Neutral theory of molecular evolution
The neutral theory of molecular evolution is "the theory that at the molecular level evolutionary changes and polymorphisms are mainly due to mutations that are nearly enough neutral with respect to natural selection that their behavior and fate are mainly determined by mutation and random drift"  According to Kimura, the theory "is not antagonistic to the cherished view that evolution of form and function is guided by Darwinian selection, but it brings out another facet of the evolutionary process by emphasizing the much greater role of mutation pressure and random drift"  Following the proposal of the theory by Kimura, King and Jukes in 1968-1969, Ohta proposed a "nearly neutral theory", which differs significantly from the original. The proposal of the neutral and nearly neutral theories was followed by a sustained "neutralist-selectionist" controversy over the interpretation of patterns of molecular divergence and polymorphism, peaking in the 1980s. Subsequently, neutral models became a fixture of evolutionary analysis. There is no consensus among evolutionary scientists as to which theory most closely corresponds with the observed data.
While some scientists, such as Sueoka (1962), had hinted that perhaps neutral mutations were widespread, a coherent theory of neutral evolution was proposed by Motoo Kimura in 1968, and was proposed independently by King and Jukes in 1969.
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. The observed overdispersion of the molecular clock is not predicted by or compatible with neutral theory.
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
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 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. Koonin (2009) claims:
- "Equally outdated is the (neo)Darwinian notion of the adaptive nature of evolution: clearly, genomes show very little if any signs of optimal design, and random drift constrained by purifying in all likelihood contributes (much) more to genome evolution than Darwinian selection."
A simplified neutral model is often tested using the McDonald-Kreitman test, and has not been supported in all species. Even in those species in which adaptive changes are rare, background selection at linked sites may violate neutral theory's assumptions regarding genetic drift. 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. Such tests as the HKA test and McDonald-Kreitman test, use the Neutral Theory model to look for directed evolution (i.e. positive selection). 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. 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. These observations do not contradict the possibility that many or most substitutions are neutral, but these observations are better explained if selection at linked sites rather than genetic drift is driving changes in the frequencies of neutral alleles.
Implications for evolvability in asexual populations
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. 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 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".
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