"Fitness" from Darwin to CRISPR

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Only 20 standard amino acids are used to synthesize proteins because these are the amino acids that are directly encoded by the genetic code. The genetic code is a set of rules that specifies which amino acid corresponds to each codon, which is a sequence of three nucleotides. There are 64 possible codons, but only 20 of these codons specify amino acids. The other codons either signal the start or stop of translation or are used to regulate translation.


The precise reason why there are only 20 standard amino acids remains a topic of ongoing scientific debate till now. 

The genetic code is redundant, meaning that more than one codon can code for the same amino acid. 

Francis Crick called the genetic code a "frozen accident" because he believed that it was unlikely that the code was designed. Crick argued that the code is more likely the result of random mutations that have accumulated over time. However, some researchers have argued that the redundancy of the code is evidence of some degree of design. They argue that the redundancy helps to protect against errors and allows for efficient translation, which suggests that the code has been optimized for its function.

The debate over whether the genetic code is a frozen accident or a product of design is being settled recently. There is no doubt that the code is a remarkable and complex system that plays a vital role in life.

Francis Crick, one of the co-discoverers of the structure of DNA, argued that the redundancy of the genetic code, meaning that multiple codons can specify the same amino acid, is evidence for neutral evolution. 


Neutral evolution is the idea that some genetic changes are neither beneficial nor harmful, and therefore have no effect on an organism's fitness.

Crick argued that if all codons were equally important, then there would be no reason for the genetic code to be redundant. The fact that multiple codons can specify the same amino acid suggests that some codons are more important than others, and that mutations that change one codon to another may have little or no effect on an organism's fitness. This, he argued, is evidence for neutral evolution. Crick's argument was controversial when he first proposed it. 

Recently, the evidence suggests that Crick was wrong in his assertion that the redundancy of the genetic code is evidence for neutral evolution. Neutral evolution, once widely accepted, has been turned over in the last year.

Motoo Kimura, a Japanese geneticist, developed the Ka/Ks ratio in the 1970s to measure the strength of natural selection acting on protein-coding genes. The ratio is calculated as the number of non-synonymous substitutions (Ka) per non-synonymous site divided by the number of synonymous substitutions (Ks) per synonymous site. Synonymous substitutions are mutations that do not change the amino acid sequence of the protein, while non-synonymous substitutions do.


The Ka/Ks ratio has been used in tens of thousands of journal articles to infer natural selection. It was thought to be a powerful tool for understanding the evolutionary history of genes and for identifying genes that are important for adaptation.

The Ka/Ks ratio was a widely used  tool for evolutionary biologists.

Several recent studies have shown that synonymous substitutions, which are changes in the DNA sequence that do not change the amino acid sequence of a protein, are strongly non neutral as previously thought. This has implications for our understanding of evolution and for the use of Ka/Ks ratios, which are a measure of evolutionary selection.

The finding that synonymous substitutions are not neutral has led scientists to realize the use of Ka/Ks ratios as a measure of evolutionary selection is inaccurate. This is because synonymous substitutions can affect gene expression and other aspects of protein function, even though they do not change the amino acid sequence. NeoDarwinian dependence on amino acid sequence is not the whole story.

The finding that synonymous substitutions are not neutral is a significant development in our understanding of evolution. It will have a significant impact on our use of Ka/Ks ratios and other methods to measure evolutionary selection.

CRISPR-Cas9 technology allows for direct measurement of fitness at the nucleotide level, providing a more granular perspective on fitness compared to natural selection ratios like Ka/Ks. Natural selection ratios reflect the overall fitness of a gene or protein, but they don't capture the nuanced effects of individual nucleotides. Plus the equations do not take nonneutral synonymous substitutions into account.


CRISPR-Cas9's ability to precisely introduce mutations at specific nucleotides enables scientists to evaluate the impact of these changes on gene function and organismal fitness. This approach has revealed that even subtle nucleotide alterations can have significant consequences for fitness. For instance, studies have demonstrated that single nucleotide polymorphisms (SNPs) can influence susceptibility to diseases, drug response, and various biological processes.

By delving into the fitness landscape at the nucleotide level, CRISPR-Cas9 has expanded our understanding of how genetic variation contributes to fitness and evolution. It has also opened up new avenues for investigating the molecular basis of complex traits and developing personalized medicine strategies.

The article  "Nonsynonymous Synonymous Variants Demand for a PARADIGM SHIFT in Genetics" suggests that there is a need to reconsider some of the fundamental principles of genetics, including how we classify genetic variations and how we study evolution.

One of the key points raised in the statement is that our current methods for calculating the rate of natural selection (Ka/Ks) is inaccurate. This is because nonsynonymous synonymous variants (NSVs) - genetic variations that change the amino acid sequence of a protein - are often assumed to be neutral, meaning that they have no effect on the fitness of an organism. However, NSVs actually have a significant impact on fitness.

If NSVs are not neutral, then our current estimates of the rate of natural selection are incorect. This is because we are not taking into account the effects of NSVs on fitness. As a result, we are wrongly estimating the importance of natural selection in evolution.

The authors also suggests that we need to reconsider how we classify genetic variations. NSVs are currently classified as either synonymous or nonsynonymous, depending on whether or not they change the amino acid sequence of a protein. However, this classification system does not take into account the fact that NSVs can have different effects on fitness.

If we want to develop a more accurate understanding of evolution, we need to develop new ways of classifying genetic variations. These new classifications should take into account the effects of genetic variations on fitness.

The authors concludes by calling for a paradigm shift in genetics. This suggests that we need to fundamentally change the way we think about genetics. We need to be more open to new ideas and we need to be willing to challenge our current understanding of how genes work.

Overall, the statement is a call to action for geneticists. It suggests that we need to take a fresh look at some of the fundamental principles of genetics and that we need to be open to new ideas. If we do this, we may be able to develop a more accurate understanding of evolution.

As this article concludes "There is a need to evaluate and reflect principles of numerous aspects in genetics, ranging from variation naming and classification to evolutionary calculations."

60 years of natural calculations are wrong.

Darwin would no doubt approve. If only neodarwinist's would.

Ref:

https://pubmed.ncbi.nlm.nih.gov/37920730/

https://www.nature.com/articles/s41579-023-00864-8

https://www.nature.com/articles/s41586-022-04823-w

https://www.nature.com/articles/d41586-022-01091-6


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