I would like to understand the reason behind the silent mutation and nonsense mutation in house keeping genes. Since I am working with multidrug resistant bacteria, i would like to know if there is any positive correlation between this silent mutation and resistance(or survival of the organism).
Nithin,
you probably chose not the best term. By definition: silent mutations are mutations in DNA that do not significantly alter the phenotype of the organism.
When they occur in ORF they either do not result in a change to the amino acid sequence of a protein (a "synonymous substitution"), or result in the insertion of an alternative amino acid with similar properties. In both cases they can be 'silent" under certain conditions of growth only, and you always can find a test that will differentiate organism with such mutation and "wild-type". Even synonymous substitution can change gene expression. Again, a nonsense mutation in house-keeping gene (single copy and essential for bacteria life by definition) can be lethal in most of cases.
Thanks Alex iam aware of these things.
What i intent to know was, will these silent mutation make any change in the rate of protein production(or gene expression). if so a method to study using some bioinformatics tool (i have the sequence information of the genes). iam totally unaware whether it could be studied. If you have any idea on it please tell me. If iam wrong please correct me.
Sorry i used nonsense mutation, but it is missense mutation.
Thank you.
Hi Nithin,
1. The classic view of 'Silent mutation' is that silent mutations do not cause changes in the amino acid sequence, hence the protein is supposed still to be functional, and pose no consequence for the organisms.
2. However, recently this view has changed. Researchers have found that silent mutations do cause changes and affect the organism [see attachment 1]. Some examples are:
[1] Silent mutation have greatly changed the mRNA structures and reduce the translation speed. For one study, the assay showed that an unexpected one-third of silent mutations caused protein translation to slow down, in some cases decreasing the speed by as much as five-fold [see attachments 2].
[2] Artificially induced silent mutations (by introducing 5 rare codons) has significantly changed a protein's property. See paper: "Silent mutations result in HlyA hypersecretion by reducing intracellular HlyA protein aggregates " [ http://www.ncbi.nlm.nih.gov/pubmed/18553505 ]
3. If a protein's property can be changed by silent mutations [as stated in the above [2] study], silent mutations might also have the ability to induce 'drug resistance' of a bacteria by altering a specific gene. This can due to the changed protein cannot be recognized by antibiotics anymore. However, this has to be checked out experimentally. For your experiments, you can consider to design and introduce some artificial silent mutations on a particular gene (in your case, you said " a house-keeping gene") and see any drug-resistance occur for the bacteria. Some companies provide 'codon usage' service, such as GeneScrip. You can use their services to change your gene with a price (not cheap).
Synonymous mutation can be related to misfolding and dysfunction of the protein.
I recently proposed that translational rate is modulated by pairs of consecutive codons or bicodons [1]. By a statistical analysis of coding sequences, we compute a rate translational measure of all bicodons. We found that bicodons associated with sequences encoding low abundant proteins are involved in translational rate attenuation. Furthermore, we observe that the misfolding in many protein, such MDR1 gene [2], is better explained by a big change in the translational rate due to the synonymous bicodon variant, rather than by a relatively small change in the codon usage.
1.- Coding translational rates: the hidden genetic code
http://biorxiv.org/content/early/2016/07/08/062935
2.- Kimchi-Sarfaty, et al. A silent polymorphism in the MDR1 gene changes substrate specificity.
Science 315, 525–528 (2007).
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