Detwiler: Questions Behe, Polyphen, and Ratchets


(John Detwiler) #81

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.

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.

(S. Joshua Swamidass) #82

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:

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.


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:

(John Detwiler) #84

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.

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

I’m not against looking at it.

(S. Joshua Swamidass) #85

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

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?

(Mikkel R.) #86

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.


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.


I couldn’t care less who you voted for. :sunglasses:

(Dave Carlson) #88

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.

(S. Joshua Swamidass) #89

@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.

(John Detwiler) #90

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

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

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.


Their age was determined by evidence, not simply assumed.

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.

(John Detwiler) #92

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

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?

(John Detwiler) #94

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

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.

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.

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

(John Detwiler) #95

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:

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?

(John Mercer) #97

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.

(John Mercer) #98

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

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

(John Mercer) #99

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?

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

(John Detwiler) #100

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 :slight_smile: 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.