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. The theory was introduced by Motoo Kimura in the late 1960s and early 1970s, and although it was received by some as an argument against Darwin's theory of evolution by natural selection, Kimura maintained (and most evolutionary biologists agree) that the two theories are compatible: "The theory does not deny the role of natural selection in determining the course of adaptive evolution". However, the theory attributes a large role to genetic drift.

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 is the foundation of the molecular clock technique, which evolutionary molecular biologists use to measure how much time has passed since species diverged from a common ancestor. More sophisticated clock techniques have emerged to account for variable mutation rate.

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." 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."

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.

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", 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. Researchers typically apply such a test when they already have an estimate of the amount of time that has passed since two species or lineages diverged—for example, from radiocarbon dating at fossil excavation sites, or from historical records in the case of human families. The test compares the actual number of differences between two sequences and the number that the neutral theory predicts given the independently estimated divergence time. If the actual number of differences is much less than the prediction, the null hypothesis has failed, and researchers may reasonably assume that selection has acted on the sequences in question. Thus such tests contribute to the ongoing investigation into the extent to which molecular evolution is neutral.

In a series of recent papers, Swiss researcher Andreas Wagner 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.

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".

See also

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

References

• 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.{{cite book}}: CS1 maint: multiple names: authors list (link)
• Kimura, M. (1968). "Evolutionary rate at the molecular level". Nature. 217 (5129): 624–626. doi:10.1038/217624a0. PMID 5637732. [1]
• Kimura, M. (1983). The Neutral Theory of Molecular Evolution. Cambridge University Press, Cambridge. ISBN 0-521-23109-4.
• King, J.L. and Jukes, T.H. (1969). "Non-Darwinian Evolution". Science. 164 (881): 788–798. doi:10.1126/science.164.3881.788. PMID 5767777.{{cite journal}}: CS1 maint: multiple names: authors list (link) [2]
• Lewontin, R. (1974). The Genetic Basis of Evolutionary Change. Columbia University Press. ISBN 0-231-03392-3.
• Ohta, T. (1973). "Slightly deleterious mutant substitutions in evolution". Nature. 246 (5428): 96–98. doi:10.1038/246096a0. PMID 4585855.
• Ohta, T. and Gillespie, J.H. (1996). "Development of Neutral and Nearly Neutral Theories". Theoretical Population Biology. 49 (2): 128–142. doi:10.1006/tpbi.1996.0007. PMID 8813019.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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• Provine W.B. Rise of the null selection hypothesis. In Cain A.J. and Provine W.B. 1991. Genes and ecology in history. In Berry R.J. et al. (eds) Genes in ecology: the 33rd Symposium of the British Ecological Society. Blackwell, Oxford, pp. 15–23
• Duret, L. (2008). "Neutral Theory: The Null Hypothesis of Molecular Evolution". Nature Education. 1 (1). [4]
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