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