Crossing fitness valleys via double substitutions within codons

Area of Science:

• Evolutionary biology
• Molecular evolution
• Genomics

Background:

• Single nucleotide substitutions in protein-coding genes are classified as synonymous (S) or non-synonymous (N).
• Non-synonymous substitutions generally have a greater fitness effect and are often removed by purifying selection.
• Deleterious substitutions may be rescued by secondary mutations, potentially becoming subject to positive selection.

Purpose of the Study:

• To investigate the evolutionary forces acting on within-codon double substitutions.
• To differentiate the effects of selection from mutational biases in double substitutions.
• To understand how selection shapes the evolutionary landscape of protein-coding genes.

Main Methods:

• Analyzed within-codon double substitutions in 37 prokaryotic genome groups.
• Compared double substitutions within codons to double synonymous substitutions in adjacent codons.
• Classified double substitutions into four types: SS, SN, NS, and NN, based on the nature of the first and second substitutions.

Main Results:

• Synonymous-synonymous (SS) double substitutions evolve neutrally.
• Synonymous-non-synonymous (SN) double substitutions are under purifying selection.
• Non-synonymous-synonymous (NS) double substitutions show positive selection on the second step.
• Non-synonymous-non-synonymous (NN) double substitutions exhibit heterogeneous selection pressures (purifying, positive, or neutral).

Conclusions:

• Protein evolution is largely conservative, but double substitutions can be influenced by positive selection.
• The second substitution in a double substitution can be positively selected if the first is deleterious.
• Positive selection on double substitutions can facilitate the crossing of fitness valleys.