Unstable DNA repair genes shaped by their own sequence modifying phenotypes

Area of Science:

• Evolutionary biology
• Genetics
• Bioinformatics

Background:

• Natural selection generally favors genetic stability by avoiding unstable DNA sequences.
• However, unstable sequences are found in DNA repair genes, leading to debates about selection favoring variability over stability.
• This paradox is particularly evident in DNA mismatch repair (MMR) genes.

Purpose of the Study:

• To propose and provide evidence for a new evolutionary mechanism that resolves the paradox of genetic instability in DNA repair genes.
• To investigate the role of gene-dependent mutation biases and meiotic recombination in maintaining unstable sequences.
• To test the hypothesis that MMR genes actively maintain an overrepresentation of unstable sequences within and around themselves.

Main Methods:

• Bioinformatic analysis of DNA sequences, focusing on nucleotide repeat content.
• Comparative analysis of mononucleotide repeat frequencies in regions surrounding MMR genes versus other RefSeq genes.
• Development and application of a mathematical model to assess the frequency of monorepeats.

Main Results:

• A significant 31% excess of mononucleotide repeats was observed in regions surrounding seven human MMR genes compared to other RefSeq genes.
• Specific MMR genes, PMS2 and MSH6, showed particularly high enrichment of monorepeats.
• A mathematical model supported the proposed mechanism as sufficient to explain the observed repeat excess.

Conclusions:

• Unstable sequences within MMR genes are maintained by the MMR mechanism itself, a form of phenotype acting on genotype.
• This evolutionary mechanism resolves the paradox of genetically unstable DNA repair genes.
• An equilibrium exists where the MMR system's phenotype influences its own genetic stability.