Causes and Mechanisms Leading to Genetic Entropy
One of the primary mechanisms contributing to genetic entropy is the universal tendency of methylated cytosine to mutate into thymine. This CpG->TpG transition is not effectively repaired by the cell if replication occurs before the repair. As a result, there is a gradual increase in the AT content of the genome.
The increase in AT content can lead to several problems:
- Genetic Instability: Higher AT content can cause chromosomal breakages and structural abnormalities.
- Loss of Regulatory Elements: CpG sites are often found in promoter regions, and their mutation can disrupt gene regulation.
- Increased Mutation Rates: High AT regions are more prone to further mutations.
To counterbalance the rising AT content, cells employ various mechanisms to maintain GC-AT content equilibrium. One significant method is GC-biased gene conversion (gBGC) during meiotic recombination, where passive DNA is rearranged to increase GC content. However, this process often leads to a loss of genetic information.
In conclusion, while repair mechanisms work to mitigate these changes, they are not entirely efficient. The accumulation of mutations, especially the irreversible CpG->TpG changes, leads to a progressive loss of biological information over time, supporting the concept of genetic entropy.
Chromosomal Structural Fragility and AT Content
Multiple studies have shown that chromosomal structural fragility may be associated with specific DNA sequences, particularly AT-rich regions:
AT-Rich Sequences and Fragility: AT-rich sequences can cause the formation of DNA secondary structures, which may lead to replication disturbances and consequently chromosomal breaks. For example, AT-rich minisatellites and microsatellites are known to have fragile sites.
Fragile Sites: Research has shown that AT-rich regions containing repetitive sequences can act as "fragile sites," which are prone to breaks during replication stress or other cellular stresses.
Chromosome Fusions
Chromosome fusions, where two chromosomes join to form a single chromosome, can result from various mechanisms, including repair errors of breaks:
Telomere Shortening and Fusions: Telomere shortening can lead to unprotected chromosome ends, resulting in breaks and fusions. AT-rich sequences in telomere regions may be involved in this process.
Non-Homologous End Joining (NHEJ): Chromosome fusions can occur when broken chromosome ends join together through the NHEJ mechanism. This process is more error-prone, especially in AT-rich sequences, which can complicate precise joining.
Instability of AT-Rich Regions
A common observation is that AT-rich regions are generally more unstable than GC-rich regions:
Genomic Instability: AT-rich regions may be more unstable and prone to mutations, leading to structural changes in chromosomes, such as fusions and breaks.
Summary and conclusions:
- There is a universal tendency of methylated cytosine to mutate into thymine. A methylated cytosine is ~20,000 more prone to turn to thymine than non-methylated cytosine.
- Adaptation needs often result in changing methylation patterns (epigenetic regulation).
- This CpG->TpG transition is not effectively repaired by the cell if replication occurs before the repair.
- There is a gradual increase in the AT content of the genome.
- The only way the cell can balance the GC-AT ratio is gBGC gene conversion. DNA is rearranged.
- DNA is passive information.
- In this procedure information is typically lost.
- High AT content is associated with chromosomal structural fragility, chromosome breakages, and fusions.
- Genetic entropy is an inevitable universal biological phenomenon.
- Evolution never happened.
Example Studies:
Ruiz-Herrera et al. (2006): The study demonstrated that AT-rich regions are more prone to chromosomal structural rearrangements in some animal species.
Zlotorynski et al. (2003): The study focused on fragile sites and showed that these regions are often AT-rich and associated with chromosomal instability.
