"Nonsynonymous Synonymous Variants Demand for a Paradigm Shift in Genetics"-review

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The article "Nonsynonymous Synonymous Variants Demand for a Paradigm Shift in Genetics" by Li et al. (2023) discusses the importance of synonymous variants in genetics. Synonymous variants are genetic variations that do not change the amino acid sequence of the protein that is encoded by the gene. They have traditionally been considered to be neutral, meaning that they do not have any effect on the fitness of an individual. However, recent research has shown that synonymous variants can have a variety of effects on gene expression and protein function.

For example, synonymous variants can affect the rate at which mRNA is translated into protein. They can also affect the stability of mRNA and the way that proteins fold. In addition, synonymous variants can interact with other genetic variants to produce different effects.

This new understanding of synonymous variants has led to a call for a paradigm shift in genetics. In the past, geneticists have focused on nonsynonymous variants, which are genetic variations that do change the amino acid sequence of the protein that is encoded by the gene. However, it is now clear that synonymous variants can also play an important role in disease and other traits.

The authors of the article argue that it is important to rethink the way that we interpret genetic data. We need to consider the effects of both synonymous and nonsynonymous variants in order to get a complete picture of the genetic basis of disease and other traits.

This article has important implications for the future of genetics research and clinical practice. By understanding the role of synonymous variants, we may be able to develop new diagnostic tests and treatments for a variety of diseases.

Here are some specific examples of how synonymous variants can affect gene expression and protein function:

  • Synonymous variants can affect the rate at which mRNA is translated into protein by changing the codon usage. Codons are the three-nucleotide sequences that encode amino acids. Some codons are translated more efficiently than others. By changing the codon usage, synonymous variants can affect the amount of protein that is produced.

  • Synonymous variants can affect the stability of mRNA by changing the RNA structure. mRNA molecules are constantly being degraded by the cell. Synonymous variants that destabilize mRNA can lead to decreased protein production.

  • Synonymous variants can affect the way that proteins fold. Protein folding is a complex process that is essential for protein function. Synonymous variants that change the amino acid sequence of a protein can also affect protein folding.

  • Synonymous variants can interact with other genetic variants to produce different effects. For example, a synonymous variant in one gene may interact with a nonsynonymous variant in another gene to increase the risk of disease.

Overall, the article is an important contribution to the field of genetics. It highlights the importance of synonymous variants in gene expression and protein function, and it calls for a paradigm shift in the way that we interpret genetic data.


The article challenges 60 years of natural selection calculations in the following ways:

  • It argues that the traditional model of natural selection, which assumes that nonsynonymous variants are either neutral or deleterious, is inadequate.

  • It presents evidence that synonymous variants can also have significant functional effects, and that these effects can be beneficial or harmful.

  • It suggests that the interaction between synonymous and nonsynonymous variants can play a major role in determining the fitness of an individual.

If these claims are correct, they would have a significant impact on our understanding of natural selection calculations and evolution. For example, it would mean that natural selection is likely to be much more complex and nuanced than we previously thought. It would also mean that traditional methods for calculating selection coefficients may be inaccurate or misleading.

One specific way in which the article challenges natural selection calculations is by arguing that the ratio of nonsynonymous to synonymous substitutions (dN/dS) is not a reliable measure of selection. dN/dS is a commonly used statistic in evolutionary biology, and it is often interpreted as a measure of the strength of purifying selection. However, the article argues that dN/dS can also be influenced by other factors, such as recombination rate and gene expression level. As a result, dN/dS is not a reliable indicator of selection pressure.

Another way in which the article challenges natural selection calculations is by arguing that the fitness effects of nonsynonymous and synonymous variants can be epistatic. This means that the effect of one variant can depend on the presence or absence of other variants. As a result, it is difficult to predict the overall fitness effects of a set of variants based on their individual effects.

The article concludes by calling for a paradigm shift in genetics. It argues that the traditional model of natural selection is no longer adequate, and that we need to develop new models that take into account the complex interactions between synonymous and nonsynonymous variants.

The paper  challenges the assumption of neo darwinism by N/S (dN/dS) equations. This assumption is that synonymous variants (variants in the DNA code that do not change the amino acid sequence of the protein) are neutral, meaning that they have little or no effect on the fitness of the organism. Nonsynonymous variants, on the other hand, are changes in the DNA code that do change the amino acid sequence of the protein, and they can have a wide range of effects on fitness, from beneficial to harmful.

The authors of the paper argue that this assumption is no longer valid, because there is growing evidence that synonymous variants can have significant effects on gene expression and protein function. For example, synonymous variants can affect the stability of mRNA molecules, the efficiency of protein translation, and the folding and structure of proteins. This means that synonymous variants can have a significant impact on the fitness of organisms, and they cannot be ignored when trying to understand the evolution of populations.

The authors also argue that the N/S equation is not a good way to measure the effects of selection on populations. This is because the N/S equation only takes into account the effects of nonsynonymous variants, and it ignores the effects of synonymous variants and other factors that can affect selection.

The authors conclude by calling for a paradigm shift in genetics. They argue that we need to develop new methods for studying the effects of selection on populations that take into account the effects of synonymous variants and other factors. 

As well we need to reevaluate 60 years and 10's of thousands of articles unaware of these findings.

There is still much that we don't know about how synonymous variants affect gene expression and protein function. However, it is clear that synonymous variants are not neutral as we once thought, and they need to be taken into account when trying to understand the evolution of populations.

The paper challenges neo darwinism in several ways.

First, it shows that synonymous variants, which were previously thought to be neutral, can actually have a significant impact on gene expression and protein function. This suggests that the genetic code is more complex than previously thought, and that evolution may be driven by forces other than simply the selection of beneficial mutations.

Second, the paper shows that the rate of synonymous substitutions is much higher than the rate of nonsynonymous substitutions. This is difficult to explain under the neo darwinian model, which predicts that synonymous substitutions should be neutral and therefore should not occur at a higher rate than nonsynonymous substitutions.

Third, the paper shows that synonymous variants can be used to predict the expression of genes more accurately than nonsynonymous variants. This suggests that synonymous variants play an important role in gene regulation, which is a complex process that is not fully understood.

Overall, the paper suggests that neo darwinism needs to be updated or replaced to account for the new findings about synonymous variants. This is a significant challenge, as neo darwinism is the dominant paradigm in evolutionary biology.

These findings suggest that synonymous variants can have a significant impact on the fitness of individuals, and therefore on the course of evolution.

It is important to note that the paper's conclusions suggest that neo darwinism needs to be updated or replaced to account for the new findings about synonymous variants. This is a significant challenge, and it's doubtful neo darwinism can survive in its current form.

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