Editing Neutral theory of molecular evolution

{{Short description|Theory of evolution by changes at the molecular level}}
[[File:The Neutral Theory of Molecular Evolution.jpg|frameless|right]]

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 [[mutation|mutant]] [[allele]]s that are selectively [[Neutral mutation|neutral]]. The theory applies only for evolution at the molecular level, and is compatible with [[Phenotype|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 [[purifying selection|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 [[gamete]]s are sampled in each generation of a species, the neutral theory suggests that a mutant allele can arise within a population and reach [[Fixation (population genetics)|fixation]] by chance, rather than by selective advantage.<ref name=Kimura83>{{cite book |last=Kimura |first=Motoo |author-link=Motoo Kimura |date=1983 |title=The neutral theory of molecular evolution |publisher=Cambridge University Press |isbn=978-0-521-31793-1 }}</ref>

The theory was introduced by the Japanese biologist [[Motoo Kimura]] in 1968, and independently by two American biologists [[Jack Lester King]] and [[Thomas H. Jukes|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.

Neutral theory is frequently used as the [[null hypothesis]], as opposed to [[Adaptation|adaptive]] explanations, for describing the emergence of morphological or genetic features in organisms and populations. This has been suggested in a number of areas, including in explaining genetic variation between populations of one nominal species,<ref>{{Cite journal |last=Fenchel |first=Tom |date=2005-11-11 |title=Cosmopolitan microbes and their 'cryptic' species |url=https://www.int-res.com/abstracts/ame/v41/n1/p49-54/ |journal=Aquatic Microbial Ecology |language=en |volume=41 |issue=1 |pages=49–54 |doi=10.3354/ame041049 |issn=0948-3055|doi-access=free }}</ref> the emergence of complex subcellular machinery,<ref name=":2" /> and the convergent emergence of several typical microbial morphologies.<ref>{{Cite journal |last1=Lahr |first1=Daniel J. G. |last2=Laughinghouse |first2=Haywood Dail |last3=Oliverio |first3=Angela M. |last4=Gao |first4=Feng |last5=Katz |first5=Laura A. |date=2014 |title=How discordant morphological and molecular evolution among microorganisms can revise our notions of biodiversity on Earth: Prospects & Overviews |journal=BioEssays |language=en |volume=36 |issue=10 |pages=950–959 |doi=10.1002/bies.201400056 |pmc=4288574 |pmid=25156897}}</ref>

==Origins==

While some scientists, such as Freese (1962)<ref>{{cite journal |last=Freese |first=E. |title=On the evolution of the base composition of DNA. |journal=Journal of Theoretical Biology |date=July 1962 |volume=3 |issue=1 |pages=82–101 |doi=10.1016/S0022-5193(62)80005-8 |bibcode=1962JThBi...3...82F }}</ref> and Freese and Yoshida (1965),<ref>{{cite book |last1=Freese |first1=E. |last2=Yoshida |first2=A. |date=1965 |chapter=The role of mutations in evolution. |editor1=Bryson, V. |editor2=Vogel, H. J. |title=Evolving Genes and Proteins |pages=341–355 |publisher=Academic |location=New York }}</ref> had suggested that neutral [[mutation]]s were probably widespread, the original mathematical derivation of the theory had been published by [[R.A. Fisher]] in 1930.<ref>Fisher R.A. 1930. The distribution of gene ratios for rare mutations. ''Proceedings of the Royal Society of Edinburgh'' volume 50, pages 205-230.</ref> Fisher, however, gave a reasoned argument for believing that, in practice, neutral gene substitutions would be very rare.<ref>R.J. Berry, T.J. Crawford, G.M. Hewitt 1992. ''Genes in Ecology.'' Blackwell Scientific Publications, Oxford. pp.29-54 J.R.G.Turner: Stochastic processes in populations: the horse behind the cart?.</ref> A coherent theory of neutral evolution was first proposed by [[Motoo Kimura]] in 1968<ref name="pmid5637732">{{cite journal |last=Kimura |first=Motoo |author-link=Motoo Kimura |title=Evolutionary rate at the molecular level |journal=Nature |volume=217 |issue=5129 |pages=624–6 |date=February 1968 |pmid=5637732 |doi=10.1038/217624a0 |bibcode=1968Natur.217..624K |s2cid=4161261 }}</ref> and by King and Jukes independently in 1969.<ref name="pmid5767777">{{cite journal |last1=King |first1=J. L. |last2=Jukes |first2=T. H. |title=Non-Darwinian evolution |journal=Science |volume=164 |issue=3881 |pages=788–98 |date=May 1969 |pmid=5767777 |doi=10.1126/science.164.3881.788 |bibcode=1969Sci...164..788L }}</ref> Kimura initially focused on differences among species; King and Jukes focused on differences within species.

Many [[molecular biology|molecular biologists]] and [[population genetics|population geneticists]] also contributed to the development of the neutral theory.<ref name="Kimura83" /><ref name="Nei2005">{{cite journal |last=Nei |first=Masatoshi |author-link=Masatoshi Nei |title=Selectionism and neutralism in molecular evolution |journal=Molecular Biology and Evolution |volume=22 |issue=12 |pages=2318–2342 |date=December 2005 |pmid=16120807 |pmc=1513187 |doi=10.1093/molbev/msi242 }}</ref><ref name="Nei2013">{{cite book |last=Nei |first=Masatoshi |author-link=Masatoshi Nei |date=2013 |title=Mutation-driven evolution |publisher=Oxford University Press}}</ref> The principles of [[population genetics]], established by [[J. B. S. Haldane|J.B.S. Haldane]], [[Ronald Fisher|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 [[Genetic load|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 [[protein]]s, extremely high evolutionary rates were observed in proteins such as [[fibrinopeptide]]s and the C chain of the [[proinsulin]] molecule, which both have little to no functionality compared to their active molecules. Kimura and [[Tomoko Ohta|Ohta]] also estimated that the [[Hemoglobin subunit alpha|alpha]] and [[Hemoglobin subunit beta|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.<ref>{{Cite journal|last=Kimura|first=M.|title=The Rate of Molecular Evolution Considered from the Standpoint of Population Genetics|date=1969-08-01|journal=Proceedings of the National Academy of Sciences|volume=63|issue=4|pages=1181–1188|doi=10.1073/pnas.63.4.1181|pmid=5260917|pmc=223447|bibcode=1969PNAS...63.1181K |issn=0027-8424|doi-access=free}}</ref>

There is evidence that rates of [[nucleotide]] substitution are particularly high in the third position of a [[codon]], where there is little functional constraint.<ref>{{Cite journal|last1=Bofkin|first1=L.|last2=Goldman|first2=N.|date=2006-11-13|title=Variation in Evolutionary Processes at Different Codon Positions|journal=Molecular Biology and Evolution|volume=24|issue=2|pages=513–521|doi=10.1093/molbev/msl178|pmid=17119011|issn=0737-4038|doi-access=free}}</ref> This view is based in part on the [[Codon degeneracy|degenerate genetic code]], in which sequences of three nucleotides ([[codon]]s) 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 substitution|synonymous or silent substitution]]). Such changes are presumed to have little or no biological effect.<ref>{{Citation|last=Crick|first=F.H.C.|title=Codon—Anticodon Pairing: The Wobble Hypothesis|date=1989|url=http://dx.doi.org/10.1016/b978-0-12-131200-8.50026-5|work=Molecular Biology|pages=370–377|publisher=Elsevier|doi=10.1016/b978-0-12-131200-8.50026-5|isbn=978-0-12-131200-8|access-date=2021-04-03|url-access=subscription}}</ref>

== Quantitative theory ==
[[Motoo Kimura|Kimura]] also developed the [[infinite sites model]] (ISM) to provide insight into evolutionary rates of [[mutant allele]]s. If <math>v</math> were to represent the rate of mutation of [[gamete]]s per generation of <math>N</math> individuals, each with two sets of [[chromosome]]s, the total number of new mutants in each generation is <math>2Nv</math>. Now let <math>k</math> represent the evolution rate in terms of a mutant allele <math>\mu</math> becoming fixed in a population.<ref name=":0">{{cite journal |last=Kimura |first=Motoo |author-link=Motoo Kimura |title=The neutral theory of molecular evolution |journal=[[Scientific American]] |volume=241 |issue=5 |pages=98–100, 102, 108 passim |date=November 1979 |pmid=504979 |doi=10.1038/scientificamerican1179-98 |bibcode=1979SciAm.241e..98K |jstor=24965339 |s2cid=5119551 }}</ref>

:<math>k=2Nv\mu</math>

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

:<math>k=v</math>

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.<ref name="Zuckerkand62">{{cite book |last1=Zuckerkandl |first1=Emile |author1-link=Emile Zuckerkandl |last2=Pauling |first2=Linus B. |author2-link=Linus Pauling |year=1962 |title=Horizons in Biochemistry |chapter-url=https://archive.org/details/horizonsinbioche0000kash |chapter-url-access=registration |chapter=Molecular disease, evolution, and genetic heterogeneity |editor1=Kasha, M. |editor2=Pullman, B. |pages=[https://archive.org/details/horizonsinbioche0000kash/page/189 189–225] |publisher=Academic Press}}</ref> The ISM also demonstrates a constancy that is observed in molecular [[Lineage (genetic)|lineage]]s.

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 [[Fixation (population genetics)|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 [[Proportionality (mathematics)|proportional]] to the [[effective population size]].

==The "neutralist–selectionist" debate==
{{see also|History of evolutionary thought|History of molecular evolution}}

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

A [[genetic polymorphism]] means that different forms of particular genes, and hence of the [[protein]]s 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]].<ref name="Kimura83" /> Studies by Richard K. Koehn and W. F. Eanes demonstrated a correlation between polymorphism and [[Molecular mass|molecular weight]] of their molecular [[Protein subunit|subunits]].<ref>{{cite journal |last=Eanes |first=Walter F. |date=November 1999 |title=Analysis of Selection on Enzyme Polymorphisms |journal=Annual Review of Ecology and Systematics |volume=30 |issue=1 |pages=301–326 |doi=10.1146/annurev.ecolsys.30.1.301|bibcode=1999AnRES..30..301E }}</ref> 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.<ref name=":0" />

According to the neutral theory of molecular evolution, the amount of [[genetic variation]] within a species should be [[Proportionality (mathematics)|proportional]] to the [[effective population size]]. Levels of genetic diversity vary much less than census population sizes, giving rise to the "paradox of variation" .<ref>{{cite book |last=Lewontin |first=Richard C. |author-link=Richard Lewontin |title=The genetic basis of evolutionary change |date=1973 |publisher=Columbia University Press |isbn=978-0231033923 |edition=4th printing |url-access=registration |url=https://archive.org/details/geneticbasisofev00lewo}}</ref> 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]]<ref>{{cite journal |last=Kreitman |first=M. |title=Methods to detect selection in populations with applications to the human |journal=Annual Review of Genomics and Human Genetics |volume=1 |issue=1 |pages=539–59 |year=2000 |pmid=11701640 |doi=10.1146/annurev.genom.1.1.539 |doi-access=free }}</ref>), and many authors claimed detection of selection.<ref name="pmid11875569">{{cite journal |last1=Fay |first1=J. C. |last2=Wyckoff |first2=G. J. |last3=Wu |first3=C. I. |title=Testing the neutral theory of molecular evolution with genomic data from Drosophila |journal=Nature |volume=415 |issue=6875 |pages=1024–6 |date=February 2002 |pmid=11875569 |doi=10.1038/4151024a |bibcode=2002Natur.415.1024F |s2cid=4420010 }}</ref><ref name="pmid17988176">{{cite journal |last=Begun |first=D. J. |author2=Holloway, A. K. |author3=Stevens, K. |author4=Hillier, L. W. |author5=Poh, Y. P. |author6=Hahn, M. W. |author7=Nista, P. M. |author8=Jones, C. D. |author9=Kern, A. D. |author10=Dewey, C. N. |author11=Pachter, L. |author12=Myers, E. |author13=Langley, C. H. |title=Population genomics: whole-genome analysis of polymorphism and divergence in Drosophila simulans |journal=PLOS Biology |volume=5 |issue=11 |pages=e310 |date=November 2007 |pmid=17988176 |pmc=2062478 |doi=10.1371/journal.pbio.0050310 |doi-access=free }}</ref><ref name="pmid17284599">{{cite journal |last1=Shapiro |first1=J. A. |author2=Huang, W. |author3=Zhang, C. |author4=Hubisz, M. J. |author5=Lu, J. |author6=Turissini, D. A. |author7=Fang, S. |author8=Wang, H. Y. |author9=Hudson, RR |author10=Nielsen, R. |author11=Chen, Z. |author12=Wu, C. I. |title=Adaptive genic evolution in the Drosophila genomes |journal=PNAS |volume=104 |issue=7 |pages=2271–6 |date=February 2007 |pmid=17284599 |pmc=1892965 |doi=10.1073/pnas.0610385104 |bibcode=2007PNAS..104.2271S|doi-access=free }}</ref><ref name="Hahn">{{cite journal |last=Hahn |first=M. W. |title=Toward a selection theory of molecular evolution |journal=Evolution; International Journal of Organic Evolution |volume=62 |issue=2 |pages=255–65 |date=February 2008 |pmid=18302709 |doi=10.1111/j.1558-5646.2007.00308.x |doi-access=free }}</ref><ref name="pmid19411596">{{cite journal |last=Akey |first=J. M. |title=Constructing genomic maps of positive selection in humans: where do we go from here? |journal=Genome Research |volume=19 |issue=5 |pages=711–22 |date=May 2009 |pmid=19411596 |pmc=3647533 |doi=10.1101/gr.086652.108 }}</ref><ref>{{cite journal |last1=Kern |first1=A. D. |last2=Hahn |first2=M. W. |title=The Neutral Theory in Light of Natural Selection |journal=Molecular Biology and Evolution |volume=35 |issue=6 |pages=1366–1371 |date=June 2018 |pmid=29722831 |pmc=5967545 |doi=10.1093/molbev/msy092 }}</ref> 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.<ref>{{cite journal |last=Jensen |first=J.D. |author2=Payseur, B. A. |author3=Stephan, W. |author4=Aquadro C. F. |author5=Lynch, M. Charlesworth, D. |author6=Charlesworth, B. |title=The importance of the Neutral Theory in 1968 and 50 years on: A response to Kern and Hahn 2018 |journal=Evolution; International Journal of Organic Evolution |volume=73 |issue=1 |pages=111–114 |date=January 2019 |pmid=30460993 |pmc=6496948 |doi=10.1111/evo.13650 }}</ref>

==Nearly neutral theory==
[[Tomoko Ohta]] also emphasized the importance of [[Nearly neutral theory of molecular evolution|nearly neutral]] mutations, in particularly slightly deleterious mutations.<ref name="Ohta2002">{{cite journal |last=Ohta |first=T. |title=Near-neutrality in evolution of genes and gene regulation |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=99 |issue=25 |pages=16134–7 |date=December 2002 |pmid=12461171 |pmc=138577 |doi=10.1073/pnas.252626899 |bibcode=2002PNAS...9916134O |doi-access=free }}</ref> The [[Nearly neutral theory of molecular evolution|Nearly neutral theory]] stems from the prediction of neutral theory that the balance between selection and genetic drift depends on [[effective population size]].<ref>{{Cite journal |last=Ohta |first=Tomoko |date=1973 |title=Slightly Deleterious Mutant Substitutions in Evolution |url=https://www.nature.com/articles/246096a0 |journal=Nature |language= |volume=246 |issue=5428 |pages=96–98 |doi=10.1038/246096a0 |pmid=4585855 |bibcode=1973Natur.246...96O |s2cid=4226804 |issn=1476-4687|url-access=subscription }}</ref> Nearly neutral mutations are those that carry selection coefficients less than the inverse of twice the effective population size.<ref name="Kimura833">{{cite book |last=Kimura |first=Motoo |title=The neutral theory of molecular evolution |date=1983 |publisher=Cambridge University Press |isbn=978-0-521-31793-1 |author-link=Motoo Kimura}}</ref> 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.<ref name="Kimura83" /><ref name="Nei2005" /><ref name="Nei2013" /> The effective population size affects whether slightly deleterious mutations can be treated as neutral or as deleterious.<ref name=":05">{{Cite journal |last=Hughes |first=Austin L. |date=2008 |title=Near Neutrality: the leading edge of the Neutral Theory of Molecular Evolution |url=http://dx.doi.org/10.1196/annals.1438.001 |journal=Annals of the New York Academy of Sciences |volume=1133 |issue=1 |pages=162–179 |doi=10.1196/annals.1438.001 |pmid=18559820 |issn=0077-8923|pmc=2707937 |bibcode=2008NYASA1133..162H }}</ref> In large populations, selection can decrease the frequency of slightly deleterious mutations, therefore acting as if they are deleterious. However, in small populations, genetic drift can more easily overcome selection, causing slightly deleterious mutations to act as if they are neutral and drift to fixation or loss.<ref name=":05"/>

== Constructive neutral evolution ==
{{Further|Constructive neutral evolution}}
The groundworks for the theory of [[constructive neutral evolution]] (CNE) was laid by two papers in the 1990s.<ref>{{Cite journal|last1=Covello|first1=Patrick S.|last2=Gray|first2=MichaelW.|date=1993|title=On the evolution of RNA editing|url=https://linkinghub.elsevier.com/retrieve/pii/0168952593900116|journal=Trends in Genetics|language=en|volume=9|issue=8|pages=265–268|doi=10.1016/0168-9525(93)90011-6|pmid=8379005 |url-access=subscription}}</ref><ref>{{Cite journal|last=Stoltzfus|first=Arlin|date=1999|title=On the Possibility of Constructive Neutral Evolution|url=http://link.springer.com/10.1007/PL00006540|journal=Journal of Molecular Evolution|language=en|volume=49|issue=2|pages=169–181|doi=10.1007/PL00006540|pmid=10441669 |bibcode=1999JMolE..49..169S |s2cid=1743092 |issn=0022-2844}}</ref><ref name=":1">{{Cite journal|last1=Muñoz-Gómez|first1=Sergio A.|last2=Bilolikar|first2=Gaurav|last3=Wideman|first3=Jeremy G.|last4=Geiler-Samerotte|first4=Kerry|date=2021-04-01|title=Constructive Neutral Evolution 20 Years Later|url=https://doi.org/10.1007/s00239-021-09996-y|journal=Journal of Molecular Evolution|language=en|volume=89|issue=3|pages=172–182|doi=10.1007/s00239-021-09996-y|issn=1432-1432|pmc=7982386|pmid=33604782|bibcode=2021JMolE..89..172M }}</ref> Constructive neutral evolution is a theory which suggests that complex structures and processes can emerge through neutral transitions. Although a separate theory altogether, the emphasis on neutrality as a process whereby neutral alleles are randomly fixed by [[genetic drift]] finds some inspiration from the earlier attempt by the neutral theory to invoke its importance in evolution.<ref name=":1" /> Conceptually, there are two components A and B (which may represent two proteins) which interact with each other. A, which performs a function for the system, does not depend on its interaction with B for its functionality, and the interaction itself may have randomly arisen in an individual with the ability to disappear without an effect on the fitness of A. This present yet currently unnecessary interaction is therefore called an "excess capacity" of the system. However, a mutation may occur which compromises the ability of A to perform its function independently. However, the A:B interaction that has already emerged sustains the capacity of A to perform its initial function. Therefore, the emergence of the A:B interaction "presuppresses" the deleterious nature of the mutation, making it a neutral change in the genome that is capable of spreading through the population via random genetic drift. Hence, A has gained a dependency on its interaction with B.<ref>{{Cite journal|last=Speijer|first=Dave|date=2011|title=Does constructive neutral evolution play an important role in the origin of cellular complexity?: Making sense of the origins and uses of biological complexity|url=https://onlinelibrary.wiley.com/doi/10.1002/bies.201100010|journal=BioEssays|language=en|volume=33|issue=5|pages=344–349|doi=10.1002/bies.201100010|pmid=21381061 |s2cid=205470421 |url-access=subscription}}</ref> In this case, the loss of B or the A:B interaction would have a negative effect on fitness and so purifying selection would eliminate individuals where this occurs. While each of these steps are individually reversible (for example, A may regain the capacity to function independently or the A:B interaction may be lost), a random sequence of mutations tends to further reduce the capacity of A to function independently and a random walk through the dependency space may very well result in a configuration in which a return to functional independence of A is far too unlikely to occur, which makes CNE a one-directional or "ratchet-like" process.<ref>{{Cite journal|last=Stoltzfus|first=Arlin|date=2012-10-13|title=Constructive neutral evolution: exploring evolutionary theory's curious disconnect|journal=Biology Direct|volume=7|issue=1|pages=35|doi=10.1186/1745-6150-7-35|issn=1745-6150|pmc=3534586|pmid=23062217 |doi-access=free }}</ref> CNE, which does not invoke adaptationist mechanisms for the origins of more complex systems (which involve more parts and interactions contributing to the whole), has seen application in the understanding of the evolutionary origins of the spliceosomal eukaryotic complex, RNA editing, additional ribosomal proteins beyond the core, the emergence of long-noncoding RNA from junk DNA, and so forth.<ref>{{Cite journal|last1=Gray|first1=Michael W.|last2=Lukeš|first2=Julius|last3=Archibald|first3=John M.|last4=Keeling|first4=Patrick J.|last5=Doolittle|first5=W. Ford|date=2010-11-12|title=Irremediable Complexity?|url=https://www.science.org/doi/10.1126/science.1198594|journal=Science|language=en|volume=330|issue=6006|pages=920–921|doi=10.1126/science.1198594|pmid=21071654 |bibcode=2010Sci...330..920G |s2cid=206530279 |issn=0036-8075|url-access=subscription}}</ref><ref>{{Cite journal|last1=Lukeš|first1=Julius|last2=Archibald|first2=John M.|last3=Keeling|first3=Patrick J.|last4=Doolittle|first4=W. Ford|last5=Gray|first5=Michael W.|date=2011|title=How a neutral evolutionary ratchet can build cellular complexity|url=https://onlinelibrary.wiley.com/doi/10.1002/iub.489|journal=IUBMB Life|language=en|volume=63|issue=7|pages=528–537|doi=10.1002/iub.489|pmid=21698757 |s2cid=7306575 |url-access=subscription}}</ref><ref>{{Cite journal|last1=Lamech|first1=Lilian T.|last2=Mallam|first2=Anna L.|last3=Lambowitz|first3=Alan M.|date=2014-12-23|editor-last=Herschlag|editor-first=Daniel|title=Evolution of RNA-Protein Interactions: Non-Specific Binding Led to RNA Splicing Activity of Fungal Mitochondrial Tyrosyl-tRNA Synthetases|journal=PLOS Biology|language=en|volume=12|issue=12|pages=e1002028|doi=10.1371/journal.pbio.1002028|issn=1545-7885|pmc=4275181|pmid=25536042 |doi-access=free }}</ref><ref>{{Cite journal|last1=Palazzo|first1=Alexander F.|last2=Koonin|first2=Eugene V.|date=2020-11-25|title=Functional Long Non-coding RNAs Evolve from Junk Transcripts|journal=Cell|language=en|volume=183|issue=5|pages=1151–1161|doi=10.1016/j.cell.2020.09.047|pmid=33068526 |s2cid=222815635 |doi-access=free}}</ref> In some cases, [[ancestral sequence reconstruction]] techniques have afforded the ability for experimental demonstration of some proposed examples of CNE, as in heterooligomeric ring protein complexes in some fungal lineages.<ref>{{Cite journal|last1=Finnigan|first1=Gregory C.|last2=Hanson-Smith|first2=Victor|last3=Stevens|first3=Tom H.|last4=Thornton|first4=Joseph W.|date=2012-01-09|title=Evolution of increased complexity in a molecular machine|journal=Nature|language=en|volume=481|issue=7381|pages=360–364|doi=10.1038/nature10724|issn=0028-0836|pmc=3979732|pmid=22230956|bibcode=2012Natur.481..360F }}</ref>

CNE has also been put forwards as the null hypothesis for explaining complex structures, and thus adaptationist explanations for the emergence of complexity must be rigorously tested on a case-by-case basis against this null hypothesis prior to acceptance. Grounds for invoking CNE as a null include that it does not presume that changes offered an adaptive benefit to the host or that they were directionally selected for, while maintaining the importance of more rigorous demonstrations of adaptation when invoked so as to avoid the excessive flaws of adaptationism criticized by Gould and Lewontin.<ref>{{Cite journal|last1=Gould|first1=S. J.|last2=Lewontin|first2=R. C.|last3=Maynard Smith|first3=J.|last4=Holliday|first4=Robin|date=1979-09-21|title=The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme|url=https://royalsocietypublishing.org/doi/10.1098/rspb.1979.0086|journal=Proceedings of the Royal Society of London. Series B. Biological Sciences|volume=205|issue=1161|pages=581–598|doi=10.1098/rspb.1979.0086|pmid=42062 |bibcode=1979RSPSB.205..581G |s2cid=2129408 |url-access=subscription}}</ref><ref name=":2">{{Cite journal|last=Koonin|first=Eugene V.|date=2016|title=Splendor and misery of adaptation, or the importance of neutral null for understanding evolution|journal=BMC Biology|language=en|volume=14|issue=1|pages=114|doi=10.1186/s12915-016-0338-2|issn=1741-7007|pmc=5180405|pmid=28010725 |doi-access=free }}</ref><ref>{{Cite journal|last1=Brunet|first1=T. D. P.|last2=Doolittle|first2=W. Ford|date=2018-03-19|title=The generality of Constructive Neutral Evolution|url=https://doi.org/10.1007/s10539-018-9614-6|journal=Biology & Philosophy|language=en|volume=33|issue=1|pages=2|doi=10.1007/s10539-018-9614-6|s2cid=90290787 |issn=1572-8404|url-access=subscription}}</ref>

== Empirical evidence for the neutral theory ==
Predictions derived from the neutral theory are generally supported in studies of molecular evolution.<ref name=":27">{{Cite journal |last1=Nei |first1=Masatoshi |last2=Suzuki |first2=Yoshiyuki |last3=Nozawa |first3=Masafumi |date=2010-09-01 |title=The Neutral Theory of Molecular Evolution in the Genomic Era |url=https://www.annualreviews.org/doi/10.1146/annurev-genom-082908-150129 |journal=Annual Review of Genomics and Human Genetics |language=en |volume=11 |issue=1 |pages=265–289 |doi=10.1146/annurev-genom-082908-150129 |pmid=20565254 |issn=1527-8204|url-access=subscription }}</ref> One of corollaries of the neutral theory is that the efficiency of positive selection is higher in populations or species with higher [[effective population size]]s.<ref name=":32">{{Cite journal |last1=Bakewell |first1=Margaret A. |last2=Shi |first2=Peng |last3=Zhang |first3=Jianzhi |date=May 2007 |title=More genes underwent positive selection in chimpanzee evolution than in human evolution |journal=Proceedings of the National Academy of Sciences |language=en |volume=104 |issue=18 |pages=7489–7494 |bibcode=2007PNAS..104.7489B |doi=10.1073/pnas.0701705104 |issn=0027-8424 |pmc=1863478 |pmid=17449636 |doi-access=free}}</ref> This relationship between the effective population size and selection efficiency was evidenced by genomic studies of species including chimpanzee and human<ref name=":32"/> and domesticated species.<ref>{{Cite journal |last1=Chen |first1=Jianhai |last2=Ni |first2=Pan |last3=Li |first3=Xinyun |last4=Han |first4=Jianlin |last5=Jakovlić |first5=Ivan |last6=Zhang |first6=Chengjun |last7=Zhao |first7=Shuhong |date=2018-01-19 |title=Population size may shape the accumulation of functional mutations following domestication |journal=BMC Evolutionary Biology |volume=18 |issue=1 |pages=4 |doi=10.1186/s12862-018-1120-6 |issn=1471-2148 |pmc=5775542 |pmid=29351740 |doi-access=free |bibcode=2018BMCEE..18....4C }}</ref> In small populations (e.g., a [[population bottleneck]] during a [[speciation]] event), slightly deleterious mutations should accumulate. Data from various species supports this prediction in that the ratio of nonsynonymous to synonymous nucleotide substitutions between species generally exceeds that within species.<ref name=":05"/> In addition, nucleotide and amino acid substitutions generally accumulate over time in a linear fashion, which is consistent with neutral theory.<ref name=":27"/> Arguments against the neutral theory cite evidence of widespread positive selection and [[selective sweep]]s in genomic data.<ref>{{Cite journal |last1=Kern |first1=Andrew D |last2=Hahn |first2=Matthew W |date=2018-06-01 |editor-last=Kumar |editor-first=Sudhir |title=The Neutral Theory in Light of Natural Selection |url=https://academic.oup.com/mbe/article/35/6/1366/4990884 |journal=Molecular Biology and Evolution |language=en |volume=35 |issue=6 |pages=1366–1371 |doi=10.1093/molbev/msy092 |issn=0737-4038|doi-access=free |pmid=29722831 |pmc=5967545 }}</ref> Empirical support for the neutral theory may vary depending on the type of genomic data studied and the statistical tools used to detect positive selection.<ref name=":27"/> For example, Bayesian methods for the detection of selected codon sites and [[McDonald–Kreitman test|McDonald-Kreitman tests]] have been criticized for their rate of erroneous identification of positive selection.<ref name=":05"/><ref name=":27"/>

== See also ==
* [[Adaptive evolution in the human genome]]
* [[Coalescent theory]]
* [[Evolution of biological complexity]]
* [[Masatoshi Nei]]
* [[Molecular evolution]]
* [[Tomoko Ohta]]
* [[Unified neutral theory of biodiversity]]

==References<!-- ZoolRes26:225. -->==
{{reflist|30em}}

== External links ==
* [http://www.evolution.berkeley.edu/evolibrary/article/0_0_0/misconcep_08 Misconceptions about natural selection and adaptation: the neutral theory] at http://evolution.berkeley.edu.
* {{Cite journal|date=July 2018|title=Celebrating 50 years of the Neutral Theory|url=https://academic.oup.com/mbe/pages/neutral_theory|journal=[[Molecular Biology and Evolution]]}}

{{Population genetics}}

[[Category:Population genetics]]
[[Category:Molecular evolution]]
[[Category:Neutral theory]]