Emailing an author to ask if what they are very clearly saying is actually what they’re saying is kind of off-putting, I think. I suppose explaining that creationists are misinterpreting what they’re clearly saying might help (at least if they’re familiar with creationists), but the question is absurd. The quotation in question is a blatant quote-mine and treating it as if that were somehow in doubt is too large a concession to either mendacity or irrationality, take your pick.
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Whether the DFE differs between coding and non-coding is not under dispute. It’s irrelevant to this point. You simply have never backed up your claim of quotemining.
Kimura contradicted his own model in later writings. I contacted Dr Eyre-Walker about that personally, and he agreed. I was very clearly referring to Kimura’s 1979 model, which Dr Eyre-Walker is still using at least in some sense, and is in basic agreement with that formulation of neutral theory, per his own words.
See, I thought you were saying you had something new to present. Instead you just want to keep rehashing your same old arguments that have been long debunked.
Paul, you cannot claim that most mutations are deleterious when the authors show the DFE for coding regions is predominately deleterious and the DFE for non-coding regions is predominately not deleterious.
He didn’t and you know it. You viewed his works through the lens of Sanford and GE and were floored when I made you read his words verbatim. The /r/genetics response you got was, “He did not contradict himself.”
Please share your correspondence with us. I would like to know the exact question you asked and what the exact response was. I will forward this to Adam and ask if he has any comments.
Kimura was consistent with his work throughout his lifetime–albeit wrong in some places. Just about everyone uses neutral theory in one way or another, Eyre-Walker included.
You aren’t debunking anything. You are evading the contradiction in your claim and what the authors wrote. You’ve now claimed to have corresponded with Adam over this issue. I hope you have accurately represented your correspondence or it would be very embarrassing for you.
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I already addressed that misleading claim on your part. They were using the word “deleterious” in that place to mean “not neutral”. But even effectively neutral mutations are deleterious on a smaller scale. That was made clear in both Kimura and in these authors’ writing. Ironically, you are now guilty of quotemining them.
No, I would not want to publish his private email to me online without his permission (which I didn’t ask for at the time). So if you want to believe I’m lying, that’s your prerogative. Kimura’s own self-contradictory words are enough to demonstrate it, comparing his 1979 paper with some of the stuff he wrote in the early 90s (which you like to quote).
No, Kimura was not consistent. His early model rejected the idea of strict neutrality and made no provision for it at all. This is also the view held by Dr Eyre-Walker et al.
I certainly have. I have kept the emails to prove it, but again, out of courtesy I will not publish them online as they were not written for that purpose and I didn’t get permission to do so.
Then please ask for permission. 
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Then do not go public on the basis of privileged correspondence.
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They were using the word “deleterious” in that place to mean “not neutral”.
I am going to ask you again:
Do Eyre-Walker and Keightley believe that most mutations are deleterious?
Great. I am writing an email to him as we speak. Did you contact him under the name Paul Price and did you explain your creationist viewpoint on the subject?
I would like to jog Adam’s memory about the conversation and I suspect those details will be helpful.
Wonderful. I will ask Adam if he rejects Kimura and Ohta’s Neutral and Nearly Neutral models in assessing DFE.
Wonderful. I will ask Adam to comment on his conversation with you and ask if I can share those comments publicly on this forum.
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I cannot answer any better than to simply let Keightly answer that question:
“In summary, the vast majority of mutations are deleterious. This is one of the most
well-established principles of evolutionary genetics, supported by both molecular and
quantitative-genetic data.”
Keightley P.D., and Lynch, M., Toward a realistic model of mutations affecting fitness,
Evolution, 57(3):683–5, 2003.
Alright, I have asked for permission. I will share his statement if he indicates he’s alright with it.
There’s a difference in merely giving my own generalized statement “he agreed” (which is a true statement) and actually sharing a copy of that correspondence online. At least, to my mind there is. If he wanted his views on that subject to be kept to entirely to himself, I don’t believe he would have broadcast them via email to a complete stranger like me. Given that we don’t know one another, calling his email “privileged” is a stretch to say the least.
I have also shot him an email asking if he cares to have it shared or not. So now he’ll have two people asking him about it.
Yes, I did use my real name. And no, my views were not the subject of our correspondence.
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Could you supply a quote where they apply these qualifications to non-functional DNA?
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I sense an Annie Hall/Marshall McLuhan moment coming up…
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I received a response from Dr Eyre-Walker, and he doesn’t care if I share his answer.
Here is my original email to him:
Dear Dr. Eyre-Walker,
I enjoyed reading your and Dr. Keightley’s 2007 paper ‘The distribution of fitness effects of new mutations’. I see that you cited Dr Motoo Kimura’s work in discussing effectively neutral mutations. But according to the best I can understand him, Dr. Kimura seems to have gone against his own model in later years. In his 1979 paper, he wrote:
“Under the present model, effectively neutral, but, in fact, very slightly deleterious mutants accumulate continuously in every species… the rate of loss of fitness per generation may amount to 10^-7 per generation. Whether such a small rate of deterioration in fitness constitutes a threat to the survival and welfare of the species (not to the individual) is a moot point, but this will easily be taken care of by adaptive gene substitutions that must occur from time to time (say once every few hundred generations).”
And:
“Note that … the frequency of strictly neutral mutations (for which [selective disadvantage]= 0) is zero in the present model …”
Kimura, M., Model of effectively neutral mutations in which selective constraint is incorporated, Proc. Natl. Acad. Sci. USA 76(7):3440–3444, 1979.
The terminology that Kimura used in 1979 was:
strictly neutral: no fitness effect, s = 0 [Frequency = 0]
effectively neutral (aka nearly neutral): very small, non-selectable effect, very frequent
But in his last paper from 1991 he seems to have changed his mind:
“…by ‘selectively neutral’ I mean selectively equivalent: namely, mutant forms can do the job equally well in terms of survival and reproduction of individuals possessing them. The neutral changes are often referred to as ‘evolutionary noise’, but, I want to emphasize that this is a misnomer, because, neutral changes do not impair genetic information, even if the process of substitution is random.”
https://www.jstage.jst.go.jp/article/jjg/66/4/66_4_367/_article
The above quote looks like a blatant contradiction in terms of Kimura’s earlier model from 1979, but I don’t see where Kimura acknowledged that he was going against his own theory with this statement.
In your paper, you wrote,
“… it seems unlikely that any mutation is truly neutral in the sense that it has no effect on fitness. All mutations must have some effect, even if that effect is vanishingly small. However, there is a class of mutations that we can term effectively neutral. These are mutations for which Nes is much less than 1, the fate of which is largely determined by random genetic drift.”
and,
“… particularly for multicellular organisms … most mutations, even if they are deleterious, have such small effects that one cannot measure their fitness consequences.”
This appears to go along with Kimura’s 1979 model, but does not harmonize with Kimura’s later statements about ‘selectively neutral’ mutations. I am not sure what he even meant by the term, since it differs from what he called them in 1979.
Why did you decide to base your paper on Kimura’s earlier work, and why did Kimura change his mind?I appreciate any insight you might be able to offer, and I thank you kindly for your time in responding.
Regards,
Paul Price
Response from Dr Eyre-Walker follows:
Dear Paul
I think the critical point is to distinguish between “selectively neutral” and “effectively neutral”; I believe these terms have been used fairly consistently to mean s = 0 and |Ns|<1. Despite being a co-author on the first paper, with Tomoko Ohta, that proposed the theory of nearly neutral mutations, and written his 1979 paper in which he analyses the model in some depth, he seems to have largely shied away from the model in his later work. I’m not sure why, but this might have been due to the fact that Tomoko Ohta was the originator of this idea, and there might have been some professional jealousy involved. Tomoko Steen (CCed), who knows Tomoko Ohta, quite well, might be able to shed some light on this.
In terms of my own writing I stand by the statement in Peter and my review; its clear that all mutations must have some selective effect, its really how those selection coefficients scale relative to the effective population size that is important.
I hope this helps.
Best wishes
Adam
Snipped text restored:
I demonstrated the context in the post you were replying to - which demonstration you omitted from your response.
That you’re willing to quote-mine in order to defend your quote-mine is unsurprising.
P.S. Since you now claim to have read the cited paper, you should know that any conclusion about all mutations is not justified by the evidence in it, since that evidence refers to mutations in protein-coding regions. Even if you weren’t quote mining you’d still be quoting an unjustified claim. That’s no better.
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Where does Adam agree that “Kimura contradicted his own model in later writings”? I don’t see it. I only see that Adam said “[Kimura] shied away from the model in his later work.” ‘Shied away from’ does not necessarily mean ‘contradicted’.
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Well, for starters, I quoted the contradiction in my original email, reproduced above. Dr Eyre-Walker agreed with my statement. That was what was contextually meant by his statement. But apparently there’s no end to the lengths you’ll go to dodge this? It’s not my problem if you don’t want to accept reality. I’ve gone the extra mile as it is.
No it isn’t, so no he didn’t.
No it does not necessarily mean that, but in context it’s also not clear to me there’s any real difference here.
What Adam writes does seem, to me, to confirm that Kimura contradicted his earlier work. What else is there to be understood by “shied away from”, if it does not mean he changed his work in ways that was not compatible with his earlier work, and led to non-identical conclusions?
He “shied away from” it by not using it again, and instead started using something else, that had subtly different implications that means you can’t directly substitute one for the other. That seems to me to straightforwardly imply a contradiction.
I have to say that to my eyes it appears that on this specific question, Adam agrees with @PDPrice about Kimura contradicting his earlier work. That question has now been settled to my satisfaction. You’d have to show there is some additional context that I am unaware of here to change my mind.
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I don’t think it’s that clear cut. Using a different model doesn’t necessarily mean contradicting a previous one, and Adam doesn’t say he agrees with anything. But you have more grasp of these models than I do, so I’ll accept your conclusion.
If I understand the situation correctly . . .
Kimura started with neutral mutations that were absolutely neutral. Later, he realized that such an absolute definition wasn’t accurate and moved to effectively neutral which allows for neutral mutations to be deleterious or beneficial but have so little effect in a given population that they reach fixation according to random chance.
It’s a subtle yet important distinction. I would call it a refinement, but I can see how people could also call it a contradiction.
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I’m not sure how else to explain this:
Dr. Eyre-Walker did not agree that Kimura contradicted his terms nor his model.
The basis of our conversation was how neutral was defined in Kimura’s work and the evidence for DFE ratios.
Kimura never contradicted his model. Kimura did distance himself from Ohta’s nearly neutral model as I have explained to you on multiple occasions now. You can read about his hesitation in accepting the pervasive existence of slightly deleterious mutations in his 1991 paper:
Recently, Ohta and Tachida (1990) applied the concept of “near neutrality” to explain the puzzling observation regarding nucleotide versus allozyme heterozygosities in D.similans, on which I have mentioned in one of the above sections. These authors assume that mutations causing protein polymorphisms are subject to stronger selection on the average (such as Nes’=0.5) compared with mutants that involve in DNA polymorphisms (such as Nes’=O.l), even if the absolute sizes of the selection coefficient (denoted by s’) are very small in the ordinary sense. Taking into account the fact that D. similans has a much larger panmictic population than D. melanogaster which has the subdivided population structure, these authors claim that the contrasting pattern of polymorphisms in these two species can be understood by assuming nearly neutral mutations. Whether such very slightly deleterious mutations are really prevalent in nature or not, I think, remains to be investigated for many genes in various organisms.
(pg. 378)
KIMURA, M. The neutral theory of molecular evolution: A review of recent evidence. Japanese J. Genet. 66 , 367–386 (1991).
Ohta additionally provides some commentary on her work with Kimura after he passed:
This has been called the infinite-site model, and has become yet another standard method for understanding the mechanisms of maintaining DNA polymorphisms. He and I collaborated in analyzing another popular model for treating protein polymorphisms measured by electrophoresis (15), the so-called stepwise mutation model, which has provoked much interest among mathematicians. The model has recently been revived for studying microsatellite DNA polymorphisms.
The neutral theory and the progress of these stochastic problems are not at all independent. In fact, Kimura’s analyses of diffusion models started earlier and provided the background on which to propose the neutral theory of molecular evolution. He was one of the few scientists talented in both mathematics and biology. In 1983, he published a comprehensive treatment of the subject in a book (5) that has become a standard reference work in evolution.
He always loved an elegant and simple theory. Therefore, he did not like the nearly neutral theory (14), which is very complicated, but rather preferred the strictly neutral theory, which is so elegant. Since I believed that both random genetic drift and selection are important for molecular evolution, we had arguments once in a while. Unlike most Japanese professors, he not only allowed me, a junior researcher, to criticize some aspects of his theory, but also paid attention to my opinions. The nearly neutral theory is presented impartially in his book. He was such a generous person, and I am deeply obliged to him.
During the 1980s, more data on DNA sequences appeared and it became very clear that those parts of the genome that do not specify genetic information are evolving rapidly. Such data were thought to be in accord with the neutrality prediction rather than that of the selection theory. In particular, the unraveling in 1981 (10, 11) of the most rapid evolution of pseudogenes provided strong evidence for the neutral theory, to Kimura’s great delight. With the accumulation of such data, he had returned to the original strictly neutral theory, and to the view that the complicated nearly neutral theory was not useful (6).
Ohta, T. Motoo Kimura. Annu. Rev. Genet. 30 , 1–5 (1996).
Tomoko Y. Steen has also provided commentary on the differences between Kimura’s and Ohta’s models:
The “status quo” meant that gene function was already close to its optimum in general, and advantageous mutations were extremely rare. Ohta incorporated this “status quo” argument to her nearly neutral theory in the early 1970s; therefore, Ohta did not see any need to discuss slightly advantageous mutations back then.
Toward the end of the 1980s, however, increasing amounts of data showed the existence of slightly advantageous mutations and the effects of positive selection on them. Therefore, Ohta modified her original nearly neutral theory by incorporating the fate of slightly advantageous mutations, and proposed this modified theory as “nearly neutral theory of molecular evolution” in a series of two papers published in 1990 and1991.
There is also much confusion for the differences between Kimura’s neutral theory and Ohta’s nearly neutral theory. The main difference between Ohta’s nearly neutral theory and Kimura’s neutral theory is while Kimura put his focus on so-called “strictly neutral mutations” (this phrase is specified by Ohta), Ohta was more interested in the evolutionary mechanisms of the “border line mutations” or the “nearly neutral mutations,” (i.e. mutations which are not strictly neutral nor are strongly selected).
The most notable yet overlooked difference between these two theories is the effect of population sizes. Simply, population size does not effect on neutral mutations. For nearly neutral mutations in small populations, the effects of selection are also extremely limited and the fate of them is also determined by random genetic drift just like neutral mutations. However, the effects of selection are not ignorable in a large population for nearly neutral mutations.
The nearly neutral theory in general requires many more parameters because of the characteristics of these mutations. For this reason, the most frequent criticism of the nearly neutral theory is that it is too complex. Neutralists, including Kimura, argue that a theory needs to be simple, easy to be understood, accepted, and applied. Yet, Ohta argues that her theory explains the “actual natural populations” better.
https://authors.library.caltech.edu/5456/1/hrst.mit.edu/hrs/evolution/public/nearlyneutral.html
This page was written by Tomoko Y. Steen. It was last updated 9/9/2004.
As many others have noted, GE is premised on the DFE of slightly deleterious mutations—which is what our conversation was about. GE prefers the early works of neutral and nearly neutral theory because they only consider deleterious DFE. As Tomoko points out, the models were modified to incorporate the evidence for slightly advantageous DFE. You will also note this is the perspective given by Eyre-Walker throughout his works. I’m not sure why you choose to ignore the evidenced DFE for all mutations and focus on only deleterious mutations. One might wonder why you prefer to use a model from 1979 which was modified as more evidence became available. You may also note that modification is not contradiction. Neutral Theory and Nearly Neutral Theory are not contradictory.
This is the entire contention surrounding our discussions. You cannot simply assert the DFE is overwhelming deleterious. There is literally no evidence for this claim. The best available evidence strongly suggests that most mutations are neutral with respect to the fitness conferred. I have very clearly laid out the differences in functional consequences of the mutations versus the operational consequences of how the mutations are propagated. Neutral theory is premised on this distinction.
As I have stated in the past, you can tap dance around the semantics of the language used in these publications until you are blue in the face—it does not matter. The conferred fitness from the mutations—whether you call them slightly deleterious, effectively neutral, selectively neutral, strictly neutral—is not evidenced. Until you can provide evidence that the mutations do indeed cause a fitness decline in the population, GE is dead in the water.
Here is the Reddit link for the post you made in /r/genetics. You might recall that you used an alternate account to post the question after I made you realize Kimura was using the terminology in the way I suggested:
https://removeddit.com/r/genetics/comments/eqgyzz/population_genetics_why_did_kimura_contradict/
You will notice other users commenting that Kimura’s purported “contradiction” is not apparent. As Eyre-Walker correctly suggests, Kimura shies away from Nearly Neutral Theory–but that does not indicate he contradicted his earlier work.
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No the other way around, he started with them having extremely subtle but real fitness differences, but then later changed that to mean no actual fitness differences. That’s what I understand those quotes to be saying.
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