Neutral theory of molecular evolution

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The neutral theory of molecular evolution holds that at the molecular level most evolutionary changes and most of the variation within and between species is not caused by natural selection but by random drift of mutant alleles that are neutral. A neutral mutation is one that does not affect an organism's ability to survive and reproduce. The neutral theory allows for the possibility that most mutations are deleterious, but holds that because these are rapidly purged by natural selection, they do not make significant contributions to variation within and between species at the molecular level. Mutations that are not deleterious are assumed to be mostly neutral rather than beneficial. In addition to assuming the primacy of neutral mutations, the theory also assumes that the fate of neutral mutations is determined by the sampling processes described by specific models of random genetic drift.[1]

According to Kimura, the theory applies only for evolution at the molecular level, and phenotypic evolution is controlled by natural selection, as postulated by Charles Darwin. The proposal of the neutral theory was followed by an extensive "neutralist-selectionist" controversy over the interpretation of patterns of molecular divergence and polymorphism, peaking in the 1970s and 1980s. The controversy is still unsettled among evolutionary biologists.


While some scientists, such as Freese (1962) [2] and Freese and Yoshida (1965),[3] had suggested that neutral mutations were probably widespread, a coherent theory of neutral evolution was proposed by Motoo Kimura in 1968,[4] and by King and Jukes independently in 1969.[5]

Kimura, King, and Jukes suggested that when one compares the genomes of existing species, the vast majority of molecular differences are selectively "neutral", i.e. the molecular changes represented by these differences do not influence the fitness of organisms. As a result, the theory regards these genomic features as neither subject to, nor explicable by, natural selection. This view is based in part on the degenerate genetic code, in which sequences of three nucleotides (codons) may differ and yet encode the same amino acid (GCC and GCA both encode alanine, for example). Consequently, many potential single-nucleotide changes are in effect "silent" or "unexpressed" (see synonymous or silent substitution). Such changes are presumed to have little or no biological effect. However, it should be noted that the original theory was based on the constancy of the rates of amino acid substitutions and hypothesized that the majority of the substitutions were also neutral.

A second hypothesis of the neutral theory is that most evolutionary change is the result of genetic drift acting on neutral alleles. A new allele arises typically through the spontaneous mutation of a single nucleotide within the sequence of a gene. In single-celled organisms, such an event immediately contributes a new allele to the population, and this allele is subject to drift. In sexually reproducing multicellular organisms, the nucleotide substitution must arise within one of the many sex cells that an individual carries. Then only if that sex cell participates in the genesis of an embryo does the mutation contribute a new allele to the population. Neutral substitutions create new neutral alleles.

Through drift, these new alleles may become more common within the population. They may subsequently be lost, or in rare cases they may become fixed, meaning that the new allele becomes standard in the population.

According to the theory of genetic drift, when comparing divergent populations, most of the single-nucleotide differences can be assumed to have accumulated at the same rate as the mutation rate. This latter rate, it has been argued, is predictable from the error rate of nucleotide sequence formation at the time of DNA replication. Thus the neutral theory provides a rationale for the molecular clock, although the discovery of a molecular clock predated neutral theory.[6]

Many molecular biologists and population geneticists also contributed to the development of the neutral theory, which is different from the neo-Darwinian theory.[1][7][8]

Neutral theory does not deny the occurrence of natural selection. Hughes writes: "Evolutionary biologists typically distinguish two main types of natural selection: purifying selection, which acts to eliminate deleterious mutations; and positive (Darwinian) selection, which favors advantageous mutations. Positive selection can, in turn, be further subdivided into directional selection, which tends toward fixation of an advantageous allele, and balancing selection, which maintains a polymorphism. The neutral theory of molecular evolution predicts that purifying selection is ubiquitous, but that both forms of positive selection are rare, whereas not denying the importance of positive selection in the origin of adaptations."[9] In another essay, Hughes writes: "Purifying selection is the norm in the evolution of protein coding genes. Positive selection is a relative rarity — but of great interest, precisely because it represents a departure from the norm."[10] A more general and more recent view of molecular evolution is presented by Nei.[8]

The "neutralist–selectionist" debate[edit]

A heated debate arose when Kimura's theory was published, largely revolving around the relative percentages of alleles that are "neutral" versus "non-neutral" in any given genome. Contrary to the perception of many onlookers, the debate was not about whether natural selection does occur. Kimura argued that molecular evolution is dominated by selectively neutral evolution but at the phenotypic level, changes in characters were probably dominated by natural selection rather than genetic drift.[11]

After flirting (in 1973) with the idea that slightly deleterious mutations may be common, Tomoko Ohta emphasized the importance of nearly neutral mutations.[12] However, the population dynamics of these mutations is essentially the same as that of neutral mutations unless selection coefficients are significantly greater or smaller than 0.[7][8] Note also that the neutral theory does not assume the strict neutrality of alleles but that the allele frequency changes are dominated by genetic drift.[1]

There are a large number of statistical methods for testing neutral evolution (e.g., McDonald-Kreitman test [13]), and many authors claimed detection of selection [Fay et al. 2002,[14] Begun et al. 2007,[15] Shapiro et al. 2007,[16] Hahn 2008,[17] Akey 2009.[18]] However, Nei et al. (2010).[19] have indicated that these methods depend on many assumptions which are not biologically justified.

Implications for evolvability in asexual populations[edit]

In a series of recent papers, Andreas Wagner[20] proposed a reconciliation between selectionism and neutralism. He demonstrated how evolutionary change involving several independent stepwise mutations might take place. In pure selectionism such change would be impossible because each step must occur independently. This assumes that selection is so fast that when a mutation becomes fixed by natural selection, the fixation happens fast and is complete before the next favorable mutation appears. In Wagner's model, "innovation occurs via cycles of exploration of nearly neutral spaces," which he refers to as a neutralist regime. During a neutralist regime, neutral mutations accumulate, and so genetic diversity increases. When a new phenotype with higher fitness occurs, its genotype sweeps through the population to fixation, and genetic diversity is reduced during the selectionist regime.[20]

Wagner uses RNA sequences as genotype, and the final folded structure of RNA as the phenotype. The work is made possible by the existence of a computationally efficient algorithm which predicts RNA structure from an RNA sequence. The work shows that RNA phenotype is robust enough to permit considerable variation in the underlying genotypes. This phenotype robustness promotes structure evolvability. The likelihood that a mutation is deleterious is smaller in populations with more robust phenotypes. As genetic diversity increases under such a neutralist regime, opportunities for an advantageous mutation increase. Wagner writes: "Populations evolving on large neutral networks can access greater amounts of variation." He explains the limitations of his work:

"This work leaves three important open questions. First, how robust and evolvable are biologically important phenotypes, such as RNA structures? To answer this question is currently impossible... no reliable and tractable method to do this is currently available. Second, how general is the positive association between phenotypic robustness and evolvability?... Does it occur in many other biological systems? Third, this work does not ask about the evolutionary forces that might cause high evolvability, of which there may be many".[21]

See also[edit]


  1. ^ a b c Kimura, Motoo. (1983). The neutral theory of molecular evolution. Cambridge
  2. ^ Freese, E. (1962). On the evolution of base composition of DNA. J THeor Biol, 3:82-101.
  3. ^ Freese, E. and Yoshida, A. (1965). The role of mutations in evolution. In V Bryson, and H J Vogel, eds. Evolving Genes and Proteins, pp. 341-55. Academic, New York.
  4. ^ Kimura M. (1968). Evolutionary Rate at the Molecular Level. Nature 217:624-6.
  5. ^ King JL, Jukes TH. (1969). Non-Darwinian Evolution. Science 164:788-97.
  6. ^ Zuckerkandl, E. and Pauling, L.B. (1962). "Molecular disease, evolution, and genetic heterogeneity". In Kasha, M. and Pullman, B (editors). Horizons in Biochemistry. Academic Press, New York. pp. 189–225. 
  7. ^ a b Nei, M. (2005). Selectionism and neutralism in molecular evolution. Mol Biol Evol, 22: 2318-42
  8. ^ a b c Nei, M. (2013). Mutation-driven evolution. Oxford University Press, Oxford
  9. ^ Hughes, Austin L. (2007). "Looking for Darwin in all the wrong places: the misguided quest for positive selection at the nucleotide sequence level". Heredity 99 (4): 364–373. doi:10.1038/sj.hdy.6801031. PMID 17622265. 
  10. ^ Hughes, Austin L. (2000). Adaptive Evolution of Genes and Genomes. Oxford University Press. p. 53. ISBN 0-19-511626-7. 
  11. ^ Provine (1991)
  12. ^ Ohta, T. (2002). "Near-neutrality in evolution of genes and gene regulation". PNAS 99 (25): 16134–16137. doi:10.1073/pnas.252626899. PMC 138577. PMID 12461171. 
  13. ^ Kreitman, Martin (2000). "M D S P A H". Annual Review of Genomics and Human Genetics 1 (1): 539–559. doi:10.1146/annurev.genom.1.1.539. PMID 11701640. 
  14. ^ Fay, J. C., Wyckoff, G. J., and Wu, C. I. (2002). Testing the neutral theory of molecular evolution with genomic data from Drosophila. Nature, 415:1024-6
  15. ^ Begun, D. J., Holloway, A. K., Stevens, K., Hillier, L. W., Poh, Y. P. et al. (2007). Population genomics: whole-genome analysis of polymorphism and divergence in Drosophila simulans. PLoS Biol, 5:e310.
  16. ^ Shapiro J. A., Huang W., Zhang C., Hubisz M. J., Lu J. et al. 2007. Adaptive genic evolution in the Drosophila genomes. Proc Natl Acad Sci USA 104:2271–76.
  17. ^ Hahn, M.W. (2008). "Toward a selection theory of molecular evolution". Evolution 62: 255–265. doi:10.1111/j.1558-5646.2007.00308.x. PMID 18302709. 
  18. ^ Akey J. M. (2009). Constructing genomic maps of positive selection in humans: where do we go from here? Genome Res 19:711–22.
  19. ^ Nei, M., Suzuki, Y., and M. Nozawa. (2010). The neutral theory of molecular evolution in the genomic era. Ann Rev Genomics Hum Genet. 11:265-89.
  20. ^ a b Wagner A. (2008). "Neutralism and selectionism: a network-based reconciliation". Nature Reviews Genetics 9 (12): 965–974. doi:10.1038/nrg2473. PMID 18957969. 
  21. ^ Wagner A. (2007). "Robustness and evolvability: a paradox resolved". Proceedings of the Royal Society 275 (1630): 91–100. doi:10.1098/rspb.2007.1137. PMC 2562401. PMID 17971325. 

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