Silent Mutations, a Hidden Hazard

HMND
5 min readApr 20, 2023

👉🏻 Read this sentenсe сarefully, what dо yоu think is wrоng with it?

At first glance, everything is in order, you’ve managed to read and comprehend everything without an issue.

But here is what this sentence looks like in edit mode

The editor shows that there are typos in the words “sentence” “carefully” and “wrong”. Weird, right? In the above sentence, all the “C”s and “O”s have been replaced with Cyrillic letters that look exactly the same.

This is pretty much how silent mutations work. Silent mutations are changes in the genetic code that do not alter the primary structure of the gene product — the protein, in contrast to explicit mutations that change the structure and sometimes the function of the encoded protein directly.

Let’s take a closer look at how it works in the human body, shall we? Take a look at the below table of mRNA triplets that encode our most basic bodily amino acids.

Observe the lower left cell. We see that the GUC triplet encodes the amino acid Val, or valine. Notice that GUC, GUU, GUA and GUG all encode Valine. If one of these triplets, which are in their rightful place, is replaced by another from this list, this will be a silent mutation.

Silent mutations occur for completely different reasons, ranging from negative environmental conditions, whether it is ultraviolet radiation from the sun, or pharmacological drugs, to spontaneous errors in DNA copying during cell division.

It is also worth remembering that DNA is conditionally divided into 2 types of sequences of the genetic code — coding and non-coding. Silent mutations can also occur in the non-coding region, knowing that this phenomenon does not affect the change in the primary structure of the protein.

Just how harmful are silent mutations?

Silent mutations can affect the rate of protein synthesis on an mRNA template. During protein synthesis, transport of individual amino acids to the assembly point is carried out by strictly defined tRNAs. And if the tRNA needed for the mutant triplet is much less than for the original one, the process can be delayed.

Such a slowdown will lead to a change in the rate of expression (product synthesis) of the gene, in connection with which there will be a lack of a certain protein in the cell.

Silent mutations can also change the structure of the encoded protein, which can disrupt its functions.

Innocent at first glance, silent mutations can destroy or build new binding sites for transcription factors, molecules that regulate the rate of protein synthesis. In this connection, the necessary regulators are turned off and new ones appear where they are not needed, which can lead to an acceleration or deceleration of a whole cascade of negative processes in the body.

During protein synthesis, only coding regions remain in mRNA, non-coding regions are removed, this process is called splicing. Silent mutations in non-coding regions can disrupt the normal splicing process, which leads to the inclusion of unnecessary structures in the protein or the exclusion of the necessary ones, which most often leads to a violation of its functionality.

The accumulation of errors in the genetic code leads to the development of cancer and, moreover, ensures its aggressiveness and resistance to treatment. Although silent mutations are 20 times less common than explicit ones, the degree of their harmfulness in carcinogenesis can be equal. Silent mutations are indeed much more common in cancer cells than in normal cells. Also interesting is the fact that the degree of pathogenicity is determined by the total number of mutations contained in one gene, and there are also combinations of silent and ordinary mutations, which are a real explosive mixture.

A complete diagnosis of silent mutations is possible with the help of genome sequencing. This technology is being intensively developed, and latest advancements in this field enable detecting even single-nucleotide changes in the structure of the genetic code, even in non-coding regions of the genome.

But the interpretation of the obtained results is very difficult. So far, science was not able to sequence the genomes of everyone on earth, we can’t even know for sure if our world’s computational power would be enough to process all this data. This constraint forces scientists to work with the genomes of those few percents of people who have sequenced their genetic material.

Nowadays, scientists are comparing the detected silent mutations with the patient’s phenotype, but nevertheless, computer modelling is also widely used and, soon enough, rapidly developing AI/ML algorithms will also get involved in solving this issue. Today, research is mainly based on global databases like The Cancer Genome Atlas (TCGA).

At HMND we’ve contributed to the development of a software solution that combines patient phenotypes and computer modelling (in-silico) methods at the same time to help discover variants that could potentially lead to actual mutations.

To understand the scope of ongoing research, here’s a flow chart of one of the teams involved in the study of the pathogenicity of silent mutations.

Gutman, T., Goren, G., Efroni, O. et al. Estimating the predictive power of silent mutations on cancer classification and prognosis. npj Genom. Med. 6, 67 (2021). https://doi.org/10.1038/s41525-021-00229-1

The road ahead

Timely diagnosis and interpretation of silent mutations, along with obvious/detectable mutations, will make it possible to predict in advance possible diseases not only for a particular person, but also for entire populations.

Silent mutations are considered to contribute to the development of various diseases such as cancer, Alzheimer’s or Parkinson’s. With the right diagnostic tools at hand, medical specialists will be able to predict and to intervene before these diseases take a toll, which will greatly reduce the subsequent burden on both healthcare and the economy.

Unfortunately, to date, resource investment in the study of silent mutations remains comparably small, but the emergence of entire scientific teams paying attention to this problem is an encouraging trend that can broaden our understanding of disease dynamics, and make the future safer for all of us.

--

--

HMND

We envision the future and help you drive innovation.