"Fitness" stands to replace Natural Selection

Motoo Kimura's 1968 article "Evolutionary Rate at the Molecular Level" was one of the first to introduce the Ka/Ks ratio and to discuss its use in inferring selection. The Ka/Ks ratio is a measure of the rate of nonsynonymous mutations (Ka) to synonymous mutations (Ks) in a gene. It is used to infer the selective pressure on a gene, with a higher Ka/Ks ratio indicating greater positive selection.

Kimura argued that the majority of molecular evolution is caused by neutral mutations, which are mutations that do not have a significant effect on the fitness of an individual. 

He believed that less than 6% of mutations fell under NeoDarwinisms random mutations.

Kimura's article had a major impact on the field of evolutionary biology and it led to the widespread adoption of the Ka/Ks ratio as a tool for studying the evolution of genes and genomes. Over 30,000 articles claiming the case for natural selection as measured by the Ka/Ks method have been published since Kimura's article. 

The majority of scientists who are selectionist reject Kimura's neutral theory of evolution, yet use Kimura's own Ka/Ks ratio to establish a selectionist model of selection.

Selectionist scientists use Ka/Ks as a "null" model to calculate a change from neutrality (selection). A Ka/Ks of zero (null hypothesis) indicates no selection so any deviation from zero indicates NeoDarwinian selection.

However, the recent measurement of fitness using Cas9-CRISPR-DMS challenges the Ka/Ks measurement of selection. Cas9-CRISPR-DMS is a technique that can be used to introduce mutations into DNA in a targeted way. This technique has been used to show that many genes that have a high Ka/Ks ratio are actually not essential for fitness. This shows that the Ka/Ks ratio is not a reliable indicator of selection.

Cas9 CRISPR fitness refers to the use of CRISPR-Cas9 technology to identify and characterize genes that are essential for the growth and survival of a cell or organism. This is done by creating a library of CRISPR guide RNAs (gRNAs) that target different genes, and then screening this library to see which genes, when knocked out, cause the cell or organism to be less fit. As such it is the new gold standard for "fitness" not natural selection. One possible explanation for this discrepancy with Cas9 Crispr measurements and that of the Ka/Ks ratio is Ka/Ks is calculated using data from multiple populations, while Cas9-CRISPR-DMS studies are conducted on a single population. Cas9-CRISPR-DMS studies are only detecting selection that is happening in the population that is being studied.

Another explanation is that the Ka/Ks ratio are not a good measure of fitness. For example, it is possible that a gene with a high Ka/Ks ratio is under pressure for reasons other than natural selection.

Overall, the Cas9-CRISPR-DMS technique is a powerful new tool for measuring fitness and has the potential to revolutionize our understanding of genetics by excluding ka/Ks errors. Other reasons to consider when comparing the Ka/Ks ratio to Cas9-CRISPR-DMS.

• The Ka/Ks ratio is a population-level measure, while Cas9-CRISPR-DMS is an individual-level measure. This means that the Ka/Ks ratio  cannot tell us about selection that is happening at the individual level. Cas9-CRISPR-DMS, on the other hand, can tell us about selection that is happening at the individual level.

•  Cas9-CRISPR-DMS is a measure of fitness at the individual level. This means that the Ka/Ks ratio cannot tell us how important that gene is for fitness. Cas9-CRISPR-DMS, on the other hand, can tell us how important a gene is for fitness.

• Cas9-CRISPR-DMS is a measure of selection at a single point in time. This means that the Ka/Ks ratio cannot tell us about selection that is happening right now. 

Kimura's theory depends on mostly neutral mutations and genetic drift.

Genetic drift is a random change in the genes of a population over time. It is more likely to happen in small populations, where some alleles may be lost by chance. Genetic drift can lead to the loss of alleles, which can reduce genetic diversity and increase the risk of extinction. It can also lead to the fixation of alleles, meaning that a particular allele becomes the only allele present in the population.

Genetic drift is one of the forces that drives change, but it is important to note that it is random and does not necessarily lead to changes that are beneficial to the population. However, over time, genetic drift can lead to significant changes in the genetic makeup of a population. As such it is not controlled by natural selection.

Here is an analogy:

Imagine a jar of marbles, with some red and some blue. The red marbles represent one allele, and the blue marbles represent another allele. If you randomly draw a small handful of marbles from the jar, the allele frequencies in the handful of marbles may not be the same as the allele frequencies in the entire jar.

Genetic drift is like randomly sampling marbles from a jar. It is a random process that can lead to changes in allele frequencies in a population without NeoDarwinism.

Epigenetics, codon bias, GC bias, and AT mutation bias can all affect genetic drift in a major way. Kimura's work was posited before the discovery of these factors.

Epigenetics is the study of how gene expression is regulated without changes to the DNA sequence as opposed to NeoDarwinian random mutations. Epigenetic changes can be inherited, and they can influence the expression of genes for generations. Epigenetic changes can overcome genetic drift by stabilizing gene expression patterns, even in the face of random mutations.

For example, epigenetic changes can be used to silence genes that are harmful or to activate genes that are beneficial. This can help to maintain the fitness of a population by biasing mutations. 

Codon bias is the preferential use of certain codons over others, even when the codons code for the same amino acid. Codon bias can vary between species and between different genes within the same species. 

Note the GC bias in the left column

Codon bias can overcome genetic drift by influencing the rate of translation and the stability of mRNA. Genes that are biased towards codons that are highly abundant in the cell are more likely to be translated efficiently and accurately.

GC bias is the preferential use of guanine (G) and cytosine (C) nucleotides over adenine (A) and thymine (T) nucleotides. GC bias can vary between species and between different regions of the genome within the same species. GC bias can overcome genetic drift by making certain regions of the genome more resistant to mutation. GC-rich regions are less likely to mutate to AT-rich regions, and vice versa.

AT mutation bias is the tendency of AT nucleotides to mutate more frequently than GC nucleotides. This is because AT nucleotides are more likely to be deaminated. This is because a methyl group is placed on a cytosine epigenetically which can spontaneously convert a C to T thus forming an AT pair. AT mutation bias can be overcome by GC bias, as GC-rich regions are less likely to mutate to AT-rich regions.

It is important to note that epigenetics, codon bias, GC bias, and AT mutation bias can all interact with each other in complex ways. For example, epigenetic changes can influence codon bias, and codon bias can influence GC bias. As a result, it is difficult to isolate the effects of each of these factors on genetic drift.

Overall, epigenetics, codon bias, GC bias, and AT mutation bias can all play a role in overcoming genetic drift. These factors can help to stabilize gene expression patterns, influence the rate of translation, and protect important genes from harmful mutations.

Epigenetics, codon bias, GC bias, and AT mutation bias are all important factors that can influence the evolution of organisms. By overcoming genetic drift, these factors can help to ensure that organisms can maintain their fitness and adapt to changing conditions.

In summary, kimura's theory needs extension to include it in an extended model of evolution whereas neo Darwinism needs outright replacement.