Download Scientist finds the gene that determines major sensitivity to bitter taste

Scientist finds the gene that determines major sensitivity to bitter taste
More than 10 million American high school and college students have tested their ability
to taste, but what do they --and we-- still need to learn?
February 20, 2003
Bethesda, Maryland - For the first time, in a collaboration between the National Institutes
of Health, the University of Utah and Stanford University, scientists have identified the
gene that determines the ability to distinguish a wide class of bitter tastes according to
research published in Science, February 21, 2003. How individuals are genetically
predisposed to respond or not respond to the bitter taste of substances like nicotine and
certain foods may have broad implications for nutritional status and tobacco use.
By estimates, more than 10 million American students have been offered "taste" testing
to identify their ability to recognize or discriminate bitter taste and to introduce them to
inherited traits. In more formal research, anthropologists have tested people around the
world, over decades, for this same ability or inability to experience bitter taste.
Why are some people "tasters" and others "non-tasters" and why is it important? The
ability to taste, tested using a compound phenylthiocarbamide (PTC), is one of the best
studied inherited traits in humans. Studies over the past 70 years, have demonstrated that
taste variation is common in the U.S. population: about 30% of the population are PTC (a
prototype of a class of bitter substances) non-tasters, while 70% are tasters of PTC,
experiencing it as intensely bitter. The ability to taste PTC has been known to be
dominantly inherited.
Previous studies had demonstrated that PTC status affects dietary choices. Other earlier
investigation suggests that non-tasters may not experience the bitter taste of nicotine in
cigarettes and may be at greater risk for prolonged smoking.
Dennis Drayna, Ph.D., National Institute on Deafness and Other Communication
Disorders, NIH, project leader of the collaboration, explained,"We have identified a gene
on chromosome 7 that exists in five different forms throughout the world. One of these
forms confers a severe deficit in taste ability, while the other forms produce intermediate
to fully sensitive taste abilities. This gene codes for part of the bitter taste receptor
complex which exists in cells on the tongue. . . A study with this breadth could not have
been done without outstanding collaboration," said Drayna. Drayna conducted all the
taste testing of subjects in this study. His NIDCD collaborator, Un-kyung Kim, Ph.D.
performed molecular biological studies and gene identification studies.
At Stanford University, Neil Risch, Ph.D. provided a powerful statistical analytic strategy
and Eric Jorgenson lent his expertise in the analysis of quantitative traits. Mark Leppert,
Ph.D. a key collaborator at the University of Utah, directs the W.M. Keck Foundation /
University of Utah Genetic Reference Project (UGRP) project, which assembles
significant data about large Utah families. These families have been extensively
genetically analyzed in the past, and this data includes the results of extensive medical
testing and evaluation of family members and creates genetic informational databases.
Using information from a variety of populations and individuals with differences in their
ability to sense PTC, these investigators identified the small region on 7q that shows
strong linkage disequilibrium between SNP markers (single nucleotide polymorphisms),
and PTC sensitivity in unrelated subjects gathered at the NIH. SNPs are the DNA
sequence variations that occur when a single nucleotide (A,T,C,or G) in the genome
sequence is altered. The region on 7 q contains a single gene, the investigators are calling
PTC, that encodes a member of the known TAS2R bitter taste receptor family.
The investigators have dramatically demonstrated that the linkage disequilibrium
between SNP markers and taster status exists across unrelated individuals from across the
world. Those millions of Europeans, Asians, and individuals from other populations
around the world who are non-tasters descended from a common ancestor who emerged
from Africa far back in prehistory.
Human DNA sequences are overwhelmingly similar, with some small, but sometimes
important differences. For example, variations in DNA sequence can have a major impact
on how humans respond to disease or to factors that effect health, such as food or
tobacco. SNP analysis is an extremely powerful tool for use in population studies,
because SNPs tend to be stable across time.
These scientists identified three coding SNPs giving rise to 5 forms of the gene
worldwide. These differing forms of the gene completely explain the bimodal (taster vs.
non-tasters) distribution of taste sensitivity. This accounts for the inheritance of what has
been called genetic"taste insensitivity," and also explains 55-85% of the overall variance
in PTC sensitivity. Taster status was associated with specific forms of the gene,
demonstrating the direct influence of this gene on PTC taste sensitivity, and, further, that
variant sites interact with one another within the encoded gene product.
“This research promises to open a pathway to better understanding about what drives
certain human behaviors including those associated with smoking and eating. It is this
kind of collaboration and focused effort that will yield far-reaching benefit. This is how
basic science launches new ways to think about human behavior and its foundations,"
said James F. Battey, Jr., M.D., Ph.D., Director of the National Institute on Deafness and
Other Communication Disorders.
NIDCD is one of the institutes of the National Institutes of Health within the Department
of Health and Human Services. NIDCD supports and conducts research and research
training on the normal and disordered processes of hearing, balance, smell, taste, voice,
speech and language and provides health information, based upon scientific discovery, to
the public. For more information about NIDCD programs: www.nidcd.nih.gov
The Stanford Genetics Department, Stanford University, studies the genetic basis for
diseases and traits and to expand the application of genetic methods and analysis to other
fields through interdisciplinary research. The other collaborators on this research were the
Department of Human Genetics, University of Utah and Department of Psychiatry,
University of Utah Medical Center.
By Melissa Lee Phillips
Neuroscience for Kids Consultant
July 15, 2003
In 1931, a chemist named Arthur Fox sat at his DuPont Company lab bench, mixing a
powdered chemical. He accidentally let a bit of the powder blow into the air around him.
Fox and another scientist got some of the chemical into their mouths. Dr. Fox's colleague
exclaimed how bitter the powder tasted. Fox was surprised -- he had been much closer to
the chemical, but he tasted nothing at all. Both men tasted the chemical again. Again, Fox
said the chemical was tasteless, but his co-worker insisted it was very bitter. Fox handed
out crystals of the chemical, which were not poisonous, to his friends, family members
and fellow scientists and asked them if they tasted anything. Some people, like Fox,
tasted nothing; others found the chemical somewhat bitter or intensely bitter.
Dr. Fox's chemical, called phenylthiocarbamide (PTC), has been used widely since its
discovery to detect genetic variation in tasting abilities. Studies soon after the incident in
Fox's lab showed that there is a genetic component that influences how PTC tastes.
Scientists found that people were much more likely to find PTC bitter if other members
of their family also found it bitter. The evidence was so strong for a genetic link that PTC
tasting ability was used as evidence in paternity tests before DNA tests were available.
More than 70 years later, a single gene underlying this variation was discovered and
reported by Un-kyung Kim and colleagues from the National Institute on Deafness and
Other Communication Disorders. This was something of a surprise, because for many
years, scientists suspected that more than one -- possibly many -- genes were responsible
for PTC taste sensitivity. Geneticists argued for years about how many genes might be
responsible for this variation and where these genes might be located on our
chromosomes.
Using molecular genetics techniques with a variety of families, Kim isolated an area on
chromosome 7 that was likely to contain a gene affecting PTC tasting ability. This region,
however, also contained more than 150 other genes. Of these, nine were known to
produce proteins for bitter taste receptors on the tongue. To narrow down their search, the
researchers figured out the DNA sequences of all nine of these genes. They looked to see
if different people had different versions of the same gene for any of these, and, if so, if
any gene variations correlated with PTC sensitivity.
The researchers found a single gene for a bitter taste receptor that completely explains
different PTC tasting abilities. There are actually three versions of this gene that differ
from one another only slightly. This small difference in the gene, and in the protein that it
makes, eventually forms a tongue taste receptor that has a different shape from a
"normal" bitter taste receptor. This altered shape means that the person's receptors will
not respond to PTC and the person will not think the PTC tastes bitter. Since all people
have two copies of every gene, different combinations of the bitter taste gene (two copies
of form 1; one copy of form 1 and one of form 2; two copies of form 3; etc.) determine
whether someone finds PTC intensely bitter, somewhat bitter, or without taste at all.
Some scientists are now interested in potential health applications of genetic taste studies.
For example, people who find PTC bitter are suspected to find the taste of cigarettes
bitter, which could make strong tasters less likely to smoke. There are also possible
correlations between the ability to taste PTC and preferences for certain foods, which
could influence a person's diet. These types of correlations are very uncertain, however:
it's going to be a while before a phenylthiocarbamide gene provides an excuse for why
some of us think that broccoli is just too bitter to eat.
TEXT
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 PTC
taste sensitivity.
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). Ability to taste has been thought to be dominant. Reddy and Rao (1989)
reexamined 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.
The incidence of inability to taste PTC is much lower in blacks than in whites in North
America: 3% as compared with 30% (Allison and Blumberg, 1959). Shepard (1986)
suggested that the difference in incidence of newborn athyreotic cretinism (218700) in
the 2 races may have a basis in this difference in the PTC taste polymorphism. It has long
been proposed that a relationship of PTC nontasting to cretinism exists (e.g., Shepard,
1961). PTC is structurally similar to 6-n-propylthiouracil (PROP) and 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
athyreotic cretins are nontasters. 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.
Tepper (1998) reviewed the literature for the ability to taste PTC and PROP and the
implications for food preference and dietary habits. PROP and PTC are members of a
class of compounds known as thioureas. The compounds carry the chemical group NC=S, which is responsible for their characteristic bitter taste (Bartoshuk et al., 1994;
Drewnowski and Rock, 1995). 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, brussel 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 bittertasting 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.
MAPPING
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.
Linkage of PTC and blood group Kell (KEL; 110900), mapped to chromosome 7,
had been reported by several workers (Chautard-Freire-Maia, 1974). Crandall and
Spence (1974) tested linkage 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). Spence et al. (1984) analyzed two new sets of
data on the PTC-KEL linkage. In the original report PTC-KEL linkage, Conneally
et al. (1976) gave the maximum likelihood estimate of theta as 0.045. 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).
There was statistically significant evidence of heterogeneity among the published
studies.
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 complex trait, 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
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. Prodi et al. (2002) had reported linkage to this region in a Sardinian genetic
isolate.
MOLECULAR GENETICS
Kim et al. (2003) cloned the TAS2R38 gene (607751) and identified 3 coding
SNPs giving rise to 5 haplotypes worldwide that completely explain 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.
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 (305900) in 1956; Nacetylation 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.
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.