Neutral theory of molecular evolution

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The neutral theory of molecular evolution is an influential theory, which was introduced with effect by Motoo Kimura in the late 1960s and early 1970s. The theory states that the vast majority of evolutionary changes at the molecular level are caused by random drift of selectively neutral mutants.^[1] Although the theory was received by some as an argument against Darwin's theory of evolution by natural selection, Kimura maintained, and most modern 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" (Kimura, 1986). However, the theory attributes a large role to genetic drift.

Contents 1 Overview 2 The "neutralist–selectionist" debate 3 See also 4 References

[edit] Overview

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

According to Kimura, when one compares the genomes of existing species, the vast majority of molecular differences are selectively "neutral." That is, 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 too were neutral.

A second assertion or 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 and offspring 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 looking between 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. While the mutation rate is not considered to be constant, diverse and more sophisticated clock techniques have emerged.

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. Austin Hughes writes: "Evolutionary biologists typically distinguish two main types of natural selection: (1) purifying selection, which acts to eliminate deleterious mutations and (2) 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."^[2] In another essay, Hughes writes: "Purifiying 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."^[3]

[edit] The "neutralist–selectionist" debate

A heated debate arose on the initial publication of Kimura's theory, in which discussion largely revolved 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 or not natural selection acts at all. 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 (Provine 1991).

After flirting with the idea that slightly deleterious mutations might be quite common (Ohta, 1973), Tomoko Ohta, Kimura's student, made an important generalisation of the neutral theory by including the concept of "near-neutrality",^[4][5] 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 quarrel 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.^[6]

In a series of recent papers, Swiss researcher Andreas Wagner proposed a reconciliation between selectionism and neutralism. Wagner's 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, so that the next step can occur. In Wagner's model, "innovation occurs via cycles of exploration of nearly neutral spaces," which Wagner 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.^[7]

Wagner's model for his ideas 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 hold 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." Wagner's summary 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".^[8]

[edit] See also

• 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

[edit] 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 edition. Sinauer Associates. ISBN 0-87893-266-6. 
• Kimura, M. (1968). "Evolutionary rate at the molecular level". Nature 217: 624–626. doi:10.1038/217624a0.  [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: 788–798. doi:10.1126/science.164.3881.788. PMID 5767777.  [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: 96–98. doi:10.1038/246096a0. 
• Ohta, T. and Gillespie, J.H (1996). "Development of Neutral and Nearly Neutral Theories". Theoretical Population Biology 49: 128–142. doi:10.1006/tpbi.1996.0007. 
• Sueoka, N. (1962). "On the genetic basis of variation and heterogeneity of DNA base composition". PNAS USA 48: 582–592. doi:10.1073/pnas.48.4.582.  [3]
• Kimura, M. (1986). "DNA and the Neutral Theory". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 312 (1154): 343–354. doi:10.1098/rstb.1986.0012. 
• 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, p15-23.
• Duret, L. (2008). "Neutral Theory: The Null Hypothesis of Molecular Evolution". Nature Education 1(1).  [4]
• Nei M (2005-08-24). "Selectionism and neutralism in molecular evolution". Molecular Biology and Evolution 22 (12): 2318-2342. PMID 16120807. 

v • d • e Topics in population genetics Key concepts Hardy-Weinberg law · Genetic linkage · Linkage disequilibrium · Fisher's fundamental theorem · Neutral theory · Price equation Selection Natural · Sexual · Artificial · Ecological Effects of selection on genomic variation Genetic hitchhiking · Background selection Genetic drift Small population size · Population bottleneck · Founder effect · Coalescence · Balding–Nichols model Founders R.A. Fisher · J. B. S. Haldane · Sewall Wright Related topics Evolution · Microevolution · Evolutionary game theory · Fitness landscape · Genetic genealogy List of evolutionary biology topics