Why does the target-recognition site in PRDM9 have unusually high mutation rates?

Area of Science:

• Genetics
• Evolutionary Biology
• Population Genetics

Background:

• The PRDM9 gene determines recombination hotspot locations in mammals.
• PRDM9 exhibits exceptionally high mutation rates within the human genome.
• This high mutation rate impacts hotspot longevity and the overall recombination landscape.

Purpose of the Study:

• To investigate the evolutionary drivers behind PRDM9's high mutation rate.
• To model the evolution of mutation rates at PRDM9 and its target sites.
• To understand the interplay between PRDM9 mutation rates, recombination, and genomic variability.

Main Methods:

• Formulation and analysis of population genetics models.
• Modeling modifiers of mutation rates at the PRDM9 locus.
• Modeling modifiers of mutation rates at PRDM9's target sites.
• Considering factors like linkage disequilibrium and genetic drift.

Main Results:

• Natural selection favors high mutation rates at PRDM9 and low mutation rates at its target sites.
• Linkage disequilibrium and genetic drift suggest high mutation rates at PRDM9 are more likely to evolve.
• Modifiers of PRDM9 mutation rates are likely to evolve in close linkage with the PRDM9 locus.
• PRDM9's zinc-finger structure correlates with high intrinsic mutation rates.

Conclusions:

• The study provides an exception to the reduction principle in modifier theory.
• High mutation rates at PRDM9 are evolutionarily favored and likely driven by its structure.
• Red-queen dynamics in PRDM9 coevolution may create a fluctuating environment promoting high mutation rates at PRDM9.