The impact of non-neutral synonymous mutations when inferring selection on nonsynonymous mutations

Area of Science:

• Evolutionary genetics
• Population genetics
• Molecular evolution

Background:

• The distribution of fitness effects (DFE) is key to understanding mutation impact.
• Current methods assume neutral evolution of synonymous variants, which may be inaccurate.
• Selection on synonymous mutations can affect inferences of nonsynonymous mutation effects.

Purpose of the Study:

• To investigate the impact of selection on synonymous mutations on DFE inference.
• To assess the reliability of current computational methods under selection.
• To determine if biases in demographic parameter estimation affect DFE inference.

Main Methods:

• Simulated models of selection on synonymous mutations using SLiM.
• Inferred the DFE of nonsynonymous mutations using Fit∂a∂i.
• Compared inferred parameters and DFEs with and without accounting for synonymous selection.

Main Results:

• Selection on synonymous variants led to inaccurate inferences of recent population growth.
• Pervasive synonymous selection inflated the proportion of highly deleterious and nearly neutral nonsynonymous mutations.
• Biases were eliminated when correct demographic parameters were used.

Conclusions:

• Unmodeled selection on synonymous mutations can significantly bias DFE inference.
• Accurate demographic parameter estimation is essential for reliable DFE analysis.
• This highlights the need to consider selection on synonymous sites in evolutionary studies.