30 years of Natural Selection (Ka/Ks) down the drain


The Ka/Ks ratio, also known as the ω or dN/dS ratio, is a measure of the balance between neutral mutations, purifying selection, and beneficial mutations acting on a set of homologous protein-coding genes. It is calculated as the ratio of the number of nonsynonymous substitutions per non-synonymous site (Ka), in a given period of time, to the number of synonymous substitutions per synonymous site (Ks), in the same period. The latter are assumed to be neutral, so that the ratio indicates the net balance between deleterious and beneficial mutations.

  • A ratio greater than 1 implies positive or Darwinian selection (driving change);

  • Less than 1 implies purifying or stabilizing selection (acting against change);

  • A ratio of exactly 1 indicates neutral (i.e. no) selection.

The Ka/Ks ratio is a post hoc measure of selection. This means that it can only be used to infer the presence of selection after it has already occurred. 

The reason why the Ka/Ks ratio is post hoc is that it is based on the number of substitutions that have already occurred. It cannot be used to predict whether or not selection will occur in the future. Here are some of the limitations of the Ka/Ks ratio:

  • It is only a measure of selection at the amino acid level. It cannot be used to assess selection at the nucleotide level.

  • It is sensitive to the divergence time between the two genes being compared.

  • It can be affected by the presence of neutral polymorphisms.

According to a 2018 study, there were over 10,000 papers that used the Ka/Ks ratio to study protein evolution. The study, which was published in the journal Molecular Biology and Evolution, analyzed the use of the Ka/Ks ratio in papers published between 1990 and 2017. The study found that the use of the Ka/Ks ratio has increased significantly over time, with the number of papers using the ratio increasing by an average of 13% per year. 

Synonymous mutations can also have a negative impact on fitness, even if they do not change the amino acid sequence. For 30 years they were assumed to be neutral.  This is because synonymous mutations can alter the expression of the gene, or they can disrupt the binding of regulatory proteins. As a result, the ka/ks ratio can overestimate the amount of selective pressure on a gene.

A study published in 2015 found that synonymous mutations can account for up to 40% of the fitness costs of deleterious mutations. This means that the ka/ks ratio can be up to 40% too high when estimating the selective pressure (ie natural selection) on a gene.

Codon bias is the preferential use of certain codons over others to encode the same amino acid. This can occur for a variety of reasons, including the availability of tRNA molecules that carry the specific amino acid, the efficiency of translation, and the stability of the resulting protein.

Codon bias invalidates the ka/ks ratio because it can affect the efficiency of translation. If a protein is encoded by codons that are inefficiently translated, then the folded protein will be less stable than if it were encoded by codons that are efficiently translated.

This is because the efficiency of translation can affect the folding rate of proteins. If a protein is translated inefficiently, then it will take longer for the protein to fold. This gives the unfolded protein more time to interact with other unfolded proteins, which can lead to the formation of aggregates. Aggregates are unstable and can lead to the degradation of proteins.

Therefore, codon bias can invalidate the ka/ks ratio because it can affect the efficiency of translation, which in turn can affect the stability of proteins.

In addition, codon bias can also affect the ka/ks ratio by influencing the stability of the mRNA transcript. For example, if a transcript is encoded by codons that are inefficiently translated, then it will be more likely to be degraded by RNAse enzymes. This can lead to a decrease in the amount of folded protein that is produced, which can also lower the ka/ks ratio.

Overall, codon bias can have a significant impact on the ka/ks ratio. This is because it can affect both the efficiency of translation and the stability of the mRNA transcript. As a result, ka/ks ratios that are calculated for proteins that are encoded by codons with different degrees of bias may not be comparable.

In short 30 years of calculating natural selection down the drain just to prop up a 170 years old theory by a Victorian naturalist.


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