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How to attack neo-Darwinism
and still end up in evolution textbooks

The neutralist – selectionist controversy

a review by Gert Korthof
1 Jan 1999 (updated 8 Jun 2022)

 
The
neutral theory
of molecular
evolution
 
 
 
  Motoo Kimura
     "Looking back, I think that it is a curious human nature, that if a certain doctrine is constantly being spoken of favorably by the majority, endorsed by top authorities in their books and taught in classes, then a belief is gradually built up in one's mind, eventually becoming the guiding principle and the basis of value judgement. At any rate, this was the time when the panselectionist or 'neo-Darwinian' position was most secure in the history of biology: the heyday of the traditional 'synthetic theory' of evolution."
(p. 22).
 		 
    I included Kimura on this website to show that a critique of Darwinism is possible, without being ridiculed or ignored by the scientific community. Kimura's 'Neutral Theory' got a firm place in the standard textbooks (2) on evolution and population genetics, despite being clearly anti-selectionist. In the beginning orthodox Darwinists did not exactly like Kimura's theory, because he was telling the scientific community that all-powerful Natural Selection was not so powerful after all. Natural selection had its limitations. On the molecular level the power of Natural Selection was greatly minimised, if not banished at all. Randomness took its place. Molecular variation in proteins and DNA was uncovered that had no influence on the fitness of the individual organism: in other words: is selectively neutral. One could even doubt if Natural Selection was of any importance in the traditional areas of morphology and anatomy.
   Why then did Kimura find its place in evolution textbooks, unlike other anti-Darwinists?
  • Before the publication of his Neutral Theory Kimura was already a recognized leader in theoretical population genetics
  • Kimura built his theory on accepted knowledge in population genetics and extended it
  • The Neutral Theory had testable consequences such as "changes in DNA that are less likely to be subject to natural selection occur more rapidly".
  • The growing evidence supporting the Neutral Theory
  • The Neutral Theory made a lasting contribution to population genetics theory
  • The Neutral Theory is more like a theory in physics or chemistry (predictions, laws)
  • Kimura still allowed for negative selection to eliminate most new mutations
  • Kimura did not deny the existence of natural selection on morphological levels
Kimura shows that critique of neo-Darwinism can be incorporated into neo-Darwinism if there is evidence and a good theory, which contributes to the progress of science.

book   "The neutral theory of molecular evolution"
by Motoo Kimura
Cambridge University Press.
1983, reprinted 1986 (paperback) (1)
367 pages

Contents:
  1. From Lamarck to population genetics ...1
  2. Overdevelopment of the synthetic theory and the proposal of the neutral theory ...15
  3. The neutral mutation-random drift hypothesis as an evolutionary paradigm ...34
  4. Molecular evolutionary rates contrasted with phenotypic evolutionary rates ...55
  5. Some features of molecular evolution ...98
  6. Definition, types and action of natural selection ...117
  7. Molecular structure, selective constraint and the rate of evolution ...149
  8. Population genetics at the molecular level ...194
  9. Summary and conclusion ...305
    References ...328
    Author Index ...354
    Subject Index ..361-367

What are neutral mutations?

Neutral (or silent or synonymous) mutations occur when the change of a single DNA nucleotide (A,T,C,G) within a gene does not affect the sequence of amino acids that make up the gene's protein (15). The sequence of amino acids determines the 3-D structure of the protein, and that determines the function of the protein in the cell, and that determines the fitness of the organism. So, if the protein is not changed it will have no effect on the phenotype and the fitness of the organism. In other words: it will be neutral.
Remarkably, it has been forgotten by most Darwinists, that Charles Darwin distinguished three kinds of variations: advantageous, deleterious, and neutral (13). He wrote at the beginning of chapter 'Natural Selection' of his The Origin of Species: "Variations neither useful nor injurious would not be affected by natural selection, and would be left a fluctuating element" (14). However, Darwin did not elaborate on this idea, and it has not become part of the Modern Synthesis (19).

Were neo-Darwinists really opposed to 'neutralism' in the 70's and 80's?

The (nearly) neutral theory is a major departure from the Modern Synthesis selectionist paradigm as it explicitly posits that the majority of mutations fixed during evolution are not affected by Darwinian (positive) selection (18). By the 1980s many evolutionary geneticists had accepted the neutral theory (19). An important exception was Ernst Mayr. Consider Ernst Mayr's Populations, Species, and Evolution (1971) (3). After summarising the evidence for genetic drift (King and Jukes (1969), Kimura(1969), Fitch and Margoliash (1970)), Mayr notes that a number of considerations largely deprive the evidence of its cogency:
  1. There are several other properties of populations that, when only superficially analyzed, appear to have no obvious selective advantage. However, the mere fact that such traits have become established makes it highly probable that they are the result of selection.
  2. More and more sites even in the largest molecules are found to have specific functions. A "functionless site" is simply one the function of which has not yet been determined. (page 137 in (3)). (see also: (12), (15)
  3. Available observations on allele polymorphism are not consistent with the neutrality theory.
  4. A random replacement of amino acids unquestionably occurs occasionally in evolution, but it appears at present that it does not anywhere near approach selection in importance as an evolutionary factor.
  5. Chance causes disorder, selection causes order.
It is clear from the first two points that Mayr treats 'function' and 'natural selection' virtually as an axiom. So neutralism is almost excluded by definition. The other points concern evidence. Much evidence has been produced since 1970, but in 1982 Mayr still concludes:
My own feeling is that selection is far more important than admitted by the promoters of non-Darwinian evolution, but that indeed there is a random component in much of the variation at some gene loci." (4)
So according to Mayr (1982) selection is still more important than neutral mutations or 'Random-Walk Evolution' as he calls it.

Stephen Jay Gould (5) told an interesting anecdote about Ernst Mayr at a meeting of the Evolution Society. Ernst Mayr attacked the claim that single base mutations in DNA that do not result in a different amino acid are not detected by natural selection (neutral mutations or silent mutations). Mayr claimed that such changes could not a priori and in principle be neutral. These mutations must have some effect on the organism, perhaps energetic, that selection can "see" even if the coded amino acid does not change (12). According to Gould this is a clear example of dogmatism. However, there is now a growing body of evidence that 'silent' point mutations do have effect for example on the rate of translation at ribosomes (17), (21). The cause is that multiple codons can code for the same amino acid. Those equivalent codons do not have equal frequncies in the DNA of an organism. There are frequent and rare codons. The frequent silent mutations apparently speed up and the rare silent mutations slow down protein synthesis. Therefore, they have an effect on fitness. So, Mayr was right afterall, but wrong in basing his claims on a priori principles instead of on empirical data.

   In his One Long Argument (1991) Mayr tells us about the neutral theory of evolution that
"Although, this theory was at first vigorously opposed by most evolutionists, including myself, the high frequency of "neutral" base-pair replacements is now well established. On the other hand, the selective significance of numerous alleles that had been considered neutral by neutrality enthousiasts has also been established (for instance by Nevo,1983)." (8).
   According to Mark Ridley, Ernst Mayr still rejects the neutral theory in his What Evolution is (2002).
"I'd rate Motoo Kimura's neutral theory as among the biggest, if not the biggest, contribution to evolutionary biology in the past 35 years. Mayr dismisses it in a short paragraph, as if it were an elementary conceptual mistake. He does not make his objection completely clear. However, he objects to the definition of evolution as changes in gene frequency. Neutrality is a property of genes, and neutral drift produces changes in gene frequency. For Mayr, neutral evolution is impossible because the sorts of change produced by neutral drift are not real evolution." (6)
At his 100th birthday Mayr summarises the importance of neutralism by omitting it in an overview of 80 years of evolutionary biology:
"It would seem justified to assert that, so far, no revision of the Darwinian paradigm has become necessary as a consequence of the spectacular discoveries of molecular biology". (10).
   Please note that 'the neutral theory of evolution' is not sufficient to explain complex life and adaptations. In that sense it is not a theory of evolution. However it is accepted that the neutral theory explains a lot of differences in DNA. Kimura:
"Of course, Darwinian change is necessary to explain change at the phenotypic level -fish becoming man- but in terms of molecules, the vast majority of them are not like that." (7)
This is an important admission. If evolution is defined at the morfological level, the evolution of adaptations such as eyes and brains, then natural selection is very important.

The nearly neutral theory

Later it became clear that the exact form of molecular evolution does not neatly fit the original neutral theory, "purely neutral", in several respects. The modified theory, "the nearly neutral theory", posits a class of nearly neutral mutations and can account for several observations that presented problems for Kimura's purely neutral theory (9).

neutral theory
From Giorgio Bernardi (13)
First diagram: Darwin postulated the existence of deleterious, advantageous, and neutral changes
Second: The neo-Darwinians (or selectionists) neglected neutral changes
Third: These were reintroduced and amplified by Kimura, who developed the neutral theory of evolution
Fourth: The nearly neutral theory was proposed by Ohta to include intermediates between neutral and advantageous, as well as between neutral and deleterious changes.
Fifth: In the neoselectionist theory, the critical changes are responsible for the transition from point mutations to regional changes.

Weak neutralism

Recently, population geneticist Kondrashov described Kimura's theory as weak neutralism. He says that "in 1968 Kimura made his modest proposal that most allele substitutions and polymorphisms do not substantially affect an organism's fitness and are governed, not by positive or balancing selection, but by random drift. Kimura still allowed for negative selection to eliminate most new mutations, so his proposal can be regarded as 'weak neutralism'." (11). Kondrashov also points out that the relative power of selection and neutralism depends on which parts of a genome are considered: non-protein-coding versus protein-coding sites and which organisms: insects (fruitfly) or mammals (humans). In mammals negative selection is weak or inefficient resulting in much junk DNA, while in fruitflies efficient selection eliminates much junk DNA. Presumably this is because large animals have small populations and reproduce slowly, while small animals have large populations and reproduce quickly.

The Current Status of the Neutral Theory

The Neutral Theory of molecular evolution explains the clocklike evolution of DNA. It also explains that silent substitutions outnumber replacement substitutions in most genes. So, the Neutral Theory is extraordinary useful. However, from studies in fruit flies it appears that the main claim of the Neutral Theory, that the vast majority of nucleotide changes that become fixed in populations are selectively neutral, is wrong (16). Also a growing body of evidence shows that 'silent' (synonymous) mutations do have effects on fitness (15), so are not silent at all. It seems, afterall, Mayr was -at least partially- right.

Neutral (or silent or synonymous) mutations are mutations that do not change the amino acid in the protein. A good example of sequences that accumulate neutral mutations are introns. Introns are spliced out from the gene before they can get translated to proteins. So, there can be no selection pressure on intronic sequences. However, in the early 2000's scientists discovered that some "silent" mutations do effect proteins. Synonymous mutations in the end of exons (the protein coding part of a gene) close to the exon-intron border destroy the definition of the border. As a consequence the splicing machinery does not recognize the end of the exon and does not remove the intron. A longer protein will be produced with unknown properties or more likely a nonfunctional or harmful protein. In other words: a synonymous mutation that is not neutral (20).

Mutations matter even if proteins stay the same

Mutations matter even if proteins stay the same
blue star* = synonymous, red star* = non-synonymous mutation. ©Nature
Synonymous mutations change DNA and mRNA sequence.
Non-synonymous mutations change DNA, mRNA and protein sequence.

On 8 June 2022 Nature published a News and Views article: 'Mutations matter even if proteins stay the same' (22). Shen et al. present evidence that synonymous mutations in yeast are frequently just as harmful as the non-synonymous mutations that alter proteins, upending a common assumption about molecular evolution. An unexpected effect of some synonymous mutations is that the sequence of the messenger RNA transcribed by a gene can affect its shape and stability. Also, synonymous mutations can affect protein abundance in the cell. So, for many genes and mutations in yeast, synonymous mutations are often strongly non-neutral. The concept 'synonymous mutation' is not synonymous with 'neutral or silent mutation'. Synonymous mutations often have fitness effects.

Notes

  1. The Cambridge University Press paperback edition of (February 22, 1985) is available at amazon (July 2007). There is also a collection of papers by Kimura: Population Genetics, Molecular Evolution, and the Neutral Theory: Selected Papers, University of Chicago Press, 1994. (The essays cover 40 years of Kimura's contributions to the understanding of how genetic variation affects evolutionary change). Further there is a chapter 'Natural Selection and Neutral Evolution' written by Kimura in What Darwin Began (L.R. Godfrey,1985, ed). See also Further Reading section.
  2. There are 15 (!) publications of Kimura listed in the bibliography of Hartl and Clark's Principles of Population Genetics (1997). Later I found that Kimura published a textbook An Introduction to Population Genetics Theory in 1970 with J. Crow.
  3. Paperback, Second printing 1971, pages 117 and 127,128. This is the abridgement of Animal Species and Evolution,1963,1970.
  4. Ernst Mayr (1982) The Growth of Biological Thought. Diversity, Evolution and Inheritance, page 593.
  5. Stephen J Gould(2002) The Structure of Evolutionary Theory, p521.
  6. Mark Ridley, Nature 417, 223-224 (2002) 16 May 2002.
  7. Kimura (1985) The neutral theory of molecular evolution, New Scientist, pp41-46.
  8. Ernst Mayr (1991) One Long Argument, p. 152. Paperback.
  9. See chapter 7 of Mark Ridley (2004) Evolution Third Edition.
  10. Ernst Mayr (2004) 80 Years of Watching the Evolutionary Scenery. (free) Science, Vol 305, Issue 5680, 46-47 , 2 July 2004.
  11. Alexey S. Kondrashov (2005) "Fruitfly genome is not junk", Nature, 437, 20 Oct 2005, p.1106.
  12. Only recently a rare case of a phenotypic effect of the combination of 2 or 3 'neutral mutations' in the same gene was discovered. A possible explanation is that some codons have a lower translation efficiency and that the combination of 2 or more of them slow down the cell's proteinmaking machinery noticeably. Mary Beckman (2006) The Sound of a Silent Mutation, ScienceNOW Daily News 22 December 2006. Furthermore, infrequent codons in mRNA appear to be slowly translated, whereas frequent codons are rapidly translated. In this way synonymous codons can cause different protein folding while having exactly the same amino acid sequence (Anton A. Komar, Science 26 January 2007 pp. 466 - 467). Another factor is mRNA stability: in Escherichia coli of 150 "synonymous" versions of a gene for green fluorescent protein, the amount of protein varied 250-fold, in large part because codons differentially affected the stability of the messenger RNA (Science).
  13. Giorgio Bernardi (2007) 'The neoselectionist theory of genome evolution', PNAS May 15, 2007 vol. 104 , no. 20 , 8385-8390 (free access)
  14. The Complete Works of Charles Darwin Online.
  15. Unexpectedly recently synonymous mutations have been discovered that do change the phenotype. The cause is a slowdown of translation which causes the protein to fold into a different structure. Patrick Goymer (2007) 'Genetic variation: Synonymous mutations break their silence', Nature Reviews Genetics 8, 92 (February 2007). See also: Chamary, J. V. & Parmley, J. L. & Hurst, L. D. 'Hearing silence: non-neutral evolution at synonymous sites in mammals'. Nature Rev. Genet. 7, 98-108 (2006). In a very interesting article Grzegorz Kudla et al (2009) that silent (synonymous) mutations, that is mutations in the third base position (they encode the same amino acid sequence) effect the rate of protein synthesis and cell growth (Science 10 April 2009). Chamary and Hurst (2009) wrote a very readable overview of 'silent' mutations 'The price of silent mutations', Scientific American, June 2009, pp34-41. It appears that bases in protein coding exons can be also intron splicing recognition sites, and that a synonymous mutation can prevent intron splicing, resulting in mutated proteins.
  16. Scott Freeman and Jon Herron (2007) Evolutionary Analysis, page 263-264.
  17. Introducing hundreds of silent mutations into a poliovirus can slow down the virus enough to make it work as a live vaccine in mice. See: Martin Enserink (2008) "'Biased' Viruses Suggest New Vaccine Strategy for Polio and Other Diseases", Science, 27 Jun 2008.
  18. Eugene V. Koonin (2009) Darwinian evolution in the light of genomics, Nucleic Acids Research 2009, Vol. 37, No. 4 1011-1034.
  19. "By the 1980s many evolutionary geneticists had accepted the neutral theory. But the data bearing on it were mostly indirect; more direct, critical tests were lacking." H. Allen Orr (2009) Testing Natural Selection with Genetics, Scientific American, Jan 2009.
  20. J. V. Chamary and Laurence D. Hurst (2009) 'The price of silent mutations', Scientific American, June 2009, pp34-41. The sequences that define the border are called exonic splicing enhancers or ESE. The splicing machinery is called spliceosome. An intron is the non-coding part of a gene.
  21. "The choice of a particular synonymous substitution can define transcriptional or translational regulatory elements, translation speed, mRNA folding, gene expression, co-translational folding, and protein production levels, and is likely to have further undiscovered roles." and some synonymous substitutions can be deleterious and some they are position specific. So, there are allowed and disallowed synonymous substitutions. Kaihang Wang et al (2016) Defining synonymous codon compression schemes by genome recoding Nature, 539, 59–64 (03 November 2016).
  22. Nathaniel Sharp (2022) Mutations matter even if proteins stay the same, Nature 8 June 2022. This is a News and Views article. The original research article is: Synonymous mutations in representative yeast genes are mostly strongly non-neutral. See also: Most 'silent' genetic mutations are harmful, not neutral -- a finding with broad implications, ScienceDaily 8 June 2022.


Further Reading

  • Fred Hoyle(1999) Mathematics of Evolution criticised Kimura's calculation of the cost of substitution. See: review on this site.
  • Kimura, M. Evolutionary rate at the molecular level. The Classic Text (pdf).
  • King, J.L. & Jukes, T.H. Non-Darwinian evolution. The Classic Text (pdf).
  • Erik van Nimwegen (2006) 'Influenza Escapes Immunity Along Neutral Networks', Science, 22 Dec 2006 p.1884. Summary: a network of neutral mutations play a key role in the evolution of human influenza A.
  • Tomoko Ohta "Near neutrality and its implications for evolution", in: Andres Moya and Enrique Font (2004) "Evolution From Molecules to Ecosystems".
  • Driving Force Of Evolution? Evolution Of Proteins Linked To Species' Metabolic Rate, Science Daily, October 8, 2007.
  • Carl Woese: from scientific dissident to textbook orthodoxy. The proposal of the Archaea as the third domain of life was attacked and ridiculed, but 20 years later became mainstream science, and 30 years later became textbook orthodoxy.
  • Excellent overview of Kimura's work is: James F. Crow (2008) "Motoo Kimura and the Rise of Neutralism", pp. 265-281. in: Oren Harman and Michael R. Dietrich (2008) Rebels, Mavericks, and Heretics in Biology.
  • J. V. Chamary and Laurence D. Hurst (2009) How Trivial DNA Changes Can Hurt Health, Scientific American June 2009. is about silent mutations. Very useful.
  • Michael Lynch (2007) The frailty of adaptive hypotheses for the origins of organismal complexity, PNAS May 15, 2007 vol. 104 free full text: "Most biologists are so convinced that all aspects of biodiversity arise from adaptive processes that virtually no attention is given to the null hypothesis of neutral evolution".
  • Eugene V. Koonin (2009) Darwinian evolution in the light of genomics, Nucleic Acids Research, 2009, Vol. 37, No. 4 1011-1034 free full text.
  • Masatoshi Nei, Yoshiyuki Suzuki, and Masafumi Nozawa (2010) The Neutral Theory of Molecular Evolution in the Genomic Era, Annual Review of Genomics and Human Genetics, Vol. 11: 265-289 (September 2010) . [is a defence of the neutral theory of molecular evolution and concludes that recent data on genomic evolution are generally consistent with the neutral theory.]
  • wikipedia: Silent mutation and synonymous mutation.

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Copyright © 1999/2001 G.Korthof First published: 01-01-1999 Last update: 8 Jun 2022 Nov 2016 Notes/FR: 8 Jun 2022