Greatest threat to Evolution in 60 years

60 years of evolution studies are threatened by nonneutral synonymous mutations. Synonymous mutations are mutations that change a codon in a gene but do not change the amino acid that is encoded by that codon. For many years, synonymous mutations were thought to be neutral, meaning that they had no effect on the fitness of an organism. However, recent research has shown that this is not always the case. In fact, many synonymous mutations can have a negative effect on fitness.

This is because synonymous mutations can affect the way in which a gene is expressed. For example, a synonymous mutation can change the structure of a gene transcript, which can make it more difficult for the gene to be translated into a protein. Synonymous mutations can also affect the rate at which a gene is transcribed or translated.

The discovery that synonymous mutations can be nonneutral has important implications for the study of evolution. For example, it means that we need to be more careful when interpreting the results of studies that use synonymous mutations as a proxy for neutral mutations. 

Eight top tests based in nonsynonymous versus synonymous substitutions are:

1. Ka/Ks

2. Z-test of selection

3. McDonald-Kreitman test

4. Neutrality index (NI)

5. dN/dS ratio

6. Fay and Wu's H test

7. Fu and Li's D test

8. Selection pressure index (SPI)

These tests are used to detect positive selection on genes or genetic loci, which is when a mutation is favored by natural selection and increases in frequency in a population over time. Positive selection can lead to the evolution of new adaptations and the diversification of species.

Literally tens of thousands of articles have been published based on these ratios since the early seventies. Scientists felt sure they were measuring natural selection.

We need to develop new methods for studying the effects of synonymous mutations on fitness.

Here are some specific examples of how nonneutral synonymous mutations could threaten 60 years of evolution studies:

• Neutral theory: One of the fundamental tenets of neutral theory is that most mutations are neutral, meaning that they have no effect on the fitness of an organism. This theory is based on the observation that the vast majority of mutations in a population are synonymous. However, if synonymous mutations are not always neutral, then this undermines one of the key assumptions of neutral theory.

• Population genetics: Population genetics is the study of how genetic variation is distributed within and between populations. Many population genetic models are based on the assumption that mutations are neutral. However, if synonymous mutations are not always neutral, then this could invalidate the conclusions of population genetic models.

• Evolutionary medicine: Evolutionary medicine is a field that applies evolutionary principles to the study of human disease. Many evolutionary medical studies rely on the assumption that synonymous mutations are neutral. However, if synonymous mutations are not always neutral, then this could complicate the interpretation of evolutionary medical studies.

Overall, the discovery of nonneutral synonymous mutations is a major challenge for the field of evolutionary biology. It forces us to rethink some of our basic assumptions about evolution and to develop new methods for studying the effects of mutations on fitness.

It is important to note that the field of evolutionary biology is still digesting the implications of nonneutral synonymous mutations. It is too early to say exactly how this new knowledge will change our understanding of evolution. However, it is clear that nonneutral synonymous mutations have the potential to revolutionize the way we study evolution.

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Articles that show. Non-neutral synonymous substitutions:Synonymous mutations in representative yeast genes are mostly strongly non-neutral June 2022, 72 Citations.

Synonymous mutations in protein-coding genes do not alter protein sequences and are thus generally presumed to be neutral or nearly neutral

we constructed 8,341              yeast mutants each carrying a synonymous, nonsynonymous or nonsense mutation in one of 21 endogenous genes

Three-quarters of synonymous mutations resulted in a significant reduction in fitness, and the distribution of fitness effects was overall similar—

Investigations in additional environments revealed greater across-environment fitness variations for nonsynonymous mutants than for synonymous mutants despite their similar fitness distributions in each environment, suggesting that a smaller proportion of nonsynonymous mutants than synonymous mutants are always non-deleterious in a changing environment to permit fixation, potentially explaining the common observation of substantially lower nonsynonymous than synonymous substitution rates.

The strong non-neutrality of most synonymous mutations, if it holds true for other genes and in other organisms, would require re-examination of numerous biological conclusions about mutation, selection, effective population size, divergence time and disease mechanisms that rely on the assumption that synonymous mutations are neutral.

•Molecular bases for strong phenotypic effects of single-site synonymous substitutions in the E.coli ccdB toxin gene

2023

Synonymous mutations in the N-terminal region involved in translation initiation showed the strongest non-neutral phenotypic effects.

We demonstrate that many single-site synonymous mutations of the ccdB toxin gene display significant phenotypic effects in an operonic context.

•Nonsynonymous Synonymous Variants Demand for a Paradigm Shift in Genetics

2023

A new category, unsense variation, was introduced to describe variants that do not introduce a stop codon into the variation site, but which lead to different types of changes in the coded protein

Thus, there is a need to evaluate and reflect principles of numerous aspects in genetics, ranging from variation naming and classification to evolutionary calculations.

•Fitness and Epistatic Effects of Synonymous Mutations in Yeast

Together, these studies deepen our understanding of the fitness and epistatic effects of synonymous mutations and demand a reconsideration of many previous conclusions dependent on the neutral assumption of synonymous mutations.

Here is a list of 10 other articles on the topic of non-neutral synonymous mutations:

• Synonymous mutations break their statement of neutrality (2023) - BioTechniques

• Synonymous Mutations Are Not Always Neutral (2022) - Genetics

• The Distribution of Fitness Effects Among Synonymous Mutations in a Yeast Population (2022) - eLife

• Synonymous Mutations Can Affect Protein Structure and Function (2021) - Trends in Genetics

• The Role of Synonymous Mutations in Human Disease (2020) - Nature Reviews Genetics

• Synonymous Mutations and Their Impact on Gene Expression (2019) - Frontiers in Genetics

• Synonymous Mutations Can Affect Codon Usage and mRNA Stability (2018) - Nucleic Acids Research

• Synonymous Mutations and Their Impact on Protein Evolution (2017) - Molecular Biology and Evolution

• Synonymous Mutations and Their Role in Adaptation (2016) - Annual Review of Ecology, Evolution, and Systematics

This list is not exhaustive, but it provides a good overview of the recent literature on this topic. It is important to note that the field of research on non-neutral synonymous mutations is still relatively young and evolving rapidly, so it is likely that new insights will be made in the coming years.

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Link to Google Scholar: non-neutral synonymous substitutions for more articles.