Individual differences in taste perception directly related to genetic variation in taste receptors

Why do brussels sprouts taste bitterly repellent to one person and bland - or even delicious - to the next?



A study published in the February 22 issue of Current Biology confirms the influential role of genetics in determining the wide range of human sensitivity to taste, ultimately impacting how we each perceive the world in a slightly different way.



"Each human carries their own distinctive set of taste receptors which gives them a unique perception of how foods and medicines taste," explains Monell Chemical Senses Center psychophysicist Paul Breslin, PhD, who shares first authorship and is a corresponding contributor for the study. "This paper shows that a single gene codes for multiple forms of a taste receptor, with each form having a differing sensitivity to taste compounds. Further, a person's perceptual sensitivity to these bitter tasting compounds corresponds strikingly well with their genetically-determined receptor sensitivity."



In the paper, researchers at the Monell Center and collaborating institutions related individual perception of the bitter-tasting compounds PTC and PROP to variation in a bitter taste receptor gene known as hTAS2R38.



The researchers cloned two forms (haplotypes) of the hTAS2R38 gene and expressed the corresponding receptors in a cell culture. The two haplotypes, known as PAV and AVI, vary with respect to amino acid substitutions encoded at certain positions on the taste receptor protein.



In the cell culture experiments, small amounts of the bitter compounds activated cells expressing the PAV form of the receptor, whereas cells expressing the AVI form were unresponsive to the same compounds. Cells expressing other haplotypes (eg PVI, AAI or AAV) had intermediate sensitivity to the bitter compounds.



Other experiments examined bitterness perception in human subjects. People with the PAV form of the hTAS2R38 gene were most sensitive to the bitter taste of PROP and PTC. Subjects homozygous for the AVI haplotype were 100 to 1000 times less sensitive to bitter taste of the two compounds, confirming the lack of response in the cell culture experiment. These data implicate the responsive PAV haplotype as a major determinant of sensitivity to the bitter taste of PROP and PTC in humans.



"These data answer a long-standing question about why humans differ in their ability to taste some bitter compounds," explains study co-author Danielle Reed, PhD, a Monell geneticist. "Now we can expand our use of this procedure to understand why people are sensitive to other types or tastes, such as sweet or umami, or other types of bitter compounds. We would then be able to test people for their innate ability or inability to taste a variety of flavors and foods." Such knowledge may someday be used to help patients consume beneficial bitter-tasting compounds, such as pharmaceuticals and health-promoting bitter-tasting plants.



The studies demonstrate that variations in a single bitter receptor gene can code for different taste receptors, each sensitive to distinct bitter taste compounds. Thus, while each human may have 25 or so bitter receptor taste genes, because each gene can code for multiple receptors with differing sensitivities, there may be hundreds of different bitter taste receptors in the human population as a whole, leading to wide individual variation in perception of bitterness.
















The existence of both bitter "tasters" and "non-tasters" has the scientists curious for more answers. Breslin comments, "From a human evolutionary perspective, we want to understand how and why both tasters and non-tasters evolved and were maintained in the gene pool." Reed continues, "Usually when we see a trait like this, there is a biological advantage to maintaining the variation. We're wondering what that could be."



Sharing first authorship of the paper with Breslin is Bernd Bufe from the German Institute of Human Nutrition (DIFE). Also contributing to the studies were Wolfgang Meyerhof and Christina Kuhn at the German Institute of Human Nutrition; Un-Kyung Kim and Dennis Drayna from the National Institute on Deafness and Other Communication Disorders at the National Institutes of Health; Jay P. Slack from the Givuadan Flavors Corporation; and Christopher D. Tharp of Monell.



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The Monell Chemical Senses Center is a nonprofit basic research institute based in Philadelphia, Pennsylvania. For 35 years, Monell has been the nation's leading research center focused on understanding the senses of smell, taste and chemical irritation: how they function and affect lives from before birth through old age. Using a multidisciplinary approach, scientists collaborate in the areas of: sensation and perception, neuroscience and molecular biology, environmental and occupational health, nutrition and appetite, health and well being, and chemical ecology and communication. For more information about Monell, please visit monell.



Contact: Paul Breslin

breslinmonell

Monell Chemical Senses Center

Nature more than nurture decides how religious we are

A study published in the current issue of Journal of Personality studied adult male monozygotic (MZ) and dizygotic (DZ)
twins to find that difference in religiousness are influenced by both genes and environment. But during the transition from
adolescence to adulthood, genetic factors increase in importance while shared environmental factors decrease. Environmental
factors (i.e. parenting and family life) influence a child's religiousness, but their effects decline with the transition
into adulthood. An analysis of self-reported religiousness showed that MZ twins maintained their religious similarity over
time, while the DZ twins became more dissimilar. "These correlations suggest low genetic and high environmental influences
when the twins were young but a larger genetic influence as the twins age" the authors state.


Participants for this study were 169 MZ and 104 DZ male twin pairs from Minnesota. Religiousness was tested using self-report
of nine items that measured the centrality of religion in their lives. The twins graded the frequency in which they partook
in religious activities such as reading scripture or other religious material and the importance of religious faith in daily
life. They also reported on their mother's, their father's, and their own religiousness when they were growing up. They were
also asked to report on the current and past religiousness of their brother. The factors were divided into subscales--
external aspects of religion, like observing religious holidays, that might be the most susceptible to environmental
influence and internal aspects, like seeking help through prayer, that might be the most susceptible to heritable influence.
The external items were found to be more environmentally and less genetically influenced during childhood, but more
genetically influenced in adulthood. The internal scale showed a similar pattern, but the genetic influences seemed to be
slightly larger in childhood compared to the external scale and so more consistent across the two ages. "Like other
personality traits, adult religiousness is heritable, and though changes in religiousness occur during development, it is
fairly stable," the authors conclude.


This article is published in the latest issue of the Journal of Personality. Media wishing to receive a PDF of this article
please contact journalnewsbos.blackwellpublishing


Journal of Personality publishes scientific investigations in the field of personality. It focuses particularly on
personality and behavior dynamics, personality development, and individual differences in the cognitive, affective, and
interpersonal domains.


Laura B. Koenig, M.A., is a graduate student in the department of Psychology at the University of Minnesota. Her research
includes investigating the environmental influences on religiousness in adoptees and the genetic and environmental
connections between religiousness, antisocial, and prosocial behavior.


Contact: Jill Yablonski

Journalnewsbos.blackwellpublishing

781-388-8448

Blackwell Publishing Ltd.

blackwellpublishing

Spread Of Breast Cancer Driven By A Genetic 'Gang Of 4'

Studies of human tumor cells implanted in mice have shown that the abnormal activation of four genes drives the spread of breast cancer to the lungs. The new studies by Howard Hughes Medical Institute researchers reveal that the aberrant genes work together to promote the growth of primary breast tumors. Cooperation among the four genes also enables cancerous cells to escape into the bloodstream and penetrate through blood vessels into lung tissues.



Although shutting off these genes individually can slow cancer growth and metastasis, the researchers found that turning off all four together had a far more dramatic effect on halting cancer growth and metastasis. Metastasis occurs when cells from a primary tumor break off and invade another organ. It is the deadliest transformation that a cancer can undergo, and therefore researchers have been looking for specific genes that propel metastasis.



In the newly published experiments, the researchers also found that they could reduce the growth and spread of human breast tumors in mice by simultaneously targeting two of the proteins produced by these genes, using drugs already on the market. The researchers are exploring clinical testing of combination therapy with the drugs - cetuximab (trade name Erbitux) and celecoxib (Celebrex) - to treat breast cancer metastasis.



The research team, led by Howard Hughes Medical Institute investigator Joan Massagu?© at the Memorial Sloan-Kettering Cancer Center, published its findings in articles in the journal Nature and in the online early edition of the Proceedings of the National Academy of Sciences.



In an earlier study, Massagu?© and his colleagues had identified 18 genes whose abnormal activity is associated with breast cancer's ability to spread to the lungs. In the new study published in Nature, Massagu?© and his colleagues at Sloan-Kettering, along with researchers from Hospital Clinic de Barcelona and the Institute for Research in Biomedecine in Spain, focused on four of these genes. These genes, which code for proteins called epiregulin, COX2, and matrix metalloproteinases 1 and 2, were already known to help regulate growth and remodeling of blood vessels, said Massagu?©.



"Our understanding of the genes for these four proteins and their behavior in metastasis led us to hypothesize that they might be cooperating with each other in a way that would give an advantage to cells in the primary tumor," said Massagu?©. "These same genes, we believed, might also be used for some related purpose in the target organ, the lung."



To test this idea, the researchers silenced various combinations of the four genes in human breast cancer cells that had metastasized to the lung, and then tested these cells in mice. To silence the four genes, the scientists used a technique called RNA interference, in which RNA molecules are tailored to suppress expression of target genes.
















"We found that depriving aggressive metastatic tumor cells of these genes decreased both their ability to grow large aggressive tumors in the mouse mammary gland and also the ability to release cells from these tumors into the circulation," said Massagu?©. "The remarkable thing was that while silencing these genes individually was effective, silencing the quartet nearly completely eliminated tumor growth and spread."



Microscopic analysis of blood vessel structure in the tumors revealed that knocking down all four genes greatly reduced growth of the tangle of blood vessels typically seen in tumors. Further experiments revealed that the tumor blood vessels that did form allowed fewer cancer cells to escape into circulation.



The researchers next explored how loss of the four abnormal genes affected the metastatic capability of the cells in the lung. They injected cells deficient in the four genes directly into the circulatory system of mice. "When these cells reached the lung capillaries, they just got stuck there," said Massagu?©. "We concluded that metastatic cells use these same genes to loosen up cells in capillaries, so that the cells can penetrate the lung tissue to grow there.



"These findings provide a beautiful explanation for how the genes that we identified in breast cancer patients as being associated with lung metastasis manipulate blood vessels to give them an advantage both in the primary tumors and in the lung," he said.



Two drugs already on the market act directly on proteins produced by the genes Massagu?©'s group had been studying. Cetuximab is an antibody that blocks the action of epiregulin and is used to treat advanced colorectal cancer. Celecoxib is an inhibitor of COX2 that is used as an anti-inflammatory, and is being tested in clinical trials against many types of cancer. The researchers also tested whether cetuximab and celecoxib would work effectively in concert to reduce metastasis in mice.



"We found that the combination of these two inhibitory drugs was effective, even though the drugs individually were not very effective," said Massagu?©. "This really nailed the case that if we can inactivate these genes in concert, it will affect metastasis," he said.



Massagu?© said that while clinical trials of the drug combination are being discussed, "there are already treatments to diminish the chance of metastasis in breast cancer, so such trials would have to be designed very carefully to understand how and whether the new drug combination would be of additional benefit." In the article published in the Proceedings of the National Academy of Sciences, Massagu?© and his colleagues explored how the entire group of 18 genes, called the 'lung metastasis gene-expression signature' (LMS) influenced both breast tumor growth and spread to the lungs. Co-authors on the paper were from the University of Chicago, The Netherlands Cancer Institute, Veridex L.L.C., The Cleveland Clinic and the Erasmus Medical Center in The Netherlands.



"There has been an undeniable link between tumor size and growth and metastatic risk, but the molecules and mechanisms underlying this link have remained unresolved," said Massagu?©. "The hypothesis we wanted to test was that these signature genes play a role in both primary tumor growth and metastasis to the lung."



After analyzing 738 human breast cancer tumors, the researchers concluded that those in which the LMS genes were abnormally active were, indeed, more likely to develop lung metastases. They also found that the activity of these LMS genes gave cancer cells a growth advantage by allowing tumors to develop a rich network of blood vessels to deliver oxygen and nutrients, said Massagu?©.



Although large tumors are more likely to metastasize, Massagu?© said his group's findings indicated that the activity of the LMS genes was also critical to the metastasis process. "As the tumors grow and become enriched with LMS-positive cells, because the genes give them an advantage, they reach a point where the tumor becomes richly vascularized," said Massagu?©. "Then, they can massively execute the advantage the LMS genes provide them to metastasize to the lung."



Massagu?© said he and his colleagues will explore in more detail the function of other LMS genes, in addition to the four reported in the Nature paper. They plan to investigate whether shutting down other LMS genes will affect metastasis of breast cancer to the lung, and whether the LMS genes influence breast cancer metastasis to other sites, such as the bone and brain. Finally, they will explore whether the LMS genes play a corresponding role in metastasis of other cancers -- such as sarcoma, melanoma and colon cancer -- to the lung, said Massagu?©.






Contact: Jim Keeley


Howard Hughes Medical Institute



View drug information on Erbitux.

Key Nerve Navigation Pathway Identified

Newly launched nerve cells in a growing embryo must chart their course to distant destinations, and many of the means they use to navigate have yet to surface. In a study published in the current issue of the journal Neuron, scientists at the Salk Institute for Biological Studies have recovered a key signal that guides motor neurons -- the nascent cells that extend from the spinal cord and must find their way down the length of limbs such as arms, wings and legs.



The Salk study, led by Samuel Pfaff, Ph.D, a professor in the Gene Expression Laboratory, identifies a mutation they christened Magellan, after the Portuguese mariner whose ship Victoria was first to circumnavigate the globe. The Magellan mutation occurs in a gene that normally pilots motor neurons on the correct course employing a newly discovered mechanism, their results demonstrate.



In the mutants, growing neurons can be seen leaving the spinal cord normally but then appear to lose direction. The elongating cells develop "kinks" and sometimes fold back on themselves or become entwined in a spiral, forming coils outside the spinal cord. "They appear to become lost in a traffic roundabout," described Pfaff, who observed the growing neurons with fluorescent technology.



Understanding how motor neurons reach the appropriate targets is necessary for the implementation of novel therapies, including embryonic stem cell replacement for the treatment of presently incurable disorders such as Lou Gehrig's disease, in which motor neurons undergo irreversible decay.



"Embryonic studies provide useful insights on how to replicate the system in an adult," said Pfaff. And, as he also pointed out, the mechanisms used by motor neurons are likely to be similar to those used in other parts of the central nervous system, such as the brain. The Magellan mutation discovered by Pfaff's group was found in mice, but the affected gene, called Phr1, has also been identified in other model systems, including fruit flies and the worm species C. elegans.



A growing nerve bears at its bow a structure called the growth cone, a region rich in the receptor molecules whose job is to receive cues from the environment, much as ancient mariners who observed the stars and set their course accordingly. During development, the growth cone continuously pushes forward, while the lengthening neuron behind it matures into the part of the cell called the axon. Once the growing cell "lands" at its target in a muscle cell, it is the axon that will relay the messages that allow an animal to control and move its limbs at will.



In Magellan mutants, Pfaff's team discovered that the growth cone becomes disordered. Rather than forming a distinct "cap" on the developing neuron, the cone is dispersed in pieces along both the forward end and the axon extending behind it.
















"The defect is found in the structure of the neuron itself," said Pfaff, noting that the fundamental pieces, such as the receptors capable of reading cues, all seem to be present. Without the correct orientation of receptors, however, signals cannot be read accurately, resulting in growth going off course.



"A precise gradient normally exists across the cone," said Pfaff, "which is disrupted in the Magellan mutants." As a result, cells lose their polarity. They literally do not know the front end from the back end, according to Pfaff. This sense of polarity is a universal feature common to all growing neurons. Therefore, "Phr1 is likely to play a role in most growing neurons to ensure their structure is retained at the same time they are growing larger," he said.



Pfaff and his group identified Magellan using a novel system they had developed, in which individual motor neurons and axons can be visualized fluorescently. They were able to screen more than a quarter of a million mutations, and the mutations of interest were rapidly mapped to known genes as a result of the availability of the sequenced mouse genome -- a byproduct of the effort to sequence entire genomes such as that in the human.



The Magellan mutation is located in a gene known as Phr1, which is also active in other parts of the nervous system, indicating that it most likely functions to steer other types of neurons, such as those that enervate sensory organs or connect different regions of the brain. Studies of Magellan may therefore shed light on how a variety of neurological disorders might be treated with cell replacement strategies.







Lead author on the study is Joseph W. Lewcock, formerly a postdoctoral fellow in Pfaff's laboratory and currently at Genentech, Inc. Additional Salk authors include postdoctoral fellow Nicolas Genoud and senior research assistant Karen Lettieri.



The study, titled "The ubiquitin ligase Phr1 regulates axon outgrowth through modulation of microtubule dynamics," was supported by the National Institute for Neurological Disorders and Stroke.



The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.



Source: Gina Kirchweger


Salk Institute

Genetic Risk Factors Identified For Sudden Cardiac Death

Building on these findings, the Helmholtz scientists and their clinical partners want to obtain further insights into the pathogenesic mechanisms of the disease and gain perspectives for early diagnosis and therapy. The results of the genome-wide study have been published online in the journal Nature Genetics.



Together with scientists of the international research consortium QTSCD (QT Interval and Sudden Cardiac Death), Dr. Arne Pfeufer of the Institute of human Genetics at Helmholtz Zentrum M??nchen has identified 10 gene variants which predispose to an elevated risk for arrhythmias and SCD. In interaction with other, still undiscovered factors, these gene variants influence heart repolarization and raise or lower the risk of cardiac arrhythmias. In their study, the scientists examined the electrocardiograms of more than 15,000 persons from Germany, Italy and the U.S.



"The results of a second science consortium, QTGEN, were nearly identical to our findings," said Pfeufer. This provides assurance for the scientists involved in the study - the Munich research team led by Professor Thomas Meitinger, institute director at Helmholtz Zentrum M??nchen and holder of the chair in human genetics at the Technische Universit?¤t M??nchen (TUM) and Assistant Professor Stefan K?¤?¤b, MD, senior physician at the University Hospital of Munich, Campus Grosshadern, along with their German, Italian and American colleagues - that their approach was correct and that the findings are absolutely reliable.



"For clinicians, an important indicator for increased arrhythmia risk is the QT interval in the ECG," Stefan K?¤?¤b explained. The QT interval describes the time span needed to send the electrical impulse into the heart ventricles and then to recharge. A prolonged QT interval can - depending on the underlying disease - increase the risk of arrhythmias and SCD up to five-fold.



The scientists were not looking for rare variants carried by only a few people. Rather, they were particularly interested in common gene variants, which in each person can influence the length of the QT interval. They do not increase the personal disease risk as single genes, but rather in combination of genetic factors and in context with other risk factors such as medications or ischemia.



"We view this form of genome-wide search for common gene variants associated with widespread diseases as a very promising approach for making discoveries in totally uncharted territory," said Thomas Meitinger, describing the method. "In contrast to the study of single genes, this genome-wide approach offers entirely new starting points for the investigation of common diseases such as sudden cardiac death."



The provision of highly valid population-based data of test persons from the KORA study platform headed by Professor H.-Erich Wichmann, director of the Institute of Epidemiology at Helmholtz Zentrum M??nchen, formed an essential basis for the successful realization of the research project.
















The QTSCD study arose from long-standing close collaboration between human geneticists, cardiologists, epidemiologists and informaticians of Helmholtz Zentrum M??nchen, the university hospital Klinikum rechts der Isar of the Technische Universit?¤t M??nchen and the university hospital of Ludwig Maximilian University (LMU), Campus Grosshadern. Other partners of Helmholtz Zentrum M??nchen in the QTSCD consortium were the scientists of the Heinz Nixdorf RECALL Study in Essen and the research center Life & Brain of the University of Bonn. Professor Aravinda Chakravarti of John Hopkins University in Baltimore was director of the project.



In a next step, follow-up studies shall confirm the connection between the new gene variants and sudden cardiac death. "We want to collect and evaluate further data on the respective individual genetic risk for arrhythmias in a large number of patients," Dr. K?¤?¤b said. The common objective of the Helmholtz scientists and their clinical partners through these studies is to gain further insights into pathogenetic mechanisms and thus gain perspectives for improved risk prediction and more successful therapy.



Notes:



In Germany the research project was funded by Germany's Federal Ministry for Education and Research (BMBF) within the framework of the National Genome Research Network (NGFN). Funds were also provided by the Excellence Initiative of Ludwig Maximilian University Munich and the French Fondation Leducq to combat cardiovascular disease.



The Institute of Human Genetics at Helmholtz Zentrum M??nchen (Director: Professor Thomas Meitinger, PhD) is concerned with the identification of disease genes and the characterization of their functions. The focus of the research projects is on genome-wide DNA and RNA studies to elucidate the genetic causes of complex diseases, particularly in the fields of neurology and cardiology. Another focus is the systemic analysis of the interaction of genetic variance and environmental factors, using proteomic methods.



The Institute of Epidemiology at Helmholtz Zentrum M??nchen (Director: Professor H.-Erich Wichmann, MD, PhD) is concerned with methodological problems of quantifying small risks, with the effect of particles and airborne pollutants on the lung and the cardiovascular system as well as the regional distribution and development of respiratory diseases and allergies. A new focus of the Institute is the molecular analysis of complex diseases (e.g. asthma, type 2 diabetes, myocardial infarction). The central objective is to investigate the role of environmental influences and genetic disposition on human health, using epidemiological methods.



KORA (Cooperative Health Research in the Region of Augsburg) is an investigation platform for population-based health research in the fields of epidemiology, health economics, and health care. KORA is a network of surveys representative for the population and follow-up studies building on these. The unique feature of this platform is the broad participation of external partners in the planning, implementation and financing of individual projects.



Helmholtz Zentrum M??nchen is the German Research Center for Environmental Health. As leading center oriented toward Environmental Health, it focuses on chronic and complex diseases which develop from the interaction of environmental factors and individual genetic disposition. Helmholtz Zentrum M??nchen has around 1680 staff members. The head office of the center is located in Neuherberg to the north of Munich on a 50-hectare research campus. Helmholtz Zentrum M??nchen belongs to the Helmholtz Association, Germany's largest research organization, a community of 15 scientific-technical and medical-biological research centers with a total of 26,500 staff members.



Original Publications:



QTCSD

Pfeufer, A. et al: Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nature Genetics online - Publication March 22, 2009 (DOI 10.1038/ng.362)



QTGEN

Newton-Cheh, C. et al. Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat. Genet. Advance online publication March 22, 2009 (DOI: 10.1038/ng.361



Source: Sven Winkler


Helmholtz Zentrum M??nchen - German Research Center for Environmental Health