Editing Silent mutation (section)

=== Multi-Drug Resistance Gene 1 ===
{{main|P-glycoprotein}}
Around 99.8% of genes that undergo mutations are deemed silent because the nucleotide change does not change the amino acid being translated.<ref name="Weber">{{Cite book|url=https://books.google.com/books?id=xWpnDAAAQBAJ&q=+MDR1&pg=PA359|title=Pharmacogenetics|last=Weber|first=Wendell|date=2008-04-02|publisher=Oxford University Press, USA|isbn=9780195341515|language=en}}</ref> Although silent mutations are not supposed to have an effect on the phenotypic outcome, some mutations prove otherwise like the Multi-Drug Resistance Gene 1. MDR1 codes for the P-glycoprotein which helps get rid of drugs in the body. It is located in the intestines, liver, pancreas, and brain. MDR 1 is located in the same places that CYP3A4 is located in, which is an enzyme that helps get rid of toxins or drugs from the liver and intestines. Silent mutations like MDR 1 do express a change in phenotypic response. A study done on mice showed when they did not have enough of the MDR 1 gene, their body did not recognize the ivermectin or cyclosporine drug, leading to the creation of toxins in their bodies.<ref name="Weber"/>

MDR1 has over fifty single nucleotide polymorphisms (SNP's) which are changes in the nucleotide base sequence.<ref name="Dudek 2007">{{Cite book|url=https://books.google.com/books?id=g-d--DOdnQAC&q=silent+mutations&pg=PA106|title=High-yield Cell and Molecular Biology|last=Dudek|first=Ronald W.|date=2007|publisher=Lippincott Williams & Wilkins|isbn=9780781768870|language=en}}</ref><ref name="Weber"/> In MDR1 the gene exon 26 which represents 3535C can mutate to 3535T which then changes the transfer RNA into one that is not often as seen, leading to changes in the outcome during translation. This is an example of how some silent mutations are not always silent.<ref name="Strachan">{{Cite book|url=https://books.google.com/books?id=dSwWBAAAQBAJ&q=silent+mutations|title=Human Molecular Genetics|last1=Strachan|first1=Tom|last2=Read|first2=Andrew|date=2018-03-29|publisher=Garland Science|isbn=9781136844072|language=en}}</ref> The multi-drug resistance genes at Exon 26 C3435T, exon 21 G2677T/A, and exon 12 C1236T have been studied to have SNP's that occur at the same time, therefore making the phenotypic "function "change. This suggests a haplotype dependency between exon 26 and other exon that have polymorphisms. For example, efavirenz and nelfinavir are two types of drugs that help decrease the HIV infection in a person's body. When the SNP from exon 26 is coupled with other SNP exons, the drugs have a lower chance of maintaining the HIV infection. Although, when the TT nucleotides in exon 26 are expressed the patient has a lower concentration of the virus but when the genotype morphs into CC or CT the infection is able to spread like normal leaving the MDR 1 gene almost defenseless. These changes in bases of exon 26 for MDR 1 show a correlation between the MDR 1 gene mutations and the ability of the antiretroviral drugs to suppress the HIV infection.<ref name="Weber"/>

Exon 26 has also been studied as to whether it is haplotype dependent or not. The presence of the SNP of exon 26 changes phenotypic functions when it is paired with the presence of mutations from exons 12 and 21. But when acting alone, it does not affect the phenotypic outcome as strongly. An example of exon 26’s haplotype dependency is seen when looking at chemotherapy. Since MDR 1 removes drugs from our cells, inhibitors have been used to block MRD 1's ability to remove drugs, thus letting beneficial drugs like chemotherapy and immunosuppressants aid the body in recovery more efficiently. MDR1 has different proteins that help exile these specific drugs from cancer cells.<ref name="The Sound of a Silent Mutation">{{Cite news|url=https://www.science.org/content/article/sound-silent-mutation-rev2|title=The Sound of a Silent Mutation|date=2006-12-22|work=Science {{!}} AAAS|access-date=2018-11-18|language=en}}</ref> Verapamil and cyclosporine A are common inhibitors for MDR 1.<ref name="Weber"/> Unfortunately, when C3435T is mutated with a mutation from either exon 12 or exon 21 (or if all three mutations occur at the same time creating a haplotype), the inhibitors are less likely to weaken the function of MDR1. Multiple silent mutated genes tend to be more resistant against these inhibitors.<ref name="The Sound of a Silent Mutation"/>

Looking at the molecular level, the reason why C3435T in exon 26 of MDR 1 gene is not silent is because of the pace at which the amino acids are being translated to proteins.<ref name="Strachan"/> mRNA’s secondary structures can fold which means different codons correspond to different folding's of the mRNA. For example, when exon 26 changes ATC to ATT both codons produce the same amino acid but ATC is seen more often than the mutation codon. As a consequence, the amount of time it takes for the ribosome to produce its protein confirmation is changed. This leads to a protein structure different from the usual shape of the protein which leads to different functions of the protein.<ref name="Campbell">{{Cite book|url=https://books.google.com/books?id=crAnYWLB09QC&q=%22silent+mutation%22&pg=PA348|title=Biochemistry|last1=Campbell|first1=Mary K.|last2=Farrell|first2=Shawn O.|date=2011-01-01|publisher=Cengage Learning|isbn=978-0840068583|language=en}}</ref>

Other reasons behind MDR1’s “silent mutation” occurs in messenger RNA. In mRNA, codons also work as exon splicing enhancers. Codons decide when to cut out introns based on the codon it is reading in mRNA.<ref name="Dudek 2007"/> The mutated codons have a higher risk of making a mistake when splicing introns out of the mRNA sequence leading to the wrong exons being produced. Therefore, making a change to the mature messenger RNA.<ref name="Campbell"/> Mutations in the Multi-Drug Resistance Gene 1 show how silent mutations can have an effect on the outcome of the phenotype.