Why time matters: codon evolution and the temporal dynamics of dN/dS

Area of Science:

• Evolutionary genetics
• Population genetics
• Molecular evolution

Background:

• The ratio of divergence at nonsynonymous and synonymous sites (dN/dS) is a key metric in evolutionary genetics.
• Traditional dN/dS estimation often overlooks the influence of ancestral and lineage-specific polymorphisms, particularly in closely related species.

Purpose of the Study:

• To develop a population genetics-based codon model to accurately estimate dN/dS.
• To investigate the impact of polymorphisms on dN/dS estimations in closely related lineages.

Main Methods:

• Formulation of a codon model grounded in population genetic theory.
• Derivation of analytical expressions for dN/dS using Poisson random field approximation within a Markovian framework.
• Validation of analytical derivations through extensive simulations.

Main Results:

• Simulations and analytical derivations confirm that polymorphisms substantially bias dN/dS at short evolutionary time scales.
• The expected dN/dS value requires significant time to stabilize, converging to a limit considering only fixed differences.
• Fluctuations in the ratio of stochastic variables can produce extreme dN/dS values, even under neutrality, especially at short timescales or low mutation rates.

Conclusions:

• The study highlights the critical impact of polymorphisms on dN/dS estimates, especially for closely related lineages.
• Findings necessitate a re-evaluation of dN/dS interpretation, the McDonald-Kreitman test, and related evolutionary statistics.
• Accurate dN/dS estimation requires accounting for population genetic factors and evolutionary time scales.