en>Khazar2: clean-up, MOS:HYPHEN, replaced: highly- → highly , widely- → widely using AWB

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clean-up, MOS:HYPHEN, replaced: highly- → highly , widely- → widely using AWB

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[[File:Neofunctionalization after a gene duplication event.png|thumb|Neofunctionalization is the process by which a gene acquires a new function after a gene duplication event. The figure shows that once a gene duplication event has occurred one gene copy retains the original ancestral function (represented by the green paralog), while the other acquires mutations that allow it to diverge and develop a new function (represented by the blue paralog).]]
'''Neofunctionalization''', one of the possible outcomes of [[functional divergence]], occurs when one gene copy, or [[paralog]], takes on a totally new function after a [[gene duplication]] event. Neofunctionalization is an adaptive mutation process; meaning one of the gene copies must mutate to develop a function that was not present in the ancestral gene.<ref>{{cite journal|last=Kleinjan|first=Dirk A.|coauthors=Bancewicz, Ruth M., Gautier, Philippe, Dahm, Ralf, Schonthaler, Helia B., Damante, Giuseppe, Seawright, Anne, Hever, Ann M., Yeyati, Patricia L., van Heyningen, Veronica, Coutinho, Pedro|title=Subfunctionalization of Duplicated Zebrafish pax6 Genes by cis-Regulatory Divergence|journal=PLoS Genetics|date=1 January 2008|volume=4|issue=2|pages=e29|doi=10.1371/journal.pgen.0040029}}</ref><ref>S. Rastogi and D. A. Liberles, “Subfunctionalization of duplicated genes as a transition state to neofunctionalization,” BMC Evolutionary Biology, vol. 5, no. 1, p. 28, 2005</ref><ref>B. Conrad and S. E. Antonarakis, “Gene duplication: a drive for phenotypic diversity and cause of human disease.,” Annual review of genomics and human genetics, vol. 8, pp. 17-35, Jan. 2007</ref> In other words, one of the duplicates retains its original function, while the other accumulates molecular changes such that, in time, it can perform a different task.<ref>S. Ohno, Evolution by Gene Duplication. New York, Heidelberg, Berlin: Springer-Verlag, 1970, pp. 59-87</ref> This process is thought to be free of selective pressure because one gene copy can mutate without adversely affecting the fitness of the organism since ancestral function is retained in the other copy.<ref>M. Sémon and K. H. Wolfe, “Preferential subfunctionalization of slow-evolving genes after allopolyploidization in Xenopus laevis.,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 24, pp. 8333-8, Jun. 2008</ref><ref>R. De Smet and Y. Van de Peer, “Redundancy and rewiring of genetic networks following genome-wide duplication events.,” Current opinion in plant biology, pp. 1-9, Feb. 2012</ref><ref>J. G. Ruby, A. Stark, W. K. Johnston, M. Kellis, D. P. Bartel, and E. C. Lai, “Evolution, biogenesis, expression, and target predictions of a substantially expanded set of Drosophila microRNAs.,” Genome research, vol. 17, no. 12, pp. 1850-64, Dec. 2007</ref><ref>D. (University of H. Graur and W.-H. (University of C. Li, Fundamentals of Molecular Evolution, Second. Sinauer Associates, Inc.,, 2000</ref>

==The process==
The process of Neofunctionalization begins with a gene duplication event, which is thought to occur as a defense mechanism against the accumulation of deleterious mutations.<ref>G. D. Amoutzias, Y. He, J. Gordon, D. Mossialos, S. G. Oliver, and Y. Van de Peer, “Posttranslational regulation impacts the fate of duplicated genes.,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 7, pp. 2967-71, Feb. 2010</ref><ref>R. De Smet and Y. Van de Peer, “Redundancy and rewiring of genetic networks following genome-wide duplication events.,” Current opinion in plant biology, pp. 1-9, Feb. 2012</ref><ref>D. (University of H. Graur and W.-H. (University of C. Li, Fundamentals of Molecular Evolution, Second. Sinauer Associates, Inc.,, 2000</ref> Following the gene duplication event there are two identical copies of the ancestral gene performing exactly the same function. This redundancy allows one the copies to take on a new function. In the event that the new function is advantageous, natural selection positively selects for it and the new mutation becomes fixed in the population.<ref>B. Conrad and S. E. Antonarakis, “Gene duplication: a drive for phenotypic diversity and cause of human disease.,” Annual review of genomics and human genetics, vol. 8, pp. 17-35, Jan. 2007</ref><ref>H. Innan, “Population genetic models of duplicated genes.,” Genetica, vol. 137, no. 1, pp. 19-37, Sep. 2009</ref>
The occurrence of Neofunctionalization can most often be attributed to changes in the coding region or changes in the regulatory elements of a gene.<ref>D. (University of H. Graur and W.-H. (University of C. Li, Fundamentals of Molecular Evolution, Second. Sinauer Associates, Inc.,, 2000</ref> It is much more rare to see major changes in protein function, such as subunit structure or substrate and ligand affinity, as a result of Neofunctionalization.<ref>D. (University of H. Graur and W.-H. (University of C. Li, Fundamentals of Molecular Evolution, Second. Sinauer Associates, Inc.,, 2000</ref>

==Selective Constraints==

Neofunctionalization is also commonly referred to as "mutation during non-functionality” or “mutation during redundancy”.<ref>A. Hughes, Adaptive Evolution of Genes and Genomes. New York: Oxford University Press, 1999</ref> Regardless of if the mutation arises after non-functionality of a gene or due to redundant gene copies, the important aspect is that in both scenarios one copy of the duplicated gene is freed from selective constraints and by chance acquires a new function which is then improved by natural selection.<ref>D. (University of H. Graur and W.-H. (University of C. Li, Fundamentals of Molecular Evolution, Second. Sinauer Associates, Inc.,, 2000</ref> This process is thought to occur very rarely in evolution for two major reasons. The first reason is that functional changes typically require a large number of amino acid changes; which has a low probability of occurrence. Secondly, because deleterious mutations occur much more frequently than advantageous mutations in evolution.<ref>D. (University of H. Graur and W.-H. (University of C. Li, Fundamentals of Molecular Evolution, Second. Sinauer Associates, Inc.,, 2000</ref> This makes the likelihood that gene function is lost over time (i.e. pseudogenization) far greater than the likelihood of the emergence of a new gene function.<ref>H. Innan, “Population genetic models of duplicated genes.,” Genetica, vol. 137, no. 1, pp. 19-37, Sep. 2009</ref>
Walsh discovered that the relative probability of Neofunctionalization is determined by the selective advantage and the relative rate of advantageous mutations.<ref>M. Lynch and a Force, “The probability of duplicate gene preservation by subfunctionalization.,” Genetics, vol. 154, no. 1, pp. 459-73, Jan. 2000</ref> This was proven in his derivation of the relative probability of Neofunctionalization to pseudogenization, which is given by: <math>\frac{\rho\,\!S-1}{1 - e^s}</math> where ρ is the ratio of advantageous mutation rate to null mutation rate and S is the population selection 4NeS (Ne: effective population size S: selection intensity).<ref>M. Lynch and a Force, “The probability of duplicate gene preservation by subfunctionalization.,” Genetics, vol. 154, no. 1, pp. 459-73, Jan. 2000</ref>

==Classical Model==
In 1935, originally proposed Neofunctionalization as a possible outcome of a gene duplication event. In 1970, Ohno suggested that Neofunctionalization was the only evolutionary mechanism that gave rise to new gene functions in a population.<ref>[8D. (University of H. Graur and W.-H. (University of C. Li, Fundamentals of Molecular Evolution, Second. Sinauer Associates, Inc.,, 2000</ref> He also believed that Neofunctionalization was the only alternative to pseudogenization.<ref>S. Rastogi and D. A. Liberles, “Subfunctionalization of duplicated genes as a transition state to neofunctionalization,” BMC Evolutionary Biology, vol. 5, no. 1, p. 28, 2005</ref> Ohta (1987) was among the first to suggest that other mechanisms may exist for the preservation of duplicated genes in the population.<ref>D. (University of H. Graur and W.-H. (University of C. Li, Fundamentals of Molecular Evolution, Second. Sinauer Associates, Inc.,, 2000</ref> Today, subfunctionalization is a widely excepted alternative fixation process for gene duplicates in the population and is currently the only other possible outcome of functional divergence.<ref>S. Rastogi and D. A. Liberles, “Subfunctionalization of duplicated genes as a transition state to neofunctionalization,” BMC Evolutionary Biology, vol. 5, no. 1, p. 28, 2005</ref>

==Neosubfunctionalization==
Neosubfunctionalization occurs when Neofunctionalization is the end result of [[subfunctionalization]]. In other words, once a gene duplication event occurs forming parologs that after an evolutionary period subfunctionalize, one gene copy continues on this evolutionary journey and accumulates mutations that give rise to a new function.<ref>X. He and J. Zhang, “Rapid subfunctionalization accompanied by prolonged and substantial neofunctionalization in duplicate gene evolution.,” Genetics, vol. 169, no. 2, pp. 1157-1164, 2005</ref><ref>D. (University of H. Graur and W.-H. (University of C. Li, Fundamentals of Molecular Evolution, Second. Sinauer Associates, Inc.,, 2000</ref> Some believe that Neofunctionalization is the end stage for all subfunctionalized genes. For instance, according to Rastogi and Liberles “Neofunctionalization is the terminal fate of all duplicate gene copies retained in the genome and subfuctionlization merely exist as a transient sate to preserve the duplicate gene copy.”<ref>S. Rastogi and D. A. Liberles, “Subfunctionalization of duplicated genes as a transition state to neofunctionalization,” BMC Evolutionary Biology, vol. 5, no. 1, p. 28, 2005</ref> The results of their study become punctuated as population size increases.

==Antifreeze Protein==
[[File:Antartic Zoarcid Fish.jpg|thumb|The Antarctic Zoarcid Fish provides a vivid example of Neofunctionalization. The development of an antifreeze protein from an ancestral Sialic Acid Synthase (SAS) gene illustrates the acquisition process of advantageous adaptations after a gene duplication event. As in the case of the Antarctic Zoarcid Fish most new functionalities that arise as a result of Neofunctionalization are very minor changes: such as the mutations that allowed the Antarctic Zordic Fish to enhance its existing but rudimentary antifreeze functionality<ref>C. Deng, C.-H. C. Cheng, H. Ye, X. He, and L. Chen, “Evolution of an antifreeze protein by neofunctionalization under escape from adaptive conflict.,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 50, pp. 21593-8, Dec. 2010</ref>]]

The evolution of the antifreeze protein in the Antarctic zoarcid fish provides a prime example of Neofunctionalization after gene duplication. In the case of the Antarctic zoarcid fish type III antifreeze protein gene diverged from a parologus copy of sialic acid synthase (SAS) gene.<ref>C. Deng, C.-H. C. Cheng, H. Ye, X. He, and L. Chen, “Evolution of an antifreeze protein by neofunctionalization under escape from adaptive conflict.,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 50, pp. 21593-8, Dec. 2010</ref> The ancestral SAS gene was found to have both sialic acid synthase and rudimentary ice-binding functionalities. After duplication one of the paralogs began to accumulate mutations that lead to the replacement of SAS domains of the gene allowing for further development and optimization of the antifreeze functionality.<ref>C. Deng, C.-H. C. Cheng, H. Ye, X. He, and L. Chen, “Evolution of an antifreeze protein by neofunctionalization under escape from adaptive conflict.,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 50, pp. 21593-8, Dec. 2010</ref> The new gene is now capable of noncolligative freezing-point depression, and thus is neofunctionalized.<ref>C. Deng, C.-H. C. Cheng, H. Ye, X. He, and L. Chen, “Evolution of an antifreeze protein by neofunctionalization under escape from adaptive conflict.,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 50, pp. 21593-8, Dec. 2010</ref> This specialization allows Antarctic zoarcid fish to survive in the frigid temperatures of the Antarctic Seas.

==Model Limitations==
Limitations exist in Neofunctionalization as model for functional divergence primarily because: (1) the amount of nucleotide changes giving rise to a new function must be very minimal; making the probability for [[Pseudogene|pseudogenization]] much higher than neofunctionalization after a gene duplication event.<ref>D. (University of H. Graur and W.-H. (University of C. Li, Fundamentals of Molecular Evolution, Second. Sinauer Associates, Inc.,, 2000</ref>
(2) After a gene duplication event both copies may be subjected to selective pressure equivalent to that constraining the ancestral gene; meaning that neither copy is available for Neofunctionalization.<ref>D. (University of H. Graur and W.-H. (University of C. Li, Fundamentals of Molecular Evolution, Second. Sinauer Associates, Inc.,, 2000</ref>
(3) In many cases positive Darwinian selection presents a more parsimonious explanation for the divergence of multigene families.<ref>D. (University of H. Graur and W.-H. (University of C. Li, Fundamentals of Molecular Evolution, Second. Sinauer Associates, Inc.,, 2000</ref>

== See also ==
* [[Subfunctionalization]]

==References==
<references />

[[Category:Genetics]]

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en>Khazar2: clean-up, MOS:HYPHEN, replaced: highly- → highly , widely- → widely using AWB