Study challenges 60 year evolutionary assumption that synonymous mutations are neutral.


The article "Synonymous mutations in representative yeast genes are mostly strongly non-neutral" by Shen et al. (2022) challenges the 60 year evolutionary assumption that synonymous mutations are neutral. Synonymous mutations are single-base changes in a DNA sequence that do not alter the amino acid sequence of the encoded protein. This means that they are not expected to have any direct effect on the function of the protein.

However, Shen et al. found that most synonymous mutations in yeast genes had a significant negative effect on fitness. They measured the fitness of yeast strains with different synonymous mutations using a growth assay. They found that the fitness of strains with synonymous mutations was on average 10% lower than the fitness of wild-type strains.

The authors also found that the distribution of fitness effects of synonymous mutations was similar to the distribution of fitness effects of nonsynonymous mutations. This suggests that synonymous mutations are not neutral, but rather have a wide range of fitness effects, some of which are deleterious.

The authors propose several possible explanations for the non-neutrality of synonymous mutations. One possibility is that synonymous mutations can affect the level of mRNA expression of the mutated gene. This can happen if the mutation changes the structure of the mRNA molecule, making it less stable or less efficiently translated into protein.

Another possibility is that synonymous mutations can affect the folding or stability of the encoded protein. This can happen if the mutation changes the amino acid sequence in a way that disrupts the protein's structure.

The authors also suggest that the non-neutrality of synonymous mutations may be due to epistasis, which is the interaction between different mutations. For example, a synonymous mutation that has a small negative effect on fitness may become more harmful if it is combined with another mutation that also has a negative effect on fitness.

The findings of Shen et al. challenge the traditional view of synonymous mutations as being neutral. However, it is important to note that this study was conducted in yeast, and it is not clear whether the results would be the same in other organisms. More research is needed to confirm the non-neutrality of synonymous mutations in other organisms.

The non-neutrality of synonymous mutations has important implications for our understanding of evolution. For example, it means that synonymous mutations can contribute to the evolution of new genes and new proteins. It also means that synonymous mutations can be under selection, which can lead to the accumulation of beneficial mutations in populations. 

This affects the 30 year practice of calculating natural selection via the Ka/Ks ratio as these are no longer accurate. It's estimated 20,000 journal articles claimed natural selection using the Ka/Ks ratio.

The findings of Shen et al. also have implications for the design of gene therapies. Synonymous mutations are often used as targets for gene therapies, because they are thought to be harmless. However, the findings of this study suggest that synonymous mutations may not be as harmless as previously thought. This means that gene therapists need to be careful when targeting synonymous mutations, as they may have unintended consequences.

Overall, the findings of Shen et al. are a significant challenge to the traditional view of synonymous mutations. More research is needed to confirm these findings in other organisms, but if they are true, they will have important implications for our understanding of evolution and gene therapy.

The study by Shen et al. has a few limitations. First, it was conducted in yeast, and it is not clear whether the results would be the same in other organisms. Second, the study only looked at a small number of genes, so it is possible that the results do not apply to all genes. Third, the study only looked at the effects of synonymous mutations on fitness, and it is possible that they have other effects, such as affecting the expression of other genes.

What are the implications of the study for the design of gene therapies?

The study by Shen et al. suggests that synonymous mutations may not be as harmless as previously thought. This means that gene therapists need to be careful when targeting synonymous mutations, as they may have unintended consequences. For example, a gene therapy that targets a synonymous mutation could potentially lead to the accumulation of harmful mutations in the population.

What are the future directions of research on synonymous mutations?

The future directions of research on synonymous mutations include:

  • Conducting more studies in other organisms to confirm the findings of Shen et al.

  • Studying the mechanisms by which synonymous mutations can affect fitness.

  • Investigating the implications of synonymous mutations for the design of gene therapies.

  • Studying the role of synonymous mutations in evolution.

Article Snippets

Synonymous mutations break their statement of neutrality

Although previously thought to be neutral, research in yeast suggests that synonymous point mutations may have strongly nonneutral effects

A group of researchers from the University of Michigan (MI, USA) have evidence that synonymous, or silent, mutations can be harmful to yeast growth. Using budding yeast, researchers compared the fitness of over 8,000 mutant strains containing different types of mutations in one of the 21 genes targeted. Importantly, this study demonstrates that synonymous point mutations should not be ignored, as they often have been, when investigating the mutations underlying certain diseases in humans.  

Synonymous mutations account for almost one-third of point mutations. They describe single-base misspellings in codons that do not change the amino acid expression.

It has been assumed in the past that because synonymous mutations do not change the amino acid expression, and therefore protein sequence, they have no effect on the organism. The current research builds upon anecdotal evidence of some synonymous mutations being nonneutral. 

Researchers re-engineered CRISPR protein Cas7-11 to fit into a single viral vector, making it more viable for RNA editing in living cells.

Researchers introduced these three types of point mutations to different mutant yeast strains using CRISPR/Cas9 to compare how rapidly the yeast reproduced in relation to the control strain, denoting the effect of the mutation.

They discovered that 75.9% of synonymous mutations were significantly harmful and 1.3% were significantly helpful.  

We also studied the mechanisms through which synonymous mutations affect fitness and found that at least one reason is that both synonymous and nonsynonymous mutations alter the gene-expression level, and the extent of this expression effect predicts the fitness effect.” 

Senior author Jianzhi Zhang was shocked by their results: “Our results imply that synonymous mutations are nearly as important as nonsynonymous mutations in causing disease and call for strengthened effort in predicting and identifying pathogenic synonymous mutations.”

In the future, researchers hope to explore how their findings apply to other organisms as they see no reason why their results should be restricted to yeast. This study illuminates the potential role of synonymous mutations in causing disease and the importance of recognizing these mutations as disease indicators.  

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