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To Smell, or Not to Smell—That Is the Question: Genetic Differences Affecting Taste and Smell

Bruce Nash
DNA Learning Center (DNALC), Cold Spring Harbor Laboratory, NY

Read part 1 of this article, “Making Scents of the World: Nobel Prize-Winning Research.”

In a previous Carolina Tips® article, Dave Micklos discussed how his dog, Harley, smells much more of the world than he does. This discrepancy in smelling capabilities stems from significant differences in the human and dog repertoires of G-protein-coupled receptors (GPCRs). In fact, these differences exist not only between species but also within species. It is estimated that most humans have 2 different versions, or alleles, for around 200 of their olfactory receptor (OR) genes. This means that any 2 human beings will likely have different combinations of the OR alleles and that they perceive the world of smell differently.

For instance, due to the chemical cis-3-hexen-1-ol, the smell of fresh-cut grass is strong for individuals with an intact odorant receptor called OR2J3. Two missense mutations that change amino acids in the receptor eliminate the odor. Likewise, a missense mutation in OR5A1 eliminates the ability to smell β-ionone, a floral smell in violets and other flowers. OR mutations may be the reason why some people fail to “stop and smell the roses.”

Like smell, taste is a fundamental sense that has enormous effects on our quality of life and, until recently, our ability to survive. Most people can tell you that mammals distinguish several basic tastes: sweet, sour, bitter, and salty. Fewer know about umami, the savory taste of the amino acid monosodium glutamate (MSG). Recently, evidence has emerged regarding the ability of humans to discretely recognize fats, carbonation, and calcium. Each taste presumably helped our ancestors thrive. The ability to taste bitter compounds protects us from harmful alkaloids found in plants; sweet and fatty foods are high in energy; salts are necessary in small amounts; umami is the flavor of meat protein; and carbon dioxide is a by-product of fermentation.

The role of GPCRs in taste

GPCRs are responsible for detecting most kinds of taste compounds, and the repertoire of taste receptors differs from species to species. Genes required to sense flavors that no longer offer a selective advantage are free to mutate and lose function in animals with different diets. Many carnivores, including cats, have lost their ability to taste sweetness due to mutations that inactivate sweet taste receptor genes. Although it evolved from carnivores, the giant panda has lost its umami taste gene. With their exclusive diet of blood, vampire bats have largely lost sweet, umami, and bitter taste detection. Many whales may have lost the ability to taste anything other than salt; swallowing their food whole may have something to do with this. Genetic differences in taste receptors also affect how humans experience taste. For example, some people find saccharin bitter due to variation in taste receptors TAS2R43 and TAS2R44, while mutations in TAS1R3 affect the perceived sweetness of sucrose.

The science behind tasters and non-tasters

In 1932, working at the forerunner of Cold Spring Harbor Laboratory, Albert Blakeslee detected genetic differences in people’s ability to taste the bitter compound PTC. Differences in PTC tasting were also measured in chimpanzees as early as 1939. This suggested that humans and chimps had inherited the same tasting and non-tasting alleles from a common ancestor. The mathematical geneticist Raymond Fischer argued that selection for both alleles—called balancing selection or heterozygote advantage—had maintained both taster and non-taster alleles over millions of years of evolution.

In 2003, Dennis Drayna cloned and sequenced the TAS2R38 receptor and identified 3 mutations in the gene that strongly correlate with PTC tasting. In 2006, Stephen Wooding found that 2 different mutations in TAS2R38 reduce PTC sensitivity in chimpanzees, refuting the hypothesis that human and chimp variation had a common evolutionary origin. Even so, there is strong genetic evidence for balancing selection. Different TAS2R38 alleles are maintained at high levels in human populations throughout the world. Two of the human mutations are estimated to be a million years old, and 1 was also present in Neanderthals. Their ancient age and widespread distribution strongly suggests that tasting and non-tasting alleles have been maintained by natural selection.

But what advantages are offered by the different TAS2R38 alleles? One possibility is that they allow individuals to taste different compounds. The non-tasting alleles of many olfactory and taste receptors are caused by stop codons that produce shortened, nonfunctional receptors. However, missense mutations create the non-taster TAS2R38 alleles, which encode receptor proteins with 3 amino acid substitutions. Although these alleles may be ineffective in detecting PTC, they may bind other taste molecules. Interestingly, PTC non-tasters find bignay berries (a type of Indian wild currant) bitter, while PTC tasters don’t—suggesting that the non-taster allele can respond to a bitter compound in these berries, while the taster allele cannot.

GPCRs’ impact on cellular functions and diseases

GPCRs related to taste and smell receptors are important for many different cell-surface functions and are implicated in a number of diseases. For example, mutations in dopamine receptors are associated with attention-deficit disorder, depression, and anxiety, while mutations in adrenergic receptors are associated with obesity and asthma. Almost a third of prescription drugs target GPCRs, so it makes sense that polymorphisms in GPCRs influence drug efficacy and side effects. Mutations in the β-adrenergic receptor modulate the effects of the high blood pressure and heart attack prevention drug  propranolol—the first drug to target a GPCR. Changes to dopamine receptors affect drugs that treat schizophrenia and Parkinson’s disease. Serotonin receptor mutations affect responses to anti-depression and anxiety drugs—including Prozac® and Paxil®—and can increase the risk of side effects, such as weight gain or involuntary movements. Bitter taste is a common side effect of many drugs and is a major reason why patients fail to take some medicines. This is probably due to off-target effects, when drug molecules bind to taste receptors as well as the intended target. Research on taste receptors offers a potential solution to this problem: blocking the sensation of bitterness or “tuning” a drug to individual variations in taste.

The recent discovery that taste receptors are expressed widely and have “extrasensory” functions makes the receptors further candidates for drug development. Some bitter taste receptors are expressed in the lungs, where they open airways following inhalation of bitter compounds, suggesting new drugs for asthma and other lung diseases. Taste receptors are also expressed in the upper airway, where they help detect compounds produced during bacterial infection. Mutations in TAS2R38 are associated with increased risk of chronic sinusitis, which is probably due to defects in sensing Gram-negative bacteria. Other taste receptors recognize different bacteria. In each case, receptor binding to bacterial compounds leads to the production of antibacterial compounds called beta-defensins. Thus, patients with sinusitis may benefit from inhaling bitter substances.

As mentioned in the previous Carolina Tips® article, students can use the Carolina kit Using a Single Nucleotide Polymorphism (SNP) to Predict Bitter Tasting Ability (items #211376 through 211381) to examine a mutation in the TAS2R38 gene that predicts PTC tasting ability. Students may then contemplate the implications of genetic variation in personal taste, human evolution, and health the next time they enjoy broccoli or bignay berry pie.

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