The death of the neutral theory of evolution

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"The death of the neutral theory", is a bit provocative, but it does reflect the fact that the neutral theory of molecular evolution has been challenged in recent years. 

On a personal note I believed Kimuras theory since college in biology till the discovery of epigenetics.

The neutral theory of molecular evolution, proposed by Motoo Kimura in 1968, is a theory that explains the high rate of molecular evolution and the large amount of intraspecific variability at the molecular level through random genetic drift, rather than natural selection.

Kimura argued that most mutations are neutral, meaning that they have no effect on the fitness of an organism. These neutral mutations can be fixed in a population by random genetic drift, which is the process by which alleles become more or less frequent in a population due to chance.

The neutral theory has been supported by a number of lines of evidence, including the observation that the rate of molecular evolution is much faster than the rate of phenotypic evolution.

The neutral theory states that most mutations are neutral, meaning that they do not have a significant impact on the fitness of an individual. This is in contrast to the alternative view that most mutations are harmful and are therefore removed from the population by natural (purifying) selection leaving beneficial mutations per "selectionists' holding to NeoDarwinism.

One of the recent main challenges to the neutral theory comes from the fact that non-neutral synonymous mutations (NNSM) exist. Synonymous mutations are mutations that do not change the amino acid sequence of a protein, and they are generally thought to be neutral. However, studies have shown that synonymous mutations can have a significant impact on gene expression, protein folding, and other cellular processes under the term "fitness" as opposed to natural selection. Fitness is at the gene level not the population level as with natural selection. This due to the new Cas9 Crispr genetic engineering tool. It's changed everything.

NNSM challenges the neutral theory from the fact that the Ka/Ks ratio is not always a reliable indicator of the type of selection pressure acting on a gene. The Ka/Ks ratio is the ratio of non-synonymous substitutions to synonymous substitutions. A Ka/Ks ratio greater than 1 is generally thought to be indicative of positive selection, while a Ka/Ks ratio less than 1 is generally thought to be indicative of purifying selection. 

However, studies have shown that the Ka/Ks ratio can be affected by a number of factors, including biased gene conversion and the presence of NNSM. 

Cas9 Crisper NNSM "fitness" measurements invalidates the top natural selection formulas as they depend on nonsynonymous to synonymous ratios.

Exa: Seven top tests based in nonsynonymous versus synonymous substitutions are:

  1. Ka/Ks

  2. Z-test of selection

  3. McDonald-Kreitman test

  4. Neutrality index (NI)

  5. dN/dS ratio

  6. Fay and Wu's H test

  7. Fu and Li's D test

  8. Selection pressure index (SPI)

In short, the evidence suggests that the neutral theory of molecular evolution is not an accurate description of how evolution works. Most mutations are likely to have some impact on fitness, even if that impact is small. 

The implications of this for the field of molecular biology are significant. For example, if the Ka/Ks ratio is not always a reliable indicator of the type of selection pressure acting on a gene, then it may be more difficult to identify genes that are under positive selection. This could make it more difficult to study the evolution of complex traits and diseases.

Overall, the death of the neutral theory is a good thing for science. It means that we are now more aware of the complexity of evolution and the many factors that can influence it. This new understanding will lead to new discoveries and new ways to improve human health and well-being.

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