# Detwiler: Questions Behe, Polyphen, and Ratchets

**URL:** <https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088>\
**Category:** Conversation\
**Tags:** Science\
**Created:** [March 5, 2019, 3:31pm UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088 "2019-03-05T15:31:27Z")\
**Posts on this page:** 20\
**Page:** 5

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**Author:** ![John\_Detwiler](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/john_detwiler/32/3683_2.png) [@John\_Detwiler](https://discourse.peacefulscience.org/u/John_Detwiler)\
**Post date:** [March 7, 2019, 3:22pm UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/81 "2019-03-07T15:22:29Z")

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> [@swamidass](#):
>
> It does not predict stability. Period

It scores for progress toward known folds. Known folds have enough stability to fold. I think right now there are only just over 400 known folds. I don’t see how this wouldn’t be expected to correlate with stability even from just a sequence perspective.

> [@swamidass](#):
>
> Negative selections weeds out mutations when they destabilizing too much. This prevents proteins from destabilizing entirely with time.

Obviously, but your problem is not broken proteins that kill an organism, it’s the build up of many many almost broken proteins that still function well enough to keep an organism alive and well enough to reproduce. I didn’t post those links just to show that snps often break proteins. I think it’s a pretty safe bet that somewhere between being completely denatured and the original stability, there is an area of less stability that is still viable. But you knew this or you wouldn’t have brought up neutral evolution.

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**Author:** ![swamidass](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/swamidass/32/3_2.png) [@swamidass](https://discourse.peacefulscience.org/u/swamidass)\
**Post date:** [March 7, 2019, 3:26pm UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/82 "2019-03-07T15:26:57Z")

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> [@John\_Detwiler](#):
>
> > It does not predict stability. Period
> 
> It scores for progress toward known folds. Known folds have enough stability to fold. I think right now there are only just over 400 known folds. I don’t see how this wouldn’t be expected to correlate with stability even from just a sequence perspective.

Why not just use a predictor designed to predict stability? There is just no point it treating an apple like its an orange, when an orange is easily available. This is pointless thing to resist. There is publicly available software to do this. Take a look at this:

> **[STRUM: Structure-based stability change prediction upon single-point mutation](https://seq2fun.dcmb.med.umich.edu//STRUM/)**
>
> STRUM: Structure-based stability change prediction upon single-point mutation

> [@John\_Detwiler](#):
>
> > Negative selections weeds out mutations when they destabilizing too much. This prevents proteins from destabilizing entirely with time.
> 
> Obviously, but your problem is not broken proteins that kill an organism, it’s the build up of many many almost broken proteins that still function well enough to keep an organism alive and well enough to reproduce. I didn’t post those links just to show that snps often break proteins.

Usually SNPs don’t break proteins. You know that right?

So the math of population genetics, and simulations too, shows that this isn’t a problem. When you are ready to learn about it we are here to teach you.

> [@Forum Disclaimer](https://discourse.peacefulscience.org/t/forum-disclaimer/186/1):
>
> If you must dispute mainstream science, it is not our aim to change your mind. Rather, we hope that you might understand what you reject, and that, perhaps, we might understand you too. We might also find ways to see how your most deeply held beliefs are not threatened.

---

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**Author:** ![T\_aquaticus](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/t_aquaticus/32/1249_2.png) [@T\_aquaticus](https://discourse.peacefulscience.org/u/T_aquaticus)\
**Post date:** [March 7, 2019, 4:01pm UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/83 "2019-03-07T16:01:53Z")

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> [@John\_Detwiler](#):
>
> Obviously, but your problem is not broken proteins that kill an organism, it’s the build up of many many almost broken proteins that still function well enough to keep an organism alive and well enough to reproduce.

If one additional slightly broken protein prevents reproduction then that additional mutation will be strongly selected against. In your model, not all slightly deleterious mutations have the same effects since the most recent mutations will have a very strong deleterious effect.

In fact, this scenario is exactly what the evidence supports:

> [@](#):
>
> To determine whether selection is slowing the effects of Muller’s ratchet, we determined the age of the _Candidatus_ Riesia/sucking louse assemblage and analyzed the nucleotide substitution rates of several p-endosymbiont lineages that differ in the length of time that they have been associated with their insect hosts. We find that _Riesia_ is the youngest p-endosymbiont known to date, and has been associated with its louse hosts for only 13–25 My. Further, it is the fastest evolving p-endosymbiont with substitution rates of 19–34% per 50 My. When comparing _Riesia_ to other insect p-endosymbionts, we find that nucleotide substitution rates decrease dramatically as the age of endosymbiosis increases.
> 
> _A decrease in nucleotide substitution rates over time suggests that selection may be limiting the effects of Muller’s ratchet by removing individuals with the highest mutational loads and decreasing the rate at which new mutations become fixed._ This countering effect of selection could slow the overall rate of endosymbiont extinction.  
> [Mutational Meltdown in Primary Endosymbionts: Selection Limits Muller's Ratchet](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0004969)  
> emphasis mine

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<div class="post-metadata">

**Author:** ![John\_Detwiler](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/john_detwiler/32/3683_2.png) [@John\_Detwiler](https://discourse.peacefulscience.org/u/John_Detwiler)\
**Post date:** [March 7, 2019, 4:18pm UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/84 "2019-03-07T16:18:53Z")

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> [@swamidass](#):
>
> This is pointless thing to resist. There is publicly available software to do this.

I’m totally for checking it out. A couple nights ago I was on the site but I don’t have an academic email address for them to send the results. I also could not find in the paper where the precise index of the mutations were listed. They are illustrated graphically but in the downloadable methods section, I could not find an explicit description, nor would I expect one given the number of proteins and mutations. I don’t have time to do much more than copy and paste these things around atm.

> [@swamidass](#):
>
> Usually SNPs don’t break proteins. You know that right?

actually I meant amino acid substitutions, which also don’t usually break a protein - only about 30% of the time.

> [@swamidass](#):
>
> So the math of population genetics, and simulations too, shows that this isn’t a problem.

I’m not against looking at it.

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<div class="post-metadata">

**Author:** ![swamidass](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/swamidass/32/3_2.png) [@swamidass](https://discourse.peacefulscience.org/u/swamidass)\
**Post date:** [March 7, 2019, 4:21pm UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/85 "2019-03-07T16:21:33Z")

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> [@John\_Detwiler](#):
>
> > Usually SNPs don’t break proteins. You know that right?
> 
> actually I meant amino acid substitutions, which also don’t usually break a protein - only about 30% of the time.

That is not true either. Did you follow what @Rumraket explained to you?

> [@John\_Detwiler](#):
>
> > So the math of population genetics, and simulations too, shows that this isn’t a problem.
> 
> I’m not against looking at it.

For humans, there are about 3 billion bases in the genome, and about 100 mutations each generation. Of these mutations, what percentage do you think are miss-sense mutations?

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**Author:** ![Rumraket](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/rumraket/32/9328_2.png) [@Rumraket](https://discourse.peacefulscience.org/u/Rumraket)\
**Post date:** [March 7, 2019, 4:26pm UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/86 "2019-03-07T16:26:02Z")

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> [@John\_Detwiler](#):
>
> It’s why humanity and most metazoa probably wouldn’t survive another million years.

Where have you published this conclusion?

> I think Haldane’s dillema is still a real problem since it doesn’t seem to me that most larger metazoa have enough offspring to eliminate accumulating deleterious proteins let alone fix new more beneficial ones.

Why?

> In fact, it demonstrably plays a role in our current fecundity.

What plays a role in our current fecundity? Homo sapiens is currently in an exponential population growth under relaxed selection due to agriculture and medical science. It would certainly be a mistake to extrapolate this pattern to the entirety of the biosphere.

> I don’t even think recombination could get around this problem even without the effects of gene conversion which seem to operate many orders of magnitude faster.

So now you’ve told us what you think. Next you should do the work that shows your conclusions are correct and publish them.

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<div class="post-metadata">

**Author:** ![Patrick](https://avatars.discourse-cdn.com/v4/letter/p/b2d939/32.png) [@Patrick](https://discourse.peacefulscience.org/u/Patrick)\
**Post date:** [March 7, 2019, 4:29pm UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/87 "2019-03-07T16:29:11Z")

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> [@John\_Detwiler](#):
>
> So you agree that just because I didn’t vote for Hillary doesn’t mean I love Trump?

I couldn’t care less who you voted for. 🕶

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<div class="post-metadata">

**Author:** ![davecarlson](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/davecarlson/32/2139_2.png) [@davecarlson](https://discourse.peacefulscience.org/u/davecarlson)\
**Post date:** [March 7, 2019, 4:41pm UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/88 "2019-03-07T16:41:09Z")

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> [@John\_Detwiler](#):
>
> I’m totally for checking it out. A couple nights ago I was on the site but I don’t have an academic email address for them to send the results.

You can also download the software, install, and run it locally. Doesn’t seem like any email is required for this.  
If you can’t/don’t want to do this, I can compile on my lab’s server and run whatever stability predictions you want. Just point me to the sequences you want to check.

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<div class="post-metadata">

**Author:** ![swamidass](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/swamidass/32/3_2.png) [@swamidass](https://discourse.peacefulscience.org/u/swamidass)\
**Post date:** [March 7, 2019, 4:57pm UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/89 "2019-03-07T16:57:21Z")

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@John_Detwiler, you can also use this one, from the lab in which I did my PhD. Believe it or not, computational modeling of biochemistry is in my wheelhouse.

[http://mupro.proteomics.ics.uci.edu/](http://mupro.proteomics.ics.uci.edu/)

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<div class="post-metadata">

**Author:** ![John\_Detwiler](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/john_detwiler/32/3683_2.png) [@John\_Detwiler](https://discourse.peacefulscience.org/u/John_Detwiler)\
**Post date:** [March 7, 2019, 5:36pm UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/90 "2019-03-07T17:36:23Z")

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> [@T\_aquaticus](#):
>
> If one additional slightly broken protein prevents reproduction then that additional mutation will be strongly selected against.

I’m pretty sure that anything that prevents reproduction will be selected against.

> [@T\_aquaticus](#):
>
> In your model, not all slightly deleterious mutations have the same effects since the most recent mutations will have a very strong deleterious effect.

I think you should say that mutations with strong deleterious effect are more likely to be recent. That is not saying the same thing.

> [@T\_aquaticus](#):
>
> we determined the age of the _Candidatus_ Riesia/sucking louse assemblage

It seems they did this by assuming the thing we are ultimately questioning if you read the age determination section. Also I don’t really think mutation rates inferred from common ancestry have fared well when measured directly.

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<div class="post-metadata">

**Author:** ![T\_aquaticus](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/t_aquaticus/32/1249_2.png) [@T\_aquaticus](https://discourse.peacefulscience.org/u/T_aquaticus)\
**Post date:** [March 7, 2019, 5:47pm UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/91 "2019-03-07T17:47:43Z")

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> [@John\_Detwiler](#):
>
> It seems they did this by assuming the thing we are ultimately questioning if you read the age determination section.

Their age was determined by evidence, not simply assumed.

> [@John\_Detwiler](#):
>
> Also I don’t really think mutation rates inferred from common ancestry have fared well when measured directly.

In this case, they are measuring the rate of base substitution, not necessarily the mutation rate. What they see is stronger conservation of sequence through time which supports the conclusion of stronger negative selection through time.

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<div class="post-metadata">

**Author:** ![John\_Detwiler](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/john_detwiler/32/3683_2.png) [@John\_Detwiler](https://discourse.peacefulscience.org/u/John_Detwiler)\
**Post date:** [March 7, 2019, 5:59pm UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/92 "2019-03-07T17:59:50Z")

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> [@swamidass](#):
>
> That is not true either. Did you follow what @Rumraket explained to you?

Experimental evidence seems to show it’s true. Not sure which thing Rumraket said should convince me otherwise.

> [@swamidass](#):
>
> Of these mutations, what percentage do you think are miss-sense mutations?

probably just under 3/4 from quickly looking at the table. Not sure how many are deletions and I think additions are rare. Why?

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<div class="post-metadata">

**Author:** ![T\_aquaticus](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/t_aquaticus/32/1249_2.png) [@T\_aquaticus](https://discourse.peacefulscience.org/u/T_aquaticus)\
**Post date:** [March 7, 2019, 6:15pm UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/93 "2019-03-07T18:15:55Z")

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> [@John\_Detwiler](#):
>
> probably just under 3/4 from quickly looking at the table. Not sure how many are deletions and I think additions are rare. Why?

Hint: How many bases in the 3 billion base human genome code for an amino acid?

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<div class="post-metadata">

**Author:** ![John\_Detwiler](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/john_detwiler/32/3683_2.png) [@John\_Detwiler](https://discourse.peacefulscience.org/u/John_Detwiler)\
**Post date:** [March 7, 2019, 6:17pm UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/94 "2019-03-07T18:17:41Z")

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> [@Rumraket](#):
>
> Where have you published this conclusion?

I’m not a writer or professional researcher. Sorry man.

> [@Rumraket](#):
>
> > I think Haldane’s dillema is still a real problem since it doesn’t seem to me that most larger metazoa have enough offspring to eliminate accumulating deleterious proteins let alone fix new more beneficial ones.
> 
> Why?

Because of things like Behe’s rule. Because it seems that every day new disease causing mutations are arising, but we aren’t getting anywhere close to that number of new beneficial proteins found. Because of the fine tuned nature of protein protein interactions and the types of machines they produce. I think a lot of people imagine that building machines is easy if they never try. There’s a lot of other reasons. Right now I’m hoping to find out the locations of the mutations in these polar bear genes so I can check it in a more quantitative way.

> [@Rumraket](#):
>
> What plays a role in our current fecundity? Homo sapiens is currently in an exponential population growth under relaxed selection due to agriculture and medical science. It would certainly be a mistake to extrapolate this pattern to the entirety of the biosphere.

I believe he was talking about negative selection. I don’t think it’s controversial that some people die because of mutations. Just because a population grows does not mean negative selection is not operating. I certainly think our genome can endure a good bit more degradation before advances in medicine and agriculture are unable to support more life than mutations prevent.

> [@Rumraket](#):
>
> So now you’ve told us what you think. Next you should do the work that shows your conclusions are correct and publish them.

Why I already have a job. This is just a hobby.

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<div class="post-metadata">

**Author:** ![John\_Detwiler](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/john_detwiler/32/3683_2.png) [@John\_Detwiler](https://discourse.peacefulscience.org/u/John_Detwiler)\
**Post date:** [March 7, 2019, 6:22pm UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/95 "2019-03-07T18:22:04Z")

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oh right, I was just thinking about coding regions. So about one percent of that figure then. Why?

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<div class="post-metadata">

**Author:** ![T\_aquaticus](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/t_aquaticus/32/1249_2.png) [@T\_aquaticus](https://discourse.peacefulscience.org/u/T_aquaticus)\
**Post date:** [March 7, 2019, 6:30pm UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/96 "2019-03-07T18:30:24Z")

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> [@John\_Detwiler](#):
>
> oh right, I was just thinking about coding regions. So about one percent of that figure then. Why?

> [@John\_Detwiler](#):
>
> oh right, I was just thinking about coding regions. So about one percent of that figure then. Why?

It is important to the original question:

> [@swamidass](#):
>
> For humans, there are about 3 billion bases in the genome, and about 100 mutations each generation. Of these mutations, what percentage do you think are miss-sense mutations?

Those 100 mutations are spread across the entire genome. I think it would be more accurate to say that those 100 mutations are spread across the entire diploid genome which is 6 billion bases, and even that is a simplification since the father contributes many more mutations than the mother. Anyway . . .

Let’s just stick with 100 mutations across 3 billion bases to make it simple. If 1% of those bases actually code for an amino acid, what percentage of those mutations even have a chance of being missense mutations? I would say just 1 out of every 100 mutations affects a base in a coding region. We would also have to take 3rd base wobble into account, so less than 1 out of every 100 mutations will be a missense mutation. In fact, about 90% of mutations will occur in DNA with no DNA sequence specific activity so the vast majority of mutations are going to be neutral.

Does this sound right to you?

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<div class="post-metadata">

**Author:** ![Mercer](https://avatars.discourse-cdn.com/v4/letter/m/e274bd/32.png) [@Mercer](https://discourse.peacefulscience.org/u/Mercer)\
**Post date:** [March 8, 2019, 12:21am UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/97 "2019-03-08T00:21:41Z")

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> [@Rumraket](#):
>
> Which is interesting and curious in it’s own right I agree, but that hardly constitutes a trend I feel comfortable extrapolating to a general phenomenon for most proteins.

I don’t think it’s that curious. I think that my saying that the direction of a process is basically 50/50 is saying that there’s NOT a trend.

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<div class="post-metadata">

**Author:** ![Mercer](https://avatars.discourse-cdn.com/v4/letter/m/e274bd/32.png) [@Mercer](https://discourse.peacefulscience.org/u/Mercer)\
**Post date:** [March 8, 2019, 12:29am UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/98 "2019-03-08T00:29:39Z")

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> [@John\_Detwiler](#):
>
> But Polyphen does this as you can see in it’s scoring description. I think you’re focusing on function again.

Function is what matters for evolution. Conflating structure with function leads to a great deal of confusion.

> [@John\_Detwiler](#):
>
> > Mercer: I think that you’re not understanding the basis of folding.
> 
> I know it’s an ongoing area of research. I had an idea that the barrel shaped protein chaperones often pack proteins into bring the residues close enough for them to somehow become quantumly entangled and effectively “quantumly compute” themselves to the lowest energy solution. But some Russian guy beat me to it. There are also great theories about local nucleation points. I also have theories that there are superimposed codes that force chaperones to allow certain points to begin folding on their own. I’m pretty sure there is more than one variable that controls folding though

I am now far more certain that you’re not understanding the basis of folding.

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<div class="post-metadata">

**Author:** ![Mercer](https://avatars.discourse-cdn.com/v4/letter/m/e274bd/32.png) [@Mercer](https://discourse.peacefulscience.org/u/Mercer)\
**Post date:** [March 8, 2019, 12:34am UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/99 "2019-03-08T00:34:33Z")

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> [@John\_Detwiler](#):
>
> Because it seems that every day new disease causing mutations are arising,

There’s a fundamental misunderstanding.

First, it seems that way because we are discovering new disease-causing mutations. Are you familiar with the concept of polymorphism?

> [@John\_Detwiler](#):
>
> …but we aren’t getting anywhere close to that number of new beneficial proteins found.

How many proteins (in genetic terminology, orthologs) do you think (or would you guess) are in chimps but not in humans? The converse?

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<div class="post-metadata">

**Author:** ![John\_Detwiler](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/john_detwiler/32/3683_2.png) [@John\_Detwiler](https://discourse.peacefulscience.org/u/John_Detwiler)\
**Post date:** [March 9, 2019, 3:29am UTC](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/100 "2019-03-09T03:29:43Z")

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> [@T\_aquaticus](#):
>
> In fact, about 90% of mutations will occur in DNA with no DNA sequence specific activity so the vast majority of mutations are going to be neutral.
> 
> Does this sound right to you?

The numbers are right, but I think it remains to be seen what all the transcripts of non coding genes do. I believe it is the view of Dan Graur and other evolutionary sciencers 🙂 that if an organism can reproduce, that nothing is lost. But creationists don’t require that organisms always have a minimal amount of “value” or “fitness” below which they must die. I think everyone here agrees that negative selection does not always instantly kill an organism. When people talk about “neutral” mutations and traits, they are talking about selective advantage at that moment. I’m trying to get at what may be a moving baseline in protein stability which would have far less impact at the moment as long as everything still folds.

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