Neofunctionalization

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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 after a gene duplication event.png
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. [1] [2] [3] 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. [4]

Contents

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. [5] [6] [7] 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. [3] [8] The occurrence of Neofunctionalization can most often be attributed to changes in the coding region or changes in the regulatory elements of a gene. [6] 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. [6]

Selective constraints

Neofunctionalization is also commonly referred to as "mutation during non-functionality" or "mutation during redundancy". [9] 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. [6] 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. [6] 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. [8] Walsh discovered that the relative probability of Neofunctionalization is determined by the selective advantage and the relative rate of advantageous mutations. [10] This was proven in his derivation of the relative probability of Neofunctionalization to pseudogenization, which is given by: 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). [10]

Classical model

In 1936, Muller originally proposed Neofunctionalization as a possible outcome of a gene duplication event. [11] In 1970, Ohno suggested that Neofunctionalization was the only evolutionary mechanism that gave rise to new gene functions in a population. [6] He also believed that Neofunctionalization was the only alternative to pseudogenization. [2] Ohta (1987) was among the first to suggest that other mechanisms may exist for the preservation of duplicated genes in the population. [6] Today, subfunctionalization is a widely accepted alternative fixation process for gene duplicates in the population and is currently the only other possible outcome of functional divergence. [2]

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. [6] [12] 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 state to preserve the duplicate gene copy." [2] The results of their study become punctuated as population size increases.

Examples

The evolution of the antifreeze protein in the Antarctic zoarcid fish L. dearborni provides a prime example of Neofunctionalization after gene duplication. In the case of the Antarctic zoarcid fish type III antifreeze protein gene (AFPIII; P12102 ) diverged from a paralogous copy of sialic acid synthase (SAS) gene. [13] 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. [13] The new gene is now capable of noncolligative freezing-point depression, and thus is neofunctionalized. [13] 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 pseudogenization much higher than neofunctionalization after a gene duplication event. [6]
  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. [6]
  3. In many cases positive Darwinian selection presents a more parsimonious explanation for the divergence of multigene families. [6]

See also

Related Research Articles

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Microevolution is the change in allele frequencies that occurs over time within a population. This change is due to four different processes: mutation, selection, gene flow and genetic drift. This change happens over a relatively short amount of time compared to the changes termed macroevolution.

Mutation Alteration in the nucleotide sequence of a genome

In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis, or meiosis or other types of damage to DNA, which then may undergo error-prone repair, cause an error during other forms of repair, or cause an error during replication. Mutations may also result from insertion or deletion of segments of DNA due to mobile genetic elements.

Molecular evolution Process of change in the sequence composition of cellular molecules across generations

Molecular evolution is the process of change in the sequence composition of cellular molecules such as DNA, RNA, and proteins across generations. The field of molecular evolution uses principles of evolutionary biology and population genetics to explain patterns in these changes. Major topics in molecular evolution concern the rates and impacts of single nucleotide changes, neutral evolution vs. natural selection, origins of new genes, the genetic nature of complex traits, the genetic basis of speciation, evolution of development, and ways that evolutionary forces influence genomic and phenotypic changes.

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.

Population genetics Subfield of genetics

Population genetics is a subfield of genetics that deals with genetic differences within and between populations, and is a part of evolutionary biology. Studies in this branch of biology examine such phenomena as adaptation, speciation, and population structure.

Pseudogene Functionless relative of a gene

Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Most arise as superfluous copies of functional genes, either directly by DNA duplication or indirectly by reverse transcription of an mRNA transcript. Pseudogenes are usually identified when genome sequence analysis finds gene-like sequences that lack regulatory sequences needed for transcription or translation, or whose coding sequences are obviously defective due to frameshifts or premature stop codons.

Gene duplication is a major mechanism through which new genetic material is generated during molecular evolution. It can be defined as any duplication of a region of DNA that contains a gene. Gene duplications can arise as products of several types of errors in DNA replication and repair machinery as well as through fortuitous capture by selfish genetic elements. Common sources of gene duplications include ectopic recombination, retrotransposition event, aneuploidy, polyploidy, and replication slippage.

Gene family Set of several similar genes

A gene family is a set of several similar genes, formed by duplication of a single original gene, and generally with similar biochemical functions. One such family are the genes for human hemoglobin subunits; the ten genes are in two clusters on different chromosomes, called the α-globin and β-globin loci. These two gene clusters are thought to have arisen as a result of a precursor gene being duplicated approximately 500 million years ago.

Sequence homology Shared ancestry between DNA, RNA or protein sequences

Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a speciation event (orthologs), or a duplication event (paralogs), or else a horizontal gene transfer event (xenologs).

Paleopolyploidy State of having undergone whole genome duplication in deep evolutionary time

Paleopolyploidy is the result of genome duplications which occurred at least several million years ago (MYA). Such an event could either double the genome of a single species (autopolyploidy) or combine those of two species (allopolyploidy). Because of functional redundancy, genes are rapidly silenced or lost from the duplicated genomes. Most paleopolyploids, through evolutionary time, have lost their polyploid status through a process called diploidization, and are currently considered diploids e.g. baker's yeast, Arabidopsis thaliana, and perhaps humans.

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Gene cluster

A gene family is a set of homologous genes within one organism. A gene cluster is a group of two or more genes found within an organism's DNA that encode similar polypeptides, or proteins, which collectively share a generalized function and are often located within a few thousand base pairs of each other. The size of gene clusters can vary significantly, from a few genes to several hundred genes. Portions of the DNA sequence of each gene within a gene cluster are found to be identical; however, the resulting protein of each gene is distinctive from the resulting protein of another gene within the cluster. Genes found in a gene cluster may be observed near one another on the same chromosome or on different, but homologous chromosomes. An example of a gene cluster is the Hox gene, which is made up of eight genes and is part of the Homeobox gene family.

Gene redundancy

Gene redundancy is the existence of multiple genes in the genome of an organism that perform the same function. Gene redundancy can result from gene duplication. Such duplication events are responsible for many sets of paralogous genes. When an individual gene in such a set is disrupted by mutation or targeted knockout, there can be little effect on phenotype as a result of gene redundancy, whereas the effect is large for the knockout of a gene with only one copy. Gene knockout is a method utilized in some studies aiming to characterize the maintenance and fitness effects functional overlap.

Functional divergence is the process by which genes, after gene duplication, shift in function from an ancestral function. Functional divergence can result in either subfunctionalization, where a paralog specializes one of several ancestral functions, or neofunctionalization, where a totally new functional capability evolves. It is thought that this process of gene duplication and functional divergence is a major originator of molecular novelty and has produced the many large protein families that exist today.

Subfunctionalization

Subfunctionalization was proposed by Stoltzfus (1999) and Force et al. (1999) as one of the possible outcomes of functional divergence that occurs after a gene duplication event, in which pairs of genes that originate from duplication, or paralogs, take on separate functions. Subfunctionalization is a neutral mutation process of constructive neutral evolution; meaning that no new adaptations are formed. During the process of gene duplication paralogs simply undergo a division of labor by retaining different parts (subfunctions) of their original ancestral function. This partitioning event occurs because of segmental gene silencing leading to the formation of paralogs that are no longer duplicates, because each gene only retains a single function. It is important to note that the ancestral gene was capable of performing both functions and the descendant duplicate genes can now only perform one of the original ancestral functions.

Evolution by gene duplication is an event by which a gene or part of a gene can have two identical copies that can not be distinguished from each other. This phenomenon is understood to be an important source of novelty in evolution, providing for an expanded repertoire of molecular activities. The underlying mutational event of duplication may be a conventional gene duplication mutation within a chromosome, or a larger-scale event involving whole chromosomes (aneuploidy) or whole genomes (polyploidy). A classic view, owing to Susumu Ohno, which is known as Ohno model, he explains how duplication creates redundancy, the redundant copy accumulates beneficial mutations which provides fuel for innovation. Knowledge of evolution by gene duplication has advanced more rapidly in the past 15 years due to new genomic data, more powerful computational methods of comparative inference, and new evolutionary models.

Unequal crossing over Chromosomal crossover resulting in gene duplication or deletion

Unequal crossing over is a type of gene duplication or deletion event that deletes a sequence in one strand and replaces it with a duplication from its sister chromatid in mitosis or from its homologous chromosome during meiosis. It is a type of chromosomal crossover between homologous sequences that are not paired precisely. Normally genes are responsible for occurrence of crossing over. It exchanges sequences of different links between chromosomes. Along with gene conversion, it is believed to be the main driver for the generation of gene duplications and is a source of mutation in the genome.

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References

  1. ↑ Kleinjan DA, Bancewicz RM, Gautier P, Dahm R, Schonthaler HB, Damante G, et al. (February 2008). "Subfunctionalization of duplicated zebrafish pax6 genes by cis-regulatory divergence". PLOS Genetics. 4 (2): e29. doi:10.1371/journal.pgen.0040029. PMC   2242813 . PMID   18282108.
  2. 1 2 3 4 Rastogi S, Liberles DA (April 2005). "Subfunctionalization of duplicated genes as a transition state to neofunctionalization". BMC Evolutionary Biology. 5 (1): 28. doi:10.1186/1471-2148-5-28. PMC   1112588 . PMID   15831095.
  3. 1 2 Conrad B, Antonarakis SE (2007). "Gene duplication: a drive for phenotypic diversity and cause of human disease". Annual Review of Genomics and Human Genetics. 8: 17–35. doi:10.1146/annurev.genom.8.021307.110233. PMID   17386002.
  4. ↑ Ohno (1970). Evolution by Gene Duplication. New York, Heidelberg, Berlin: Springer-Verlag. pp. 59–87. ISBN   978-3-540-05225-8.
  5. ↑ De Smet R, Van de Peer Y (April 2012). "Redundancy and rewiring of genetic networks following genome-wide duplication events". Current Opinion in Plant Biology. 15 (2): 168–76. doi:10.1016/j.pbi.2012.01.003. PMID   22305522.
  6. 1 2 3 4 5 6 7 8 9 10 11 Graur D, Li WH (2000). Fundamentals of molecular evolution (2nd ed.). Sunderland, Mass.: Sinauer Associates. ISBN   978-0-87893-266-5.
  7. ↑ Amoutzias GD, He Y, Gordon J, Mossialos D, Oliver SG, Van de Peer Y (February 2010). "Posttranslational regulation impacts the fate of duplicated genes". Proceedings of the National Academy of Sciences of the United States of America. 107 (7): 2967–71. Bibcode:2010PNAS..107.2967A. doi: 10.1073/pnas.0911603107 . PMC   2840353 . PMID   20080574.
  8. 1 2 Innan H (September 2009). "Population genetic models of duplicated genes". Genetica. 137 (1): 19–37. doi:10.1007/s10709-009-9355-1. PMID   19266289. S2CID   31795158.
  9. ↑ Hughes AL (1999). Adaptive evolution of genes and genomes. New York: Oxford University Press. ISBN   978-0-19-511626-7.
  10. 1 2 Lynch M, Force A (January 2000). "The probability of duplicate gene preservation by subfunctionalization". Genetics. 154 (1): 459–73. doi:10.1093/genetics/154.1.459. PMC   1460895 . PMID   10629003.
  11. ↑ Muller HJ (May 1936). "Bar duplication". Science. 83 (2161): 528–30. Bibcode:1936Sci....83..528M. doi:10.1126/science.83.2161.528-a. PMID   17806465. S2CID   5426313.
  12. ↑ He X, Zhang J (February 2005). "Rapid subfunctionalization accompanied by prolonged and substantial neofunctionalization in duplicate gene evolution". Genetics. 169 (2): 1157–64. doi:10.1534/genetics.104.037051. PMC   1449125 . PMID   15654095.
  13. 1 2 3 Deng C, Cheng CH, Ye H, He X, Chen L (December 2010). "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. 107 (50): 21593–8. Bibcode:2010PNAS..10721593D. doi: 10.1073/pnas.1007883107 . PMC   3003108 . PMID   21115821.
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