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Coevolution of Tetrodotoxin Resistance in Garter Snakes and the Toxicity of Newts                     (Brittany Nguyen: Tuesday 8:00) As one species begins to adapt to certain aspects of their environment, other species in the surrounding habitat also have to evolve to some extent. This evolutionary phenomenon is generally known as coevolution, or in a more common sense an “arms race” between species. For example, as Taricha (newts) evolved to produce the neurotoxin tetrodotoxin (TTX), Thamnophis sirtalis (a species of garter snakes) coevolved to produce a resistance to the toxin. As each evolves more in response to the other, they become encompassed in an evolutionary footrace. Another aspect of coevolution is the Red Queen Hypothesis. This hypothesis speculates that as one population adapts, the selection pressure placed on other species in the same environment increases. In turn, coevolution takes place. This article will discuss the mechanisms behind the coevolution of these two species and how they each affect one another. At some point, the evolution of the species will either stop, or one may become extinct due to being outcompeted by the other.

The overall genetic aspect of the adaptation of resistance to tetrodotoxin in this species of garter snakes is centered at substitutions of functional amino acids in the skeletal muscle sodium channel (Nav 1.4). According to the article “Parallel Evolution of Tetrodotoxin Resistance in Three Voltage-Gated Sodium Channel Genes in the Garter Snake Thamnophis sirtalis”, these substitutions are the major reasons for the physiological resistance against the toxin in the newts (McGlothlin et al., 2014). Since TTX binds to voltage-gated sodium channels in nerves and muscles blocking sodium ion movement and disrupting nerve impulse control, changes in the amino acids of the P loop cause the molecular environment to change and then alter the binding affinity of the toxin (Feldman et al., 2009). According to that article, substitutions that occur outside of the P loop have little to no effect on the function of the protein.

Tetrodotoxin is generally a lethal toxin that many organisms cannot take into their systems. Taricha granulosa has used this toxin as an imperative antipredator mechanism against the few predators that have the ability to prey upon them; the main predator being Thamnophis sirtalis (Hanifin et al., 1999). Theories about the evolution of the toxin within the newts include that of geographic location and the pure amount of predators in the area. Several other species have generated their own personal TTX resistance as well. Pufferfish are resistant to the toxin, allowing for them to carry it with them as a defense mechanism against predators that are TTX sensitive. Having this resistance also allows for them to prey upon other species that also contain the toxin. However, there are no known predators of pufferfish (Soong et al., 2006). This shows that coevolution does not always exist and that it is a complex occasion in which there has to be coexisting species capable of competing. In order to see the genetic basis of TTX resistance in pufferfish, a species other than garter snakes, researchers sequenced the proteins of the skeletal muscle sodium channels. This showed that just like garter snakes, pufferfish have substitutions in the pore (P) loop regions of the four domains. Some substitutions in the P loop of domain one in the nonaromatic amino acid residues of cysteine and asparagine were found to be linked to TTX resistance. In garter snakes the reason behind the resistance lies within the mutations in the outer pore of domain four of the sodium channels (Venkatesh et al., 2005).

One experiment found that there is indeed a clear link between the ecology of the newts and garter snakes. In the article “Toxicity of Dangerous Prey: Variation of Tetrodotoxin Levels within and Among Populations of the Newt Taricha granulosa,” TTX extracts were taken from seventeen adult newts were collected from six separate sites. These samples were then filtrated and used to analyze the TTX levels per population. In this study, they found that some of the newt populations did not contain any traces of TTX while all of the others did. It also aided the theory of coevolution between these newts and garter snakes in that variation among these toxin levels per location is needed. The experiment also showed geographic variation of the populations that support the theory that as newts increase the production of TTX, garter snakes evolve to have greater resistance to the toxin. In the areas that the non-toxic newts were found, garter snakes lacked any resistance. However, in the areas where newts had high levels of tetrodotoxin, the garter snakes possessed a greater resistance to the toxin. Different levels of TTX production and resistance between populations follows the geographic mosaic perspective of coevolution since it varies between populations in different location (Hanifin et al., 1999).

In a separate experiment described in the article “Parallel Arms Races between Garter Snakes and Newts Involving Tetrodotoxin as the Phenotypic Interface of Coevolution,” scientists collected sixty-eight sets of data on a similar species of TTX resistant garter snakes (Thamnophis couchii). These specimens were then analyzed for their resistance to TTX through a bioassay of their overall performance. After injection they were analyzed based upon their initial baseline speed. The data collected from the analysis showed that this species of snake had a high resistance to TTX and there was a tradeoff between locomotive performance and resistance. The researchers found that the snakes that moved the slowest post-injection were the most resistant compared to the faster moving ones. A newt species (Taricha torosa) similar to that of the previous experiment were collected and tested for TTX levels. It was found that each of them contained various levels of the toxin based upon their size. As the newt grows larger, they are capable of having more of the toxin in their glands. Within the study, it was found that the species Thamnophis couchii would be able to ingest most adult Taricha torosa without becoming fully impaired, but if the species Thamnophis sirtalis were to eat the same newts, they would not have any locomotive functions. This displayed the theory that specific predator species within an environment will be resistant enough relative to the sympatric species of prey they are consuming. Not only does this occur, but it also fits hand in hand with the Red Queen hypothesis in the sense that there is always a footrace between the species of garter snakes and newts. It has been shown through this experiment and ones from years ago that these two species are coevolving. As the newts become more toxic, the garter snakes respond and evolve to be more resistant (Brodie et al., 2004). An experiment comparing the effects of interpopulation and interspecific variation in tetrodotoxin resistance discovered differences between them. This research included sympatric Thamnophis sirtalis that coexists with Taricha granulosa, allopatric Thamnophis sirtalis that does not coexist with Taricha granulosa, and sympatric Thamnophis ordinoides. It was discovered that no matter what the dosage of TTX, the sympatric Thamnophis sirtalis showed much less reduction in motor skills than the other populations. When given concentrations of 0.00015mg of TTX, this grouping showed little to no effects while the other two groupings were reduced to less than twenty percent of their baseline speed. This study showed that TTX resistance is not a trait of the genus Thamnophis or the species sirtalis, but it is adaptation of populations that coexist with the toxic prey (Brodie et al., 1990). The main influence of the intake of the toxin and the exposure length of the snakes to the toxin is the snake’s ability to recognize its own resistance level. An unknown mechanism in which the snakes know how much toxin they can handle allows for them to either reject the newt or to ingest the newt (Williams et al., 2003).

The geographic mosaic approach explains the differences between populations that are close to one another. Many factors such as resource availability and differences in community composition can cause populations to display this mosaic. As a result, hotspots and coldspots occur within the mixture. Hotspots are the areas in which reciprocal selection is high, while coldspots are the areas that have low reciprocal selection. In an experiment done by Edmund Brodie Jr, B.J. Ridenhour, and Edmund Brodie III, data was collected from forty populations of Thamnophis sirtalis. This data was then analyzed using a bioassay based upon the whole organism performance. The team then continued by injecting the snakes with well calculated amounts of tetrodotoxin to observe their reactions. Some trials maintained the same dosage each time while others kept it at the same quantity. A few of the snakes were injected with saline as a control group and showed no effects. What this study showed was the effect of TTX on the baseline speed of the organism; if it had a large effect on the individual the speed would be less than one hundred percent, but if it had no effect it would remain at one hundred percent. The results discovered that as populations moved away from a hotspot, the resistance levels lowered. The main focus of this was that around hotspots the snakes have high resistance due to the newts having a higher toxicity and that as newts evolve to be more toxic in certain areas, garter snakes do as well (Brodie et al., 2002).

In the coevolution of species, populations enter into an arms race in which both adapt to each other. For the example given above, garter snakes started to evolve to be resistant to tetrodotoxin, the toxin found in their prey the newt. As the newts became more toxic, the garter snakes respond by having a higher level of resistance. However, it was found that only sympatric species of snakes that coexist with the toxic newts gave rise to TTX resistance. Allopatric species that did not coexist with the newts showed no resistance to the toxin. As a result, the theory of geographic mosaics of the two populations exists. This relationship is also a good example of the Red Queen hypothesis in which the two species enter an arms race.

References:

Brodie, Edmund D., III, and Edmund D. Brodie, Jr. 2008. Tetrodotoxin Resistance in Garter		 Snakes: An Evolutionary Response of Predators to Dangerous Prey. Society for the 	Study of Evolution. Volume 44: 651-659.

Brodie, Edmund D., III, Chris R. Feldman, Charles T. Hanifin, Jeffrey E. Motychak, Daniel G. Mulcahy, Becky L. Williams, and Edmund D. Brodie, Jr. 2005. Parallel Arms Races 	between Garter Snakes and Newts Involving Tetrodotoxin as the Phenotypic Interface of 	Coevolution. Journal of Chemical Ecology. Volume 31: 343-356.

Brodie, Edmund D., Jr., B. J. Ridenhour, and Edmund D. Brodie, III. 2002. The Evolution 	Response of Predators to Dangerous Prey: Hotspots and Coldspots in the Geographic 	Mosaics of Coevolution between Garter Snakes and Newts. Evolution. Volume 56(10): 	2067-2082.

Feldman, C. R., E. D. Brodie, E. D. Brodie, and M. E. Pfrender. 2009. The Evolutionary 	Origins of Beneficial Alleles during the Repeated Adaptation of Garter Snakes to Deadly 	Prey. Proceedings of the National Academy of Sciences. Volume 106.32: 13415-13420.

McGlothlin, Joel W., John P. Chuckalovcak, Daniel E. Janes, Scott V. Edwards, Chris R. Feldman, Edmund D. Brodie, Jr., Michael E. Pfrender, and Edmund D. Brodie, III. "Parallel Evolution of Tetrodotoxin Resistance in Three Voltage-Gated Sodium Channel 	Genes in the Garter Snake Thamnophis Sirtalis." Society for Molecular Biology and 	Evolution. Volume 31(11): 2836-2846.

Soong, Tuck W., and Byrappa Venkatesh. 2006. Adaptive Evolution of Tetrodotoxin 	Resistance in Animals. ScienceDirect. Volume 22.11: 621-626.

Venkatesh, Byrappa, Song Qing Lu, Nidhi Dandona, Shean Long See, Sydney Brenner, and	Tuck Wah Soong. 2005. Genetic Basis of Tetrodotoxin Resistance in Pufferfishes. Current Biology. Volume 15.22: 2069-2072.

Williams, Becky L., Edmund D. Brodie, Jr., and Edmund D. Brodie, III. 2003. Coevolution of 	Deadly Toxins and Predator Resistance: Self-Assessment of Resistance by Garter Snakes 	Leads 	to Behavioral Rejection of Toxic Newt Prey. Herpetologica. Volume 59(2): 155-	163.

https://en.wikipedia.org/wiki/Tetrodotoxin#cite_note-6

Even though the toxin acts as a defense mechanism, some predators such as Thamnophis sertalis have developed a resistance to TTX which allows for them to prey upon these toxic newts.[6]

[6] Brodie, Edmund D., III, Edmund D. Brodie, Jr. "Tetrodotoxin Resistance in Garter Snakes: An Evolutionary Response of Predators to Dangerous Prey." Society for the Study of Evolution, 26 Sept. 2008. Web. 15 Sept. 2014.

3 Suggestions and Talk Entries:

Tetrodotoxin Resistance[edit] A great section to add to this would be their adaptation to tetrodotoxin (TTX), a potent neurotoxin. A common prey of garter snakes is the Taricha granulosa, also known as newts. These newts however, contain TTX. Snake populations in the same environment as the newts have developed a higher tolerance towards the toxin and are therefore able to hunt them. [1] Nguyen.332 (talk) 05:23, 1 October 2014 (UTC)

Jump up ^ Soong, Tuck W., and Byrappa Venkatesh. "Adaptive Evolution of Tetrodotoxin Resistance in Animals." ScienceDirect 22.11 (2006): 621-26. Web. 15 Sept. 2014

Tetrodotoxin Resistance[edit] A great section to add to this would be their adaptation to tetrodotoxin (TTX), a potent neurotoxin. A common prey of garter snakes is the Taricha granulosa, also known as newts. These newts however, contain TTX. Snake populations in the same environment as the newts have developed a higher tolerance towards the toxin and are therefore able to hunt them. [1] Nguyen.332 (talk) 05:23, 1 October 2014 (UTC)

Co-evolution of Garter Snakes and Newts[edit] A great study in the field of evolution involves the co-evolution of species. A specific example of this would be between garter snakes and newts. Since newts have developed the defensive mechanism of secreting tetrodotoxin from their skin, garter snakes have in turn adapted to have resistance to the toxin. [2]Nguyen.332 (talk) 19:20, 1 October 2014 (UTC)

Jump up ^ Soong, Tuck W., and Byrappa Venkatesh. "Adaptive Evolution of Tetrodotoxin Resistance in Animals." ScienceDirect 22.11 (2006): 621-26. Web. 15 Sept. 2014 Jump up ^ Soong, Tuck W., and Byrappa Venkatesh. "Adaptive Evolution of Tetrodotoxin Resistance in Animals." ScienceDirect 22.11 (2006): 621-26. Web. 15 Sept. 2014.

Topic Selection and Annotated Bibliographies Brittany Nguyen Evolution 3310 Matthew Holding (Tuesday 8:00) Topic: How mutations affect tetrodotoxin resistance in garter snakes and pufferfish.

Brodie, Edmund D., III, and Edmund D. Brodie, Jr. "Tetrodotoxin Resistance in Garter Snakes:		An Evolutionary Response of Predators to Dangerous Prey." Http://www.usfca.edu/. Society for the Study of Evolution, 26 Sept. 2008. Web. 15 Sept. 2014.

In this article, the researchers go over evidence supporting how garter snakes have evolved a resistance to tetrodotoxin due to toxicity of the newt which it preys upon. They believe that the evolution of the garter snakes was a response to the newt’s harmful quality. Another point this article made was that resistance to tetrodotoxin may increase due to selection.

Feldman, C. R., E. D. Brodie, E. D. Brodie, and M. E. Pfrender. "The Evolutionary Origins of 	Beneficial Alleles during the Repeated Adaptation of Garter Snakes to Deadly Prey." Proceedings of the National Academy of Sciences 106.32 (2009): 13415-3420. Web. 15 	Sept. 2014.

The main point of this article is to research the molecular basis in which garter snakes have adapted to tetrodotoxin and how they have obtained a resistance. Through experiments the scientists tested whether or not mutations, the transmission of advantageous alleles, or separating of existing variations is responsible for the adaptation. Their results showed that the evolution has occurred many times on different occasions due to mutations.

McGlothlin, Joel W., John P. Chuckalovcak, Daniel E. Janes, Scott V. Edwards, Chris R. Feldman, Edmund D. Brodie, Jr., Michael E. Pfrender, and Edmund D. Brodie, III. "Parallel Evolution of Tetrodotoxin Resistance in Three Voltage-Gated Sodium Channel 	Genes in the Garter Snake Thamnophis Sirtalis." Society for Molecular Biology and 	Evolution (2014): 1-11. Web. 15 Sept. 2014.

Experiments using bacterial artificial chromosome library scans were done to see the relationship between tetrodotoxin resistance in garter snakes and voltage-gated sodium channel genes. Results from the research showed that the molecular basis of this adaptation can repeat itself through generations and be predictable based upon function.

Soong, Tuck W., and Byrappa Venkatesh. "Adaptive Evolution of Tetrodotoxin Resistance in 	Animals." ScienceDirect 22.11 (2006): 621-26. Web. 15 Sept. 2014.

In this article, the scientists discovered through their research that animals like the garter snake and pufferfish have a tetrodotoxin resistance due to substitutions in different P-loop regions within the sodium channels. It was also found that there are different levels of resistance in garter snakes due to the amount of substitutions in the loop.

Venkatesh, Byrappa, Song Qing Lu, Nidhi Dandona, Shean Long See, Sydney Brenner, and	Tuck Wah Soong. "Genetic Basis of Tetrodotoxin Resistance in Pufferfishes." Current		Biology 15.22 (2005): 2069-072. Web. 15 Sept. 2014.

By comparing the sodium channels from two separate pufferfishes and a tetrodotoxin-sensitive zebrafish, the scientists were able to investigate the genetic basis of resistance in pufferfishes. Mutations in the P-loop were found to be important for the binding of tetrodotoxin while those outside of that region did not change the sensitivity of the channels.