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= Final Draft = The Genetic Basis and Evolution of the Bitter Taste Ability One of the most dynamic evolutionary adaptations to arise in multiple species has been the development of bitter taste receptors. This phenomenon has been widely studied in the field of evolutionary biology because of its role in the identification of toxins often found on the leaves of inedible plants. A palette more sensitive to these bitter tastes would, theoretically, has an advantage over members of the population less sensitive to these poisonous substances because they would be much less likely to ingest toxic plants. Bitter taste genes have been found in a variety of species, and the same genes have been well characterized in several common laboratory animals such as primates and mice, as well as in humans. The primary gene responsible for encoding this ability in humans is the TAS2R gene family which contains 25 functional loci as well as 11 pseudogenes. The development of this gene has been well characterized, with proof that the ability evolved before the human migration out of Africa (Risso et al., 2014). The gene continues to evolve, for better or for worse, in the present day. The primary selective adaptation that arises from bitter taste is to detect poisonous compounds, as most poisonous compounds in nature are bitter. However, this trait is not exclusively positive, as bitter compounds exist in nature that are not poisonous. Exclusive rejection of these compounds would in fact be a negative trait, as it would make it more difficulty to find food. Toxic and bitter compounds do, however, exist in different diets at different frequencies. Sensitivities to bitter compounds should follow the requirements of different diets logically, as species that can afford to reject plants due to their low plant diet (carnivores) have a higher sensitivity to bitter compounds than those that exclusively ingest plants. Exposure to the bitter marker quinine hydrochloride supported this fact, as the sensitivities to bitter compounds were highest in carnivores, followed by omnivores, then grazers and browsers (Glendinning, 1994). This identifies toxic plants as the primary selective force for bitter taste. This phenomenon is confirmed with genetic analysis. One measure of positive selection is the ratio of synonymous to non-synonymous mutations at certain gene loci. If the rate of synonymous mutation is higher than the rate of non-synonymous mutation, then the trait created by the non-synonymous mutation is being selected for relative to the neutral synonymous mutations. For the bitter taste gene family, TAS2R, this ratio is over one in the loci responsible for the extracellular binding domains of the receptors (Shi et al., 2003). This indicates that the part of the receptor responsible for binding the bitter ligands is under positive selective pressure. The bitter taste receptor family, T2R (TAS2R), is encoded on two chromosomes, 7 and 12. Genes on the same chromosome have shown remarkable similarity with each other, suggesting that the primary mutagenic forces in evolution of TAS2R are duplication events (Fischer et al., 2004). These events have occurred in at least 7 primate species: chimpanzee, bonobo, human, gorilla, orangutan, rhesus, and baboon (Fischer et al., 2004). The high variety among primate and rodent populations additionally suggests that, while selective constraint on these genes certainly exists, its effect is rather low. Members of the T2R family encode alpha subunits of G protein coupled receptors, which are involved in intracellular taste transduction, not only on the taste buds but also in the pancreas and gastrointestinal tract. The mechanism of transduction is shown by exposure of the endocrine and gastrointestinal cells containing the receptors to bitter compounds, most famously phenylthiocarbamide (PTC). Exposure to PTC causes an intracellular cascade as evidenced by a large and rapid increase in intracellular calcium ions (Wu et al., 2002). TAS2R homologues have been found in a variety of species, including mice, rats, chickens, and zebrafish. The most widely studied population, primates, has shown a great deal of gene conservation in both functional genes and pseudogenes. While there are 25 functional TAS2R genes and 11 pseudogenes in humans, there are 33 functional and 3 pseudogenes in mice. Additionally, zebrafish and chickens have three and four loci, respectively. The similarity among these genes shows an orthology, or distant common ancestor, among the species. The variety in the number of functional genes and the presence of the pseudogenes shows a differential selective constraint on the various populations of fish, birds, and mammals. Even the closely related primate species show these differences as well, as the proportion of pseudogene to functional gene is 29% in humans, as opposed to a range of 15% to 28% for apes and monkeys, though this range is relatively small. (Risso et al., 2014). This would suggest, despite the presence of a distant common ancestor in all of these organisms, that the different environments have caused divergence in their pseudogenes. In addition to evidence of a common ancestor being responsible for the presence of TAS2R in many species, it is also notable that more recent events have caused convergent evolution among species. The locus for the receptor variant that binds PTC in humans, TAS2R38, also exists in chimpanzees with the same function. The alleles at this locus in humans, however, do not exist in chimpanzees, and the alleles in chimpanzees do not exist in humans (Wooding et al., 2006). It can be concluded from the shared function derived from a different genetic structure that the ability to taste PTC arose independently in chimpanzees and humans, and thus is an example of convergent evolution. The pseudogenes mentioned earlier are produced by a number of gene silencing events, the rate of which is constant throughout primate species. Several of these pseudogenes do maintain a role in modulating taste response, however. By studying the silencing events in humans, it is possible to theorize the selective pressures on humans throughout their evolutionary history. As is the case with the usual distribution of human genetic variation, the highest rate of diversity in TAS2R pseudogenes was often found in African populations. This was not the case with two pseudogene loci: TAS2R6P and TAS2R18P, where the highest diversity was found in non-African populations. This suggests that the functional versions of these genes arose before the human migration out of Africa into an area where selective constraint did not remove nonfunctional versions of these gene loci. This allowed the pseudogene frequency to increase, creating genetic variance at those loci (Risso et al., 2013). This is an example of relaxed environmental constraint allowing silencing mutations to lead to pseudogenization of once important loci. The gene locus, TAS2R16, also tells a story about bitter taste evolution. Varying rates of positive selection in different areas of the world give an indication of the selective pressures and events in those areas. At this locus, the 172Asn allele is the most common, especially in areas of Eurasia and in pygmy tribes in Africa, where it is nearly fixed. This suggests that the gene has had a relaxed selective constraint in most areas of Africa in comparison to Eurasia. This has been attributed to the increased knowledge of toxic plants in the area that arose around 10,000 years ago. The increased frequency of 172Asn in Eurasia suggests that the migration out of Africa into areas with different climates and foliage rendered the knowledge of toxic plants in Africa useless, forcing the populations to rely once again on the 172Asn allele, causing higher rates of positive selection. The high rate of 172Asn in Pygmy populations is more difficult to explain. The effective population size of these isolated populations is quite small, indicating that genetic drift explained by the founder effect is the cause of these atypically high rates (Li et al., 2011). The different environments that have contained humans have placed different levels of selection on the population, forcing a wide variety in at the TAS2R loci across humanity. Neutral evolution in the bitter taste trait in humans is well documented by evolutionary biologists. In all human populations there have been high rates of synonymous and non-synonymous substitutions that cause pseudogenization. These events cause alleles that are present to this day because of relaxed selective constrain by the environment. It is interesting to note that the genes under neutral evolution in humans are very similar to several genes in chimpanzees in both their synonymous and non-synonymous mutation rates, suggesting that relaxed selective constraint started before the divergence of the two species (Wang, Thomas, and Zhang, 2004). The cause of this relaxed constraint was primarily in lifestyle changes in hominids. Roughly two million years ago, the hominid diet shifted from a primarily vegetarian diet to an increasingly meat based diet. This led to a reduction in the amount of toxic foods regularly encountered our early ancestors. Additionally, the use of fire began around 800,000 years ago, which further detoxified food and led to a decreased dependence on TAS2R to detect poisonous food. Evolutionary biologists have theorized how, with fire being an exclusively human tool, relaxed selective constraint has been found in chimpanzees as well. Meat does account for about 15% of the chimpanzee diet, with much of the other 85% being made up of ripe fruits, which very rarely contains toxins. This comes in contrast to other primates whose diets are entirely composed of leaves, unripe fruits, and bark, which have comparatively high levels of toxins (Wang, Thomas, and Zhang, 2004). The differences in diets between chimpanzees and other primates accounts for the differential levels of selective constraint. Relaxed selective constraint has a few interesting implications for humans. One is that the loss of certain alleles would not decrease our evolutional fitness, making such losses possible, causing a decrease in bitter taste sensitivity across time. Another is that supported nonsynonymous mutations would create alleles that segregate in the population, creating a high variability in bitter sensitivity between individuals. Finally, mutations could create new alleles that bind to different tastants, creating tastes that have not yet been experienced. It is important to note that in evolutionary terms, this relaxed constraint is rather recent, so any significant changes would most likely have yet to occur (Wang, Thomas, and Zhang, 2004). While one would usually associate relaxed constraint with a gradual decline in ability, it also has the effect of allowing variety to be introduced into the population, which could have very interesting and exciting consequences. The ability to taste bitter compounds is well studied in the field of evolutionary biology because of its well defined role in detecting poisons. It is an interesting case study, as the history of the genetics of the bitter taste receptor family, TAS2R, contains a wide variety of evolutionary phenomena: positive selection, neutral evolution, genetic drift, the founder effect, environmental constraint, mutation, gene silencing, orthology, paralogy, and homology. The development of this trait is an outstanding example of many forces in the field of evolutionary biology. References Fischer, et al. 2004. Evolution of Bitter Taste Receptors in Humans and Apes. Molecular Biology and Evolution. 22:432-436. Glendinning, J. 1994. Is the bitter rejection response always adaptive? Physiology and Behavior, 56:1217-1222. Li, et al. 2011. Selection on the human bitter taste gene, TAS2R16, in Eurasian populations. Human Biology. 83:363-377. Risso, et al. 2014. Genetic variation in taste receptor pseudogenes provides evidence for a          dynamic role in human evolution. BMC Evolutionary Biology. 14:1-23. Shi, P., Zhang, J., Yang, H., and Y. Zhang. 2003. Adaptive diversification of bitter taste receptor genes in mammalian evolution. Molecular Biological Evolution. 20:805-814. Wang, X., Thomas, S., and J. Zhang. 2004. Relaxation of selective constraint and loss of function in the evolution of human bitter taste receptor genes. Human Molecular Genetics. 13: 2671-2678. Wooding et al. 2006. Independent evolution of bitter taste sensitivity in humans in chimpanzees. Nature. 440:930-934. Wu et al. 2001. Expression of bitter taste receptors of the T2R family in the gastrointestinal tract and enterendocrine STC-1 cells. Proceedings of the National Academy of Sciences of the United States of America. 99:2392-2397.

Wikipedia Contribution
I created the article "Bitter Taste Evolution," which can be found here: https://en.wikipedia.org/wiki/Bitter_Taste_Evolution. The text is as follows:

=Bitter Taste Evolution= One of the most dynamic evolutionary adaptations to arise in multiple species has been the development of bitter taste receptors. This phenomenon has been widely studied in the field of evolutionary biology because of its role in the identification of toxins often found on the leaves of inedible plants. A palette more sensitive to these bitter tastes would, theoretically, has an advantage over members of the population less sensitive to these poisonous substances because they would be much less likely to ingest toxic plants. Bitter taste genes have been found in a variety of species, and the same genes have been well characterized in several common laboratory animals such as primates and mice, as well as in humans. The primary gene responsible for encoding this ability in humans is the TAS2R gene family which contains 25 functional loci as well as 11 pseudogenes. The development of this gene has been well characterized, with proof that the ability evolved before the human migration out of Africa. The gene continues to evolve, for better or for worse, in the present day.

TAS2R
The bitter taste receptor family, T2R (TAS2R), is encoded on two chromosomes, 7 and 12. Genes on the same chromosome have shown remarkable similarity with each other, suggesting that the primary mutagenic forces in evolution of TAS2R are duplication events. These events have occurred in at least 7 primate species: chimpanzee, bonobo, human, gorilla, orangutan, rhesus, and baboon. The high variety among primate and rodent populations additionally suggests that, while selective constraint on these genes certainly exists, its effect is rather low. Members of the T2R family encode alpha subunits of G protein coupled receptors, which are involved in intracellular taste transduction, not only on the taste buds but also in the pancreas and gastrointestinal tract. The mechanism of transduction is shown by exposure of the endocrine and gastrointestinal cells containing the receptors to bitter compounds, most famously phenylthiocarbamide (PTC). Exposure to PTC causes an intracellular cascade as evidenced by a large and rapid increase in intracellular calcium ions.

Toxins as the Primary Selective Force
The primary selective adaptation that arises from bitter taste is to detect poisonous compounds, as most poisonous compounds in nature are bitter. However, this trait is not exclusively positive, as bitter compounds exist in nature that are not poisonous. Exclusive rejection of these compounds would in fact be a negative trait, as it would make it more difficulty to find food. Toxic and bitter compounds do, however, exist in different diets at different frequencies. Sensitivities to bitter compounds should follow the requirements of different diets logically, as species that can afford to reject plants due to their low plant diet (carnivores) have a higher sensitivity to bitter compounds than those that exclusively ingest plants. Exposure to the bitter marker quinine hydrochloride supported this fact, as the sensitivities to bitter compounds were highest in carnivores, followed by omnivores, then grazers and browsers. This identifies toxic plants as the primary selective force for bitter taste. This phenomenon is confirmed with genetic analysis. One measure of positive selection is the ratio of synonymous to non-synonymous mutations at certain gene loci. If the rate of synonymous mutation is higher than the rate of non-synonymous mutation, then the trait created by the non-synonymous mutation is being selected for relative to the neutral synonymous mutations. For the bitter taste gene family, TAS2R, this ratio is over one in the loci responsible for the extracellular binding domains of the receptors. This indicates that the part of the receptor responsible for binding the bitter ligands is under positive selective pressure.

TAS2R Development in Human History
The pseudogenes mentioned earlier are produced by a number of gene silencing events, the rate of which is constant throughout primate species. Several of these pseudogenes do maintain a role in modulating taste response, however. By studying the silencing events in humans, it is possible to theorize the selective pressures on humans throughout their evolutionary history. As is the case with the usual distribution of human genetic variation, the highest rate of diversity in TAS2R pseudogenes was often found in African populations. This was not the case with two pseudogene loci: TAS2R6P and TAS2R18P, where the highest diversity was found in non-African populations. This suggests that the functional versions of these genes arose before the human migration out of Africa into an area where selective constraint did not remove nonfunctional versions of these gene loci. This allowed the pseudogene frequency to increase, creating genetic variance at those loci. This is an example of relaxed environmental constraint allowing silencing mutations to lead to pseudogenization of once important loci. The gene locus, TAS2R16, also tells a story about bitter taste evolution. Varying rates of positive selection in different areas of the world give an indication of the selective pressures and events in those areas. At this locus, the 172Asn allele is the most common, especially in areas of Eurasia and in pygmy tribes in Africa, where it is nearly fixed. This suggests that the gene has had a relaxed selective constraint in most areas of Africa in comparison to Eurasia. This has been attributed to the increased knowledge of toxic plants in the area that arose around 10,000 years ago. The increased frequency of 172Asn in Eurasia suggests that the migration out of Africa into areas with different climates and foliage rendered the knowledge of toxic plants in Africa useless, forcing the populations to rely once again on the 172Asn allele, causing higher rates of positive selection. The high rate of 172Asn in Pygmy populations is more difficult to explain. The effective population size of these isolated populations is quite small, indicating that genetic drift explained by the founder effect is the cause of these atypically high rates. The different environments that have contained humans have placed different levels of selection on the population, forcing a wide variety in at the TAS2R loci across humanity.

Relaxed Constraint
Neutral evolution in the bitter taste trait in humans is well documented by evolutionary biologists. In all human populations there have been high rates of synonymous and non-synonymous substitutions that cause pseudogenization. These events cause alleles that are present to this day because of relaxed selective constrain by the environment. It is interesting to note that the genes under neutral evolution in humans are very similar to several genes in chimpanzees in both their synonymous and non-synonymous mutation rates, suggesting that relaxed selective constraint started before the divergence of the two species. The cause of this relaxed constraint was primarily in lifestyle changes in hominids. Roughly two million years ago, the hominid diet shifted from a primarily vegetarian diet to an increasingly meat based diet. This led to a reduction in the amount of toxic foods regularly encountered by humanity’s early ancestors. Additionally, the use of fire began around 800,000 years ago, which further detoxified food and led to a decreased dependence on TAS2R to detect poisonous food. Evolutionary biologists have theorized how, with fire being an exclusively human tool, relaxed selective constraint has been found in chimpanzees as well. Meat does account for about 15% of the chimpanzee diet, with much of the other 85% being made up of ripe fruits, which very rarely contains toxins. This comes in contrast to other primates whose diets are entirely composed of leaves, unripe fruits, and bark, which have comparatively high levels of toxins. The differences in diets between chimpanzees and other primates accounts for the differential levels of selective constraint. Relaxed selective constraint has a few interesting implications for humans. One is that the loss of certain alleles would not decrease our evolutional fitness, making such losses possible, causing a decrease in bitter taste sensitivity across time. Another is that supported nonsynonymous mutations would create alleles that segregate in the population, creating a high variability in bitter sensitivity between individuals. Finally, mutations could create new alleles that bind to different tastants, creating tastes that have not yet been experienced. It is important to note that in evolutionary terms, this relaxed constraint is rather recent, so any significant changes would most likely have yet to occur.

= Suggestions, added sentence, and citation =

This area could be improved with more elaboration on the evolutionary aspect of bitterness. Here are three areas of information that could improve that aspect:

1. Information on convergent evolution in different species towards sensitivity to the bitter compound, PTC. Specifically, the article " Independent Evolution Of Bitter-taste Sensitivity In Humans And Chimpanzees" by Wooding, et al. speaks about these separate phenomena in chimps and humans.

2. A focus on the expression of the TAS2R gene, rather than its presence in organisms sensitive to bitter compounds, could provide more information on the evolutionary forces on TAS2R. Specifically, T2R receptors are found in the enteroendocrine cell line, STC-1 which uses a calcium related signalling pathway.

3. A fact of note is that human changes in diet, avoidance of toxins, and use of fire has led to relaxed constraint in the evolution of bitter taste. This has led to continued negative evolution that has caused a reduced sensory capacity in humans when compared to other species.

Furthermore, the use of fire, changes in diet, and avoidance of toxins has led to neutral evolution in human bitter sensitivity. This has allowed several loss of function mutations that has led to a reduced sensory capacity towards bitterness in humans when compared to other species.

= Topic and Annotated Bibliography =

Topic: Bitter Taste Evolution in Mammals

Fischer, A. (2004). Evolution of Bitter Taste Receptors in Humans and Apes. Molecular Biology and Evolution, 3(22), 432-436. Retrieved September 14, 2014, from oxfordjournals.org

This article elaborates on the genetic diversity in the full range of taste receptor genes in primates and mice. More specifically, it speaks about the number of functional and pseudogenes in the different species. Additionally, lineage specific expansions and limited selective constraint are described by the article.

Shi, P. (2003). Adaptive Diversification of Bitter Taste Receptor Genes in Mammalian Evolution. Molecular Biology and Evolution, 5(20), 805-814. Retrieved September 14, 2014, from oxfordjournals.org

This article recognizes the role of the T2R gene in bitter taste evolution in mammals, more specifically in humans and mice. It identifies tandem gene duplication and increased as the main source of genetic diversity in creating new T2R genes. The T2R gene has a role in identifying poisonous substances by their bitterness and thus is positively selected for in the environment.

Wang, X. (2004). Relaxation Of Selective Constraint And Loss Of Function In The Evolution Of Human Bitter Taste Receptor Genes. Human Molecular Genetics, 13(21), 2671-2678. Retrieved September 14, 2014, from oxfordjournals.org

Wang identifies variables that have led to a relaxation of selective restraint in the TAS2R bitter taste genes in humans. Changes in diet, toxin avoidance, and use of fire have led to neutral evolution in the bitter taste of humans as shown by a number of genetic markers. This, in combination with a large number of loss of function mutations in olfactory and vision genes have led to reduced sensory capacity in humans in comparison to other species.

Wooding, S., Bufe, B., Grassi, C., Howard, M., Stone, A., Vazquez, M., ... Bamshad, M. (2006). Independent Evolution Of Bitter-taste Sensitivity In Humans And Chimpanzees. Nature, (440), 930-934. Retrieved September 14, 2014, from www.nature.com

This article expounds on the similarity between human and chimpanzee bitter sensitivity to the compound PTC. In contrast to previous research, this article shows that bitter taste in chimpanzees is controlled by two alleles of the TAS2R38 gene that are not present in humans. Rather than a shared balanced polymorphism, the diversity in chimps is created by a mutation in the start codon of the gene resulting in the use of a downstream start codon. This research shows convergent evolution in the two species from two different genetic sources.

Wu, S. (2002). Expression of bitter taste receptors of the T2R family in the gastrointestinal tract and enteroendocrine STC-1 cells. Proceedings of the National Academy of Sciences, 99(4), 2392-2397. Retrieved September 14, 2014, from pnas.org

In contrast to the other cited articles about the T2R gene, this article expounds on the expression of the gene, as opposed to its diversity in other species. T2R receptors are found in STC-1 cells, an enteroendocrine cell line. Function of the cells are also elaborated on, as exposure to bitter compounds lead to a release of intracellular Ca2+, most likely as part of a signalling pathway.