Evolutionary Ka/Ks ratios have been wrong for over 50 years.

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The Ka/Ks ratio, also known as omega (ω) or dN/dS, is a metric used in evolutionary biology to estimate the selective pressure acting on protein-coding genes. It compares the rates of non-synonymous substitutions (amino acid changes) to synonymous substitutions (silent mutations).

Over the last 50 years 30,000 papers used the Ka/Ks ratio to infer natural selection Mathematically.


Here's a breakdown of how it works:

  •  Ka: Represents the number of non-synonymous substitutions per non-synonymous site.

  •  Ks: Represents the number of synonymous substitutions per synonymous site.

By comparing these rates, the Ka/Ks ratio provides insights into the evolutionary forces shaping a gene:

  •  Ka/Ks > 1: Suggests positive selection, where beneficial mutations are favored, leading to a faster rate of amino acid changes.

  •  Ka/Ks = 1: Suggests neutral evolution, where mutations are neither beneficial nor detrimental.

  •  Ka/Ks < 1: Suggests purifying selection, where deleterious mutations are removed, leading to a slower rate of amino acid changes.


In the recent field of molecular biology, synonymous substitutions are point mutations in a gene's DNA that don't change the amino acid sequence of the protein it codes for. These substitutions were traditionally thought to be neutral, meaning they have no effect on the organism. However, recent research suggests that upwards of 75%  of synonymous substitutions can have non-neutral effects, potentially impacting evolutionary calculations, protein folding, stability, or function.


Nonneutral synonymous substitutions can affect Ka/Ks ratios in several ways, leading to misinterpretations of evolutionary pressure:

  1. Overestimation of selective pressure: If synonymous sites are under weak purifying selection, substitutions may occur at a higher rate than truly neutral sites. This can inflate Ks and underestimate Ka/Ks, making it appear that purifying selection is stronger than it actually is.

  2. Underestimation of selective pressure: Conversely, if synonymous sites are functionally important, substitutions may be less frequent than expected at neutral sites. This can deflate Ks and overestimate Ka/Ks, leading to an underestimation of purifying selection.

  3. Selection for translational efficiency: Selection can favor synonymous codons that are more efficiently translated, even if the encoded amino acid remains the same. This can lead to an increase in Ks and a decrease in Ka/Ks.

  4. Codon bias and GC content: The overall bias in codon usage and GC content can influence synonymous substitution rates. This can complicate the interpretation of Ka/Ks ratios, as it may not solely reflect selection pressure on protein function.

  5. Gene conversion: Gene conversion events can homogenize sequences between paralogs, affecting synonymous and nonsynonymous sites equally. This can lead to an artificial reduction in both Ka and Ks, making it difficult to infer selection pressure.

  6. Relaxed selection on functionally similar genes: In some cases, synonymous substitutions may be tolerated in functionally similar genes that experience relaxed purifying selection. This can also lead to an overestimation of Ks and an underestimation of Ka/Ks.

  7. Errors in phylogenetic reconstruction: Inaccurate phylogenetic reconstructions can lead to misinterpretations of synonymous and nonsynonymous substitution rates. This can distort the Ka/Ks ratio and hinder inferences about evolutionary selection.


This recent research suggests that synonymous mutations are not always neutral. They can sometimes influence RNA folding or protein-protein interactions, potentially impacting gene function. This challenges the assumption of the Ka/Ks ratio, as it can lead to misinterpretations of selection pressures.

Neo-Darwinism emphasizes the role of natural selection in evolution. If synonymous substitutions are not truly neutral, it adds complexity to how we interpret evolutionary changes detected by the Ka/Ks ratio.


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