Missense mRNA: Difference between revisions
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'''Missense [[mRNA]] |
'''Missense [[mRNA]] ''' have one or more mutated [[codon]]s that yield [[polypeptide]]s with an [[amino acid sequence]] different from the [[wild-type]] or naturally occurring polypeptide.<ref>{{cite book|title=Principles of Molecular Medicine|first1= J. Larry |last1=Jameson | name-list-format = vanc |pages=731|publisher=Springer}}</ref> Missense mRNA molecules are created when [[:wikt:template|template]] [[DNA]] strands or the mRNA strands themselves undergo a [[missense mutation]] in which a [[amino acid sequence|protein coding sequence]] is [[mutate]]d and an altered amino acid sequence is coded for. |
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== Biogenesis of missense mRNA == |
== Biogenesis of missense mRNA == |
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A [[missense mRNA]] arises from a [[missense mutation]], in the event of which a DNA nucleotide base pair in the coding region of a gene is changed such that it results in the substitution of one amino acid for another<ref>{{ |
A [[missense mRNA]] arises from a [[missense mutation]], in the event of which a DNA nucleotide base pair in the coding region of a gene is changed such that it results in the substitution of one amino acid for another<ref>{{cite journal | vauthors = Belgrader P, Maquat LE | title = Nonsense but not missense mutations can decrease the abundance of nuclear mRNA for the mouse major urinary protein, while both types of mutations can facilitate exon skipping | journal = Molecular and Cellular Biology | volume = 14 | issue = 9 | pages = 6326–36 | date = September 1994 | pmid = 8065364 | pmc = 359159 | doi = 10.1128/mcb.14.9.6326 }}</ref>. The [[point mutation]] is [[Nonsynonymous substitution|nonsynonymous]] because it alters the RNA codon in the mRNA transcript such that translation results in amino acid change. An amino acid change may not result in appreciable changes in protein structure depending on whether the amino acid change is [[Conservative mutation|conservative]] or non-conservative. This owes to the similar physicochemical properties exhibited by some amino acids<ref>{{Cite web|url=https://www.genome.gov/genetics-glossary/Missense-Mutation|title=Missense Mutation|website=Genome.gov|language=en|access-date=2019-11-08}}</ref>. |
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Missense mRNAs may be detected as a result of two different types of point mutations - spontaneous mutations and induced mutations<ref name=":2">{{ |
Missense mRNAs may be detected as a result of two different types of point mutations - spontaneous mutations and induced mutations<ref name=":2">{{cite journal |last=Lodish |first=Harvey |last2=Berk |first2=Arnold |last3=Zipursky |first3=S. Lawrence |last4=Matsudaira |first4=Paul |last5=Baltimore |first5=David |last6=Darnell |first6=James | name-list-format = vanc |date=2000|title=Mutations: Types and Causes|url=https://www.ncbi.nlm.nih.gov/books/NBK21578/|journal=Molecular Cell Biology. 4th Edition|language=en}}</ref>. Spontaneous mutations occur during the DNA replication process where a non-complementary nucleotide is deposited by the [[DNA polymerase]] in the extension phase. The consecutive round of replication would result in a point mutation. If the resulting mRNA codon is one that changes the amino acid, a missense mRNA would be detected. A [[hypergeometric distribution]] study involving [[DNA polymerase beta|DNA polymerase β]] replication errors in the [[Adenomatous polyposis coli|APC gene]] revealed 282 possible substitutions that could result in missense mutations. When the APC mRNA was analyzed in the mutational spectrum, it showed 3 sites where the frequency of substitutions were high. <ref>{{cite journal | vauthors = Muniappan BP, Thilly WG | title = The DNA polymerase beta replication error spectrum in the adenomatous polyposis coli gene contains human colon tumor mutational hotspots | journal = Cancer Research | volume = 62 | issue = 11 | pages = 3271–5 | date = June 2002 | pmid = 12036944 | url = https://cancerres.aacrjournals.org/content/62/11/3271 }}</ref> |
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Induced mutations caused by [[Mutagen|mutagens]] can give rise to missense mutations<ref name=":2" />. [[Nucleoside analogue|Nucleoside analogues]] such as [[2-Aminopurine|2-aminopurine]] and [[5-Bromouracil|5-bromouracil]] can insert in place of A and T respectively. Ionizing radiation like [[X-ray|x-rays]] and [[Gamma ray|γ-rays]] can [[Deamination|deaminate]] cytosine to uracil.<ref>{{Cite web|url=https://courses.lumenlearning.com/microbiology/chapter/mutations/|title=Mutations {{!}} Microbiology|website=courses.lumenlearning.com|access-date=2019-10-09}}</ref> |
Induced mutations caused by [[Mutagen|mutagens]] can give rise to missense mutations<ref name=":2" />. [[Nucleoside analogue|Nucleoside analogues]] such as [[2-Aminopurine|2-aminopurine]] and [[5-Bromouracil|5-bromouracil]] can insert in place of A and T respectively. Ionizing radiation like [[X-ray|x-rays]] and [[Gamma ray|γ-rays]] can [[Deamination|deaminate]] cytosine to uracil.<ref>{{Cite web|url=https://courses.lumenlearning.com/microbiology/chapter/mutations/|title=Mutations {{!}} Microbiology|website=courses.lumenlearning.com|access-date=2019-10-09}}</ref> |
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Missense mRNAs may be applied synthetically in forward and reverse genetic screens used to interrogate the genome. Site-directed mutagenesis is a technique often employed to create knock-in and knock-out models that express missense mRNAs. For example, in knock-in studies, human orthologs are identified in model organisms to introduce missense mutations<ref>{{ |
Missense mRNAs may be applied synthetically in forward and reverse genetic screens used to interrogate the genome. Site-directed mutagenesis is a technique often employed to create knock-in and knock-out models that express missense mRNAs. For example, in knock-in studies, human orthologs are identified in model organisms to introduce missense mutations<ref>{{cite journal | vauthors = Tessadori F, Roessler HI, Savelberg SM, Chocron S, Kamel SM, Duran KJ, van Haelst MM, van Haaften G, Bakkers J | display-authors = 6 | title = Effective CRISPR/Cas9-based nucleotide editing in zebrafish to model human genetic cardiovascular disorders | journal = Disease Models & Mechanisms | volume = 11 | issue = 10 | pages = dmm035469 | date = October 2018 | pmid = 30355756 | pmc = 6215435 | doi = 10.1242/dmm.035469 }}</ref>, or a human gene with a substitution mutation is integrated into the genome of the model organism.<ref>{{cite journal | vauthors = Robertson NG, Jones SM, Sivakumaran TA, Giersch AB, Jurado SA, Call LM, Miller CE, Maison SF, Liberman MC, Morton CC | display-authors = 6 | title = A targeted Coch missense mutation: a knock-in mouse model for DFNA9 late-onset hearing loss and vestibular dysfunction | journal = Human Molecular Genetics | volume = 17 | issue = 21 | pages = 3426–34 | date = November 2008 | pmid = 18697796 | pmc = 2566528 | doi = 10.1093/hmg/ddn236 }}</ref> The subsequent loss-of-function or gain-of-function [[Phenotype|phenotypes]] are measured to model genetic diseases and discover novel drugs.<ref name=":0">{{cite journal | vauthors = Okamoto S, Amaishi Y, Maki I, Enoki T, Mineno J | title = Highly efficient genome editing for single-base substitutions using optimized ssODNs with Cas9-RNPs | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 4811 | date = March 2019 | pmid = 30886178 | pmc = 6423289 | doi = 10.1038/s41598-019-41121-4 | bibcode = 2019NatSR...9.4811O }}</ref> While homologous recombination has been widely used to generate single-base substitutions, novel technologies that co-inject gRNA and hCas9 mRNA of the [[CRISPR/Cas9-mediated genome editing|CRISPR/Cas9]] system, in conjunction with single-strand oligodeoxynucleotide (ssODN) donor sequences have shown efficiency in generating point mutations in the genome.<ref name=":0" /><ref>{{cite journal | vauthors = Inui M, Miyado M, Igarashi M, Tamano M, Kubo A, Yamashita S, Asahara H, Fukami M, Takada S | display-authors = 6 | title = Rapid generation of mouse models with defined point mutations by the CRISPR/Cas9 system | journal = Scientific Reports | volume = 4 | pages = 5396 | date = June 2014 | pmid = 24953798 | pmc = 4066261 | doi = 10.1038/srep05396 | bibcode = 2014NatSR...4E5396I }}</ref><ref>{{cite journal | vauthors = Prykhozhij SV, Fuller C, Steele SL, Veinotte CJ, Razaghi B, Robitaille JM, McMaster CR, Shlien A, Malkin D, Berman JN | display-authors = 6 | title = Optimized knock-in of point mutations in zebrafish using CRISPR/Cas9 | journal = Nucleic Acids Research | volume = 46 | issue = 17 | pages = e102 | date = September 2018 | pmid = 29905858 | pmc = 6158492 | doi = 10.1093/nar/gky512 }}</ref> |
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== Evolutionary Implications == |
== Evolutionary Implications == |
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=== Non-synonymous RNA editing === |
=== Non-synonymous RNA editing === |
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Substitutions can occur on the level of both the DNA and RNA. RNA editing-dependent amino acid substitutions can produce missense mRNA's of which occur through hydrolytic deaminase reactions. Two of the most prevalent deaminase reactions occur through the Apolipoprotein B mRNA editing enzyme ([[APOBEC]]) and the adenosine deaminase acting on RNA enzyme ([[ADAR]]) which are responsible for the conversion of [[cytidine]] to [[uridine]] (C-to-U), and the deamination of [[adenosine]] to [[inosine]] (A-to-I), respectively. <ref>{{ |
Substitutions can occur on the level of both the DNA and RNA. RNA editing-dependent amino acid substitutions can produce missense mRNA's of which occur through hydrolytic deaminase reactions. Two of the most prevalent deaminase reactions occur through the Apolipoprotein B mRNA editing enzyme ([[APOBEC]]) and the adenosine deaminase acting on RNA enzyme ([[ADAR]]) which are responsible for the conversion of [[cytidine]] to [[uridine]] (C-to-U), and the deamination of [[adenosine]] to [[inosine]] (A-to-I), respectively. <ref>{{cite journal | vauthors = Meier JC, Kankowski S, Krestel H, Hetsch F | title = RNA Editing-Systemic Relevance and Clue to Disease Mechanisms? | language = English | journal = Frontiers in Molecular Neuroscience | volume = 9 | pages = 124 | date = 2016 | pmid = 27932948 | pmc = 5120146 | doi = 10.3389/fnmol.2016.00124 }}</ref> Such selective substitutions of uridine for cytidine, and inosine for adenosine in RNA editing can produce differential isoforms of missense mRNA transcripts, and confer transcriptome diversity and enhanced protein function in response to selective pressures. <ref name=":1">{{cite journal | vauthors = Yablonovitch AL, Deng P, Jacobson D, Li JB | title = The evolution and adaptation of A-to-I RNA editing | journal = PLoS Genetics | volume = 13 | issue = 11 | pages = e1007064 | date = November 2017 | pmid = 29182635 | pmc = 5705066 | doi = 10.1371/journal.pgen.1007064 }}</ref> |
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==References== |
== References == |
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{{Reflist}} |
{{Reflist}} |
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[[Category:RNA]] |
[[Category:RNA]] |
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[[Category:Molecular biology]] |
[[Category:Molecular biology]] |
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{{molecular-cell-biology-stub}} |
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Revision as of 10:58, 21 December 2019
Missense mRNA have one or more mutated codons that yield polypeptides with an amino acid sequence different from the wild-type or naturally occurring polypeptide.[1] Missense mRNA molecules are created when template DNA strands or the mRNA strands themselves undergo a missense mutation in which a protein coding sequence is mutated and an altered amino acid sequence is coded for.
Biogenesis of missense mRNA
A missense mRNA arises from a missense mutation, in the event of which a DNA nucleotide base pair in the coding region of a gene is changed such that it results in the substitution of one amino acid for another[2]. The point mutation is nonsynonymous because it alters the RNA codon in the mRNA transcript such that translation results in amino acid change. An amino acid change may not result in appreciable changes in protein structure depending on whether the amino acid change is conservative or non-conservative. This owes to the similar physicochemical properties exhibited by some amino acids[3].
Missense mRNAs may be detected as a result of two different types of point mutations - spontaneous mutations and induced mutations[4]. Spontaneous mutations occur during the DNA replication process where a non-complementary nucleotide is deposited by the DNA polymerase in the extension phase. The consecutive round of replication would result in a point mutation. If the resulting mRNA codon is one that changes the amino acid, a missense mRNA would be detected. A hypergeometric distribution study involving DNA polymerase β replication errors in the APC gene revealed 282 possible substitutions that could result in missense mutations. When the APC mRNA was analyzed in the mutational spectrum, it showed 3 sites where the frequency of substitutions were high. [5]
Induced mutations caused by mutagens can give rise to missense mutations[4]. Nucleoside analogues such as 2-aminopurine and 5-bromouracil can insert in place of A and T respectively. Ionizing radiation like x-rays and γ-rays can deaminate cytosine to uracil.[6]
Missense mRNAs may be applied synthetically in forward and reverse genetic screens used to interrogate the genome. Site-directed mutagenesis is a technique often employed to create knock-in and knock-out models that express missense mRNAs. For example, in knock-in studies, human orthologs are identified in model organisms to introduce missense mutations[7], or a human gene with a substitution mutation is integrated into the genome of the model organism.[8] The subsequent loss-of-function or gain-of-function phenotypes are measured to model genetic diseases and discover novel drugs.[9] While homologous recombination has been widely used to generate single-base substitutions, novel technologies that co-inject gRNA and hCas9 mRNA of the CRISPR/Cas9 system, in conjunction with single-strand oligodeoxynucleotide (ssODN) donor sequences have shown efficiency in generating point mutations in the genome.[9][10][11]
Evolutionary Implications
Non-synonymous RNA editing
Substitutions can occur on the level of both the DNA and RNA. RNA editing-dependent amino acid substitutions can produce missense mRNA's of which occur through hydrolytic deaminase reactions. Two of the most prevalent deaminase reactions occur through the Apolipoprotein B mRNA editing enzyme (APOBEC) and the adenosine deaminase acting on RNA enzyme (ADAR) which are responsible for the conversion of cytidine to uridine (C-to-U), and the deamination of adenosine to inosine (A-to-I), respectively. [12] Such selective substitutions of uridine for cytidine, and inosine for adenosine in RNA editing can produce differential isoforms of missense mRNA transcripts, and confer transcriptome diversity and enhanced protein function in response to selective pressures. [13]
References
- ^ Jameson, J. Larry. Principles of Molecular Medicine. Springer. p. 731.
{{cite book}}: Unknown parameter|name-list-format=ignored (|name-list-style=suggested) (help) - ^ Belgrader P, Maquat LE (September 1994). "Nonsense but not missense mutations can decrease the abundance of nuclear mRNA for the mouse major urinary protein, while both types of mutations can facilitate exon skipping". Molecular and Cellular Biology. 14 (9): 6326–36. doi:10.1128/mcb.14.9.6326. PMC 359159. PMID 8065364.
- ^ "Missense Mutation". Genome.gov. Retrieved 2019-11-08.
- ^ a b Lodish, Harvey; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Darnell, James (2000). "Mutations: Types and Causes". Molecular Cell Biology. 4th Edition.
{{cite journal}}: Unknown parameter|name-list-format=ignored (|name-list-style=suggested) (help) - ^ Muniappan BP, Thilly WG (June 2002). "The DNA polymerase beta replication error spectrum in the adenomatous polyposis coli gene contains human colon tumor mutational hotspots". Cancer Research. 62 (11): 3271–5. PMID 12036944.
- ^ "Mutations | Microbiology". courses.lumenlearning.com. Retrieved 2019-10-09.
- ^ Tessadori F, Roessler HI, Savelberg SM, Chocron S, Kamel SM, Duran KJ, et al. (October 2018). "Effective CRISPR/Cas9-based nucleotide editing in zebrafish to model human genetic cardiovascular disorders". Disease Models & Mechanisms. 11 (10): dmm035469. doi:10.1242/dmm.035469. PMC 6215435. PMID 30355756.
- ^ Robertson NG, Jones SM, Sivakumaran TA, Giersch AB, Jurado SA, Call LM, et al. (November 2008). "A targeted Coch missense mutation: a knock-in mouse model for DFNA9 late-onset hearing loss and vestibular dysfunction". Human Molecular Genetics. 17 (21): 3426–34. doi:10.1093/hmg/ddn236. PMC 2566528. PMID 18697796.
- ^ a b Okamoto S, Amaishi Y, Maki I, Enoki T, Mineno J (March 2019). "Highly efficient genome editing for single-base substitutions using optimized ssODNs with Cas9-RNPs". Scientific Reports. 9 (1): 4811. Bibcode:2019NatSR...9.4811O. doi:10.1038/s41598-019-41121-4. PMC 6423289. PMID 30886178.
- ^ Inui M, Miyado M, Igarashi M, Tamano M, Kubo A, Yamashita S, et al. (June 2014). "Rapid generation of mouse models with defined point mutations by the CRISPR/Cas9 system". Scientific Reports. 4: 5396. Bibcode:2014NatSR...4E5396I. doi:10.1038/srep05396. PMC 4066261. PMID 24953798.
- ^ Prykhozhij SV, Fuller C, Steele SL, Veinotte CJ, Razaghi B, Robitaille JM, et al. (September 2018). "Optimized knock-in of point mutations in zebrafish using CRISPR/Cas9". Nucleic Acids Research. 46 (17): e102. doi:10.1093/nar/gky512. PMC 6158492. PMID 29905858.
- ^ Meier JC, Kankowski S, Krestel H, Hetsch F (2016). "RNA Editing-Systemic Relevance and Clue to Disease Mechanisms?". Frontiers in Molecular Neuroscience. 9: 124. doi:10.3389/fnmol.2016.00124. PMC 5120146. PMID 27932948.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Yablonovitch AL, Deng P, Jacobson D, Li JB (November 2017). "The evolution and adaptation of A-to-I RNA editing". PLoS Genetics. 13 (11): e1007064. doi:10.1371/journal.pgen.1007064. PMC 5705066. PMID 29182635.
{{cite journal}}: CS1 maint: unflagged free DOI (link)
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