The neutral theory of molecular evolution holds that most evolutionary changes occur at the molecular level, and most of the variation within and between species, are due to random genetic drift of mutant alleles that are selectively neutral. The theory applies only for evolution at the molecular level, and is compatible with phenotypic evolution being shaped by natural selection as postulated by Charles Darwin. The neutral theory allows for the possibility that most mutations are deleterious, but holds that because these are rapidly removed by natural selection, they do not make significant contributions to variation within and between species at the molecular level. A neutral mutation is one that does not affect an organism's ability to survive and reproduce. The neutral theory assumes that most mutations that are not deleterious are neutral rather than beneficial. Because only a fraction of gametes are sampled in each generation of a species, the neutral theory suggests that a mutant allele can arise within a population and reach fixation by chance, rather than by selective advantage.[1]

The theory was introduced by the Japanese biologist Motoo Kimura in 1968, and independently by two American biologists Jack Lester King and Thomas Hughes Jukes in 1969, and described in detail by Kimura in his 1983 monograph The Neutral Theory of Molecular Evolution. The proposal of the neutral theory was followed by an extensive "neutralist-selectionist" controversy over the interpretation of patterns of molecular divergence and gene polymorphism, peaking in the 1970s and 1980s.

## Origins

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 initially focused on differences among species, King and Jukes on differences within species.

Many molecular biologists and population geneticists also contributed to the development of the neutral theory.[1][6][7] Principles of population genetics, established by J.B.S. Haldane, R.A. Fisher and Sewall Wright, created a mathematical approach to analyzing gene frequencies that contributed to the development of Kimura's theory.

Haldane's dilemma regarding the cost of selection was used as motivation by Kimura. Haldane estimated that it takes about 300 generations for a beneficial mutation to become fixed in a mammalian lineage, meaning that the number of substitutions (1.5 per year) in the evolution between humans and chimpanzees was too high to be explained by beneficial mutations.

## Functional constraint

The neutral theory holds that as functional constraint diminishes, the probability that a mutation is neutral rises, and so should the rate of sequence divergence.

When comparing various proteins, extremely high evolutionary rates were observed in proteins such as fibrinopeptides and the C chain of the proinsulin molecule, which both have little to no functionality compared to their active molecules. Kimura and Ohta also estimated that the alpha and beta chains on the surface of a hemoglobin protein evolve at a rate almost ten times faster than the inside pockets, which would imply that the overall molecular structure of hemoglobin is less significant than the inside where the iron-containing heme groups reside.[8]

There is evidence that rates of nucleotide substitution are particularly high in the third position of a codon, where there is little functional constraint.[9] 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.[10]

## Quantitative theory

Kimura also developed the infinite sites model (ISM) to provide insight into evolutionary rates of mutant alleles. If ${\displaystyle v}$ were to represent the rate of mutation of gametes per generation of ${\displaystyle N}$ individuals, each with two sets of chromosomes, the total number of new mutants in each generation is ${\displaystyle 2Nv}$. Now let ${\displaystyle k}$ represent the evolution rate in terms of a mutant allele ${\displaystyle \mu }$ becoming fixed in a population.[11]

${\displaystyle k=2Nv\mu }$

According to ISM, selectively neutral mutations appear at rate ${\displaystyle \mu }$ in each of the ${\displaystyle 2N}$ copies of a gene, and fix with probability ${\displaystyle 1/(2N)}$. Because any of the ${\displaystyle 2N}$ genes have the ability to become fixed in a population, ${\displaystyle 1/2N}$ is equal to ${\displaystyle \mu }$, resulting in the rate of evolutionary rate equation:

${\displaystyle k=v}$

This means that if all mutations were neutral, the rate at which fixed differences accumulate between divergent populations is predicted to be equal to the per-individual mutation rate, independent of population size. When the proportion of mutations that are neutral is constant, so is the divergence rate between populations. This provides a rationale for the molecular clock - which predated neutral theory.[12] The ISM also demonstrates a constancy that is observed in molecular lineages.

This stochastic process is assumed to obey equations describing random genetic drift by means of accidents of sampling, rather than for example genetic hitchhiking of a neutral allele due to genetic linkage with non-neutral alleles. After appearing by mutation, a neutral allele may become more common within the population via genetic drift. Usually, it will be lost, or in rare cases it may become fixed, meaning that the new allele becomes standard in the population.

According to the neutral theory of molecular evolution, the amount of genetic variation within a species should be proportional to the effective population size.

## The "neutralist–selectionist" debate

A heated debate arose when Kimura's theory was published, largely revolving around the relative percentages of polymorphic and fixed alleles that are "neutral" versus "non-neutral".

A genetic polymorphism means that different forms of particular genes, and hence of the proteins that they produce, are co-existing within a species. Selectionists claimed that such polymorphisms are maintained by balancing selection, while neutralists view the variation of a protein as a transient phase of molecular evolution.[1] Studies by Richard K. Koehn and W. F. Eanes demonstrated a correlation between polymorphism and molecular weight of their molecular subunits.[13] This is consistent with the neutral theory assumption that larger subunits should have higher rates of neutral mutation. Selectionists, on the other hand, contribute environmental conditions to be the major determinants of polymorphisms rather than structural and functional factors.[11]

According to the neutral theory of molecular evolution, the amount of genetic variation within a species should be proportional to the effective population size. Levels of genetic diversity vary much less than census population sizes, giving rise to the "paradox of variation" .[14] While high levels of genetic diversity were one of the original arguments in favor of neutral theory, the paradox of variation has been one of the strongest arguments against neutral theory.

There are a large number of statistical methods for testing whether neutral theory is a good description of evolution (e.g., McDonald-Kreitman test[15]), and many authors claimed detection of selection (Fay et al. 2002,[16] Begun et al. 2007,[17] Shapiro et al. 2007,[18] Hahn 2008,[19] Akey 2009,[20] Kern 2018[21]). Some researchers have nevertheless argued that the neutral theory still stands, while expanding the definition of neutral theory to include background selection at linked sites.[22]

## Nearly neutral theory

Tomoko Ohta also emphasized the importance of nearly neutral mutations, in particularly slightly deleterious mutations.[23] The population dynamics of nearly neutral mutations are only slightly different from those of neutral mutations unless the absolute magnitude of the selection coefficient is greater than 1/N, where N is the effective population size in respect of selection.[1][6][7] The value of N may therefore affect how many mutations can be treated as neutral and how many as deleterious.

## References

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3. ^ Freese, E.; Yoshida, A. (1965). "The role of mutations in evolution.". In Bryson, V.; Vogel, H. J. (eds.). Evolving Genes and Proteins. New York: Academic. pp. 341–355.
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