Ambush hypothesis: Difference between revisions
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The '''ambush hypothesis''' is a hypothesis in the field of [[molecular genetics]] that suggests that the prevalence of “hidden” or [[Frameshift mutation|off-frame]] [[Stop codon|stop codons]] in [[DNA]] selectively deters off-frame [[Translation (biology)|translation]] of [[Messenger RNA|mRNA]] to save energy, molecular resources, and to reduce strain on biosynthetic machinery by truncating the production of non-functional, potentially cytotoxic protein products.<ref name=":0">{{Cite journal |last=Seligmann |first=Hervé |last2=Pollock |first2=David D. |date=2004 |title=The Ambush Hypothesis: Hidden Stop Codons Prevent Off-Frame Gene Reading |url=http://www.liebertpub.com/doi/10.1089/dna.2004.23.701 |journal=DNA and Cell Biology |language=en |volume=23 |issue=10 |pages=701-705 |doi=10.1089/dna.2004.23.701 |issn=1044-5498}}</ref> Typical coding sequences of DNA lack in-frame internal stop codons to avoid the premature reduction of protein products when translation proceeds normally.<ref>{{Cite book |last=Hartl |first=Daniel L., |url=http://worldcat.org/oclc/1032715856 |title=Genetics : analysis of genes and genomes |year=2019 |isbn=978-1-284-12294-7 |pages=1344 |oclc=1032715856}}</ref> The ambush hypothesis suggests that kinetic, [[Cis-regulatory element|''cis''-acting]] mechanisms are responsible for the productive frameshifting of translational units so that the [[Degeneracy (biology)|degeneracy]] of the genetic code can be used to prevent deleterious translation. [[Ribosomal frameshift|Ribosomal slippage]] is the most well described mechanism of translational frameshifting where the ribosome moves one codon position either forward (+1) or backward (-1) to translate the mRNA sequence in a different reading frame and thus produce different protein products.<ref>{{Cite journal |last=Atkins |first=John F. |last2=Loughran |first2=Gary |last3=Bhatt |first3=Pramod R. |last4=Firth |first4=Andrew E. |last5=Baranov |first5=Pavel V. |date=2016 |title=Ribosomal frameshifting and transcriptional slippage: From genetic steganography and cryptography to adventitious use |url=http://dx.doi.org/10.1093/nar/gkw530 |journal=Nucleic Acids Research |pages=7007 |doi=10.1093/nar/gkw530 |issn=0305-1048}}</ref> |
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The '''ambush hypothesis''' is a [[hypothesis]] in [[molecular genetics]] that posits that hidden ([[translational frameshift|off-frame]]) [[stop codon]]s in [[coding sequence]]s could selectively prevent off-frame [[protein translation]]. |
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In respect to codon usage, the ambush hypothesis theorizes that there is a positive correlation between the use of a codon and the amount a codon contributes to hidden stops. [[Phylogenetics|Phylogenetic analyses]] of both the nuclear and mitochondrial genomes of all major taxonomic kingdoms suggests ubiquitous off-frame stop codon existence and a positive [[correlation]] between the usage frequency of a codon and the number of ways a codon can contribute to hidden stop codons in different translational reading frames.<ref>{{Cite journal |last=Singh |first=Tiratha Raj |last2=Pardasani |first2=Kamal Raj |date=2009 |title=Ambush hypothesis revisited: Evidences for phylogenetic trends |url=https://www.sciencedirect.com/science/article/pii/S1476927109000310 |journal=Computational Biology and Chemistry |language=en |volume=33 |issue=3 |pages=239 |doi=10.1016/j.compbiolchem.2009.04.002 |issn=1476-9271}}</ref> |
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Coding sequences, by definition, lack stop codons. However, many stop codons appear off-frame within coding sequences, termed "hidden stops". It was not clear until 2004 that hidden stops could be positively selected. Seligmann and Pollock devised the ambush hypothesis to coherently describe how hidden stops could contribute to the synonymous position state.<ref>Seligmann H, Pollock DD. [https://www.ncbi.nlm.nih.gov/pubmed/15585128 The ambush hypothesis: hidden stop codons prevent off-frame gene reading.] DNA Cell Biol. 2004;23(10):701-5.</ref> |
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[[File:Figure 1. Codon usage frequencies in genomes of Borrelia and Saccharomycs cerevisiae as a function of the potential number of ways that these codons can contribute to stop motifs in off-frame contexts.png|alt=Scatterplot show positive linear correlation between potential contribution to hidden stops with average codon usage percent|thumb|Figure 1. (Seligmann & Pollock 2004) demonstrates association between codon usage frequency and potential contribution to off-frame stop codons]] |
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[[Combinatorics]] have been used across [[List of genetic codes|genetic codes]] to determine how each in-frame codon can potentially contribute to stop codons in off-frame contexts. The standard genetic code only contains 20 codons that cannot become stop codons in a frameshifted ribosomal environment (-1 frameshift: 42, +1 frameshift: 28) and 127 out of the 400 (31.75%) possible adjacent amino acid combinations in the vertebrate mitochondrial code creates an off-frame stop codon.<ref name=":0" /> This suggests that [[Point mutation|substitutions]] and synonymous codon usage are not neutral and that [[Evolutionary pressure|selective pressures]] might have readjusted codon assignments to increase the frequencies of those that can be used as hidden stops. |
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Observations that the number of off-frame stop codons is positively correlated with the expression level of a gene support the ambush hypothesis by increasing [[translational regulation]] (hidden stop frequency) to discourage off-frame reading in genes that are expressed at a high level.<ref>{{Cite journal |last=Gheysen |first=Dirk |last2=Iserentant |first2=Dirk |last3=Derom |first3=Catherine |last4=Fiers |first4=Walter |date=1982 |title=Systematic alteration of the nucleotide sequence preceding the translation initiation codon and the effects on bacterial expression of the cloned SV40 small-t antigen gene |url=https://linkinghub.elsevier.com/retrieve/pii/0378111982901007 |journal=Gene |language=en |volume=17 |issue=1 |pages=55–63 |doi=10.1016/0378-1119(82)90100-7}}</ref><ref>{{Cite journal |last=Ozbudak |first=Ertugrul M. |last2=Thattai |first2=Mukund |last3=Kurtser |first3=Iren |last4=Grossman |first4=Alan D. |last5=van Oudenaarden |first5=Alexander |date=2002 |title=Regulation of noise in the expression of a single gene |url=http://www.nature.com/articles/ng869z |journal=Nature Genetics |language=en |volume=31 |issue=1 |pages=69–73 |doi=10.1038/ng869 |issn=1061-4036}}</ref> The positive correlation indicates that the off-frame translation of larger genes with higher expression levels likely costs a cell more energy, resources, and pathway efficiency than translating smaller, more rare genes in a shifted reading frame.<ref name=":0" /> Off-frame stop codon frequency is negatively correlated with [[gestation]] time in primates and though there are many factors that link molecular translational efficiency to the rate of [[morphogenesis]], these findings suggests that not only individual cells but entire organisms may benefit from the development of hidden stop codons to effectively halt off-frame synthesis.<ref name=":0" /> |
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They argued that hidden stops would prevent off-frame protein translation, and their selective cost would compensate for energy saving, reducing efficiency of the genomic and biosynthetic machinery. It is not clear whether or not experimental data is consistent with this hypothesis. |
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The ambush hypothesis is challenged by recent observations that off-frame stop codons are directly correlated with the [[GC-content|GC content]] in the genome because stop codons are GC-poor.<ref name=":1">{{Cite journal |last=Morgens |first=David W |last2=Chang |first2=Charlotte H |last3=Cavalcanti |first3=Andre RO |date=2013 |title=Ambushing the ambush hypothesis: predicting and evaluating off-frame codon frequencies in Prokaryotic Genomes |url=http://dx.doi.org/10.1186/1471-2164-14-418 |journal=BMC Genomics |volume=14 |issue=1 |pages=3-7 |doi=10.1186/1471-2164-14-418 |issn=1471-2164}}</ref> [http://www.biomedcentral.com/1471-2164/14/418 Morgens et al. 2013] argues that previous research concerning the ambush hypothesis has relied on codon usage data which is representative of the GC content of an organism and thus not appropriate to evaluate the selective effect of off-frame stop codons.<ref name=":1" /> |
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==References== |
==References== |
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Revision as of 20:05, 11 May 2022
The ambush hypothesis is a hypothesis in the field of molecular genetics that suggests that the prevalence of “hidden” or off-frame stop codons in DNA selectively deters off-frame translation of mRNA to save energy, molecular resources, and to reduce strain on biosynthetic machinery by truncating the production of non-functional, potentially cytotoxic protein products.[1] Typical coding sequences of DNA lack in-frame internal stop codons to avoid the premature reduction of protein products when translation proceeds normally.[2] The ambush hypothesis suggests that kinetic, cis-acting mechanisms are responsible for the productive frameshifting of translational units so that the degeneracy of the genetic code can be used to prevent deleterious translation. Ribosomal slippage is the most well described mechanism of translational frameshifting where the ribosome moves one codon position either forward (+1) or backward (-1) to translate the mRNA sequence in a different reading frame and thus produce different protein products.[3]
In respect to codon usage, the ambush hypothesis theorizes that there is a positive correlation between the use of a codon and the amount a codon contributes to hidden stops. Phylogenetic analyses of both the nuclear and mitochondrial genomes of all major taxonomic kingdoms suggests ubiquitous off-frame stop codon existence and a positive correlation between the usage frequency of a codon and the number of ways a codon can contribute to hidden stop codons in different translational reading frames.[4]
Combinatorics have been used across genetic codes to determine how each in-frame codon can potentially contribute to stop codons in off-frame contexts. The standard genetic code only contains 20 codons that cannot become stop codons in a frameshifted ribosomal environment (-1 frameshift: 42, +1 frameshift: 28) and 127 out of the 400 (31.75%) possible adjacent amino acid combinations in the vertebrate mitochondrial code creates an off-frame stop codon.[1] This suggests that substitutions and synonymous codon usage are not neutral and that selective pressures might have readjusted codon assignments to increase the frequencies of those that can be used as hidden stops.
Observations that the number of off-frame stop codons is positively correlated with the expression level of a gene support the ambush hypothesis by increasing translational regulation (hidden stop frequency) to discourage off-frame reading in genes that are expressed at a high level.[5][6] The positive correlation indicates that the off-frame translation of larger genes with higher expression levels likely costs a cell more energy, resources, and pathway efficiency than translating smaller, more rare genes in a shifted reading frame.[1] Off-frame stop codon frequency is negatively correlated with gestation time in primates and though there are many factors that link molecular translational efficiency to the rate of morphogenesis, these findings suggests that not only individual cells but entire organisms may benefit from the development of hidden stop codons to effectively halt off-frame synthesis.[1]
The ambush hypothesis is challenged by recent observations that off-frame stop codons are directly correlated with the GC content in the genome because stop codons are GC-poor.[7] Morgens et al. 2013 argues that previous research concerning the ambush hypothesis has relied on codon usage data which is representative of the GC content of an organism and thus not appropriate to evaluate the selective effect of off-frame stop codons.[7]
References
- ^ a b c d Seligmann, Hervé; Pollock, David D. (2004). "The Ambush Hypothesis: Hidden Stop Codons Prevent Off-Frame Gene Reading". DNA and Cell Biology. 23 (10): 701–705. doi:10.1089/dna.2004.23.701. ISSN 1044-5498.
- ^ Hartl, Daniel L., (2019). Genetics : analysis of genes and genomes. p. 1344. ISBN 978-1-284-12294-7. OCLC 1032715856.
{{cite book}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link) - ^ Atkins, John F.; Loughran, Gary; Bhatt, Pramod R.; Firth, Andrew E.; Baranov, Pavel V. (2016). "Ribosomal frameshifting and transcriptional slippage: From genetic steganography and cryptography to adventitious use". Nucleic Acids Research: 7007. doi:10.1093/nar/gkw530. ISSN 0305-1048.
- ^ Singh, Tiratha Raj; Pardasani, Kamal Raj (2009). "Ambush hypothesis revisited: Evidences for phylogenetic trends". Computational Biology and Chemistry. 33 (3): 239. doi:10.1016/j.compbiolchem.2009.04.002. ISSN 1476-9271.
- ^ Gheysen, Dirk; Iserentant, Dirk; Derom, Catherine; Fiers, Walter (1982). "Systematic alteration of the nucleotide sequence preceding the translation initiation codon and the effects on bacterial expression of the cloned SV40 small-t antigen gene". Gene. 17 (1): 55–63. doi:10.1016/0378-1119(82)90100-7.
- ^ Ozbudak, Ertugrul M.; Thattai, Mukund; Kurtser, Iren; Grossman, Alan D.; van Oudenaarden, Alexander (2002). "Regulation of noise in the expression of a single gene". Nature Genetics. 31 (1): 69–73. doi:10.1038/ng869. ISSN 1061-4036.
- ^ a b Morgens, David W; Chang, Charlotte H; Cavalcanti, Andre RO (2013). "Ambushing the ambush hypothesis: predicting and evaluating off-frame codon frequencies in Prokaryotic Genomes". BMC Genomics. 14 (1): 3–7. doi:10.1186/1471-2164-14-418. ISSN 1471-2164.
{{cite journal}}: CS1 maint: unflagged free DOI (link)
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