted foods. Methods To determine whether genetic variation in TAS2R43 predicts BEN susceptibility, we examined genotype-phenotype associations in a case–control study. A cohort of 88 affected and 99 control subjects from western Bulgaria were genotyped with respect to two key missense variants and a polymorphic whole-gene deletion of TAS2R43 (W35S, H212R, and wt/Δ), which are known to affect taste sensitivity to aristolochic acid. Tests for association between haplotypes and BEN status were then performed. Results Three major TAS2R43 haplotypes observed in previous studies (TAS2R43-W35/H212, -S35/R212 and –Δ) were present at high frequencies (0.17, 0.36, and 0.47 respectively) in our sample, and a significant association between genotype and BEN status was present (P = 0.020; odds ratio 1.18). However, contrary to expectation, BEN was positively associated with TAS2R43-W35/H212, a highly responsive allele previously shown to confer elevated bitter sensitivity to aristolochic acid, which should drive aversion but might also affect absorption, altering toxin activation. Conclusions Our findings are at strong odds with the prediction that carriers of functional alleles of TAS2R43 are protected from BEN by an ability to detect and avoid aristolochic acid exposure. Evidence for a positive association between high-sensitivity alleles and BEN status suggests instead that possession of toxin-responsive receptor variants may paradoxically increase vulnerability, possibly by shifting attractive responses associated with low-intensity bitter sensations. The broad-spectrum tuning of the ~25-member TAS2R family as a whole toward xenobiotics points to a potentially far-reaching relevance of bitter responses to exposure-related disease in both individuals and populations.
    BMC Medical Genetics 10/2012; 13(1):96. DOI:10.1186/1471-2350-13-96 · 2.08 Impact Factor
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    ABSTRACT: Children often refuse to take medication in liquid formulation because of its unpleasant taste. Recent advances in taste genetics have provided some insight into individual differences in taste among children: due to their genotype, some prefer more intense sweetness and are more sensitive to bitter tastes and thus may have different needs for medication formulation. The aims of this study were to: (1) test the a priori hypothesis that children with the bitter-sensitive genotypes are more likely to have experienced solid medication formulations than those with the bitter-insensitive genotype; and (2) conduct post hoc analyses to examine the relationship between genotype and most preferred level of sucrose in water because sweeteners are a common component of liquid formulations. The following data were obtained from healthy, 3- to 10-year-old children who participated in 1 of 5 taste-research studies: taste genotype for alleles of the bitter-taste receptor TAS2R38; data from retrospective reports of solid medication formulation usage and favorite beverage; and most preferred level of sucrose in water, as determined psychophysically. Data from 448 children were included (245 girls, 203 boys; mean age, 7.8 years). Children with ≥1 bitter-sensitive allele (TAS2R38 PP or AP genotype) were more likely to have taken medication in solid formulation than were bitter-insensitive (AA genotype) children. Children with the PP genotype preferred higher concentrations of sucrose in water, and their favorite beverage contained more grams of sugar compared with children with the AA genotype. Taste genotype was associated with experience with solid medication formulations and preference for more intense sweetness. This finding suggests that taste genetics might be an important factor in formulation choice and compliance in the pediatric population.
    Clinical Therapeutics 03/2012; 34(3):728-33. DOI:10.1016/j.clinthera.2012.02.006 · 2.73 Impact Factor
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