The neutral theory was first proposed by Mootoo Kimura in 1968 (Kimura, 1968). The following year, a similar idea was published in a seminal paper by Jack King and Thomas Jukes (King and Jukes, 1969). King and Jukes emphasized the importance of non-Darwinian mechanisms of evolution in order to explain protein based phylogenetic trees and the molecular clock. They made it clear that neutral alleles fixed by random genetic drift play an important part in evolution.
There appears to be considerable latitude at the molecular level for random genetic changes that have no effect upon the fitness of the organism. Selectively neutral mutations, if they occur, become passively fixed as evolutionary changes through the action of random genetic drift.
The idea of selectively neutral changes at the molecular level has not been readily accepted by many classical evolutionists, perhaps because of the pervasiveness of Darwinian thought (King and Jukes, 1969).
These two papers kicked off a radical change in the way scientists looked at evolution leading to an attack on adaptationist thinking that culminated a decade later in the Gould and Lewontin spandrels paper—arguably one of the most important papers in evolutionary biology in the second half of the 20th century (Gould and Lewontin, 1979)
The fixation of neutral, or nearly-neutral, alleles by random genetic drift helped explain the C-value paradox and many aspects of genomic evolution. The fact that large fractions of eukaryotic genomes are junk DNA evolving at the neutral rate is now widely accepted even though the exact percentages of junk are hotly debated. The evolution of new functions in proteins can often only be explained by some combination of neutral alleles and adaptive alleles. Constructive neutral evolution is now accepted as a legitimate candidate for the origin of complexity.
This led Michael Lynch to declare,
The blind worship of natural selection is not evolutionary biology. It is arguably not even science. Natural selection is just one of several evolutionary mechanisms, and the failure to realize this is probably the most significant impediment to a fruitful integration of evolutionary theory with molecular, cellular, and developmental biology.
It should be emphasized here that the sins of panselectionism are by no means restricted to developmental biology, but simply follow the tradition embraced by many areas of evolutionary biology itself, including paleontology and evolutionary ecology (as cogently articulated by Gould and Lewontin 1979). The vast majority of evolutionary biologists studying morphological, physiological, and/or behavioral traits almost always interpret their results in terms of adaptive mechanisms, and they are so convinced of this approach that virtually no attention is given to the null hypothesis of neutral evolution, despite the availability of methods to do so. (Lynch, 2007, p. 369).
You might think that the enormous success of neutral theory and the importance of random genetic drift would have silenced any opposition. The only holdouts to this new (1968) way of thinking about evolution must be scientists who missed the revolution. There are lots of those types of scientists but they can't possibly defend the idea that natural selection is the only game in town.
So why is there still an ongoing neutralist-selectionist debate? Two recent papers point out that for some scientist the issue still hasn't been resolved.
de Jong, M.J., van Oosterhout, C., Hoelzel, A.R. and Janke, A. (2024) Moderating the neutralist–selectionist debate: exactly which propositions are we debating, and which arguments are valid? Biological reviews 99:23-55. [doi: 10.1111/brv.13010]
Half a century after its foundation, the neutral theory of molecular evolution continues to attract controversy. The debate has been hampered by the coexistence of different interpretations of the core proposition of the neutral theory, the ‘neutral mutation–random drift’ hypothesis. In this review, we trace the origins of these ambiguities and suggest potential solutions. We highlight the difference between the original, the revised and the nearly neutral hypothesis, and re-emphasise that none of them equates to the null hypothesis of strict neutrality. We distinguish the neutral hypothesis of protein evolution, the main focus of the ongoing debate, from the neutral hypotheses of genomic and functional DNA evolution, which for many species are generally accepted. We advocate a further distinction between a narrow and an extended neutral hypothesis (of which the latter posits that random non-conservative amino acid substitutions can cause non-ecological phenotypic divergence), and we discuss the implications for evolutionary biology beyond the domain of molecular evolution. We furthermore point out that the debate has widened from its initial focus on point mutations, and also concerns the fitness effects of large-scale mutations, which can alter the dosage of genes and regulatory sequences. We evaluate the validity of neutralist and selectionist arguments and find that the tested predictions, apart from being sensitive to violation of underlying assumptions, are often derived from the null hypothesis of strict neutrality, or equally consistent with the opposing selectionist hypothesis, except when assuming molecular panselectionism. Our review aims to facilitate a constructive neutralist–selectionist debate, and thereby to contribute to answering a key question of evolutionary biology: what proportions of amino acid and nucleotide substitutions and polymorphisms are adaptive?
Galtier, N. (2024) Half a Century of Controversy: The Neutralist/Selectionist Debate in Molecular Evolution. Genome Biology and Evolution 16:evae003. [doi: 10.1093/gbe/evae003
The neutral and nearly neutral theories, introduced more than 50 yr ago, have raised and still raise passionate discussion regarding the forces governing molecular evolution and their relative importance. The debate, initially focused on the amount of within-species polymorphism and constancy of the substitution rate, has spread, matured, and now underlies a wide range of topics and questions. The neutralist/selectionist controversy has structured the field and influences the way molecular evolutionary scientists conceive their research.
It's important to understand that some of the scientists opposed to the strict version of neutral theory are not saying that the evolution of junk DNA sequence is due to natural selection or that every visible trait is adaptive. They often have a very narrow view of the neutralist-selectionist debate. They are concerned about the evolution of coding regions in protein-coding genes and whether synonymous mutations in codons are neutral or not. They are also interested in whether any amino acid substitutions are truly neutral.
They aren't interested in any of the things I mentioned at the top of this post. If you are interested in knowing whether there's evidence to support the strict neutrality of synonymous mutations and/or amino acid substitutions then you should read these reviews. But don't think they have anything to do with overthrowing the views expressed by Michael Lynch and others.
The paper by Galtier has a nice summary of the difference between the two types of biologists. He points out that the original neutralist-selectionist controversy might have been fueled by a lack of data to resolve some of the questions but that doesn't explain why there's still a controversy.
Below, I consider yet another hypothesis and speculate that the duration and heat of the controversy might in part be explained by cultural differences among scientists.
There are several pathways for a researcher to get to study evolution at the molecular level. Many are passionate about nature and biodiversity and use DNA as a tool to better understand how organisms function and adapt to their environment. For them, natural selection is what we want to study, and building a neutralist theory is just pointless. These researchers may be frustrated by the feedback from picky reviewers who repeatedly ask for more controls and show no apparent interest in their results. Others, instead, are fascinated by genomes as biological objects and aim at understanding why they are what they are. For them, ignoring neutral and nearly neutral processes is a logical flaw, or even scientific malpractice. These scientists can be irritated by colleagues easily jumping to selectionist explanations, which often attract more attention than their subsequent refutation.
This author cannot help considering that scientists from the latter category get closer to the truth, while also recognizing that the imagination and diligence of more phenotype-oriented researchers brings exciting hypotheses to the test.
Gould, S.J. and Lewontin, R.C. (1979) The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme. Proceedings of the Royal Society of London. Series B. Biological Sciences 205:581-598. [doi: 10.1098/rspb.1979.0086]
Kimura, M. (1968) Evolutionary rate at the molecular level. Nature 217:624-626. [PDF]
King, J.L. and Jukes, T.H. (1969) Non-Darwinian evolution. Science 164:788-798. [PDF]
Lynch, M. (2007) The origins of genome architecture. Sinauer Associates, Inc. Publishers. Sunderland Massachusetts, USA
11 comments :
sorry. proffesor Moran I have a question ... how can a deleterious mutation be fixed by drift and afterward never be eliminated by puyfiying selection?
Thank you. I read the Galtier paper and this post putting it in context makes me think I understand it a bit better.
From the point of view of molecular phylogenetics, we would prefer that all sequences be evolving neutrally. It makes the models used in evaluating trees more tractable, it minimizes problems of systematic convergence, and it provides the most phylogenetic signal per unit time.
The Gould and Lewontin "spandrels" paper was not just raising the possibility of neutral mutation. It was asking whether, when you saw changes that looked like natural selection, could you conclude that your particular selection hypothesis was correct. You could not assume that, but not just because neutral change was possible. It could be that the change you saw in morphological characters was not due to selection on those characters, but selection on other characters that were genetically correlated with them.
Spandrels in cathedrals were quite deliberately put there by architects -- they weren't neutral, without them the dome would fall down. We are not justified in assuming that they are there to have a place to draw pictures of saints.
Visible change in morphological characters almost always has enough fitness effect that pure neutrality is not very plausible. Anyone want to argue that the elephant's trunk gets longer and shorter mostly by neutral mutation and genetic drift? I get the impression that Larry does.
I argued that when Zuckerkandl and Pauling proposed the molecular clock they thought that constant selection explained it, not neutral evolution.
Morgan, G. J. (1998). Emile Zuckerkandl, Linus Pauling, and the molecular evolutionary clock, 1959-1965. Journal of the History of Biology, 155-178.
https://www.researchgate.net/profile/Gregory-Morgan-2/publication/226242136_Emile_Zuckerkandl_Linus_Pauling_and_the_Molecular_Evolutionary_Clock_1959-1965/links/54d558070cf25013d02b025a/Emile-Zuckerkandl-Linus-Pauling-and-the-Molecular-Evolutionary-Clock-1959-1965.pdf
@Joe Felsenstein
Visible change in morphological characters almost always has enough fitness effect that pure neutrality is not very plausible. Anyone want to argue that the elephant's trunk gets longer and shorter mostly by neutral mutation and genetic drift? I get the impression that Larry does.
Alot of this "how important is selection vs drift" debates often seems to reduce to something like that. One guy says "look at how many mutations fix are neutral, it's almost all of them", and then another guy points at some highly adaptive morphological character and says "clearly selection is most important." I always get the sense they're talking past each other.
One guy says "look at how many mutations fix are neutral, it's almost all of them", and then another guy points at some highly adaptive morphological character and says "clearly selection is most important." I always get the sense they're talking past each other.
They are. Given the large amount of junk DNA, most mutants that fix are of course neutral. But that does not establish that mutations in coding sequences or control regions that affect morphology (for example) can be assumed to be neutral. Some of the miscommunication involves the phrase "amount of evolution", which is ambiguous as to whether it counts all changes in sequences, or only changes that affect morphology and/or behavior.
@Joe Felsenstein says, "Anyone want to argue that the elephant's trunk gets longer and shorter mostly by neutral mutation and genetic drift? I get the impression that Larry does."
Really? Why in the world world you say that?
Joe Felsenstein says, "Some of the miscommunication involves the phrase "amount of evolution", which is ambiguous as to whether it counts all changes in sequences, or only changes that affect morphology and/or behavior."
Are there many current evolutionary biologists who publish papers defending the idea that the definition of evolution is restricted to changes in morphology and/or behavior?
Are there any experts in population genetics who make such a claim?
Joe, what do you personally think about all the morphological variation we see in humans today? Do you think it's all either slightly beneficial or slightly deleterious?
Do you think that all of the morphological differences between African and Asian elephants are due to selection for beneficial traits in different environments? Could some of them (e.g. larger ears) be effectively neutral?
Are there many current evolutionary biologists who publish papers defending the idea that the definition of evolution is restricted to changes in morphology and/or behavior?
Are there any experts in population genetics who make such a claim?
Current? Perhaps not. But Ernst Mayr used to make that claim.
@Larry: Joe, what do you personally think about all the morphological variation we see in humans today? Do you think it's all either slightly beneficial or slightly deleterious?
Do you think that all of the morphological differences between African and Asian elephants are due to selection for beneficial traits in different environments? Could some of them (e.g. larger ears) be effectively neutral?
Not plausibly. If the effective population size of elephants was, say, 1,000,000 over the last millions of years, then the "drift barrier" is approximately |s| > 1/4,000,000. To have drift have much effect, you need to have selection coefficient less than that. Plausible? Not very. Especially since changes in morphological and behavioral characters such as ear size are correlated with other traits. The spandrels criticism is valid, not because neutral mutation overwhelms selection, but because selection on correlated traits is important.
Of course, selection on molecular substitutions can be much weaker.
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