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12.3 years ago
Francois Olivier Hébert
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280
Hi,
I was wondering if anybody knows any program/application/tool that can be used to assess the functional impact of a SYNONYMOUS mutation on a given protein? I've used SIFT and PolyPhen-2 to measure the functional deleterious impact of non-synonymous mutations and I know that synonymous (silent) mutations can also have a functional impact in terms of transcription time, protein folding or even protein secondary structure (Salim and Cavalcanti, 2008).
I've been looking on the web for a while and I can't find any application or program that does that, i.e that gives a measure of how potentially important a silent mutation is (does it functionally affect the protein?).
Thanks for any help!
FO
Many people are thinking about this problem. Right now there isn't a good solution without apriori knowledge (ie expression levels ect).
Thanks ! That's the impression that I had when I started looking in the literature.
I linked the article. Nowhere does it mention protein folding or 2D structure, though. The article you cite focusses on codon bias which might in fact influence transcription. Do you have other reliable sources for this claim, would be interesting to see? Imho, I do not believe that synonymous mutations can affect protein folding, function or structure; what would the mechanism be, given an identical AA sequence? The only difference would be in use different tRNA; but this is more a biochemistry than a bioinformatics question.
Indeed, it was the wrong reference, I apologize for this. I know that people have focused a lot on transcriptional timing with regards to synonymous mutations and this is something that must be studied in the lab or with other tools than bioinformatics. But Kimchi-Sarfaty et al. (2007) seem to have found evidence for differential protein folding caused by a synonymous mutation that is part of a specific haplotype. In fact, the data show that the presence of a synonymous mutation in the gene MDR1 in humans alters the protein function. They say that the use of a rare codon affects the translation rate which in turn affects protein folding (they give sources for this claim). In the case of that particular silent mutation, it appears to cause a conformational change that affects the function of the protein. Their hypothesis is that the replacement of a "common" codon by a "rare" codon in a cluster of infrequently used codons affects the timing of cotranslational folding which may result in altered protein function. I am not a biochemist, I'm a master's student in evolutionary biology, so I am not familiar with the literature on the subject (molecular mechanisms concerning protein folding and everything), but I was wondering if there was any program out there that could test this kind of data with SNP information and codon usage in a certain sequence. This might be too early in the process of understanding these mechanisms though, so it's totally possible that no tool is currently available for that. Thank you for your time and rigorous comment, I am in the process of learning how to work in research and this is the kind of interaction that one must have in order to learn. Best regards (complete reference: Kimchi-Sarfaty et al., Science, 2007, vol. 315, pp.525-528)
After reading a bit more I came to think that this is quite an interesting topic to work with, and this definitely warrants much more research imo. However, I would assume that it is too early for such a tool to exist. Feasibility of a prediction method depends on the number of available cases. I can imagine at least two approaches to develop such a tool: mechanism agnostic machine learning and classification; or understanding the mechanism and directly looking for it ("e.g. RNA hairpin loop formation leading to translational delay" -> look for hairpin loop formation (bad example maybe, a single SNP shouldn't change that much) ). Another approach could be by simulating the effect of translational timings on the dynamics of protein folds (unfortunately I do not know much about that). Unfortunately, the mechanism seems to be poorly understood.
I would try to first text mine and collect all available literature about cases of synonymous mutations changing protein structure to get an overview. Thanks for making me aware of this research question, I hope we can help you further with this.
If the synonymous mutation is near to splice site, it might affect on splicing.You can find easily articles which found causative synonymous mutation by affecting on splice sites.