The migration from Random mutations to Non random "substitutions" is yet another challenge to NeoDarwinism.

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"It is doubtful, however, whether even the most statistically minded geneticists are entirely satisfied that nothing more is involved than the sorting out of random mutations by the natural selective filter." - Conrad Waddington, father of Epigenetics

The order from most to least common causes of DNA substitutions (mutations) are:

  1. gBGC GC bias:50-60%.

  2. AT mutation bias:20-30%.

  3. DNA polymerase substitution guided by epigenetics:10-20%.

  4. Random mutations by DNA polymerases: 5-10%.

  • gBGC GC bias 

GC-biased gene conversion (gBGC) is the most common cause of DNA substitutions. It is a natural molecular force that favors GC over AT alleles irrespective of their fitness effect. gBGC occurs during meiotic recombination, when DNA is exchanged between homologous chromosomes. During this process, there is a bias towards the repair of mismatches in favor of GC bases. This can lead to a gradual increase in the GC content of a genome over time.

gBGC has been shown to be a major factor in shaping the GC content of genomes in a wide range of organisms, from bacteria to humans. It is also the most common cause of DNA substitutions in both coding and non-coding regions of the genome.

There are a number of factors that can influence the strength of gBGC in a given genome, including the effective population size, the recombination rate, and the presence of recombination hotspots. However, even in genomes with relatively weak gBGC, it is still the most common cause of DNA substitutions.

Here are some examples of how gBGC can lead to DNA substitutions:

  • If a GC/AT heterozygote undergoes gBGC, the GC allele is more likely to be fixed in the offspring. This can lead to a gradual increase in the frequency of GC alleles in the population.

  • If a GC/AT heterozygote undergoes gBGC in a coding region, the amino acid sequence of the protein may be changed. This can have a variety of effects on the protein's function, including both beneficial and deleterious effects.

  • gBGC can also lead to the formation of pseudogenes, which are copies of genes. This can happen if a gene is disrupted by a recombination event and the gBGC process repairs the damage in such a way that the gene is able to find new functions.

Overall, gBGC is a powerful natural cellular force that can have a significant impact on the DNA sequence and gene content of genomes. It is not a random process per NeoDarwinism rather it has a biased function.

  • AT mutation bias 

AT mutation bias is the second most common cause of DNA substitutions. It is a process that occurs when adenine (A) and thymine (T) nucleotides are more likely to be substituted than guanine (G) and cytosine (C) nucleotides.

AT mutation bias is thought to be due to a number of factors, including:

  • The chemical structure of DNA: A and T nucleotides are more likely to deaminate, which is a chemical reaction that converts one nucleotide into another. It's estimated that it could be as high as 50% in some cases.

Deamination of cytosine converts it to thymine, and deamination of methylcytosine converts it to uracil, which is similar to thymine. Approximately 10% of AT mutation bias is due to deamination of cytosine to thymine.

  • DNA repair mechanisms: DNA repair mechanisms are more efficient at repairing mutations that affect G and C nucleotides than mutations that affect A and T nucleotides.

AT mutation bias can have a number of important consequences for change and human health. For example, it can lead to the development of genetic diseases, such as cystic fibrosis and sickle cell anemia. It can also contribute to the development of new genes and the loss of existing genes.

  • DNA polymerase substitution guided by epigenetics 


DNA polymerase substitution guided by epigenetics is the third most common mutation. It is a process that occurs when DNA polymerase, the enzyme that copies DNA during replication, is more likely to make mistakes in regions of the genome that are epigenetically modified.

Epigenetic modifications are changes to DNA that do not alter the DNA sequence itself, but can affect how the DNA is expressed. One type of epigenetic modification is called DNA methylation, which can silence genes. 

DNA polymerase substitution guided by epigenetics is thought to be a major factor in the development of cancer. Cancer cells often have abnormal epigenetic modifications, which can lead to mutations in genes that control cell growth and division.

It is important to note that DNA polymerase substitution guided by epigenetics is a complex process and there is still much that we do not know about it. However, the research in this area is ongoing and scientists are hopeful that they will be able to develop new ways to prevent and treat cancer.

  • Random mutations by DNA polymerases 


Random DNA polymerase substitution is the least common mutation. DNA polymerases are enzymes that copy DNA during replication. They are very accurate enzymes, but they do occasionally make mistakes. These mistakes can lead to DNA substitutions.

However, random DNA polymerase substitution is less common than other causes of DNA substitutions, such as gBGC GC bias and AT mutation bias. This is because DNA polymerases have a number of proofreading mechanisms that help to correct mistakes.

Random DNA polymerase substitution can be caused by a number of factors, including:

  • Errors in DNA replication

  • Exposure to mutagens, such as UV radiation and tobacco smoke

  • DNA damage

  • Certain genetic diseases

Random DNA polymerase substitution can have a number of important consequences for evolution and human health. For example, it can lead to the development of genetic diseases, such as cancer. It can also contribute to the evolution of new genes and the loss of existing genes.

It is important to note that these four causes of DNA substitutions are not mutually exclusive. For example, a DNA substitution can be caused by a combination of gBGC GC bias and DNA polymerase substitution guided by epigenetics.

In the post-genome era, researchers have begun to discover that mutations are not as random as previously thought. 

There is also evidence that mutations can be biased towards certain types of changes. The discovery of non-random mutations has a number of implications for our understanding of evolution and disease. Researchers are still working to understand the full implications of non-random mutations, but this is an exciting area of research with the potential to revolutionize our understanding of biology and medicine.

The migration from random substitution (mutations) to non random ones is yet another challenge to NeoDarwinism.

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