Neutral theory of molecular evolution

The neutral theory of molecular evolution states that the vast majority of evolutionary changes at the molecular level are caused by random drift of selectively neutral mutants (not affecting fitness).^[1] The theory was introduced by Motoo Kimura in the late 1960s and early 1970s. Neutral theory is compatible with Darwin's theory of evolution by natural selection: adaptive changes are acknowledged as present and important, but hypothesized to be a small minority of all the changes seen fixed in DNA sequences.^[2] Since then, this hypothesis has been tested using the McDonald-Kreitman test, and has not been supported in all species.^[3] Even in those species in which adaptive changes are rare, background selection at linked sites may violate neutral theory's assumptions regarding genetic drift.^[4]

Overview

While some scientists, such as Sueoka (1962), had hinted that perhaps neutral mutations were widespread, a coherent theory of neutral evolution was first formalized by Motoo Kimura in 1968, followed by a 1969 article by Jack L. King and Thomas H. Jukes, "Non-Darwinian Evolution".

Kimura posited 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 the individual organism. 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 consistency in rates of amino acid changes, and hypothesized that the majority of those changes 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 mathematics of drift, when comparing divergent populations, most of the single-nucleotide differences can be assumed to have accumulated at the same rate as individuals with mutations are born. This latter rate, it has been argued, is predictable from the error rate of the enzymes that carry out DNA replication; these enzymes have been well studied and are highly conserved across all species. Thus the neutral theory provides a rationale for the molecular clock, although the discovery of a molecular clock predates neutral theory.^[5] The observed overdispersion of the molecular clock is not predicted by or compatible with neutral theory.

Many molecular biologists and population geneticists also contributed to the development of the neutral theory, which may be viewed as an offshoot of the modern evolutionary synthesis.

Neutral theory does not contradict natural selection, nor does it deny that selection occurs. 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."^[6] 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."^[7]

The "neutralist–selectionist" debate

See also: History of evolutionary thought and History of molecular evolution

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 sampling drift.^[8]

After flirting (in 1973) with the idea that slightly deleterious mutations may be common, Tomoko Ohta, a student of Kimura, made an important generalisation of the neutral theory by including the concept of "near-neutrality",^[9][10] that is, genes that are affected mostly by drift or mostly by selection depending on the effective size of a breeding population. The neutralist-selectionist debate has since cooled, yet the question of the relative percentages of neutral and non-neutral alleles remains. Graur & Li (2000), go as far as to say;

"There are only two predictions we are willing to make about the future of molecular evolution. The first concerns old controversies. Issues such as the neutralist-selectionist controversy or the antiquity of introns, will continue to be debated with varying degrees of ferocity, and roars of "The Neutral Theory Is Dead" and "Long Live the Neutral Theory" will continue to reverberate, sometimes in the title of a single article."

As of the early 2000s, the neutral theory is widely used as a "null model" for so-called null hypothesis testing. However, serious doubt has been cast on the neutral theory by the application of the McDonald-Kreitman test to show that a substantial proportion of amino acid changes may be due to selection.^[4] The reliance of neutral theory on genetic drift also fails to explain the "paradox of variation", where genetic diversity has not been found to depend strongly on the size of different populations: while this can be addressed by nearly neutral theory, it requires the increase in the diversity of neutral alleles with increasing population size to exactly cancel out the decrease in the proportion of alleles that are neutral with increasing population size. Neither neutral theory nor nearly neutral theory predicts the observation that genetic diversity depends on the recombination rate in that part of the genome.^[4] These observations do not contradict the possibility that many or most substitutions are neutral, however these observations are better explained if selection at linked sites rather than genetic drift is driving changes in the frequencies of neutral alleles.^[4]

Implications for evolvability in asexual populations

In a series of recent papers, Swiss researcher Andreas Wagner^[11] proposed a reconciliation between selectionism and neutralism. His proposal demonstrates 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. Each step must be favored by positive selection to become established in the genome, in order for the next step to occur. 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 a selectionist regime.^[12]

Wagner's model 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".^[13]

See also

• Adaptive Evolution in the Human Genome
• Coalescent theory
• Evolution
• Ewens's sampling formula
• John H. Gillespie
• Molecular evolution
• Nearly neutral theory of molecular evolution
• Peter Donnelly
• Tomoko Ohta
• Unified neutral theory of biodiversity
• Warren Ewens

References

1. ^ Kimura, Motoo. 1983. The neutral theory of molecular evolution. Cambridge (page xi)
2. ^ Kimura (1986)
3. ^ Fay, Justin C.. "Weighing the evidence for adaptation at the molecular level". Trends in Genetics 27 (9): 343–349. doi:10.1016/j.tig.2011.06.003. http://www.sciencedirect.com/science/article/pii/S0168952511000941. 
4. ^ ^{a b c d} Hahn, M.W. (2008). "Toward a selection theory of molecular evolution". Evolution 62: 255–265. doi:10.1111/j.1558-5646.2007.00308.x. 
5. ^ 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. 
6. ^ Hughes, Austin L. (2007-07-11). "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. 
7. ^ Hughes, Austin L.. Adaptive Evolution of Genes and Genomes. Oxford University Press. p. 53. ISBN 0195116267. 
8. ^ Provine (1991)
9. ^ Ohta, T. (1992). "The nearly neutral theory of molecular evolution". Annual Review of Ecology and Systematics 23 (1): 263–286. doi:10.1146/annurev.es.23.110192.001403. 
10. ^ 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. http://www.pnas.org/cgi/content/full/99/25/16134. 
11. ^ Website for Andreas Wagner Laboratory, Switzerland
12. ^ Wagner A. (dec 2008). "Neutralism and selectionism: a network-based reconciliation". Nature Reviews Genetics 9 (12): 965–974. doi:10.1038/nrg2473. PMID 18957969. 
13. ^ Wagner A. (2007-10-31). "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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2562401. 

• Gillespie, J. H (1991). The Causes of Molecular Evolution. Oxford University Press, New York. ISBN 0-19-506883-1. 
• Graur, D. and Li, W-H (2000). Fundamentals of Molecular Evolution, 2nd ed.. Sinauer Associates. ISBN 0-87893-266-6. 
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• Lewontin, R. (1974). The Genetic Basis of Evolutionary Change. Columbia University Press. ISBN 0-231-03392-3. 
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• Duret, L. (2008). "Neutral Theory: The Null Hypothesis of Molecular Evolution". Nature Education 1 (1).  [3]
• Nei M. (2005-08-24). "Selectionism and neutralism in molecular evolution". Molecular Biology and Evolution 22 (12): 2318–2342. doi:10.1093/molbev/msi242. PMC 1513187. PMID 16120807. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1513187.