Paul E. Turner (Yale) 2: Virus Adaptation to Environmental Change

Paul E. Turner (Yale) 2: Virus Adaptation to Environmental Change

hi i'm paul turner from the department of ecology and evolutionary biology at Yale University and the microbiology faculty at Yale School of Medicine today I'd like to present on virus adaptation or not to environmental change this talk describes how viruses have an amazing capacity to adapt to environmental challenges and yet will find that these champions of adaptation sometimes encounter environments that demonstrate that environmental change can constrain evolution and adaptation and even these so called champions can face constraint so very many challenges exists to viruses in the natural world and you can think of this at all different levels of biological organization so if you start at the base level of molecules and cells the primary challenge for viruses is that they cannot control where they exist in the environment so they might encounter some cell type and successfully enter if they have the right protein binding to recognize a protein on the cell surface or they might bump into the wrong type of cell and that protein recognition doesn't occur so therefore it's an immediate and proximate challenge to a virus to infect a cell depending on where it is in the environment and whether the proper cells exist to infect in macro organisms like us we have tissues composed of different cell types so if a virus is in your body and it's replicating in one tissue type it might be challenged to infect a different tissue that's nearby and it's incapable of doing so hosts such as humans have elaborate and beautiful immune systems some of them are adaptive meaning that they change through time and this is a way of our immune system in a way keeping pace with microbial invaders and changing at the same pace that they might evolve through evolution but viruses and other microbes when they encounter these immune systems this poses a challenge for them to continue to infect that host or that host progeny or other susceptible hosts in the air in their environment depending on whether those immune systems provide an immediate and so barrier to virus replication it's an amazing thing that some viruses infect humans and also successfully infect very different organisms that are not at all closely related to us a great example of this are the arthropods where many pathogens are vector transmitted by arthropods such as mosquitoes including viruses and this is pretty fascinating because a virus has to grow within an invertebrate and for example in a mosquito it has to grow in the mid gut and eventually get to the salivary glands in order to be present in a bite that puts the virus in the bloodstream of another host to be picked up by another mosquito that's got to be an incredible challenge for a virus to grow both successfully in an invertebrate like an arthropod as well as a vertebrate like you a human and last we have to remember that global level ecosystem changes affect all biological entities on this planet including the very smallest ones such as viruses so when you think about challenges like climate change and global warming you have to remember that this is something that is felt by all biological entities and therefore viruses can also feel the challenge of an ever warming world there are many different virus study systems that my group examines so these examples are shown in the very many beautiful forums behind me on the far left we have vesicular stomatitis virus which is an example of a single-stranded RNA virus with a negative sense genome and in the middle we have a variety of other viruses also that will infect eukaryotes but they happen to have positives single stranded RNA genomes closer to where I'm standing we have single stranded DNA filamentous page and also double stranded RNA and double stranded DNA viruses in this case both phages phage 5 6 and phage t2 so these are examples within my laboratory of the wide variety of viruses that exist in the natural world and how a single laboratory can choose to examine this great variety of virus types depending on the challenge and the question we would like to focus on a different study system whether viruses can successfully or not adapt to their environments a big tool that we use that's very popular with others and a very powerful tool would be experimental evolution a way to summarize this method is it's the ability to study evolution in action so if you have the right study system in a controlled place like a laboratory you can take that population put it in an environment that you control explicitly and then examine how does that population deal with that challenge both in terms of the traits that it evolves as well as the genotypic changes that it undergoes so both phenotype and genotype can be the focus of these studies an important thing to remember is even if a researcher is manipulating the environment in the laboratory it still can be a challenge to a population and that population can evolve through natural selection so you're talking about an artificial environment and yet natural selection can occur that's because the researcher is not determining which variants in that population will better match the environment instead that's due entirely to the mutations and the genetics of that system to meet that challenge or not and that can happen through the process of evolution by natural selection a typical design is shown here where we would begin with some ancestral type we might be interested in the case of this hypothetical diagram in three different treatments that differ in some way in their environmental challenge and we can track over the course of generations how do these independent lineages evolved to meet these challenges and the nice thing is to include replication in these experiments such as you can have lineages that are experiencing the same environment and you can look at how consistently do lineages undergo random mutation and yet the same mutations might be the ones that rise to fixation and lead to adaptation in other cases there might be different solutions to the environmental challenge and you'll see divergence between your lineages in the sense of different mutations are meeting the same challenge another way to think about these experimental evolution studies is to create a hypothetical diagram of some phenotypic trait that you would want to measure this might be growth or some other capacity of the system to meet the challenge so in this example I'm illustrating how this trait has some variation at the beginning and then we could create some sort of an ecological circumstance or an environmental challenge in these studies and through time we can keep track of how phenotypes change so you'll notice that the average phenotype along the x axis in this hypothetical example is shifting to the right meaning that the mean of the distribution is changing according to which variants are in that population and the ones that are best meeting that challenge now we can go further than a lot of systems because it's very easy for us in virus studies to take the entire genome from these evolving populations and explicitly look everywhere in the genome for where a mutation might occur in this case we can track through generational time how is the genetics changing in relation to the ecological challenge as well and this allows a lot of immediate power in making something called a phenotype genotype Association you can infer how the changing phenotype is being controlled by underlying genetics and make some base inferences about what the relationship is and I don't want to trivialize that because one has to do a lot more work to convince oneself that perhaps one mutation is responsible maybe two or three or even more complex things can occur like these mutations acting with one another through properties like epistasis so this provides an amazing amount of power to examine how evolution occurs according to the environment that you create in these types of studies the outline for what I want to talk about today is pretty much centered on these two questions we can consider environmental changes as fostering versus constraining virus adaptation depending on how the environment is constructed and these types of experiments are in the natural world and especially now that takes us to this next question of are there particular traits that can evolve in viruses match something intriguing that you see in cellular systems the investment in survival versus reproduction is often something that's seen as at odds to one another in cellular systems that you can either invest a lot in survival as an evolutionary tree but this minimizes your reproductive capacity or vice versa so an intriguing set of studies show that this same constraint or the same trade-off can happen even in non metabolizing organisms such as the viruses especially in the viruses how does environmental change foster versus constrained by recitation let's look at this question first virus emergence is an amazing iya biomechanical challenge that we face today so even though RNA viruses especially are not that prevalent among the highly prevalent viruses that exist on this planet they seem to be especially able to jump into new host species and cause harm through disease so humans see this through recently emerging pathogens such as Zika virus which is sweeping around the globe and is problematic and creating a challenge to biomedicine to protect people against Zika virus infection that can disrupt normal development at an early age a very different example but still called emergence is when a virus comes from another species enters into the human population and gets locked in and becomes very specific to humans so I began with the case of Zika virus which is not specific to humans but a great example of a specificity evolution would be HIV which came into the human population several times independently from our primate relatives especially chimpanzees and certain species of monkeys and this has led to the evolution of hiv-1 and hiv-2 independently several times a third example of emergence would be something that exists both within humans as well as in other species and a great example of that would be influenza virus so ordinarily in any year you can have plenty of the human populations seeing flu virus infection suffering influenza but what we fear is that there are certain forms or genotypes of influenza virus that will be especially virulent and cause a high degree of mortality and sweep around the globe to infect a lot of humans and adversely affect human populations more than a standard flu season and especially we fear that the large reservoir of influenza viruses that mostly exists in this planet and waterfowl might lead to a variant that can jump immediately into humans and they be passed for human to human which would be an example of a flu virus coming from a bird coming into a very different host species a mammal and causing a lot of destruction and mortality because the inability of the human immune system to deal with the challenge so these are three different examples of the same catalogued thing that thing is what's called emergence and this is a huge biomedical challenge we can think of how emergence can or cannot occur for a virus and that's what I want to focus on next there are some certain fundamental expectations if you have any lineage whether it's a virus or not and whether it's encountering an environment that is constant through time versus changing seasonally or in a temporal way through time so I'm giving two hypothetical examples of this at the top we have hypothetical evolving lineage that sees niche a and niche B and a flip-flopping fashion and each one of these little circles indicates a generation so necessarily this lineage has to grow an environment a in order to make it long enough in its environment to reach a new environment B and so on necessarily we would expect that this will select for generalization the ability to thrive in both of these environments because there is no other option now that's very different than if that lineage has the luxury of seeing only a single environment in this case environment a is the only thing it encounters but I'm underlining the word tends to select for specialization because that's only one possibility this luxury affords this possibility of being highly specific to your environment and being very good in that environment but it also is an opportunity for to occur if you have a correlated response to growing well in other environments and essentially that must be happening in emerging virus pathogens they happen to have the right genetic capacity that when they jump into a new host species like human they can just really hit the ground running and grow very well cause a lot of damage and ultimately they might be specific to that environment ultimately but initially they're highly generalized we've covered this topic in a variety of papers that I'm listing here that I won't have time to go into much detail but one can think of this challenge of virus specialism versus generalism happening a lot in the natural world and it's very easy and powerful to study this in the laboratory through the experimental evolution method that I mentioned earlier one system that we focused on a lot study how virus specialization versus generalization and just simply adaptation can happen is a model known as vesicular stomatitis virus so this is a single-stranded RNA virus with a negative sense genome that's pretty much a workhorse in molecular biology it's been used for very many decades to understand fundamentals of how RNA viruses infect and replicate in a Cell so some pictures here that I'm showing are just to reflect that we have a lot of prior knowledge for the molecular details of the system and that's great when you enter into experimental evolution studies because you don't have to go about measuring that stuff all over again you can think of the outcome of your experiments in the context of the prior knowledge so VSD has a very small genome in size it has only 11 kilobases and linked and this comprises only five genes so one can think of this as a pretty simple system and yet it has a pretty amazing capacity to do things like both reproduce in an arthropod it's an arthropod borne virus or a Narbo virus and it also can replicate in the mammal so in the case of vsv it's a safe system to use in the laboratory because it might get in a human by accident but it really doesn't cause much harm it's agriculturally important in large mammals domesticated horses etc so we do care about it disease standpoint but it's a great powerful system to use in the laboratory safely it comes from the family rhabdo Verde which also features rabies virus here's a summary of some of the data from one of our experiments where we harnessed experimental evolution to examine how does this virus deal with a constant environment versus one that is changing through time in that temporal heterogeneous way that I outlined so this is a pretty busy diagram but I'll walk you through it at the top this is merely a depiction of the vsv genome and the five genes NP mg/l and what you can see is for each one of the lineages the four lineages that saw only in this case HeLa cells those are cancer derived cells that originally came from Henrietta Lacks a long time ago and these were harnessed as an immortalized cell line that people use in a lot of studies beyond simply virus studies but these cancer derived cells provided a new challenge for VSD in this experiment and each one of the points here on the diagram are showing where these win ages changed in their genetic material relative to the ancestor after the experiment took place in this way we can catalog what are the mutations that arose and which ones fixed through natural selection to let these lineages improve in their environment we also did an experiment a challenge where the viruses had to not only evolve on HeLa cells but in an alternating fashion they had to enter into a non cancer derived cell type abbreviated as MD CK and in this way they had to become adapted to both HeLa cells as well as these non cancer cells and you'll see that we also catalogued their genetic changes through time and this has a great deal of variety even within each treatment for the mutations that fixed according to each lineage one can also catalog the exact position where each one of these mutations took place let me highlight one more thing before I move on and that is really these virus populations after this experiment are not carbon copies one another so there are many places where we do see that they underwent the same mutational change at exactly the same place and that must be evidence of some beneficial mutation coming in and fixing in these lineages and yet in some genes they underwent different mutations from even the same populations in the same treatment so this indicates that there can be other genetic solutions to the same environmental problem in a study like this keep this in mind as we go on and look at a subsequent experiment that challenged the ability of these viruses to evolve and infect yet new hosts to test what is their emergence capacity simply remember that we lump them together as specialists having seen only one constant host height or generalists that were selected to see two types and yet the lineages are not carbon copies of one another when they're drawn from each treatment here we wanted to ask a very fundamental question that's really at the root of what let's emergence occur so a popular idea is that if some pathogen has seen multiple hosts in the past it's somehow groomed through adaptation to be generalized enough that it will successfully enter and infect a new host when it sees it just randomly through encountering it in nature that's because adaptation has primed that pathogen to be good at growing in multiple hosts and through correlated response it just might grow very well in a new host such as humans so here I'm depicting a picture of Henrietta Lacks as the ultimately the person who gave rise to these HeLa cells that we used in this experiment and we asked whether viruses that evolved strictly on HeLa cells are they going to be good at growing on a variety of challenge hosts that we purchased or are we going to fit with this prediction that selected generalists were pre adapted in some way to perform well on these new hosts and they should be the ones that we would fear as typical of a successful emerging pathogen something that's groomed to grow on multiple hosts and will grow well on a challenge host when it encounters it to go to the data from an earlier paper this is pretty well supported by our study yes select the journalists emerge or they shift hosts easier this diagram is showing what is the sheer reproductive capacity of each of these virus lineages indicated by each point relative to its ability to grow in the environment that it was previously evolved on so this gives an indication of relative to its ordinary reproductive capacity is it any better or equally good at growing on a new challenge host relative to the host that it saw prior through adaptation and you'll see that all the blue points are well below the zero line that means that these specialist viruses from our study they can grow on this first challenge host I'm indicating I came from monkey cells but they grow pretty poorly compared to their capacity to grow on the HeLa cells that came from Henrietta Lacks whereas the selected generalists they saw both host types in our prior experiment one happened to be cancer derived one happened to be non cancer derived but those were different enough cell types that have provided a challenge to adapt to two things simultaneously and you'll see that on this challenge host those selected generalists actually did a better job at growing on a challenge host that was just randomly chosen presented to them all four of those triangles are very close to the zero line so in summary one could say that in this first line of evidence on the monkey cells is both a higher mean on average and lesser variance across the populations drawn from each treatment for the selected generalist to do better now if you look at all four challenge hosts is an amazing ability for the data to look highly similar no matter what the challenge host was that we randomly entered into this experiment using and to me that's fascinating because it indicates that there's hardly any of what one would call genotype by environment interaction this must be due to the capacity of these viruses to just simply grow on something new and it's not really the interaction with that new thing it's just that they can grow better on something that they've been child to infect so this provides nice evidence in for randomly chosen challenges that selected generalists can grow much better on a new host that you present them with and this gives us a little more insight at what could be the root of the emergence problem but I haven't really told you why why is this happening why is it that these selected generalists actually emerge easier at a mechanistic level here we've looked at the ability the innate immunity ability of cell types and whether selected generalists were keying in on this line of immunity and navigating their way through it and if they have a generalized ability to do that and that should carry over to other challenge types even though that challenge type would be drawn from a different species so this is a very detailed diagram but it's showing some of the inner workings at the cellular level of something that you're born with this is the innate immune capacity of your cells that when they see an invader like a virus that they will be able to undergo a cascade of events at the cellular level that gives them protection against that virus infection and interestingly the signals can go out to cells that are nearby in the tissue neighborhood to prime them to be better protected against that virus before the virus even is able to replicate enough to get to those cell types this is a wonderful ability to be immune to a pathogen that you should remember this is your innate immunity adaptive immunity which people are much more familiar with is something that is occurring much longer term that takes weeks or even longer that you see a pathogen and you mount an immune response to this uniqueness here this is just a generalized thing that controls pathogen infections so before I move on I'll say that the vs V M protein or the matrix protein is known to be the thing that interacts with the capacity of a cell to produce its anti immune response to virus infection especially interferon so ordinarily this cell is going to be producing interferon as one of these key chemicals that sit and signals go out and your interferon production occurs and other cells in the tissue to protect them but vsv as a virus can infect a cell and down regulate that response and that helps us even explain how we even did the prior experiment vsv has a great capacity just as a virus to grow in a variety of cell types because it can regulate this response however it could be that viruses like csv are highly generalized in moving between hosts because they properly regulate that immunity cascade so without very many details this is a hypothetical idea of how this can occur and what one should expect so let's imagine that the prior selection history of some virus or other pathogen this is relating its Fitness due to that prior evolution in terms of whether it saw host types that are of low or high innate immunity so in our prior experiment I highlighted in blue how these specialist viruses perform very well on HeLa cells but I didn't tell you one key bit of information about a lot of cancer cells including HeLa cells they have very low or completely absent innate immunity so what happened in that experiment probably is that the lineages of viruses evolved to infect a cell type where they didn't really have to worry at all about innate immunity as a challenge in infecting and growing in the cell type so this probably led to de-evolution or the removal of the capacity for those viruses to control innate immunity they just simply didn't need it and then when you challenge them to grow on a new host type they are very handicapped in doing so because they don't have the capacity to track the innate immunity functions within a cell whereas viruses could see necessarily in our experiment both high and low innate immunity because we use cancer derived as well as non cancer derived cells so they remained capable of navigating through both cell types and when they see a new cell type they can hit the ground running so important léa one can think of both alternating coasts as necessarily in our experiment keeping this capacity but it also could have been and we've done work like this if you take virus lineages and you grow them only on high innate immunity hosts you get a very similar capacity for them to maintain strong growth regardless of cell type so we have both good news and bad news in predicting emergence we have the ability for selected generalists to key in on innate cell function and navigate multiple cell types and you'd expect them to emerge but they don't have to do that they could still successfully emerge through a correlated response so the next question I want to cover is whether the environmental change that is presented to viruses either fosters or constrains their adaptation so now this is a similar diagram that I showed you before but note that now I'm including a different kind of a challenge here's where the lineage sees pretty much a stochastic set of environments through time in other words it's moving from environment to environment but there doesn't seem to be any pattern to what that what those environments present right so these are shown as separate colors in this diagram to illustrate how some virus lineages might have to navigate through very different environments and one can create an experiment that says well will these champions of adaptations still be able to successfully navigate through such a complex set of environments and become generalized or is this just simply too much and even in champions of adaptation like RNA viruses they'll be constrained and unable to do this this actually relates in some way to certain models that come from climate change where the prediction is really the fundamental problem for evolving lineages and climate change is that stochasticity the environment becomes more important the environment simply becomes more variable through time and will be harder for lineages to track those changes well it should be interesting to see whether viruses can successfully do this because if they cannot and this bodes pretty bad news for other organisms that have much slower and reduced capacity to evolve in the face of environmental challenges so let's see what happened one can easily construct an experiment like this but rather than creating hosts challenges through time let's think a little bit more about those climate change models and the thing that will manipulate is temperature through time so in this diagram I'm showing four different treatment groups that were created in an experiment where 37 degrees Celsius is the upper limit or pretty much the ordinary temperature for replication that we use in the laboratory for bsv 29 degrees Celsius is a lower temperature where they can still grow but it's much lower than 37 C 8 degrees lower and then we have alternating lineages that will see these two environments in a flip-flopping fashion and then we include this fourth treatment this is really the intriguing one if you take that 8 degree window and you go into the laboratory and you challenge the viruses to grow at any temperature in the 8 degree window that you randomly choose on that day it will create a very stochastic environment through time and here we want to know across generations especially 100 generations is there any different capacity of these viruses to evolve well in the face of this challenge so we can go immediately to the data that came from this experiment and the way this graph works is it shows you what is the fitness after 100 generations for each one of these lineages at each edge of the niche space so it's plotted what is their fitness at 37 C versus their fitness at 29 C and the intersection of those points leads to each point on the graph so you'll see that the lineages that evolved in a constant high temperature environment improved in that environment in other words all their data are to the right and above the dashed lines on this figure they've been proved both in terms of the environmental challenge they saw 37 C as well as 29 C which was the other environment that was constant in this experiment that's evidence of correlated selection you improve in one environment and it also allows you to improve in another environment that you haven't seen the same thing occurred for the lineages that saw only 29 C as the challenge interestingly in green we have an alternating environment where populations improved in some cases more than populations that saw only a constant environment and that's intriguing because it shows that populations can improve even though they see the challenge only half the time as their counterparts it must be that the genetics that underlies this which we've shown in papers that I won't present today is that different mutations are responsible for this improvement in an alternating environment versus in a constant one but in both cases you can have improvement relative to the ancestor most intriguing in this data set is shown in purple where all of those purple points and lines are nestled right near the intersection of the dashed lines which show the ancestral values this means that the random treatment in the pot in the experimental evolution study these lineages did not improve any more than the ancestral performance in other words the Siq a statistic of the environment was too much for them to deal with and that's bad news in terms of these champions of adaptation if they can't handle stochastic environments and that bodes ill for more complex organisms that have much slower adaptive and evolutionary capacity we wouldn't expect them to thrive either or to improve in Fitness when seeing stochastic change this is pointed to in the diagram in terms of the intersection of the points and all those purple points nestled near the dashed lines and their intercept as indicative of adaptive constraint the next question will be devices evolved survival reproduction trade-offs that we observe in cellular life here we want to examine whether the capacity to adapt in one means and that is to produce progeny it's something that detracts from the capacity to merely survive in the environment when it poses a challenge we've seen in cellular systems that you can't have your cake and eat it too in terms of these two challenges in proving through time that you can either invest in survival or reproduction but often you have an inability to improve in both simultaneously does this carry over to the virus world is an intriguing question we addressed it first in a phage called five six that infects a bacterium known as Pseudomonas Pseudomonas syringae so this bacterium is important in Plant Pathology it causes plant disease but in the laboratory we merely use it to grow the phage as a resource to examine how well does the phage evolve in environments in the laboratory so this is an RNA virus so it has the capacity to undergo error rate at a high rate and this allows a lot of mutation and rapid change through time and it has a very typical infection cycle where it infects a cell of the bacterium verse the cell for the progeny to be released and then they go on and infect more cells at the lytic phage replication cycle this picture is showing how the virus is able to first infect cells because the cells have these structures that allow them to adhere to leave surfaces and in normal wild conditions they would move across the leaf and enter into the plant in order to do infection of the plant so through time these viruses have evolved the ability to use those structures as the thing that they attach to through protein binding to get into the cell and that's what's shown in the diagram so one can first begin by examining a reaction norm or just simply the capacity four five six to grow under environmental challenges in the laboratory and even though those challenges can be amazingly brief only five minutes long in terms of heat shock this diagram is showing how the survival of a virus population of five six relative to different heat shock temperatures a high degree of mortality starts to kick in well above the normal incubation temperature in the laboratory of twenty five see when you get out to values greater than 40 C you find that this is highly impactful and deleterious to the viruses and their ability to thrive so this is indicating how in the absence of anything else you can take this fires expose it to high heat and if the heat is high enough it leads to a high degree of mortality in the virus population Kien on both 45 and 50 see where these are environments that we've manipulated in the laboratory to examine how the viruses deal with heat shocks through time as they see them and can they key in on this high heat that leads to high mortality and become better adapted to thriving in the face of heat shock this is a diagram from a recent paper we're simply showing you a typical experimental design for a study like this if you just take the virus such as in a test tube in the absence of any cells and you put it in a heating block so that it will be challenged with five minutes of high heat you can then take the viruses and grow them under normal low heat conditions where they can replicate in the presence of bacteria gather all that up remove the cells and keep churning them through the experiment in this way we're not worried about whether they can Seco evolve with the host bacteria we're mostly keying in on the thing that causes high mortality the heat shock can they key in on that and become better at thriving and improve this value which shows they're very strong mortality that they suffer under high heat environments going quickly to the data from a paper where we did such an experiment we find that thermal tolerance or heat shock selection and readily occur in these viruses and this is indicative of something that we would call environmental robustness so what is the ability of some population to thrive across different environments and maintain high fitness you'll see that the lineage is shown in red those that came out of an experiment where this virus saw intermittent heat shocks at 50 C these lineages improved way out at this temperature and you'll see this through a statistical result that they do grow better than their ancestral virus at that very high temperature now it's not like they have absolute capacity to shrug off that heat shot but they do have greater capacity to do so and interestingly you can see how there's a huge effect at the lower temperatures which ordinarily are degrading the wild type or unevolved virus and now these lineages that saw only 50c have a great capacity to thrive at very very warm temperatures and including the highest temperature that they saw in the experiment how does this occur we've done several experiments of this type and always for this virus the same key mutation is the first one and the most important one that leads to thermal tolerance evolving five six has a genome that's split up into three different segments called large medium and small in this diagram it below shows that we know what all the genes are we know basically what their functions and here we have a diagram a cut through of the virus body plan that shows you that they'll all that nucleic acid is at the center of the virus and it's surrounded by a protein shell buts Sisto viruses this is the family that 5:6 belongs to they're a little different than other bacteria phages in that they have a lipid coat around the entire shell so it's a pretty elaborate body plan for a phage but I really only want you to understand that the key mutation that provides thermal tolerance always seems to arise first on the small segment and it always seems to arrive in this license een which is we're going to be responsible for virus particles both getting in and out of the cell and it is always the same mutation the two o7f it's an amino acid substitution that I'll talk about further v 207 F seems to be the key mutation that always allows the viruses to evolve thermal tolerance and mechanistically this makes sense because when you look at the structure of this license protein a very important enzyme phenylalanine as an amino acid substitution fills a hydrophobic pocket and this makes the protein more stable under high heat so this is only one mutation coming in but it has profound significance for the thing that is causing high mortality in the virus populations it's a very simple explanation of how a single amino acid substitution can lead to a profound ability to thrive under a key environmental so now I will talk about how the reproduction is affected for this virus even though the key mutation allowed better survival its detracting from reproduction so if we look at how does this v2 o7f mutant thrive in an ordinary environment 25 C and its ability to grow on bacteria this diagram is first showing how the plaques in other words when you take a virus and you grow it on a bacterial lawn which is the background in this diagram in white each one of the particles if they hit the lawn independently they'll infect a cell and the progeny will exit that cell and affect neighboring cells and eventually you'll get this hole in the bacterial lawn called the plaque well something interesting happens when you look at the morphology of the plaques of the wild type virus which is heat sensitive versus this v2 o7f mutant that is heat tolerant in all cases the v2 ocf mutant makes this weird-looking plaque that has a bull's-eye of bull's-eyes morphology to it so that must be that cells missed being infected and killed as that plaque was produced on the lawn otherwise it wouldn't have that grayish appearance in other words it is not as effective at killing cells even though it is thermal tolerant that's shown in the bar graph here where the selection coefficient or little s that is associated with this one mutation has a huge deleterious value under normal growth conditions the wild-type relative to itself of course grows equally well so we give it a value of one where as the value for the thermal tolerant mutant is a value much much lower than one and has a negative selection coefficient of 0.25 in comparison to the data I showed you earlier it's very evident that a life history trade-off is occurring in this virus in other words it can either invest in better survival but the problem is this leads to lower reproduction this is echoing something that we see in cellular systems with the investment in either survival or reproduction but not both at the same I'm occurring simultaneously it also relates to an earlier study where the researchers found that if you just randomly take viruses that can infect a different bacteria E coli and you look at what is their mortality rate versus their multiplication rate and you plot that on the same graph there's a pretty amazing relationship for these viruses that they produced in their study or used in their study to show that these are highly correlated traits to one another so either these viruses that they studied grew well and survived poorly or had a high mortality rate or they grew poorly and survived better so it shows that if you just look at viruses from the natural environment and you look at their relationship for survival versus reproduction they show a big difference and they fall along this line you can think of our experiment as having taken any one virus on this line and can you move it up or down the line through an experimental evolution study and that's exactly what we did so the survival reproduction trade-off holds and you can move them up and down the line if you vary the environment in the right way so the bullseye plaque that I showed you before is a pretty strange morphology and there's actually even though people have used old microbiology methods to the current day the ability to visualize plaques is something that has aided back to at least the 1940s so it's an old method and yet we actually don't know very much mathematically if you construct a model about how does a plaque form this is still a pretty big challenge to mathematical biologists the three dimensionality that this plaque is growing in on an auger surface it's something that it's very hard to describe mathematically and especially if one looks through a time lapse film of these types of bullseye plaques forming this is very strange morphology that it's hard to understand how some cells are killed initially and then there's a lot of cells that do not get killed and then and then more cells get killed and so on to lead to such a complex morphology I would say that this is still an ongoing challenge to simply describe how two plaques form mathematically and mechanistic in this example from our experiment even one mutational change can lead to very different morphology that provides an even bigger challenge to describe so now we can think of the viruses and the way that they encounter challenges in the natural world as yes they have an amazing capacity to see challenges and overcome them so we do fear emergence of viruses as something that will continue to be a challenge for humans domesticated species conserving endangered species all of these realms are threatened by the emergence of viruses coming in and doing destruction however there are certain environments where these Champions of adaptations simply cannot make it so consistent with certain climates shaped climate change models we have environmental change through time as something that can constrain virus evolution and some of the fundamental trade-offs that we see in cellular systems especially survival versus reproduction carries over even into organisms that don't undergo metabolism the viruses so it's not just there shunting energy into one thing or another it shows you more of a fundamental divide in the biological world of can you invest in survival versus reproduction and get away with a co-investment in both of them and it seems like that's not the case so I'd like to end by acknowledging the people who did this work I keyed in on a lot of the work done by my current lab group as well as past lab members I've had the pleasure of working with I've had fantastic mentors and collaborators all over the world and I have to thank them deeply for their dedication to the experiments to present the data that wound up in our papers I can also thank the funders for the work NSF and its programs such as the beacon Center for experimental evolution as well as NIH Yale University and nonprofits such as project high hopes foundation have provided key funds for all the work that I showed you today you

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  1. I live where many exotic species are invasive and grow aggressively. I was wondering how soon does the species start to diverge from its native genetics and begin to show unique expressions.

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