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Author Topic:   Do you really understand the mathematics of evolution?
Kleinman
Member (Idle past 335 days)
Posts: 2142
From: United States
Joined: 10-06-2016


Message 31 of 239 (876708)
05-26-2020 9:31 AM
Reply to: Message 30 by nwr
05-25-2020 9:58 PM


Trying to give nwr more than a vague understanding of DNA evolution
Kleinman writes:
Try quoting my entire statement then perhaps you may understand what I'm saying. Here's my full quote.
Kleinman writes:
His lineages are grinding out replications until some lucky member gets the correct mutation that enables that variant to grow in the next higher concentration drug region.
Kleinman writes:
And sure the grind continues (unless extinction occurs which is the most common outcome for most lineages).
nwr writes:
I guess it is hopeless. You are continuing to make the same mistake that we often see being made by creationists. And you are damned sure that you are right, even though you are wrong.
When you said in response to my question previously:
Kleinman writes:
Are you familiar with the work of Haldane, Kimura, and many other population geneticists?
nwr writes:
Somewhat. The mathematics that they use is ordinary mathematical probability theory. Is that what you mean by "mathematics of evolution"?
You are not as familiar with "ordinary" mathematical probability theory as you think you are.
Kleinman writes:
Actually, the mathematics of evolution is more like the math of coin tossing. The mathematics of evolution consists of nested binomial probability problems where each binomial probability problem is joined to the other by the multiplication rule of probabilities.
nwr writes:
No, that's wrong.
It is you who is wrong nwr. DNA evolution is a binomial probability problem. The random trial is a replication and the two possible outcomes are, does a beneficial mutation occur or does a beneficial mutation does not occur. That is analogous to a coin toss problem where the random trial is the toss of the coin and the two possible outcomes does a head occur or does a head not occur. The major difference between the two examples is that the coin tossing problem is symmetric, ie, the possible outcomes have equal probabilities of 0.5. The DNA evolution binomial probability example is highly asymmetric, that is, the probability of a beneficial mutation occurring in a single replication is the (beneficial) mutation rate and the probability of a beneficial mutation not occurring in a single replication is 1 minus the (beneficial) mutation rate.
nwr writes:
That's about what you would get if the environment were completely static. But the environment is changing all the time. So the probabilities are changing all the time.
It doesn't matter whether the environment is static or not. The DNA evolutionary process still consists of nested binomial probability problems. The Kishony and Lenski experiments are as close to static as you can get. They hold all their variables including the selection conditions as constant as possible and it still takes billions of replications for each step improvement in fitness for their variants. If they were to change their environments at any time during the performance of the experiment, that would mean they would be changing the evolutionary trajectories for increasing fitness making those evolutionary trajectories more complex. That's why Kishony hasn't been able to get his experiment to work with two drugs (or if the step increase in drug concentration is too large) and Lenski's experiment would work even more slowly if he were to do it at a non-optimal temperature. The mathematical explanation for this is the multiplication rule of probabilities.
nwr writes:
The problem of drug resistant bacteria isn't that they show up. The problem is too much use of antibiotics will change the environment so that antibiotic-resistant bacteria become more highly favored. And then we will see many more of them and they become a problem.
You are half right here. If antibiotics are used incorrectly, what you will do is colonize your patients with drug-resistant variants. The way you do this is by using single-drug therapy on someone who is immune-compromised. What happens is you kill off the drug-sensitive variants but because the person's immune system doesn't remove the remaining drug-resistant variants, not only will you have treatment failure but the person will now be colonized by bacteria resistant to that drug. And as that colony grows, there is an increasing probability that more variants will appear resistant to higher concentrations of the drugs (just as Kishony's variants are moving to the higher drug concentrations regions).
I don't know if you paid attention to my responses to jar. Withholding antibiotics from someone who needs them not only has health consequences but economic consequences as well. Septicemia and pneumonia are the number 1 and 4 medical reasons for hospitalization. Do a search on the hospitalization cost for the treatment of those diseases and this problem is getting worse. Many of these cases could be prevented with the timely and correct usage of antibiotics with much lower costs in the outpatient environment. It is the incorrect or in your case vague understanding of evolution that is contributing to this problem.
My suggestion to you is if you want to have a better understanding of this is to watch the Kahn Academy (or various other) lectures on probability theory on YouTube. Then read this link:
Page not found - Stats & Data Science Views
And when you understand that, read this paper:
Just a moment...
When you do that you might have a better idea of what I'm talking about.

This message is a reply to:
 Message 30 by nwr, posted 05-25-2020 9:58 PM nwr has replied

Replies to this message:
 Message 32 by Phat, posted 05-26-2020 4:47 PM Kleinman has replied
 Message 34 by Taq, posted 05-26-2020 5:35 PM Kleinman has replied
 Message 36 by nwr, posted 05-26-2020 9:23 PM Kleinman has not replied

  
Phat
Member
Posts: 18262
From: Denver,Colorado USA
Joined: 12-30-2003
Member Rating: 1.1


Message 32 of 239 (876718)
05-26-2020 4:47 PM
Reply to: Message 31 by Kleinman
05-26-2020 9:31 AM


Re: Trying to give nwr more than a vague understanding of DNA evolution
all that i would add, not being a scientist or a creationist is that there is a distinct difference between chance and true randomness versus a set and measureable probability.

The only way I know to drive out evil from the country is by the constructive method of filling it with good.Calvin Coolidge
"A lie can travel half way around the world while the truth is putting on its shoes." ~Mark Twain "
As the fear of God is the beginning of wisdom, so the denial of God is the height of foolishness.-RC Sproul, Essential Truths of the Christian Faith

- You can safely assume that you've created God in your own image when it turns out that God hates all the same people you do.
Anne Lamott
I Have Strong Arguments Which I Cant Say To You~CG

This message is a reply to:
 Message 31 by Kleinman, posted 05-26-2020 9:31 AM Kleinman has replied

Replies to this message:
 Message 33 by Kleinman, posted 05-26-2020 5:29 PM Phat has not replied

  
Kleinman
Member (Idle past 335 days)
Posts: 2142
From: United States
Joined: 10-06-2016


Message 33 of 239 (876721)
05-26-2020 5:29 PM
Reply to: Message 32 by Phat
05-26-2020 4:47 PM


a distinct difference between chance & true randomness vs a set & measurable prob?
Phat writes:
all that i would add, not being a scientist or a creationist is that there is a distinct difference between chance and true randomness versus a set and measureable probability.
I think you are trying to draw a distinction using semantics when there is no mathematical difference. But, if you think I'm wrong, give us empirical examples of "chance and true randomness" and a "set and measurable probability" and show us what that distinct difference is.

This message is a reply to:
 Message 32 by Phat, posted 05-26-2020 4:47 PM Phat has not replied

  
Taq
Member
Posts: 9970
Joined: 03-06-2009
Member Rating: 5.6


Message 34 of 239 (876722)
05-26-2020 5:35 PM
Reply to: Message 31 by Kleinman
05-26-2020 9:31 AM


Re: Trying to give nwr more than a vague understanding of DNA evolution
Kleinman writes:
It is you who is wrong nwr. DNA evolution is a binomial probability problem. The random trial is a replication and the two possible outcomes are, does a beneficial mutation occur or does a beneficial mutation does not occur. That is analogous to a coin toss problem where the random trial is the toss of the coin and the two possible outcomes does a head occur or does a head not occur.
No analogy is perfect, but I don't think a coin toss is a good one. First, the benefice of a mutation can be small or great, not simply heads or tails. Second, the same mutation can be neutral or detrimental in one genetic background and beneficial in another. A lottery might be a better comparison where someone can win 5 bucks or hundreds of millions, and the winning ticket from one drawing won't necessarily be a winner in the next.
It doesn't matter whether the environment is static or not.
Umm, yes it does. Read up on fitness landscapes and niche specialization. As you near an optimum the number of beneficial changes is greatly reduced. A changing environment results in optimized species being less optimize which increases the number of potential beneficial changes.
If they were to change their environments at any time during the performance of the experiment, that would mean they would be changing the evolutionary trajectories for increasing fitness making those evolutionary trajectories more complex.
Why would it be more complex? If you changed temperature or salt concentrations at the same time I don't see how it would be more complex, as long as those conditions weren't immediately lethal.

This message is a reply to:
 Message 31 by Kleinman, posted 05-26-2020 9:31 AM Kleinman has replied

Replies to this message:
 Message 35 by Kleinman, posted 05-26-2020 7:15 PM Taq has replied

  
Kleinman
Member (Idle past 335 days)
Posts: 2142
From: United States
Joined: 10-06-2016


Message 35 of 239 (876729)
05-26-2020 7:15 PM
Reply to: Message 34 by Taq
05-26-2020 5:35 PM


Re: Trying to give nwr more than a vague understanding of DNA evolution
Kleinman writes:
It is you who is wrong nwr. DNA evolution is a binomial probability problem. The random trial is a replication and the two possible outcomes are, does a beneficial mutation occur or does a beneficial mutation does not occur. That is analogous to a coin toss problem where the random trial is the toss of the coin and the two possible outcomes does a head occur or does a head not occur.
Taq writes:
No analogy is perfect, but I don't think a coin toss is a good one. First, the benefice of a mutation can be small or great, not simply heads or tails. Second, the same mutation can be neutral or detrimental in one genetic background and beneficial in another. A lottery might be a better comparison where someone can win 5 bucks or hundreds of millions, and the winning ticket from one drawing won't necessarily be a winner in the next.
That's correct that a mutation can be neutral or detrimental in one environment (what you call a genetic background) and beneficial in another. But that doesn't make any difference in the mathematics of the evolutionary trajectory. Think of it in the context of the Kishony experiment. When Kishony is using ciprofloxacin as the selection pressure. His variants on the ciprofloxacin evolutionary trajectory are accumulating the mutations necessary for adaptation by a billion replications per evolutionary step until one of the lucky members gets the next beneficial mutation to take a step on that evolutionary trajectory and grow in the next higher drug concentration region. In his population are other members getting mutations that are beneficial for other drugs (such as trimethoprim) but his petri dish is not large enough for those variants to accumulate the billion replications for the trimethoprim resistance evolutionary trajectory. If Kishony made an even larger petri dish without any antibiotic such that he could get much, much, larger populations, he would get variants resistant to all kinds of drugs, just as Lenski's founder's populations did. Every evolutionary trajectory consists of nested binomial probability problems joined by the multiplication rule. What determines the ability of a lineage to take a particular evolutionary trajectory is the ability of each variant at each evolutionary step to replicate sufficiently to have a reasonable probability to get a beneficial mutation. And when the probability of success is given by the mutation rate, it's going to be a lot of replications at each evolutionary step as demonstrated by the Kishony and Lenski experiments.
Kleinman writes:
It doesn't matter whether the environment is static or not.
Taq writes:
Umm, yes it does. Read up on fitness landscapes and niche specialization. As you near an optimum the number of beneficial changes is greatly reduced. A changing environment results in optimized species being less optimize which increases the number of potential beneficial changes.
Umm, no it doesn't. What changes could you make to the Kishony experiment to make his populations evolve more quickly? And if you want to make the Lenski experiment evolve more rapidly, increase the carrying capacity. That would reduce the competition allowing the adapting lineage to achieve more replications in the same time interval. But if any changes to the selection conditions are made during the experiment such as changing or adding additional drugs in the Kishony experiment or adding additional selection pressures such as thermal stress in the Lenski experiment will slow the evolutionary process or possibly drive the populations to extinction.
Kleinman writes:
If they were to change their environments at any time during the performance of the experiment, that would mean they would be changing the evolutionary trajectories for increasing fitness making those evolutionary trajectories more complex.
Taq writes:
Why would it be more complex? If you changed temperature or salt concentrations at the same time I don't see how it would be more complex, as long as those conditions weren't immediately lethal.
I'll explain why the evolutionary trajectory is more complex when evolution must occur to simultaneous selection pressures using the Kishony experiment because it is easier to visualize.
Let's say that Kishony uses two drugs instead of one in his experiment. Let's say one drug requires mutations A1, A2, A3 for adaptation, and the other drug requires mutations B1, B2, B3. The 1,2 and 3 indicate drug regions 1,2 and 3 respectively. For a member of the wild-type to grow in the first region, that member needs mutations A1 and B1 (note that in the single drug experiment, A1 or B1 alone would allow growth in the first region depending on the drug).
The wild-type now starts to replicate in the drug-free region and when the colony size reaches about a billion, there is a reasonable probability of an A1 variant occurring and a B1 variant occurring. As the colony is growing the subset with the A1 and B1 mutations are growing as well but the vast majority of the population will still be wild-type (without either A1 or B1). In about 30 more doublings of the colony, the A1 and B1 subsets will achieve a billion replications and the A1 variant will have a reasonable probability of getting a B1 mutation and the B1 variant will have a reasonable probability of getting an A1 mutation. But, at the same time, the wild-type subset which had a population size of about a billion when the A1 and B1 variants appeared will also have done 30 more doublings (if the petri dish is large enough to allow this). Each different selection condition has its own particular set of mutations which might give improved fitness. Why would you think that adaptation to salt concentrations would give the require the same mutations as thermal stress? They don't. But if you want a population that adapts to both salt concentrations and thermal stress, a lineage needs to accumulate the mutations necessary for improved fitness and adaptation to both selection pressures. And that's going to take exponentially more replications than the single selection pressure environments.
If you want to see how to do the mathematics for adaptation to multiple simultaneous selection pressures, read this paper:
Just a moment...

This message is a reply to:
 Message 34 by Taq, posted 05-26-2020 5:35 PM Taq has replied

Replies to this message:
 Message 40 by Taq, posted 05-27-2020 11:59 AM Kleinman has replied

  
nwr
Member
Posts: 6408
From: Geneva, Illinois
Joined: 08-08-2005
Member Rating: 5.1


(1)
Message 36 of 239 (876733)
05-26-2020 9:23 PM
Reply to: Message 31 by Kleinman
05-26-2020 9:31 AM


Re: Trying to give nwr more than a vague understanding of DNA evolution
The random trial is a replication and the two possible outcomes are, does a beneficial mutation occur or does a beneficial mutation does not occur.
That's too simplistic.
A mutation might allow an organism to move to a slightly different environmental niche. The mutation could be detrimental in the current niche, but advantageous in the new niche.
Withholding antibiotics from someone who needs them not only has health consequences but economic consequences as well.
I'm not aware of any serious suggestions to do that. More commonly the concern is with indiscriminate use of antibiotics, or the use of antibiotics in farm animal feed because it helps to fatten the animals.

Fundamentalism - the anti-American, anti-Christian branch of American Christianity

This message is a reply to:
 Message 31 by Kleinman, posted 05-26-2020 9:31 AM Kleinman has not replied

Replies to this message:
 Message 37 by jar, posted 05-27-2020 7:33 AM nwr has seen this message but not replied

  
jar
Member (Idle past 393 days)
Posts: 34026
From: Texas!!
Joined: 04-20-2004


(1)
Message 37 of 239 (876742)
05-27-2020 7:33 AM
Reply to: Message 36 by nwr
05-26-2020 9:23 PM


Re: Trying to give nwr more than a vague understanding of DNA evolution
Or in patients that start to feel better and so stop taking the full prescribed regimen.

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Kleinman
Member (Idle past 335 days)
Posts: 2142
From: United States
Joined: 10-06-2016


Message 38 of 239 (876744)
05-27-2020 9:28 AM


Responsed to nwr and jar
Kleinman writes:
The random trial is a replication and the two possible outcomes are, does a beneficial mutation occur or does a beneficial mutation does not occur.
nwr writes:
That's too simplistic.
A mutation might allow an organism to move to a slightly different environmental niche. The mutation could be detrimental in the current niche, but advantageous in the new niche.
Sure, that's just a different variant on a different evolutionary trajectory. That's why when Kishony runs his experiment with ciprofloxacin, any variant with a mutation that might be beneficial for trimethoprim (or any other class of antibiotics for that matter) cannot successfully evolve on his plate. There's not enough carrying capacity. But the mathematics for DNA evolution for each of these evolutionary trajectories is the same. It is all a matter of being able to replicate sufficiently to accumulate the mutations necessary to adapt to the selection pressure(s) of a given environment.
Kleinman writes:
Withholding antibiotics from someone who needs them not only has health consequences but economic consequences as well.
nwr writes:
I'm not aware of any serious suggestions to do that. More commonly the concern is with indiscriminate use of antibiotics, or the use of antibiotics in farm animal feed because it helps to fatten the animals.
You should be aware of this problem. The way it happens is a patient presents to the medical provider with relatively mild symptoms, eg, clear nasal discharge, and an irritated throat. The medical provider makes a clinical judgment and tells the patient it's probably allergies or a virus and to go home and take an allergy pill or some chicken soup. The medical provider doesn't do a close follow-up or instruct the patient correctly what to do if worse and the patient ends up with a more severe bacterial infection. This is actually a common problem as indicated by the hospital admission data (septicemia and pneumonia numbers 1 and 4 respectively).
With respect to the indiscriminate use of antibiotics, the cliche, "you can't treat viral infections with antibacterial drugs", is not quite accurate. The patients that got influenza in the H1N1 epidemic about 10 years ago had about a 60% co-infection rate with bacteria and it won't surprise me if when the data is analyzed from the covid epidemic that many of the deaths are associated with bacterial co-infections. That's the reason I think they were seeing some improvement when using azithromycin for treatment. It's also possible that azithromycin has some antiviral activity.
And the use of antibiotics may have been done in food-lot raised animals that are fed starch because they don't need the cellulose digesting bacteria in their rumen but giving antibiotics to range-fed animals will prevent them from digesting grass. But, let's say that antibiotics are given to corn or grain-fed feed-lot animals, what difference does that make to people getting drug-resistant infections? We've already shown that you don't need antibiotics for the drug-resistant variants to appear. We already have these drug-resistant variants in our gut, on our skin, and on the lining of our respiratory tract. It's the misunderstanding of the mathematics of evolution which leads to incorrect usage of antibiotics and the selection of these drug-resistant variants causing these multi-drug resistant infections.
jar writes:
Or in patients that start to feel better and so stop taking the full prescribed regimen.
That's correct. The patient may still have mild residual infection and not comprehend the signs. Many physicians tell their patients, "just take all 10 days of your antibiotics" is an inadequate way of instructing patients on the usage of antibiotic. Patients need to understand what they should expect from correct antimicrobial treatment since they are the ones doing the observation of their response to treatment. I give my patients 3 rules to follow when using antibiotics. First rule, if you don't see improvement by day 2 (reduced fever, reduced pain, a sense of better well being, etc.), call me. Second rule, if antibiotic is working, stay on treatment until completely better plus 3 days (to account for assymptomatic residual infection). And third, when stopping the antibiotic, watch for relapse, if that occurs, restart antibiotics and notify me.

Replies to this message:
 Message 39 by Taq, posted 05-27-2020 11:47 AM Kleinman has not replied

  
Taq
Member
Posts: 9970
Joined: 03-06-2009
Member Rating: 5.6


(1)
Message 39 of 239 (876749)
05-27-2020 11:47 AM
Reply to: Message 38 by Kleinman
05-27-2020 9:28 AM


Re: Responsed to nwr and jar
Kleinman writes:
That's why when Kishony runs his experiment with ciprofloxacin, any variant with a mutation that might be beneficial for trimethoprim (or any other class of antibiotics for that matter) cannot successfully evolve on his plate.
I don't see why this would be the case. If resistance to cipro is gained by a single substitution mutation then it wouldn't matter if the founding population also has a single substitution for trimethoprim resistance. It is just a matter of having enough divisions to get that cipro mutation. If you took a cipro resistant colony and grew it up in large numbers on trimethoprim plates you would have the same chances of getting that mutant as you would with a cipro sensitive clone.

This message is a reply to:
 Message 38 by Kleinman, posted 05-27-2020 9:28 AM Kleinman has not replied

  
Taq
Member
Posts: 9970
Joined: 03-06-2009
Member Rating: 5.6


(2)
Message 40 of 239 (876750)
05-27-2020 11:59 AM
Reply to: Message 35 by Kleinman
05-26-2020 7:15 PM


Re: Trying to give nwr more than a vague understanding of DNA evolution
Kleinman writes:
That's correct that a mutation can be neutral or detrimental in one environment (what you call a genetic background) and beneficial in another.
Genetic background and environment are two different things. What I am talking about is epistasis:
"Epistasis is a phenomenon in genetics in which the effect of a gene mutation is dependent on the presence or absence of mutations in one or more other genes, respectively termed modifier genes."
Epistasis - Wikipedia
What changes could you make to the Kishony experiment to make his populations evolve more quickly?
You could change growth temperature, salt concentration, protein sources, carbon sources, and so on. Growing bacteria in the same environment for long periods of time moves them towards a peak in the fitness landscape where very few if any mutations improving fitness.
Fitness landscape - Wikipedia
Let's say that Kishony uses two drugs instead of one in his experiment. Let's say one drug requires mutations A1, A2, A3 for adaptation, and the other drug requires mutations B1, B2, B3.
For a single drug it would be A1, A2, and A3. It would be the same pathway, and it wouldn't be more complex. The pathways for resistance to each drug are the same no matter how many drugs are present.
Why would you think that adaptation to salt concentrations would give the require the same mutations as thermal stress?
I never said they would. If the bacteria are adapting to multiple new challenges at the same time then this will select for many new beneficial mutations in many genes. If we are measuring evolution as the fixation of beneficial mutations, then a big change in environment will result in a higher rate of evolution.
Also, there could be overlap in salt and temperature adaptations, such as chaperone proteins that could stabilize proteins in both high temps and different salt concentrations (i.e. heat shock proteins).

This message is a reply to:
 Message 35 by Kleinman, posted 05-26-2020 7:15 PM Kleinman has replied

Replies to this message:
 Message 41 by Kleinman, posted 05-27-2020 1:15 PM Taq has replied

  
Kleinman
Member (Idle past 335 days)
Posts: 2142
From: United States
Joined: 10-06-2016


Message 41 of 239 (876752)
05-27-2020 1:15 PM
Reply to: Message 40 by Taq
05-27-2020 11:59 AM


Re: Trying to give nwr more than a vague understanding of DNA evolution
Kleinman writes:
That's correct that a mutation can be neutral or detrimental in one environment (what you call a genetic background) and beneficial in another.
Taq writes:
Genetic background and environment are two different things. What I am talking about is epistasis:
"Epistasis is a phenomenon in genetics in which the effect of a gene mutation is dependent on the presence or absence of mutations in one or more other genes, respectively termed modifier genes."
Epistasis - Wikipedia
From your wikipedia link writes:
Understanding of epistasis has changed considerably through the history of genetics and so too has the use of the term. In early models of natural selection devised in the early 20th century, each gene was considered to make its own characteristic contribution to fitness, against an average background of other genes. Some introductory courses still teach population genetics this way. Because of the way that the science of population genetics was developed, evolutionary geneticists have tended to think of epistasis as the exception. However, in general, the expression of any one allele depends in a complicated way on many other alleles.
You are conflating two concepts, the creation of new alleles (DNA evolution) and the expression of any one allele (epistasis).
Kleinman writes:
What changes could you make to the Kishony experiment to make his populations evolve more quickly?
Taq writes:
You could change growth temperature, salt concentration, protein sources, carbon sources, and so on. Growing bacteria in the same environment for long periods of time moves them towards a peak in the fitness landscape where very few if any mutations improving fitness.
Fitness landscape - Wikipedia
There is no indication that Kishony's team is running their experiment at non-optimal temperatures, non-optimal salt concentrations, non-optimal protein and carbon sources or any other selection pressure.
Spatiotemporal microbial evolution on antibiotic landscapes - PMC
But even if they did, why would you think that it would take fewer than a billion replications for each evolutionary step to evolve and adapt to the antibiotic selection pressure?
Kleinman writes:
Let's say that Kishony uses two drugs instead of one in his experiment. Let's say one drug requires mutations A1, A2, A3 for adaptation, and the other drug requires mutations B1, B2, B3.
For a single drug it would be A1, A2, and A3. It would be the same pathway, and it wouldn't be more complex. The pathways for resistance to each drug are the same no matter how many drugs are present.
Why would you think that adaptation to salt concentrations would give the require the same mutations as thermal stress?
Taq writes:
I never said they would. If the bacteria are adapting to multiple new challenges at the same time then this will select for many new beneficial mutations in many genes. If we are measuring evolution as the fixation of beneficial mutations, then a big change in environment will result in a higher rate of evolution.
The key point that you are missing here is that all these beneficial mutation somehow have to end up in some common lineage for this lineage to be adapted to all these selection pressures. It doesn't help one lineage which has a beneficial mutation for a given selection pressure if a different lineage gets a beneficial mutation for a different selection pressure. Putting it into the context of the Kishony experiment, a beneficial mutation for trimethoprim doesn't help that variant when the selection pressure is ciprofloxacin. But when Kishony runs his experiment with two drugs, only when some member of the population has a beneficial mutation for both ciprofloxacin and for trimethoprim will that member be able to grow in the next higher drug concentration region.
And fixation is not required for DNA evolution to occur. If you think it does, why are the drug sensative variants still growing when the drug resistant variants have evolved? Competition and fixation only slow the DNA evolution process.
Taq writes:
Also, there could be overlap in salt and temperature adaptations, such as chaperone proteins that could stabilize proteins in both high temps and different salt concentrations (i.e. heat shock proteins).
You are speculating. Try understanding these simple evolutionary experiments. The math is not that hard. Even your slot-machine analogy is not that bad. The math really isn't much different than the binomial probability problem. When you pull on the arm of the one-armed bandit, you may have tiny chance of winning the big jackpot and you might have a better chance of winning a smaller jackpot but the joint probability of winning both has to be computed using the multiplication rule. (Of course, you won't win both on a single pull, the events are mutually exclusive).

This message is a reply to:
 Message 40 by Taq, posted 05-27-2020 11:59 AM Taq has replied

Replies to this message:
 Message 42 by Taq, posted 05-27-2020 1:34 PM Kleinman has replied

  
Taq
Member
Posts: 9970
Joined: 03-06-2009
Member Rating: 5.6


Message 42 of 239 (876753)
05-27-2020 1:34 PM
Reply to: Message 41 by Kleinman
05-27-2020 1:15 PM


Re: Trying to give nwr more than a vague understanding of DNA evolution
Kleinman writes:
You are conflating two concepts, the creation of new alleles (DNA evolution) and the expression of any one allele (epistasis).
I never confused those. Epistasis is a description of how mutations and alleles interact with one another to give rise to a phenotype.
But even if they did, why would you think that it would take fewer than a billion replications for each evolutionary step to evolve and adapt to the antibiotic selection pressure?
That's not the point. What we are saying is that big changes in environment can lead to more evolution. This is due to fitness landscapes.
The key point that you are missing here is that all these beneficial mutation somehow have to end up in some common lineage for this lineage to be adapted to all these selection pressures.
However, they don't have to be acquired all at the same time. In fact, different lineages can take different pathways, such as one lineage adapting to temperature first, followed by salt concentration. A different lineage could adapt to salt concentration first, then temperature. There could also be multiple different mutational pathways for each environmental challenge, such as bats and birds having different adaptations for flight.
But when Kishony runs his experiment with two drugs, only when some member of the population has a beneficial mutation for both ciprofloxacin and for trimethoprim will that member be able to grow in the next higher drug concentration region.
If the experiment were set up with different regions of the plate having different antibiotics then you could have lineages adapting to one drug and then the other.
And fixation is not required for DNA evolution to occur.
Then why did you say the following in a previous post?
"What this does is it forces his populations to compete for the limited resources and the more fit variant must drive the less fit variant to extinction in order to accumulate the necessary replications for improving fitness."
You are speculating.
You are also speculating when you say that adaptations to temperature and salt concentrations must be different mutations.

This message is a reply to:
 Message 41 by Kleinman, posted 05-27-2020 1:15 PM Kleinman has replied

Replies to this message:
 Message 43 by Kleinman, posted 05-27-2020 3:40 PM Taq has replied

  
Kleinman
Member (Idle past 335 days)
Posts: 2142
From: United States
Joined: 10-06-2016


Message 43 of 239 (876759)
05-27-2020 3:40 PM
Reply to: Message 42 by Taq
05-27-2020 1:34 PM


Re: Trying to give nwr more than a vague understanding of DNA evolution
Kleinman writes:
You are conflating two concepts, the creation of new alleles (DNA evolution) and the expression of any one allele (epistasis).
Taq writes:
I never confused those. Epistasis is a description of how mutations and alleles interact with one another to give rise to a phenotype.
Then, explain to us how epistasis affects the mathematics of either the Kishony or Lenski experiments. And show your math if you think you understand the mathematics of evolution.
Kleinman writes:
But even if they did, why would you think that it would take fewer than a billion replications for each evolutionary step to evolve and adapt to the antibiotic selection pressure?
Taq writes:
That's not the point. What we are saying is that big changes in environment can lead to more evolution. This is due to fitness landscapes.
And the more complex the fitness landscape, the more complex any evolutionary trajectory. And if you want to see a bottleneck in a population, have a big change in the environment, that is if the population is not driven to extinction. Big environmental changes are far more difficult for populations to adapt to. Even the Kishony experiment demonstrates this. If the step change in antibiotic concentration is too large, the experiment does not work. That's because 2 or more mutations are needed to give the necessary improvement in fitness. DNA evolution works most efficiently when only a single mutation gives improved fitness in the given environment. The reason for this is the multiplication rule which requires exponentially more replications for that evolutionary process to have a reasonable probability of occurring.
Kleinman writes:
The key point that you are missing here is that all these beneficial mutation somehow have to end up in some common lineage for this lineage to be adapted to all these selection pressures.
Taq writes:
However, they don't have to be acquired all at the same time. In fact, different lineages can take different pathways, such as one lineage adapting to temperature first, followed by salt concentration. A different lineage could adapt to salt concentration first, then temperature. There could also be multiple different mutational pathways for each environmental challenge, such as bats and birds having different adaptations for flight.
I didn't say the beneficial mutations have to occur at the same time. But the multiplication rule still applies no matter when the beneficial mutations occur. What improves the probability of this happening is the ability of the particular variant's ability to replicate.
Let's use your slot-machine analogy. Let's say there are two possible jackpots, a super jackpot, and a big jackpot. And let the probability of winning the super jackpot is one in ten million and the probability of winning the big jackpot is one in a million with each pull of the arm. Do you understand how to compute the probability of winning both of those jackpots as a function of the number of pulls on the arm? It's essentially the same math as the Kishony experiment if he were to use two drugs.
And you are still having difficulty understanding that every evolutionary pathway must obey this math. Kishony's bacteria may have multiple different sets of mutations that can give resistance to the drug used but it still is going to take a billion replications for each evolutionary step on each of these trajectories. These are the mathematical facts of life of DNA evolution.
Kleinman writes:
But when Kishony runs his experiment with two drugs, only when some member of the population has a beneficial mutation for both ciprofloxacin and for trimethoprim will that member be able to grow in the next higher drug concentration region.
Taq writes:
If the experiment were set up with different regions of the plate having different antibiotics then you could have lineages adapting to one drug and then the other.
You don't need to do that. Simply take the bacteria that has already adapted to ciprofloxacin and use those as the starter population for the trimethoprim experiment. All you are demonstrating is that DNA evolution works most efficiently a single selection pressure at a time. That's how MRSA was created except in the clinical environment. When one drug failed, go on to the next drug until that drug fails. If you are going to gamble with microbes, you should understand the rules of the game.
Kleinman writes:
And fixation is not required for DNA evolution to occur.
Taq writes:
Then why did you say the following in a previous post?
"What this does is it forces his populations to compete for the limited resources and the more fit variant must drive the less fit variant to extinction in order to accumulate the necessary replications for improving fitness."
The limited carrying capacity environment in the Lenski forces his populations to compete for the limited glucose. If Lenski were to run his experiment in 100ml of solution instead of 10ml, the more fit variant will achieve enough replications to have a reasonable probability of another beneficial mutation occurring before the less fit variants are driven to extinction, fixation is not necessary for a beneficial mutation to occur in this case. What you should try to understand is that the human body has a huge carrying capacity for microbes. The population size of these microbes easily achieves the numbers necessary for drug-resistant variants to occur. In other words, the Kishony experiment would not work in a standard-sized petri dish, you need very large populations for DNA evolution to work.
Kleinman writes:
You are speculating.
Taq writes:
You are also speculating when you say that adaptations to temperature and salt concentrations must be different mutations.
Not so. Lenski has run experiments using thermal stress for his selection condition.
https://courses.pbsci.ucsc.edu/...i_&_Bennett_AmNat_1993.pdf

This message is a reply to:
 Message 42 by Taq, posted 05-27-2020 1:34 PM Taq has replied

Replies to this message:
 Message 44 by Taq, posted 05-27-2020 6:42 PM Kleinman has replied

  
Taq
Member
Posts: 9970
Joined: 03-06-2009
Member Rating: 5.6


Message 44 of 239 (876768)
05-27-2020 6:42 PM
Reply to: Message 43 by Kleinman
05-27-2020 3:40 PM


Re: Trying to give nwr more than a vague understanding of DNA evolution
Then, explain to us how epistasis affects the mathematics of either the Kishony or Lenski experiments.
The genetic background of the population will determine the probability of arriving at a beneficial mutation.
And the more complex the fitness landscape, the more complex any evolutionary trajectory.
A complex landscape can afford multiple evolutionary pathways towards increased fitness, but each pathway is as simple as it would be in a simple landscape. If you want to define complexity as the number of possible evolutionary pathways then I would agree.
Big environmental changes are far more difficult for populations to adapt to.
That depends on a lot of factors. When the first limbed fish started pushing themselves onto land they had very little competition from other land animals. However, a poorly adapted fish will have a very tough time moving onto land now since there are a lot of well adapted tetrapods filling those niches. The K/T meteor impact produced a massive change in environment, and what resulted was the radiation of mammals and birds, one of the biggest surges in evolutionary change in the fossil record.
DNA evolution works most efficiently when only a single mutation gives improved fitness in the given environment. The reason for this is the multiplication rule which requires exponentially more replications for that evolutionary process to have a reasonable probability of occurring.
What you seem to be ignoring is that there is often more than one mutation that is beneficial, and evolution can search for those solutions in parallel. It's not as if it has to be one mutation at a time. Epistasis also demonstrates that neutral mutations can become beneficial at a future time point as they interact with new mutations and new environments.
Let's use your slot-machine analogy. Let's say there are two possible jackpots, a super jackpot, and a big jackpot. And let the probability of winning the super jackpot is one in ten million and the probability of winning the big jackpot is one in a million with each pull of the arm. Do you understand how to compute the probability of winning both of those jackpots as a function of the number of pulls on the arm?
Given the right population dynamics and environments, it is pretty simple. With an initial increase of 20 million you are almost guaranteed to get the first mutation. The winner of that jackpot starts dividing until it has 2 million offspring which nearly guarantees a winner for the next jackpot.
You don't need to do that. Simply take the bacteria that has already adapted to ciprofloxacin and use those as the starter population for the trimethoprim experiment. All you are demonstrating is that DNA evolution works most efficiently a single selection pressure at a time. That's how MRSA was created except in the clinical environment.
Those types of scenarios rarely exist outside of labs. Outside of labs, species exist in a diverse ecology and rarely do they live in a tightly controlled environment that only differs by one variable.
Not so. Lenski has run experiments using thermal stress for his selection condition.
That's one lineage of one species of bacteria. It can't be generalized to all bacteria or all life.
Edited by Taq, : No reason given.

This message is a reply to:
 Message 43 by Kleinman, posted 05-27-2020 3:40 PM Kleinman has replied

Replies to this message:
 Message 45 by Kleinman, posted 05-27-2020 10:18 PM Taq has replied

  
Kleinman
Member (Idle past 335 days)
Posts: 2142
From: United States
Joined: 10-06-2016


Message 45 of 239 (876774)
05-27-2020 10:18 PM
Reply to: Message 44 by Taq
05-27-2020 6:42 PM


Re: Trying to give nwr more than a vague understanding of DNA evolution
Kleinman writes:
That's why when Kishony runs his experiment with ciprofloxacin, any variant with a mutation that might be beneficial for trimethoprim (or any other class of antibiotics for that matter) cannot successfully evolve on his plate.
Taq writes:
I don't see why this would be the case. If resistance to cipro is gained by a single substitution mutation then it wouldn't matter if the founding population also has a single substitution for trimethoprim resistance. It is just a matter of having enough divisions to get that cipro mutation. If you took a cipro resistant colony and grew it up in large numbers on trimethoprim plates you would have the same chances of getting that mutant as you would with a cipro sensitive clone.
The reason this is the case is that the carrying capacity in the drug-free region is not large enough to accommodate both the wild-type and the drug-resistant variants multiplication. I tried to explain this in an earlier post but I'm just not getting through to you.
Try and understand it this way. Imagine you have a vast, unlimited size petri dish with infinite carrying capacity and no antibiotics. You start with a single wild-type bacterium that is sensitive to all antibiotics. This bacterium doubles, the resultant bacteria double, and on and on with members accumulating mutations at the frequency of the mutation rate. After 30 doublings, you will have a billion bacteria and for a mutation rate of e-9, you will have on average, some member with a mutation at every site in the genome. That means there will be about 1 member with a beneficial mutation for ciprofloxacin, another member with a beneficial mutation for trimethoprim but the rest of the population will have mutations at other sites or no mutations at all. Then this population continues to double for 30 more generations. You will then have a billion members with the ciprofloxacin mutation (plus any other mutations accumulated including one for the trimethoprim), a billion members with the trimethoprim mutation (plus any other mutations including one for the ciprofloxacin), and for the remaining population of a billion minus the ciprofloxacin and trimethoprim variants, you will have a quintillion members (minus a few members along the way that get either the ciprofloxacin or trimethoprim mutations). The bands in the Kishony experiment give a region where the drug-resistant variants can grow without having to compete for the depleted resources in the drug-free region. Here's a Venn Diagram of the system:
A1 and A2 are the two different variants.
Kleinman writes:
Then, explain to us how epistasis affects the mathematics of either the Kishony or Lenski experiments. And show your math if you think you understand the mathematics of evolution.
Taq writes:
The genetic background of the population will determine the probability of arriving at a beneficial mutation.
That answers that, you don't understand the mathematics of evolution so you snip out the part highlighted in red.
Kleinman writes:
And the more complex the fitness landscape, the more complex any evolutionary trajectory.
Taq writes:
A complex landscape can afford multiple evolutionary pathways towards increased fitness, but each pathway is as simple as it would be in a simple landscape. If you want to define complexity as the number of possible evolutionary pathways then I would agree.
What you refuse to accept is that the steps in every evolutionary trajectory are joint by the multiplication rule. And if it takes multiple mutations to improve fitness in an evolutionary step, you have multiple instances of the multiplication rule acting simultaneously. That's why the Kishony experiment won't work on his large petri when two drugs are used or when the step increase in drug-concentration is so large that it requires two or more mutations for that step.
Kleinman writes:
Big environmental changes are far more difficult for populations to adapt to.
Taq writes:
That depends on a lot of factors. When the first limbed fish started pushing themselves onto land they had very little competition from other land animals. However, a poorly adapted fish will have a very tough time moving onto land now since there are a lot of well adapted tetrapods filling those niches. The K/T meteor impact produced a massive change in environment, and what resulted was the radiation of mammals and birds, one of the biggest surges in evolutionary change in the fossil record.
You can't explain mathematical behavior of the Kishony or Lenski experiments so now you start storytelling. Why does it take a billion replications for every evolutionary step in the Kishony experiment? Please show your math.
Kleinman writes:
DNA evolution works most efficiently when only a single mutation gives improved fitness in the given environment. The reason for this is the multiplication rule which requires exponentially more replications for that evolutionary process to have a reasonable probability of occurring.
Taq writes:
What you seem to be ignoring is that there is often more than one mutation that is beneficial, and evolution can search for those solutions in parallel. It's not as if it has to be one mutation at a time. Epistasis also demonstrates that neutral mutations can become beneficial at a future time point as they interact with new mutations and new environments.
I havn't ignored that at all. It doesn't matter which evolutionary trajectory that a lineage takes. It doesn't change the math.
Kleinman writes:
Let's use your slot-machine analogy. Let's say there are two possible jackpots, a super jackpot, and a big jackpot. And let the probability of winning the super jackpot is one in ten million and the probability of winning the big jackpot is one in a million with each pull of the arm. Do you understand how to compute the probability of winning both of those jackpots as a function of the number of pulls on the arm?
Taq writes:
Given the right population dynamics and environments, it is pretty simple. With an initial increase of 20 million you are almost guaranteed to get the first mutation. The winner of that jackpot starts dividing until it has 2 million offspring which nearly guarantees a winner for the next jackpot.
That math will work if the mutation rate for your first case is 5e-8 and 5e-7 for you second case. For the Kishony and Lenski experiments, the beneficial mutation closer to about e-9. But the mutation rate is not the major driving factory in DNA evolution, it is the number of selection pressures the population is adapting to because each selection pressure introduces another instance of the multiplication rule in the evolutionary trajectory. This is why despite its very high mutation rate, hiv cannot evolve efficiently to 3 drug therapy.
Just a moment...
Kleinman writes:
You don't need to do that. Simply take the bacteria that have already adapted to ciprofloxacin and use those as the starter population for the trimethoprim experiment. All you are demonstrating is that DNA evolution works most efficiently a single selection pressure at a time. That's how MRSA was created except in the clinical environment.
Taq writes:
Those types of scenarios rarely exist outside of labs. Outside of labs, species exist in a diverse ecology, and rarely do they live in a tightly controlled environment that only differs by one variable.
Is that so? You are obviously not aware that single-drug therapy has been the standard of care for infectious diseases for years. That's why MRSA is so common.
Kleinman writes:
Not so. Lenski has run experiments using thermal stress for his selection condition.
Taq writes:
That's one lineage of one species of bacteria. It can't be generalized to all bacteria or all life.
What is your logic and reasoning to think that beneficial mutations for one selection pressure would be the same for a totally different selection pressure?

This message is a reply to:
 Message 44 by Taq, posted 05-27-2020 6:42 PM Taq has replied

Replies to this message:
 Message 48 by Taq, posted 05-28-2020 11:33 AM Kleinman has replied

  
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