Editing Silent mutation (section)

==Structural consequences==

=== Primary structure ===
{{main|Biomolecular structure#Primary structure}}
A nonsynonymous mutation that occurs at the genomic or transcriptional levels is one that results in an alteration to the amino acid sequence in the protein product.  A protein's [[primary structure]] refers to its amino acid sequence.  A substitution of one amino acid for another can impair protein function and tertiary structure, however its effects may be minimal or tolerated depending on how closely the properties of the amino acids involved in the swap correlate.<ref name="pmid19289044">{{cite journal | vauthors = Teng S, Madej T, Panchenko A, Alexov E | title = Modeling effects of human single nucleotide polymorphisms on protein-protein interactions | journal = Biophysical Journal | volume = 96 | issue = 6 | pages = 2178–88 | date = March 2009 | pmid = 19289044 | pmc = 2717281 | doi = 10.1016/j.bpj.2008.12.3904 | bibcode = 2009BpJ....96.2178T }}</ref>  The premature insertion of a [[stop codon]], a [[nonsense mutation]], can alter the primary structure of a protein.<ref name="pmid21089233">{{cite book |last1=Strachan |first1=Tom |last2=Read |first2=Andrew P. |name-list-style=vanc |title=Human Molecular Genetics |publisher=Wiley-Liss |edition=2nd |isbn=978-1-85996-202-2 |id=NBK7580 |year=1999 |pmid=21089233 |url=https://archive.org/details/humanmolecularge0002stra |url-access=registration }}</ref>  In this case, a truncated protein is produced.  Protein function and folding is dependent on the position in which the stop codon was inserted and the amount and composition of the sequence lost.

Conversely, silent mutations are mutations in which the amino acid sequence is not altered.<ref name="pmid21089233"/> Silent mutations lead to a change of one of the letters in the triplet code that represents a [[codon]], but despite the single base change, the amino acid that is coded for remains unchanged or similar in biochemical properties.  This is permitted by the [[degeneracy of the genetic code]].

Historically, silent mutations were thought to be of little to no significance.  However, recent research suggests that such alterations to the triplet code do affect protein translation efficiency and protein folding and function.<ref name="pmid20617253">{{cite journal | vauthors = Czech A, Fedyunin I, Zhang G, Ignatova Z | title = Silent mutations in sight: co-variations in tRNA abundance as a key to unravel consequences of silent mutations | journal = Molecular BioSystems | volume = 6 | issue = 10 | pages = 1767–72 | date = October 2010 | pmid = 20617253 | doi = 10.1039/c004796c }}</ref><ref name="pmid17716239">{{cite journal | vauthors = Komar AA | title = Silent SNPs: impact on gene function and phenotype | journal = Pharmacogenomics | volume = 8 | issue = 8 | pages = 1075–80 | date = August 2007 | pmid = 17716239 | doi = 10.2217/14622416.8.8.1075 }}</ref>

Furthermore, a change in primary structure is critical because the fully folded tertiary structure of a protein is dependent upon the primary structure.&nbsp; The discovery was made throughout a series of experiments in the 1960s that discovered that reduced and denatured RNase in its unfolded form could refold into the native tertiary form.&nbsp; The tertiary structure of a protein is a fully folded polypeptide chain with all hydrophobic R-groups folded into the interior of the protein to maximize entropy with interactions between secondary structures such as beta sheets and alpha helixes.&nbsp; Since the structure of proteins determines its function, it is critical that a protein be folded correctly into its tertiary form so that the protein will function properly.&nbsp; However, it is important to note that polypeptide chains may differ vastly in primary structure, but be very similar in tertiary structure and protein function.<ref>{{Cite web|url=https://ocw.mit.edu/courses/biology/7-88j-protein-folding-and-human-disease-spring-2015/study-materials/MIT7_88JS15_Anfinsen.pdf|title=MIT Biochemistry Lecture Notes-Protein Folding and Human Disease}}</ref>

=== Secondary structure ===
{{main|Biomolecular structure#Secondary structure}}
Silent mutations alter the [[secondary structure]] of [[mRNA]].

Secondary structure of proteins consists of interactions between the atoms of the backbone of a polypeptide chain, excluding the R-groups.&nbsp; One common type of secondary structures is the alpha helix, which is a right-handed helix that results from hydrogen bonds between the ''nth'' amino acid residue and the ''n+4th'' amino acid residue.&nbsp; The other common type of secondary structure is the beta sheet, which displays a right-handed twist, can be parallel or anti-parallel depending on the direction of the direction of the bonded polypeptides, and consists of hydrogen bonds between the carbonyl and amino groups of the backbone of two polypeptide chains.<ref>{{Cite web|url=https://www.khanacademy.org/science/biology/macromolecules/proteins-and-amino-acids/a/orders-of-protein-structure|title=Orders of protein structure|website=Khan Academy|language=en|access-date=2018-11-08}}</ref>

[[mRNA]] has a secondary structure that is not necessarily linear like that of DNA, thus the shape that accompanies complementary bonding in the structure can have significant effects. For example, if the mRNA molecule is relatively unstable, then it can be rapidly degraded by enzymes in the [[cytoplasm]]. If the RNA molecule is highly stable, and the complementary bonds are strong and resistant to unpacking prior to translation, then the gene may be under expressed.  Codon usage influences mRNA stability.<ref name="pmid21567958" />

Furthermore, since all organisms contain a slightly different genetic code, their mRNA structures differ slightly as well, however, multiple studies have been conducted that show that all properly folded mRNA structures are dependent on the primary sequence of the polypeptide chain and that the structure is maintained by dinucleotide relative abundances in the cell matrix.&nbsp; It has also been discovered that mRNA secondary structure is important for cell processes such as transcript stability and translation. The general idea is that the functional domains of mRNA fold upon each other, while the start and stop codon regions generally are more relaxed, which could aid in the signaling of initiation and termination in translation.<ref>{{cite journal | vauthors = Shabalina SA, Ogurtsov AY, Spiridonov NA | title = A periodic pattern of mRNA secondary structure created by the genetic code | journal = Nucleic Acids Research | volume = 34 | issue = 8 | pages = 2428–37 | date = 2006 | pmid = 16682450 | pmc = 1458515 | doi = 10.1093/nar/gkl287 }}</ref>

If the oncoming ribosome pauses because of a knot in the RNA, then the polypeptide could potentially have enough time to fold into a non-native structure before the [[tRNA]] molecule can add another [[amino acid]].  Silent mutations may also affect [[splicing (genetics)|splicing]], or [[Transcription (genetics)|transcriptional control]].

=== Tertiary structure ===
{{main|Biomolecular structure#Tertiary structure}}
Silent mutations affect protein folding and function.<ref name="pmid17185560"/>  Normally a misfolded protein can be refolded with the help of molecular chaperones. RNA typically produces two common misfolded proteins by tending to fold together and become stuck in different conformations and it has a difficulty singling in on the favored specific tertiary structure because of other competing structures.  RNA-binding proteins can assist RNA folding problems, however, when a silent mutation occurs in the mRNA chain, these chaperones do not bind properly to the molecule and are unable to redirect the mRNA into the correct fold.<ref>{{cite journal | vauthors = Herschlag D | title = RNA chaperones and the RNA folding problem | journal = The Journal of Biological Chemistry | volume = 270 | issue = 36 | pages = 20871–4 | date = September 1995 | pmid = 7545662 | doi = 10.1074/jbc.270.36.20871 | citeseerx = 10.1.1.328.5762 | s2cid = 14083129 | doi-access = free }}</ref>

Recent research suggests that silent mutations can have an effect on subsequent protein structure and activity.<ref>{{cite journal | vauthors = Komar AA | title = Genetics. SNPs, silent but not invisible | journal = Science | volume = 315 | issue = 5811 | pages = 466–7 | date = January 2007 | pmid = 17185559 | doi = 10.1126/science.1138239 | s2cid = 41904137 | doi-access = free }}</ref><ref>{{cite web |author=Beckman |title=The Sound of a Silent Mutation |date=22 December 2006 |work=News |publisher=Science/AAAS |url=https://www.science.org/content/article/sound-silent-mutation}}</ref> The timing and rate of protein folding can be altered, which can lead to functional impairments.<ref name="pmid22577471">{{cite journal | vauthors = Zhang Z, Miteva MA, Wang L, Alexov E | title = Analyzing effects of naturally occurring missense mutations | journal = Computational and Mathematical Methods in Medicine | volume = 2012 | pages = 1–15 | year = 2012 | pmid = 22577471 | pmc = 3346971 | doi = 10.1155/2012/805827 | doi-access = free }}</ref>