Synonymous mutations are not neutral!

The revolution of “neutral” mutations! Mutations are changes in the DNA sequence. They happen all the time, more or less randomly, even in protein-coding genes. Most mutations in these genes also cause a change in the sequence of amino acids that make up the protein encoded by this gene (non-synonymous mutations). However, it is mostly mutations that do not affect the protein sequence (synonymous mutations) that are retained during evolution. Normally, it was thought: since these mutations do not alter the protein, they have no biological effect, and therefore natural selection need not remove them. Except that a study published June 8, 2022 in the journal Nature shows that, on the contrary, synonymous mutations actually have biological consequences. And that their influence is close to most non-synonymous mutations. A great discovery that could revolutionize the study of the genetic causes of disease. To see more clearly, Science and the Future asked study author Jianzhi Zhang, an expert in evolutionary genomics at the University of Michigan (USA).

Science and the future: You show that synonymous mutations have an impact, contrary to what we thought until now. Have you ever been in doubt about this paradigm?

Jianzhi Zhang: These mutations were actually thought to have no effect as they do not affect the structure of the protein. But researchers had already begun to realize that synonymous mutations could have an effect. During translation (when messenger RNA is “translated” into protein, editor’s note), the ribosome messenger RNA reads three letters at a time, these three letters forming a codon. And we had seen that the use of synonymous codons, that is, which code for the same amino acid, was not accidental. This suggested that these codons could have different phenotypic effects. It has also been shown that the use of different synonymous codons can have an effect on the level of protein expression. Their structure does not change, but their quantity is affected. So there was scientific evidence that showed that these synonymous mutations might not be as neutral as we imagined. But the scientific community seemed to think that even if they are not completely neutral, their effect must still be minimal.

So you have decided to study this phenomenon once and for all …

Yes, we wanted to know the real effect of these mutations. For this, we selected 21 yeast genes that represent the genome of this species, and we introduced mutations in them. Thus, we created more than 8,000 mutants, and then we analyzed their growth rate. And we have seen a great variety. A few synonymous mutations were truly neutral, but the majority (75%) had a detectable effect on growth rate. Some even had very significant effects. For the majority, these effects were negative, but they were beneficial for a small proportion (1 to 2%).

And what was the common feature of these synonymous mutations with a detectable effect?

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