It's the "fittest" that thrive not the "survival of the fittest" that guides evolution

The vast majority of natural selection calculations rely on nonsynonymous to synonymous calculations. 

This is because for 60 years this axiom of NeoDarwinism thought synonymous mutations were neutral, meaning that they do not affect the fitness of an organism. Therefore, the ratio of nonsynonymous to synonymous mutations (e.g., Ka/Ks) can be used to estimate the strength of natural selection acting on a gene.

Non-neutral synonymous mutations have a significant impact on natural selection calculations. 

For example, if a gene is under strong purifying selection, then the Ka/Ks ratio will be low. However, if the gene is under relaxed purifying selection, or even positive selection, then the Ka/Ks ratio will be higher. Therefore, if non-neutral synonymous mutations are present in a gene, then the Ka/Ks ratio will not be an accurate estimate of the strength of natural selection.

In this article "The distribution of fitness effects among synonymous mutations in a gene under directional selection" by Lebeuf-Taylor et al. (2019): the authors point out that the 60 year old axiom of neutral synonymous substitution is nullified ergo measurements of evolution by nonsynonymous to synonymous mutations are simply wrong.

Synonymous mutations are nucleotide changes that do not alter the encoded amino acid. They have traditionally been assumed to be neutral, meaning that they have no effect on the fitness of an organism. However, a growing body of evidence suggests that synonymous mutations can have non-neutral effects on fitness. These effects can be either deleterious or beneficial, and they can vary in magnitude. 

The article by Lebeuf-Taylor et al. investigated the distribution of fitness effects among synonymous mutations in a gene under directional selection. Directional selection is a consistent pressure for one particular allele to increase in frequency in a population. The authors used site-directed mutagenesis to introduce synonymous mutations into the gene and then measured the fitness of the resulting mutant strains. They found that synonymous mutations had a wide range of fitness effects, from strongly deleterious to strongly beneficial.

The authors also found that the distribution of fitness effects was not symmetrical. There were more deleterious synonymous mutations than beneficial ones. The authors suggest that the non-neutral effects of synonymous mutations can be explained by their effects on gene expression and protein structure. Synonymous mutations can alter the efficiency of gene expression or the stability of protein structure, both of which can have a negative impact on fitness. The authors' findings have important implications for our understanding of evolution. They suggest that synonymous mutations can play a role in adaptation, even though they do not alter the amino acid sequence of a protein.

This severs the term "survival of the fittest" to the actual "fitness" on the individual nucleotide, cellular and organism level not the population level where natural selection is proposed.

Here is a more detailed explanation of the different ways that synonymous mutations can affect fitness:

• Effects on gene expression: Synonymous mutations can alter the efficiency of gene expression by affecting the splicing of RNA transcripts, the binding of transcription factors, or the stability of mRNA molecules.

• Effects on protein structure: Synonymous mutations can alter the stability of protein structure by changing the folding pattern of the protein or by creating new or destabilizing interactions between amino acids.

• Effects on protein function: Synonymous mutations can alter the function of a protein by changing its binding affinity for other molecules, its enzymatic activity, or its ability to interact with other proteins.

The relative importance of these different mechanisms for affecting fitness is still not fully understood. However, it is clear that synonymous mutations can have a significant impact on the fitness of an organism, even though they do not alter the amino acid sequence of a protein.

The article by Lebeuf-Taylor et al. is an important contribution to our understanding of the evolution of genes. Their findings suggest that synonymous mutations can play a role in adaptive evolution, even though they have traditionally been assumed to be neutral. This finding has implications for our understanding of how genes evolve and how they contribute to the fitness of organisms.

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Snippets

The distribution of fitness effects among synonymous mutations is highly variable, both deleterious and beneficial, resembling those of nonsynonymous mutations in the same gene. This is surprising because synonymous mutations do not change the amino acid sequence of the protein, so they were previously thought to be neutral with respect to fitness.

The mechanisms underlying the fitness effects of synonymous mutations are not fully understood, but they may include:

• Codon usage bias: Synonymous mutations can change the codon usage of a gene, which can affect the rate and efficiency of translation.

• mRNA structure: Synonymous mutations can also affect the secondary structure of the mRNA transcript, which can also affect translation.

• Transcription: Synonymous mutations can also create or destroy promoter sequences, which can affect the rate of transcription of the gene.

The authors of the study found that the fitness distribution of synonymous mutations in the gene gtsB was indistinguishable from the fitness distribution of nonsynonymous mutations in the same gene. This suggests that synonymous mutations can contribute to adaptation just as much as nonsynonymous mutations.

The authors also found that the fitness effects of synonymous mutations were not correlated with codon usage bias or mRNA stability. This suggests that the fitness effects of synonymous mutations are likely due to changes in transcription.

The authors conclude by saying that the assumption that synonymous mutations are neutral is deeply embedded in genetics, but their work shows that this assumption is not always true. Synonymous mutations can have a wide range of fitness effects, both deleterious and beneficial, and they can contribute to adaptation.

This is an important finding because it suggests that we need to be more careful when interpreting the results of studies that rely on the assumption that synonymous mutations are neutral. For example, if we are trying to identify genes that are under selection, we need to be aware that synonymous mutations in those genes could also be under selection.