Nonsynonymous substitutions at a certain locus can be compared to the synonymous substitutions at the same locus to obtain the Ka/Ks ratio. This ratio is used to measure the evolutionary rate of gene sequences.[1] If a gene has lower levels of nonsynonymous than synonymous nucleotide substitution, then it can be inferred to be functional because a Ka/Ks ratio < 1 is a hallmark of sequences that are being constrained to code for proteins.
[2] Nonsynonymous substitutions are also referred to as replacement mutations.
There are several common types of nonsynonymous substitutions.[3]
Missense mutations are nonsynonymous substitutions that arise from point mutations, mutations in a single nucleotide that result in the substitution of a different amino acid, resulting in a change to the protein encoded.
Nonsense mutations are nonsynonymous substitutions that arise when a mutation in the DNA sequence causes a protein to terminate prematurely by changing the original amino acid to a stop codon. Another type of mutation that deals with stop codons is known as a nonstop mutation or readthrough mutation, which occurs when a stop codon is exchanged for an amino acid codon, causing the protein to be longer than specified.[3]
Natural selection and the nearly neutral theoryedit
Studies have shown that diversity among nonsynonymous substitutions is significantly lower than among synonymous substitutions.[4] This is due to the fact that nonsynonymous substitutions are subject to much higher selective pressures than synonymous mutations.[5] Motoo Kimura (1968) determined that calculated mutation rates were impossibly high, unless most of the mutations that occurred were either neutral or "nearly neutral".[3] He determined that if this were true, genetic drift would be a more powerful factor in molecular evolution than natural selection.[6] The "nearly neutral" theory proposes that molecular evolution acting on nonsynonymous substitutions is driven by mutation, genetic drift, and very weak natural selection, and that it is extremely sensitive to population size.[7] In order to determine whether natural selection is taking place at a certain loci, the McDonald–Kreitman test can be performed.[8] The test consists of comparing ratios of synonymous and nonsynonymous genes between closely related species to the ratio of synonymous to nonsynonymous polymorphisms within species. If the ratios are the same, then Neutral theory of molecular evolution is true for that loci, and evolution is proceeding primarily through genetic drift. If there are more nonsynonymous substitutions between species than within a species, positive natural selection is occurring on beneficial alleles and natural selection is taking place.[3] Nonsynonymous substitutions have been found to be more common in loci involving pathogen resistance, reproductive loci involving sperm competition or egg-sperm interactions, and genes that have replicated and gained new functions, indicating that positive selection is taking place.[3]
Researchedit
Research on accurately modeling rates of mutation has been conducted for many years. A recent paper by Ziheng Yang and Rasmus Nielsen compared various methods and developed a new modeling method. They found that the new method was preferable for its smaller biases, which make it useful for large scale screening, but that the maximum-likelihood model was preferable in most scenarios because of its simplicity, and its flexibility in comparing multiple sequences while taking into account phylogeny.[9]
Further research by Yang and Nielsen found that nonsynonymous to synonymous substitution ratios varied across loci in differing evolutionary lineages. During their study of nuclear loci of primates, even-toed ungulates, and rodents, they found that the ratio varied significantly at 22 of the 48 loci studied. This result provides strong evidence against a strictly neutral theory of molecular evolution, which states that mutations are mostly neutral or deleterious, and provides support for theories that include advantageous mutations.[10]
^Ting Hu and Wolfgang Banzhaf. "Nonsynonymous to Synonymous Substitution Ratio ka/ks: Measurement for Rate of Evolution in Evolutionary Computation" (PDF). {{cite journal}}: Cite journal requires |journal= (help)
^Herron, Jon C. (2014). Evolutionary analysis. Freeman, Scott, 1955-, Hodin, Jason A., 1969-, Miner, Brooks Erin,, Sidor, Christian A. (Fifth ed.). Boston. ISBN978-0321616678. OCLC 859267755.{{cite book}}: CS1 maint: location missing publisher (link)
^ abcdeNature encyclopedia of the human genome. Cooper, David N. (David Neil), 1957-, Nature Publishing Group. London: Nature Pub. Group. 2003. ISBN978-0333803868. OCLC 51668320.{{cite book}}: CS1 maint: others (link)
^Ohta, Tomoko (2002-12-10). "Near-neutrality in evolution of genes and gene regulation". Proceedings of the National Academy of Sciences. 99 (25): 16134–16137. Bibcode:2002PNAS...9916134O. doi:10.1073/pnas.252626899. ISSN 0027-8424. PMC138577. PMID 12461171.
^Ziheng Yang and Rasmus Nielsen. (PDF). Archived from the original (PDF) on 2015-10-20. Retrieved 2017-12-02.
^Ziheng Yang and Rasmus Nielsen (1998). "Synonymous and Nonsynonymous Rate Variation in Nuclear Genes of Mammals" (PDF). Journal of Molecular Evolution. 46 (4): 409–418. Bibcode:1998JMolE..46..409Y. CiteSeerX10.1.1.19.7744. doi:10.1007/pl00006320. PMID 9541535. S2CID 13917969.
External linksedit
Synonymous and Nonsynonymousutions
Simple Methods for Estimating the Numbers of Synonymous and Nonsynonymous Nucleotide Substitutions
December 15, 2023
nonsynonymous, substitution, nonsynonymous, substitution, nucleotide, mutation, that, alters, amino, acid, sequence, protein, differ, from, synonymous, substitutions, which, alter, amino, acid, sequences, sometimes, silent, mutations, nonsynonymous, substituti. A nonsynonymous substitution is a nucleotide mutation that alters the amino acid sequence of a protein Nonsynonymous substitutions differ from synonymous substitutions which do not alter amino acid sequences and are sometimes silent mutations As nonsynonymous substitutions result in a biological change in the organism they are subject to natural selection Nonsynonymous substitutions at a certain locus can be compared to the synonymous substitutions at the same locus to obtain the Ka Ks ratio This ratio is used to measure the evolutionary rate of gene sequences 1 If a gene has lower levels of nonsynonymous than synonymous nucleotide substitution then it can be inferred to be functional because a Ka Ks ratio lt 1 is a hallmark of sequences that are being constrained to code for proteins 2 Nonsynonymous substitutions are also referred to as replacement mutations Contents 1 Types 2 Natural selection and the nearly neutral theory 3 Research 4 See also 5 References 6 External linksTypes editThere are several common types of nonsynonymous substitutions 3 Missense mutations are nonsynonymous substitutions that arise from point mutations mutations in a single nucleotide that result in the substitution of a different amino acid resulting in a change to the protein encoded Nonsense mutations are nonsynonymous substitutions that arise when a mutation in the DNA sequence causes a protein to terminate prematurely by changing the original amino acid to a stop codon Another type of mutation that deals with stop codons is known as a nonstop mutation or readthrough mutation which occurs when a stop codon is exchanged for an amino acid codon causing the protein to be longer than specified 3 Natural selection and the nearly neutral theory editStudies have shown that diversity among nonsynonymous substitutions is significantly lower than among synonymous substitutions 4 This is due to the fact that nonsynonymous substitutions are subject to much higher selective pressures than synonymous mutations 5 Motoo Kimura 1968 determined that calculated mutation rates were impossibly high unless most of the mutations that occurred were either neutral or nearly neutral 3 He determined that if this were true genetic drift would be a more powerful factor in molecular evolution than natural selection 6 The nearly neutral theory proposes that molecular evolution acting on nonsynonymous substitutions is driven by mutation genetic drift and very weak natural selection and that it is extremely sensitive to population size 7 In order to determine whether natural selection is taking place at a certain loci the McDonald Kreitman test can be performed 8 The test consists of comparing ratios of synonymous and nonsynonymous genes between closely related species to the ratio of synonymous to nonsynonymous polymorphisms within species If the ratios are the same then Neutral theory of molecular evolution is true for that loci and evolution is proceeding primarily through genetic drift If there are more nonsynonymous substitutions between species than within a species positive natural selection is occurring on beneficial alleles and natural selection is taking place 3 Nonsynonymous substitutions have been found to be more common in loci involving pathogen resistance reproductive loci involving sperm competition or egg sperm interactions and genes that have replicated and gained new functions indicating that positive selection is taking place 3 Research editResearch on accurately modeling rates of mutation has been conducted for many years A recent paper by Ziheng Yang and Rasmus Nielsen compared various methods and developed a new modeling method They found that the new method was preferable for its smaller biases which make it useful for large scale screening but that the maximum likelihood model was preferable in most scenarios because of its simplicity and its flexibility in comparing multiple sequences while taking into account phylogeny 9 Further research by Yang and Nielsen found that nonsynonymous to synonymous substitution ratios varied across loci in differing evolutionary lineages During their study of nuclear loci of primates even toed ungulates and rodents they found that the ratio varied significantly at 22 of the 48 loci studied This result provides strong evidence against a strictly neutral theory of molecular evolution which states that mutations are mostly neutral or deleterious and provides support for theories that include advantageous mutations 10 See also editMissense mutation Nonsense mutationReferences edit Ting Hu and Wolfgang Banzhaf Nonsynonymous to Synonymous Substitution Ratio ka ks Measurement for Rate of Evolution in Evolutionary Computation PDF a href Template Cite journal html title Template Cite journal cite journal a Cite journal requires journal help Herron Jon C 2014 Evolutionary analysis Freeman Scott 1955 Hodin Jason A 1969 Miner Brooks Erin Sidor Christian A Fifth ed Boston ISBN 978 0321616678 OCLC 859267755 a href Template Cite book html title Template Cite book cite book a CS1 maint location missing publisher link a b c d e Nature encyclopedia of the human genome Cooper David N David Neil 1957 Nature Publishing Group London Nature Pub Group 2003 ISBN 978 0333803868 OCLC 51668320 a href Template Cite book html title Template Cite book cite book a CS1 maint others link Li W H 1997 Molecular Evolution Sunderland MA Sinauer Associates Tomoko Ohta 1995 01 01 Synonymous and nonsynonymous substitutions in mammalian genes and the nearly neutral theory Journal of Molecular Evolution 40 1 56 63 Bibcode 1995JMolE 40 56T doi 10 1007 bf00166595 ISSN 0022 2844 PMID 7714912 Kimura Motoo 1968 Evolutionary Rate at the Molecular Level PDF Nature 217 5129 624 626 Bibcode 1968Natur 217 624K doi 10 1038 217624a0 PMID 5637732 S2CID 4161261 Akashi Hiroshi Osada Naoki Ohta Tomoko 2012 09 01 Weak Selection and Protein Evolution Genetics 192 1 15 31 doi 10 1534 genetics 112 140178 ISSN 0016 6731 PMC 3430532 PMID 22964835 Ohta Tomoko 2002 12 10 Near neutrality in evolution of genes and gene regulation Proceedings of the National Academy of Sciences 99 25 16134 16137 Bibcode 2002PNAS 9916134O doi 10 1073 pnas 252626899 ISSN 0027 8424 PMC 138577 PMID 12461171 Ziheng Yang and Rasmus Nielsen Estimating Synonymous and Nonsynonymous Substitution Rates Under Realistic Evolutionary Models PDF Archived from the original PDF on 2015 10 20 Retrieved 2017 12 02 Ziheng Yang and Rasmus Nielsen 1998 Synonymous and Nonsynonymous Rate Variation in Nuclear Genes of Mammals PDF Journal of Molecular Evolution 46 4 409 418 Bibcode 1998JMolE 46 409Y CiteSeerX 10 1 1 19 7744 doi 10 1007 pl00006320 PMID 9541535 S2CID 13917969 External links editSynonymous and Nonsynonymousutions Simple Methods for Estimating the Numbers of Synonymous and Nonsynonymous Nucleotide Substitutions Retrieved from https en wikipedia org w index php title Nonsynonymous substitution amp oldid 1102373157, wikipedia, wiki, book, 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