Are Synonymous Sites in Primates and Rodents Functionally Constrained?

Area of Science:

• Evolutionary biology
• Molecular evolution
• Genomics

Background:

• Synonymous sites in mammals were previously thought to be under selective constraint.
• Studies suggested primates had more stringent selective constraint than rodents.
• This contradicts theoretical expectations given differing effective population sizes.

Purpose of the Study:

• To resolve the contradiction between theoretical expectations and observed selective constraint at synonymous sites.
• To re-evaluate selective constraint using processed pseudogenes as a model for neutral evolution.

Main Methods:

• Utilized processed pseudogenes to model neutral evolution.
• Estimated selective constraint by comparing substitution rates at pseudosynonymous and pseudononsynonymous sites.
• Controlled for GC content effects using a maximum parsimony approach on fourfold degenerate sites.

Main Results:

• Initial analyses controlling for GC content replicated previous findings: primates showed higher selective constraint than rodents.
• However, a maximum parsimony approach controlling for GC content shifts revealed neutral evolution at synonymous sites in both primates and rodents.
• Apparent deviations from neutrality were attributed to mutation rate biases (C → A and C → T) in pseudogenes, likely due to GC content shifts.

Conclusions:

• Previous estimates of significant selective constraint at synonymous sites in primates are likely artifacts of mutation biases.
• Synonymous sites in both primates and rodents appear to evolve neutrally.
• GC content shifts in pseudogenes can create misleading patterns of apparent selective constraint.