Natural Selection- not fit to measure


The Ka/Ks ratio was developed by a number of scientists over the years, including:

  • Motoo Kimura (1924-1994), a Japanese population geneticist who is considered the father of molecular evolution.

  • Jack McDonald (born 1949), an American evolutionary biologist who developed the McDonald-Kreitman test, which is used to identify genes that are under positive selection.

  • Ziheng Yang (born 1962), a Chinese-American evolutionary biologist who developed a number of methods for estimating the Ka/Ks ratio.

  • Laurence Hurst (born 1962), a British evolutionary biologist who wrote a review article on the Ka/Ks ratio in 2002.

The Ka/Ks ratio is a measure of the relative rates of synonymous and nonsynonymous substitutions in a gene or genome. Synonymous substitutions are those that do not change the amino acid sequence of the protein encoded by the gene, while nonsynonymous substitutions do change the amino acid sequence.

A high Ka/Ks ratio indicates that a gene is under positive selection, meaning that it is evolving rapidly in response to environmental or ecological pressures. A low Ka/Ks ratio indicates that a gene is under purifying selection, meaning that it is evolving slowly to prevent harmful mutations. A Ka/Ks ratio of 1 indicates that a gene is evolving neutrally, meaning that it is not under any selective pressure.

According to a search on PubMed, there are over 30,000 articles that have used the Ka/Ks ratio. The earliest article that used the Ka/Ks ratio was published in 1997. The number of articles using the Ka/Ks ratio has been increasing steadily. Till now…

The Ka/Ks ratio can be biased by factors such as the mutation rate and the effective population size.

The deep mutational index (DMI) is a more recent measure of fitness that is not affected by these biases. It is calculated by measuring the number of mutations that are tolerated at each position in a gene. The DMI is becoming increasingly popular as a measure of fitness, and it is likely to replace the Ka/Ks ratio in many applications.

Here are some of the advantages of the DMI over the Ka/Ks ratio:

  • The DMI is not biased by the mutation rate or the effective population size.

  • The DMI can be calculated for genes of any length.

However, the DMI is more technically challenging to measure than the Ka/Ks ratio.

Overall, the DMI is a more powerful and accurate measure of fitness than the Ka/Ks ratio. This article shows why.

The article "Synonymous mutations in representative yeast genes are mostly strongly non-neutral" by Shen et al. (2022) has profound implications.

The genetic code is the set of rules that specifies how the sequence of nucleotides in DNA is translated into the sequence of amino acids in proteins. Synonymous mutations are changes in the DNA sequence that do not alter the amino acid sequence of the protein. They are therefore often thought to be neutral, meaning that they have no effect on the fitness of the organism. This is an axiom of NeoDarwinism.

However, the study by Shen et al. (2022) challenges this assumption. They used a technique called deep mutational scanning versus the Ka/Ks ratio to identify and characterize the effects of thousands of synonymous mutations in 21 yeast genes generating a library of mutant genes. This was done using CRISPR-Cas9 genome editing which is a new incredibly accurate method eclipsing past methods in particular the Ka/Ks ratio.

They found that most of these mutations (75%) had a significant negative effect on fitness that the Ka/Ks ratio ignored, and that the distribution of fitness effects was similar for synonymous and nonsynonymous mutations which violates NeoDarwinian theory.

The authors suggest that the strong non-neutrality of synonymous mutations is due to a number of factors, including:

  • The impact of synonymous mutations on mRNA expression. Synonymous mutations can alter the structure of the mRNA molecule, which can affect its stability and translation efficiency.

  • The impact of synonymous mutations on the folding and stability of the protein. Synonymous mutations can change the properties of the amino acids in the protein, which can affect its folding and stability. This particularly affects Intrinsically Disordered Proteins that make up the majority of proteins.

  • The impact of synonymous mutations on the interactions between the protein and other molecules. Synonymous mutations can change the properties of the protein's binding sites, which can affect its interactions with other molecules, such as other proteins, DNA, and RNA.

The findings of this study have important implications for our understanding of evolution and disease. They suggest that synonymous mutations are not always neutral as assumed under neodarwinism, and that they can have a significant impact on the fitness of organisms. This could lead to a major re-evaluation of the role of synonymous mutations in evolution, and could also have implications for our understanding of the genetic basis of disease. In addition those 30,000 studies over the last couple decades using the Ka/Ks ratio to declare natural selection are suspect.

In addition to the factors mentioned above, there are a few other possible explanations for the strong non-neutrality of synonymous mutations. One possibility is that some synonymous mutations can lead to the accumulation of genetic changes that are harmful to the organism. This is because synonymous mutations can create new genetic variation. Another possibility is that some synonymous mutations can have a pleiotropic effect, meaning that they affect multiple different genes or proteins. This could lead to a complex series of interactions that have a negative impact on the organism's fitness.

The study by Shen et al. (2022) is an important contribution to our understanding of the impact of synonymous mutations on evolution and disease. It raises a number of new questions that need to be addressed, but it also provides a valuable starting point for further research in this area.

Summary:

  • The study was conducted in yeast, but the authors suggest that the findings may be generalizable to other organisms.

  • The study focused on synonymous mutations in protein-coding genes. It is possible that synonymous mutations in non-coding genes may have different effects on fitness.

  • The study used a technique called deep mutational scanning, which is a powerful method for identifying and characterizing the effects of mutations. 

Overall, the study by Shen et al. (2022) provides strong evidence that synonymous mutations are not always neutral. This has important implications for our understanding of evolution especially old techniques for calculating natural selection. It will be important to further investigate the mechanisms by which synonymous mutations can affect fitness.

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