The "Drift" of Kimuras "Genetic Drift"

Genetic drift was first proposed by Motoo Kimura, a Japanese population geneticist, in 1968. Kimura's "neutral theory of molecular evolution" challenged the prevailing view at the time, which held that natural selection was the primary driving force of evolution. Kimura argued that most genetic variation is the result of neutral mutations, which have no effect on an organism's fitness. As a result, genetic drift, the random fluctuation of allele frequencies in a population, can play a significant role in evolutionary change.

The belief that most mutations are neutral has been disproven this last year due to the miracle of the Cas9 CRISPR system. If most mutations are not neutral as Kimura assumed there would be no reason to invoke genetic drift as spreading so-called neutral mutations. This writter believed Kimura from the late 70's till last year.

Ironically most biologists were not "neutralists" rather "selectionists" after Darwin. However the vast majority of them used kimuras formula (eg Ka/Ks) to "calculate" the rate of (positive) natural selection (Ka/Ks>0) apart from Kimura's null model of neutrality e.g. Ka/Ks =0. So while rejecting Kimura the "selections" in essence accepted him.

In the last year the Cas9 CRISPR system disproved Kimura and as a result the majority of "selectionists" that used kimura's formulas. Tens of thousands of articles were written from 1970- 2020 claiming "measured" natural selection based on Ka/Ks or one of 9 derivations of this formula. 

Non neutrality of mutations aside other factors over the last 20 years have also disproved his views on genetic drift.

NonDarwinian GC bias, or the preferential conversion of A and T nucleotides to G and C nucleotides during DNA repair, counteracts the effects of genetic drift, which is the random fluctuation of allele frequencies in a population. This can occur through two main mechanisms:

1. Reducing the loss of rare alleles: GC bias can help to preserve rare alleles by favoring their conversion to the more stable G and C nucleotides. This is because AT base pairs are more prone to deamination, which can lead to the loss of the A or T nucleotide. By converting these unstable AT base pairs to GC base pairs, GC bias can help to maintain the genetic diversity of a population without genetic drift.

2. Increasing the fixation of beneficial alleles: GC bias can also promote the fixation of beneficial alleles by favoring their conversion to the more stable G and C nucleotides. This is because beneficial alleles are often associated with higher GC content. By increasing the GC content of beneficial alleles, GC bias can make them more resistant to genetic drift and increase the likelihood that they will become fixed in the population.

Overall, GC bias can play an important role in maintaining genetic diversity and promoting the fixation of beneficial alleles and reducing genetic drift. It reduces the possibility of genetic drift. GC bias was discovered 30 years after genetic drift was proposed by kimura. Had Cas9 CRISPR and GC bias been known to Kimura's "neutral theory" with genetic drift would have looked dramatically different.

Mutation bias is a NonDarwinian mechanism that can reduce genetic drift by decreasing the likelihood of deleterious mutations occurring in functionally important regions of the genome. This is because mutation bias can lead to a higher proportion of mutations occurring in non-coding regions or in regions that are less important for gene function. As a result, there is a lower chance of mutations occurring that could have a negative impact on the organism's fitness, which would otherwise be more likely to be fixed in the population due to genetic drift.

Recall genetic drift proposes a random process that can lead to the loss of genetic variation and the fixation of deleterious alleles. It's proposed to be more likely to occur in small populations, where there is a smaller pool of alleles to sample from. Mutation bias can help to counteract this effect by reducing the overall mutation rate and by biasing mutations away from functionally important regions of the genome. This can help to protect populations from the effects of genetic drift and to maintain genetic variation.

Overall, mutation bias can play an important role in reducing genetic drift and in maintaining genetic variation. This is particularly important for small populations, which are more vulnerable to the effects of genetic drift.

GC bias is a non-Darwinian mechanism that causes codon bias. This means that it is not the result of natural selection, but rather is due to other factors, such as the efficiency of DNA repair. Codon bias is the non-random usage of synonymous codons, which are codons that encode the same amino acid. This bias is thought to be caused by a combination of factors, including GC bias the availability of tRNAs, the efficiency of translation, and the accuracy of transcription. Codon bias can have a significant impact on NonDarwinian fitness of an organism, and it is thought to play a role in a number of processes, including adaptation, speciation, and extinction.

One of the ways in which codon bias can affect the fitness of an organism is by reducing the effects of genetic drift. 

Codon bias can reduce the effects of genetic drift by making it more difficult for mutations to be fixed in a population. This is because mutations that change the codon usage of a gene are more likely to be deleterious than mutations that do not. As a result, mutations that change codon usage are more likely to be eliminated  and the overall level of codon bias in a population is more likely to remain constant.

As a result, codon bias can lead to the fixation of mutations that would otherwise be deleterious, and it can also lead to the acceleration of the rate of gene adaptation. These effects can have a significant impact on the fitness of an organism, and they can ultimately lead to adaptation, speciation, and extinction and reduction of genetic drift.

Synonymous substitutions are mutations that do not change the amino acid sequence of a protein, and they are generally considered to be neutral. However, nonneutral synonymous substitutions can have a significant impact on genetic drift. They've been recently discovered using the Cas9 CRISPR system.

Nonneutral synonymous substitutions can have an impact on genetic drift in two main ways:

1. By altering the codon usage bias of a gene. Nonneutral synonymous substitutions can alter the codon usage bias of a gene, which can in turn affect its fitness. This can counteract the effects of genetic drift.

2. By affecting the expression of a gene. Synonymous substitutions can sometimes affect the expression of a gene, even though they do not change the amino acid sequence of the protein. This can happen if the substitution changes the stability of the mRNA or the efficiency of translation. If a synonymous substitution affects the expression of a gene, this can also counteract the effects of genetic drift.

In addition to these two main mechanisms, nonneutral synonymous substitutions can also have a more indirect impact on genetic drift. For example, they can affect the linkage disequilibrium between genes, which can in turn affect the rate of recombination. This can make it more or less likely that certain alleles will be inherited together, which can also affect the rate of evolution.

Overall, nonneutral synonymous substitutions can have a complex and significant impact on genetic drift. They can counteract the effects of drift, and they can also affect the rate of evolution. As a result, they are an important factor to consider when studying the evolution of populations.

It's important to recall Kimura first proposed genetic drift to explain the spread of neutral mutations without Darwin. Now we know these mutations are not neutral; the need for the theory of drift is negated. But even then what drift might survive are mitigated by the non darwinian factors of GC bias, mutation bias, codon bias and in neutral synonymous substitution all of which were discovered years after kimura proposed his model. 

Admittedly Kimura had a great 50 year run. No doubt Kimura would have loved the Cas9 CRISPR system. His theory would likely have been called the "non-neutral NonDarwinian theory of molecular evolution."