Chemical Senses Advance Access originally published online on June 26, 2006
Chemical Senses 2006 31(7):599-611; doi:10.1093/chemse/bjj065
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Variation in the Human TAS1R Taste Receptor Genes
1 Department of Biology, Kyungpook National University, Daegu 702-701, Korea 2 Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA 3 National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 5 Research Court, Rockville, MD 20850, USA
Correspondence to be sent to: Dennis Drayna, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 5 Research Court, Rockville, MD 20850, USA. e-mail: drayna{at}nidcd.nih.gov
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Abstract |
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We have performed a comprehensive evaluation of single-nucleotide polymorphisms (SNPs) and haplotypes in the human TAS1R gene family, which encodes receptors for sweet and umami tastes. Complete DNA sequences of TAS1R1-, TAS1R2-, and TAS1R3-coding regions, obtained from 88 individuals of African, Asian, European, and Native American origin, revealed substantial coding and noncoding diversity: polymorphisms are common in these genes, and polymorphic sites and SNP frequencies vary widely in human populations. The genes TAS1R1 and TAS1R3, which encode proteins that act as a dimer to form the umami (glutamate) taste receptor, showed less variation than the TAS1R2 gene, which acts as a dimer with TAS1R3 to form the sweet taste receptor. The TAS1R3 gene, which encodes a subunit common to both the sweet and umami receptors, was the most conserved. Evolutionary genetic analysis indicates that these variants have come to their current frequencies under natural selection during population growth and support the view that the coding sequence variants affect receptor function. We propose that human populations likely vary little with respect to umami perception, which is controlled by one major form of the receptor that is optimized for detecting glutamate but may vary much more with respect to sweet perception.
Key words: evolution, human TAS1R genes, SNP, sweet taste, umami taste
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Introduction |
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Molecular mechanisms of sweet perception have been elucidated by studies in rodents, which have identified taste receptors encoded by the TAS1R gene family (Bachmanov et al., 2001
; Kitagawa et al., 2001; Max et al., 2001; Montmayeur et al., 2001; Nelson et al., 2001; Sainz et al., 2001). Humans carry three TAS1R (T1R) taste receptor genes in a single cluster on chromosome 1. The products of these genes are seven transmembrane domain G protein–coupled receptors that act as dimers, as TAS1R2+3 to sense sugars, and as TAS1R1+3 to perceive umami taste, a savory flavor exemplified by the taste of glutamate (Li et al., 2002; Zhao et al., 2003). The extent of variation in human TAS1R genes has not been well characterized, and potential functional consequences of such variation are unknown.
In contrast, substantial information has accumulated about variation in the TAS2R bitter receptor gene family. The TAS2R genes have been shown to be highly polymorphic (Wang et al., 2004; Kim et al., 2005), and both evolutionary genetic analyses (Wooding et al., 2004) and biochemical activity assays (Bufe et al., 2005; Soranzo et al., 2005) have suggested that much of this DNA sequence variation results in altered receptor functions. In an effort to obtain a more complete understanding of genetic and functional variation in human taste perception, we have performed a survey of polymorphism in the three TAS1R genes. We have performed evaluations of the polymorphisms within these genes in worldwide populations and measured the frequency of the alleles and haplotypes of these genes in these populations. To address the question of the potential functional significance of these polymorphisms, we performed evolutionary genetic analyses to look for evidence of natural selection in the maintenance of this variation.
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Materials and methods |
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Population samples
Human Genomic DNA was obtained from 88 unrelated individuals in eight different geographic populations, including 20 Cameroonians, 10 Northern Europeans, 10 Russians, 8 Pakistanis, 10 Hungarians, 10 Native Americans, 10 Chinese, and 10 Japanese (N = 176 chromosomes). All DNA samples except Cameroonian were purchased from Coriell Cell Repositories (http://locus.umdnj.edu/nigms/cells/humdiv.html).
Polymerase chain reaction and DNA sequencing
Single-nucleotide polymorphisms (SNPs) were discovered and assayed by sequencing genomic DNA, with sequence and genotypes assigned after sequencing both strands. Each of the six exons of all three TAS1R genes covering the coding region was amplified with the primers designed by software at the Primer3 Web site. Polymerase chain reaction (PCR) was performed in a total volume of 25 µl, containing 0.2 µM of each deoxynucleotide (Invitrogen), 15 pmol of each forward and reverse primers, 1.0–1.5 mM of MgCl2, 10 mM Tris–HCl (pH 8.3), 50 mM KCl, 0.75 U of Taq DNA polymerase (PE Biosystems), and 100 ng of genomic DNA. PCR conditions (PE9700, PE Biosystems) were as follows: 35 cycles of denaturation at 94°C for 30 s; annealing at 55°C or 57°C, depending on the primers for 30 s; and extension at 72°C for 1 min. The first step of denaturation and the last step of extension were at 95°C for 2 min and 72°C for 10 min, respectively. Five microliters of the PCR products were separated and visualized in a 2% agarose gel. Fifteen microliters of this PCR product were then treated with 0.3 U of shrimp alkaline phosphatase (USB) and 3 U of exonuclease I (USB) at 37°C for 1 h, followed by incubation at 80°C for 15 min. This was diluted with an equal volume of dH2O, and 6 µl was used for the final sequencing reaction. Sequencing reactions were performed in both directions on the PCR products in reactions containing 5 pmol of primer, 1 µl of Big Dye Terminator Ready Reaction Mix (PE Biosystems), and 1 µl of 5x dilution buffer (400 mM Tris–HCl, pH 9, and 10 mM MgCl2). Cycling conditions were 95°C for 2 min and 35 cycles of 94°C for 20 s, 55°C for 20 s, and 60°C for 4 min. Sequencing reaction products were ethanol precipitated, and the pellets were resuspended in 10 µl of formamide loading dye. An ABI 3730 DNA sequencer was used to resolve the products, and data were analyzed by using ABI Sequencing Analysis (v. 5.0) and LASERGENE-SeqMan software.
Inference of haplotypes
Some haplotypes could be specified from genotypes of individuals, while other haplotypes were inferred. Haplotypes were inferred from unphased genotype data using the PHASE 2.0.2 computer program (Stephens et al., 2001; Stephens and Donnelly, 2003).
Measures of genetic diversity
Levels and patterns of genetic diversity in each gene were measured using three statistics: 
(the mean pairwise difference between sequences in a population sample), per nucleotide, S (the number of variable nucleotide positions in the sample), and FST (a measure of population differentiation). FST values were calculated using the method of Slatkin, treating the major continental regions as populations (Slatkin, 1991).
Because the TAS1R genes encode protein subunits that interact to form a functional receptor, we also estimated receptor diversity from a combinatorial standpoint, taking the different subunits into account. Here, diversity was measured as the expected total difference in amino acid sequence across both subunits, which is approximated estimated by the sum of the mean pairwise amino acid sequence differences within subunits.
Tests of evolutionary neutrality
The hypothesis of evolutionary neutrality was tested using Tajima's D statistic, which compares the mean number of nucleotide differences between sequences with the number of variable nucleotide positions in a population sample (Tajima, 1989). This test was originally designed for use in populations that have remained constant in size. However, several lines of evidence suggest that human population sizes have increased dramatically over the last 100,000 years. Such growth can have strong effects on tests of the D statistic.
Estimates of demographic parameters based on genetic data suggest that human populations have increased at least 100-fold over the last 75,000–100,000 years (Marth et al., 1993; Rogers, 1995; Wall and Przeworski, 2000) The consensus of these studies is that ancient effective population sizes in humans were small—approximately 10,000. However, estimates of the time and magnitude of growth from that initial size vary substantially. For this reason, we used the DFSC program (Wooding et al., 2004) to test the hypothesis of neutrality under a range of population histories. For each gene, Tajima's D test was performed under the assumption that the ancient effective population size in humans was 10,000, with the onset of population expansion ranging from 0 to 200,000 years before present and the magnitude of population expansion ranging from 0- to 500-fold. These were two-tailed tests, where P indicated the probability of observing a smaller value of D, given the population history parameters.
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DNA sequence variation
We identified variation in TAS1R genes by sequencing genomic DNA from different individuals. The polymorphisms observed in these genes are shown in Table 1.
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Comparisons of aligned exonic sequences revealed 17 SNPs in TAS1R1 (including 3 synonymous and 14 nonsynonymous variants), 18 SNPs in TAS1R2 (8 synonymous and 10 nonsynonymous), and 12 SNPs in TAS1R3 (6 nonsynonymous and 6 synonymous), for a total of 47 variant nucleotide and 30 variant amino acid sites. Thus, the majority (64%) of the changes are nonconservative and result in changes in the amino acids encoded at that position. Many of these sites are newly described (www.ncbi.nlm.gov/dbSNP). Examination of the distribution of polymorphisms across the different domains of the protein shows that most (77%) of the variant amino acid positions reside in the large predicted first extracellular domain of these three receptors. This domain is hypothesized to contain the ligand-binding site for carbohydrates and dipeptide sweeteners (Pin et al., 2003
; Xu et al., 2004; Nie et al., 2005). One SNP, which substitutes an A for the normal G at position 2318 in the TAS1R1 cDNA sequence introduces a premature stop codon. SNP population frequencies
The population frequencies of the TAS1R SNPs are summarized in Table 2.
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The majority (68.%) of the SNPs in the TAS1R genes were observed in only one population, and all of the populations studied have at least one TAS1R SNP that was unique to that population. Only about half (47%) of the population-specific SNPs were uncommon within their population, with a minor allele frequency less than 10%. Only a few SNPs were widely distributed and observed in all populations, one in TAS1R1 and two in TAS1R2.
TAS1R gene haplotypes
Haplotypes are the specific group of variant forms (alleles) present at polymorphic sites across a particular region of the genome. In humans, not all possible combinations of variant sites occur naturally. Instead, studies have shown that human genes typically exist in three to five major different haplotypes in most populations (The International HapMap Consortium, 2005). Haplotypes of the TAS1R genes are important because they determine the specific receptor proteins encoded by the different forms of these genes. We first enumerated haplotypes by evaluating individuals who were homozygous for all SNPs in each gene plus individuals who were heterozygous at one SNP, allowing explicit determination of two haplotypes. Across our entire sample, we explicitly observed a minimum of 11 haplotypes in TAS1R1, 17 haplotypes in TAS1R2, and 12 haplotypes in TAS1R3. As with the SNPs, African populations revealed the greatest haplotype diversity. Also as with the SNPs, some haplotypes were observed only within one population in our sample, although not all populations showed population-specific haplotypes.
Analysis of all genotypes using PHASE revealed 12 haplotypes in TAS1R1, 26 haplotypes in TAS1R2, and 13 haplotypes in TAS1R3 (Tables 3, 4, and 5).
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Minimum spanning trees were constructed to help visualize putative evolutionary relationships among haplotypes (Figure 1). Haplotype trees were similar for TAS1R1 and TAS1R3, which were each characterized by a single common haplotype and several rare ones (Figure 1A,C). The minimum spanning tree relating TAS1R2 haplotypes was different, characterized by a large number of rare haplotypes, with many found at similar frequencies (Figure 1B).
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Measures of genetic diversity
We performed standard measures of genetic diversity to help determine how the variation we found in the TAS1R genes compares to that found in most human genes. The mean pairwise difference between sequences, per nucleotide () was highest in TAS1R2 (2.76 nt/2520 nt = 0.110%), followed by TAS1R1 (0.86 nt/2526 nt = 0.034%) and TAS1R3 (0.62 nt/2559 nt = 0.024%). These values fall within the upper 95th and lower 5th percentiles of the distribution reported in a genome-wide analysis (Sachidanandam et al., 2001), with the value for TAS1R2 being much higher than average and the values for TAS1R1 and TAS1R3 lower than average. Another comparison with values for 3305 genes (Salisbury, 2003) revealed a similar pattern, with TAS1R2 falling in the top 10th percentile and TAS1R1 and TAS1R3 falling in the lower 40th and 25th percentiles, respectively (Figure 2). Like , S was highest in TAS1R2 (n = 18), followed by TAS1R1 (n = 17) and TAS1R3 (n = 12).
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FST values were highest in TAS1R1 (FST = 0.160), followed by TAS1R3 (FST = 0.068) and TAS1R2 (FST = 0.019). Comparisons with the distributions reported for the 3305 genes by Salisbury (2003) along with values reported for
25,000 SNPs by Akey et al. (2002) revealed that while FST in TAS1R1 was slightly higher than the average across a large number of genes, FST was slightly lower than average in TAS1R2 and TAS1R3 which fell in the bottom 35th and 20th percentiles (Figure 2). Comparisons across populations revealed that our continental samples differed substantially with respect to both nucleotide and amino acid diversity (Table 6).
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In general, the patterns of diversity in the sample as a whole were reflected in the continental subsamples. For instance, TAS1R2 was the most diverse gene both in the sample as a whole and in each subsample. Among the subsamples, Africa was the most diverse at all three loci. A preponderance of diversity in Africa is common and is generally attributed to a combination of the antiquity and substructuring of African populations (Tishkoff and Verrelli, 2003
). Interestingly, while the Native American sample was the least diverse with respect to TAS1R1 and TAS1R3, it was the second most diverse with respect to TAS1R2. The combinatorial analysis of diversity confirmed that the majority of variation in the sweet and umami receptors is accounted for by TAS1R1 and TAS1R2, as opposed to TAS1R3, which is more conserved. For example, although the Native American sample was the least diverse with respect to TAS1R3, it was the second most diverse with respect to TAS1R2 and was thus the second most diverse with respect to overall variation in the sweet receptor (TAS1R2 + TAS1R3).
Tests of evolutionary neutrality
Evolutionary genetic analysis can be used to distinguish genetic variation that has been influenced by natural selection (and thus is biologically functional) from other kinds of variations. Such analyses test for statistically significant deviation from evolutionarily neutral genetic drift. Tests of Tajima's D statistic were used to examine the hypothesis of evolutionary neutrality for the sequence variants observed in the TAS1R genes. We tested our hypotheses under several different models that account for different scenarios of population growth. The hypothesis of evolutionary neutrality of the variation in TAS1R2 was rejected under realistic assumptions about population growth. For example, under the assumption that the human population size increased 100-fold, 100,000 years ago, the hypothesis of evolutionary neutrality was strongly rejected (P > 0.99). For TAS1R1 and TAS1R3, the results were less striking but still similar. Under slightly larger magnitudes of growth (e.g., 200-fold, 100,000 years ago), the hypothesis of neutrality was rejected for TAS1R1 and TAS1R3 as well, and thus all three observed values of D were significantly greater than expected. We note, however, that the comparison of D values in these genes with values calculated for roughly 3300 genes reported by Salisbury et al. (2003) suggests that these values fall within the expected range, although the value for TAS1R2 is somewhat higher than average. We hypothesize that such general conclusions regarding evolutionary neutrality using Tajima's D measures may reflect selective sweeps that have occurred commonly in human evolutionary history, and our Tajima's D measurements may indicate that such selective sweeps have occurred in the TAS1R genes.
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Discussion |
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Our survey has revealed significant nucleotide and protein sequence diversity in the TAS1R taste receptor family. This information is important for understanding receptor function as different haplotypes encode significantly different proteins, and these protein subunits may, in turn, interact to further shape taste perception in human individuals. The different forms of TAS1R2, which encodes the sweet-specific component of the receptor, are unusually diverse compared to other human genes. These differences appear unlikely to be evolutionarily neutral, and we predict that they underlie interindividual variation in sensitivity to sweet compounds.
The site of amino acid variation in the TAS1R receptor gene family is quite dissimilar from that in the TAS2R bitter receptor gene family (Kim et al., 2005). In the TAS2R family, much of the variation occurs in the transmembrane domains, and little exists in the first extracellular domain. Conversely, the TAS1Rs carry the majority of amino acid sequence variation in their first extracellular domain. Because TAS1R receptors are thought to bind carbohydrate ligands in their large first extracellular domain while TAS2R receptors are thought to bind ligands in their transmembrane domains, we hypothesize that the amino acid sequence diversity in these receptors is related to their carbohydrate recognition and binding functions. Several structure–function studies and molecular modeling studies have suggested possible ligand-binding sites within TAS1R proteins (Nofre 2001; Jiang et al., 2004, 2005; Morini et al., 2005). For example, the binding of the artificial sweetener cyclamate to the TAS1R3 subunit requires extracellular domain 3 and/or transmembrane domain 7 of this protein (Jiang et al., 2005). Since none of the SNPs described here reside in these regions, we would predict that they would not result in differences in cyclamate perception in the population.
One important source of variation in protein structure, alternative splicing of the mRNA, has been reported for TAS1R1 (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=80835). Neither did we observe any DNA sequence variants in this gene that might account for this alternative splicing nor did we observe any variants at or near splice sites in TAS1R2 and TAS1R3.
It is not surprising that among the human TAS1R genes, TAS1R3 reveals a relatively smaller degree of diversity. This gene encodes the subunit that is common to both sweet and umami tastes and thus is likely constrained by the requirement of maintaining functional interactions with both the TAS1R1 and TAS1R2 receptor proteins. TAS1R1 is intermediate in the number of nonsynonymous SNPs and in the values of and S. TAS1R2 showed high levels of S, the pairwise differences between sequences, placing this level of variation in the top 5–10% of all human genes surveyed, depending on the study used for comparison.
The high levels of diversity observed in TAS1R2, including the presence of eight nonsynonymous nucleotide substitutions, are notable. The minimum spanning tree for this gene reveals many different haplotypes that are present at low to moderate frequency (Figure 1B). This pattern of variation, in conjunction with the rejection of evolutionary neutrality by Tajima's D test, suggests that human sweet taste perception mediated by this gene may have evolved to sense a wide variety of structurally different sweet substances.
Variation in TAS1R genes has recently been compared to variation in TAS2R genes across the phylogenetic spectrum (Shi and Zhang, 2006). This study examined a number of different evolutionary genetic parameters from those examined in our study and concluded that variation in the TAS1R gene family has been under positive natural selection. This conclusion is in agreement with our results and suggests that the variants we observe are functionally significant in taste perception.
Whatever the role of selection, the prevalence of amino acid variation in the TAS1R genes raises numerous questions about the patterns of phenotypic variance that might be associated with these variants. Although heritable interstrain differences in sweet taste sensitivity have been documented in mice (Reed et al., 2004), little is known about heritable interindividual variation of sweet sensitivity in humans. The few surveys reported to date indicate that thresholds to sugars exhibit variability in the population (Blakeslee and Salmon, 1935; Pangborn, 1970, 1981), although no systematic surveys across different racial or ethnic groups have been reported.
Our findings suggest that substantial amino acid variation is present in all three TAS1R genes. Variation in these genes is localized to domains hypothesized to be involved in ligand binding. Further, this variation is not distributed uniformly among human populations. Given our findings, we hypothesize that 1) human populations will harbor more heritable variation in sweet taste sensitivity than in umami taste sensitivity, 2) human populations will differ appreciably in heritable variation, with Africans being most diverse, and 3) TAS1R3, while less than diverse than other TAS1R genes, may be an important source of covariance in sweet and umami sensitivity by virtue of the fact that it harbors amino acid substitutions that could affect both phenotypes.
Recent studies in cats have shown that the Tas1R2 gene is a pseudogene (Li et al., 2005), consistent with the observation that this species appears to be insensitive to sweet substances. While we did not observe any variants in human TAS1R2 that resulted in stop codons, we did observe one such SNP in TAS1R1. This SNP, which converts a codon encoding tryptophan to a stop, was observed solely in African populations. The known variation in human umami taste sensitivity commonly occurs in non-African populations (Lugaz et al., 2002). So, while the stop codon in TAS1R1 is unlikely to be the cause of insensitivity to glutamate, other SNPs in this gene remain as candidates for the source of this trait in humans.
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This work was supported by National Institutes of Health (NIH)/National Institute on Deafness and Other Communication Disorders Intramural research grant Z01-000046-05 to D.D., NIH/ES 12125 to S.W., and NIH/GM 59290 and NSF/BCS 0218370 to L.B.J.
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Accepted 12 May 2006
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