Chemical Senses Vol. 29
No. 8 © Oxford University Press 2004; all rights reserved
Bitter Taste Study in a Sardinian Genetic Isolate Supports the Association of Phenylthiocarbamide Sensitivity to the TAS2R38 Bitter Receptor Gene
1 Shardna Life Sciences, Cagliari, Italy, 2 National Institute of Deafness and Other Communication Disorders, Rockville, MD, USA and 3 Institute of Population Genetics, CNR, Alghero, Italy
Correspondence to be sent to: Andrea Angius, Shardna Life Sciences, Cagliari, Piazza Deffenu 4, 09125 Cagliari, Italy. e-mail: angius{at}shardna.it
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Abstract |
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Recently, a major locus on chromosome 7q was found in association with the taste sensitivity to phenylthiocarbamide (PTC) in humans. This region contains the TAS2R38 gene that encodes a member of the TAS2R bitter taste receptor family. Three SNPs within this gene demonstrated a strong association with taster status in Utah families and in an additional sample of 85 unrelated individuals. We studied a small isolated village in eastern Sardinia and carried out a genome-wide scan to map the genetic basis of PTC perception in this population. We performed both qualitative and quantitative PTC-taste linkage analysis. Qualitative analysis was carried out by defining a cut-off from the bimodal distribution of the trait and classifying subjects as tasters and non-tasters (75 and 25%, respectively). Linkage analysis on 131 subjects belonging to a unique large multi-generation pedigree comprising 239 subjects confirmed significant evidence for linkage at 7q35 also in our population. Haplotype analyses of the three SNPs inside the PTC gene allowed us to identify only two haplotypes that were associated with the non-taster phenotype (80% AVI homozygous) and to taster phenotype (40% PAV homozygous and 56% PAV/AVI heterozygous). Sex, age and haplotype effect explained 77.2 % of the total variance in PTC sensitivity.
Key words: genetic isolates, genomewide search, haplotypes, 7q35
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsElectronic database informationReferences |
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Bitter is a well-characterized taste modality in humans and variation in this ability may influence food selection and nutritional status (Drewnowski and Rock, 1995
;
Tepper, 1998;
Keller et al., 2002). The
perception of bitter taste is mediated by G-protein coupled receptors, located in taste
cells within taste bud of the tongue (Wong et
al., 1996;
Adler et al., 2000;
Chandrashekar et al., 2000),
that interact with tastants and initiate signaling cascades that culminate in
neurotransmitter release.
Among the best-studied bitter substances are
phenylthiocarbamide (PTC) and related compounds containing the C–N=S moiety,
because of the remarkable occurrence of a differential ability to taste these substances
in human populations worldwide. The inability to taste PTC and related compounds has been
known for >70 years (Fox, 1931;
Blakeslee and Salmon, 1935). Several
studies on this trait showed an autosomal recessive transmission, but other genetic
mechanisms have also been suggested (Olson et
al., 1989;
Bartoshuk et al., 1994;
Reed et al., 1995). Genetic
linkage and gene mining studies in mice have shown the presence of three gene clusters
(Capeless et al., 1992;
Lush et al., 1995;
Blizard et al., 1999;
Adler et al., 2000;
Chandrashekar et al., 2000;
Matsunami et al., 2000) on
murine chromosomes 15 and 6, associated with the sensitivity to many bitter substances
such as cyclohexamide, sucrose octacetate, raffinose undecacetate and quinine. In humans,
Reed et al. (1999) have
identified the presence of a major locus for 6-n-propyl-2-thiouracil (PROP)
sensitivity on chromosome 5p15. Subsequently, homology studies identified the TAS2R1 gene
on 5p15.2 and 2 clusters of additional genes on human chromosomes 7 and 12 respectively,
homologous to the gene cluster present on murine chromosome 6. These genes are grouped in
a family, called TAS2R, that contains 
24 members in humans. This is consistent with
the great variety of bitter compounds and the high discriminatory capability of human
bitter receptors.
The perception of PTC is most precisely measured by
administering a series of solutions of different concentrations to determine the minimal
PTC concentration detected by an individual. The cut-off value used to separate tasters
from non-tasters has differed from study to study and a high diversity in the frequency
of these two classes has also been observed (Jones and McLachlan, 1991;
Guo et al., 1998). Recently,
a small region on chromosome 7q (2.6 Mb) (Drayna
et al., 2003) was found in association with PTC taste ability. This
region was narrowed to a 150 kb interval using the Utah CEPH families (Dausset et al., 1990) and, in this
interval,
Kim et al. (2003) identified
the gene responsible for PTC taste ability, which is the TAS2R38 bitter receptor. This
gene encodes a 7-transmembrane domain, guanine nucleotide-binding protein
(G-protein)-coupled receptor that shows 30% amino acid identity with human TAS2R7,
the most closely related member of this family. This gene contains a single coding exon
1002 base pairs in length. Three common SNPs within this gene, all of which
result in amino acid changes in the protein (A49P, V262A and I296V), demonstrated a
strong association with taster status in their Caucasian Utah sample and in a replication
sample from a multi-racial population enrolled at the National Institutes of Health
(NIH).
We have studied a small isolated village (Talana, 1200 inhabitants) in
eastern Sardinia. We reconstructed the genealogy of each inhabitant using archival data
and, identifying maternal and paternal lineages, we showed that 80% of the
present-day population descended from <20 founder couples (Angius et al., 2001). In this
genetically and culturally homogeneous population, a large proportion of individuals
presenting a given trait are likely to share the same trait-predisposing gene inherited
from a common ancestor. Furthermore, inbreeding, typical of small communities such as
Talana, reduces genetic heterogeneity and increases homozygosity, providing greater power
for detection of recessive susceptibility genes. On the other hand, increased
homozygosity expected in Talana compared to outbred populations is likely to affect only
slightly marker informativeness, as highly polymorphic microsatellite markers are used in
the linkage analysis. Previous studies in the Sardinian population have shown variation
in PTC taste sensitivity (Maxia et al.,
1975), which suggested this population may be useful for refining our
understanding of the contribution of the TAS2R38 gene to PTC taste ability.
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Materials and methods |
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To define the sensitivity to PTC in the village of Talana, we initially tested 228 random individuals using a filter paper impregnated with 1 µg of dried PTC (Lab-aids Inc.). Subjects were asked to place the paper in their mouths and to rate the bitterness of taste. Subsequently, these individuals and their relatives were submitted to refined testing based on an abbreviated version of the classic Harris–Kalmus method (Harris and Kalmus, 1958
). This test employed seven (rather than the original 14) scalar
PTC solutions, starting from the most dilute (1.04 x 10–6 M) and
rising four-fold in concentration at each step to a maximum concentration of 4.27 mM.
When a subject perceived the bitter taste, he or she was submitted to a blind sorting
test that required distinguishing PTC solutions at the perceived concentration versus
natural water in order to confirm the tasted score. All together, we tested 280 persons
in Talana and calculated age- and sex-adjusted PTC scores using the corrections of
Harris and Kalmus (1958), whose
distribution showed a typical bimodal curve (Figure
1). From the minimum node in frequency
between tasters and non-tasters in the distribution of scores, we fixed a cut-off value
of 4.5 (representing a PTC concentration of 795 µM) and classified 70 individuals
(25%) as non-taster (NT) and 210 (75%) as taster (T). Among the phenotyped
subjects, we identified 131 individuals clustering in a unique large multi-generation
pedigree comprising a total of 239 individuals. These individuals were used in the
linkage analysis.
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All individuals participating in the study signed informed consent forms and all samples were taken in accordance with the Declaration of Helsinki. Genomic DNA was extracted from 7 ml of EDTA-treated blood, as described by Ciulla et al. (1988
).
Genotyping was done by the Mammalian Genotyping Service of Marshfield Laboratory,
directed by Dr James Weber. A genome-wide scan (GWS) for linkage was performed using a
set of 376 short tandem repeat polymorphism (STRP) markers with average spacing of 9.5
cM. Mean marker heterozygosity in Talana was high (0.70), although slightly lower than in
the CEPH families (0.75). We selected additional markers from the genome databases to
better investigate the regions that produced the highest scores for linkage in the
initial GWS. STRP genotyping products were analyzed using an ABI PRISM 3100 DNA Analyzer
(Applied Biosystems, Foster City, CA). Single nucleotide polymorphism (SNP) genotyping
was done by direct DNA sequencing using the Big Dye Terminator Cycle Sequencing method
(Applied Biosystems). Primer sequence were selected according to
Kim et al. (2003). Marker
allele frequencies were estimated from the entire Talana population and the Marshfield
genetic maps were used in pairwise and multipoint linkage analysis.
In order to
confirm the locus on chromosome 7 and/or to identify additional regions associated to PTC
perception, we performed qualitative and quantitative linkage analysis across the whole
genome. Qualitative analysis was carried out under a recessive genetic model with
incomplete penetrance (90%) and a gene frequency of 0.5 estimated from prevalence
of the non-taster phenotype in the Talana population. Two-point analysis was performed
using Fastlink 4.1P (Cottingham et al.,
1993) splitting the whole pedigree into eight more tractable sub-families.
Multipoint analysis was performed with Genehunter 2.1 (Kruglyak et al., 1996) on 10 smaller families due
to computational constraints and with Simwalk2 (Sobel and Lange, 1996), which allowed us to analyze the
extended eight families, in specific suggestive regions. The main advantage of multipoint
linkage analysis is that it allows retrieval of phase information from neighbouring
markers at each location of the genome, thus increasing the probability that at least one
of these is heterozygous.
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Results |
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In the qualitative analysis, the strongest evidence for linkage (Table Table 1) was obtained on chromosome 7 with a peak two-point lod score of 3.27 and a multipoint lod of 3.10 at GATA104 (155.1 cM). Adding supplementary markers in the region yielded an increased two-point lod score of 3.33 at D7S661 and a multipoint peak of 3.50 between markers D7S2513 and D7S661 (151.25–155.1 cM), a location <1 cM from the highest lod score peak previously reported (D7S498-AFM183ya3; Drayna et al., 2003
). We did
not observe significant genetic heterogeneity in the sample of families we analyzed,
indicating that the locus on chromosome 7q accounted for all of the linkage signal
observed in this very large extended family.
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On chromosome 6 we identified an interval of 26.7 cM flanked by markers D6S942 and D6S1006 (0–26.7 cM) with multipoint lod scores >2 and a peak two-point lod score of 2.46 at marker SE30 (9.2 cM). On chromosome 17 a two-point lod score of 3.09 was obtained at marker D17S974 (22.2 cM). Additional markers typed in these regions allowed us to exclude the involvement of these loci; on chromosome 6 multipoint lod scores were <2 over the whole region, while on chromosome 17 we observed a two-point lod score of –2.58 at marker D17S1852 located at 0 cM from D17S974. Notably, no significant evidence for linkage was obtained for the loci previously identified on chromosome 5 and on chromosome 12.
In order
to capture all variation of PTC taste ability, we also performed quantitative linkage
analysis using a variance components approach with SOLAR (Almasy and Blangero, 1998) on the large multigeneration
pedigree. The maximum quantitative genome-wide lod score confirmed qualitative analysis
showing a peak multipoint lod of 4.73 between markers D7S661 and D7S3070
(155.1–163.0 cM). No other lod scores were significant (all lod < 2.0) in the
rest of the genome. We next investigated two locus inheritance running a second GWS
conditional on the QTL on 7q. No other regions showed significant linkage and the only
lod score that increased in this scan did not reach significance (two-locus lod =
1.60 at 54.4 cM on 18q12.1). This locus has not been associated with any taste perception
function. These linkage results confirm in Sardinia the previously reported locus on
chromosome 7q containing the TAS2R bitter receptor gene responsible for the PTC taste
ability.
We analyzed the entire sequence of the TAS2R gene, the three common SNPs
(A49P, V262A and I296V) inside the gene and 6 additional SNPs (rs758955, rs765007,
rs1285895, rs745162, rs1285939, rs1358304) to evaluate the extension of linkage
disequilibrium in our population. P-values of allelic association were
calculated using Markov-chain method (100 000 tables evaluated) by means of the
ARLEQUIN 2.0 program (Scheneider et al.,
2000). Linkage disequilibrium test results indicated a point of high
recombination between rs1285939 and A49P located at the 5' of the gene. Beyond
this, significant linkage disequilibrium (P-value < 0.05) was observed
between A49P and rs765007 spanning a region of 260 561 basepairs. Haplotype analysis
allowed the identification of two major extended haplotypes using the following markers
A49P, V262A, I296V, rs745162, rs1285895 and rs765007. Haplotypes AVIACT and PAVGTC
accounting for 21 and 36%, respectively, of the total sample analyzed. The
homozygotes AVIACT were present in 52.5% of non-tasters whereas the PAVGTC
homozygotes account for the 59.7% of taster subjects (Figure
2).
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Within the coding sequence, haplotype analyses of the three polymorphisms that previously demonstrated a strong association with taster status allowed us to identify only two haplotypes. Named in the order of the 3 SNPs (A49P, V262A and I296V), the AVI haplotype was associated with the non-taster phenotype (80% homozygous) and the PAV haplotype associated with the taster phenotype (40% homozygous and 56% heterozygous; Table 2). In Talana we found only three genotypes: AVI/AVI, AVI/PAV and PAV/PAV. No other haplotypes were found in our sample. Our results confirmed a model of a major recessive trait locus probably modified by other genetic factors that interact with PTC taste sensitivity. The high frequencies of AVI and PAV haplotypes in our population agreed with the frequencies found previously in other populations. The complete absence of the less frequent haplotypes (<3%) observed by Kim et al. (2003
) was
consistent with the low haplotype diversity and genetic drift typical of a founder
population. Correlation of haplotypes with PTC scores showed the presence of many AVI/AVI
homozygotes associated with low values of PTC scores, while there was a larger number of
heterozygous individuals AVI/PAV and homozygotes, PAV/PAV, among the subjects whose
scores were above the cut off value of 4.5. Furthermore, we determined the effect of PTC
haplotypes on the linkage results by including diplotypes as covariate in the
quantitative analysis. Sex, age and haplotype effect explained 77.2 % of the total
variance in PTC scores. These results help refine estimates of the fraction of variance
that this locus contributes to variation in PTC sensitivity. Previous estimates varied
widely between populations, from 55% in the Caucasian Utah population to
85% in the multi-racial National Institutes of Health population. The contribution
of haplotype alone was 75 % in this culturally and genetically homogenous
population, which suggests that the contribution of this gene to the phenotype is between
these two values, closer to the upper end of the range.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsElectronic database informationReferences |
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We have confirmed the involvement of the TAS2R38 bitter receptor gene in the PTC sensitivity in the Talana genetic isolate in Sardinia. Our maximal lod scores at this locus range exceed the critical value of three for proof of linkage under analysis as a simple recessive trait. Given previous inconsistencies in linkage results (Guo and Reed, 2001
), our results
provide the first confirmation this gene linkage in a population outside North America.
We have also shown that this gene contributes a large amount of the total variance in
this trait. The sequence conservation among the various G-protein-linked receptors in
their cytoplasmic loops strengthens the hypothesis that the A49P, V262A and I296V
variants may alter the domains that contain critical sites for proper coupling with G
proteins on the intracellular side of the plasma membrane (O'Dowd et al., 1988). We exploited the favorable characteristics of our genetic isolate that allowed us to use a relatively limited number of subjects and a rather coarse map of markers to locate the relevant gene and thus validate the feasibility of this isolated population for the study of a major recessive trait locus probably influenced by other genetic factors.
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Acknowledgements |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsElectronic database informationReferences |
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We thank Dr James L. Weber and the NHLBI Mammalian genotyping Service. We thank Dr Michael Whalen for critical comments and editorial assistance. We are very grateful to the population of Talana for their collaboration and to the municipal administrations for their logistic support.
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Electronic database information |
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Helsinki declaration: http://www.wma.net/e/policy/b3.html
Genetic maps Marshfield: http://research.marshfieldclinic.org/genetics/
The Genome Database: http://www.gdb.org
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Accepted August 5, 2004
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