We have put forward a new model of protein evolution based on small, nearly neutral, compensatory amino acid replacements affecting protein folding, stability, and aggregation. Proteins are finicky molecules, marginally stable and prone to aggregation, yet they must function in a crowded cellular environment. Many common diseases are known to be due to missense mutations affecting protein stability and aggregation. Our biophysical model of protein evolution helps to understand diverse phenomena ranging from the dynamics of molecular adaptation to the clock-like rate of protein evolution.
Protein folding is a highly collaborative process, involving a multitude of interactions between amino acid residues. These interactions give rise to epistasis, wherein mutations, in addition to providing an immediate fitness effect, also modify the character of subsequent mutations to the protein. This phenomenon significantly complicates both neutral evolution and adaptive evolution. Its effects can be seen in the degree of randomness present in the molecular clock as well as in the evolution of antibiotic resistance.
In the transformation of genetic variation within species (polymorphism) into genetic differences between species (divergence), selective neutrality, near neutrality, and positive selection may each play a role, differing from one gene to the next. Synonymous nucleotide sites are often used as a uniform standard of comparison across genes, on the grounds that synonymous sites are subject to relatively weak selective constraints and so may, to a first approximation, be regarded as neutral. Hence a comparison of levels of polymorphism and divergence between synonymous sites and amino acid replacement sites in a gene are potentially informative about the magnitude of selective forces associated with amino acid replacements. An analysis of polymorphism and divergence in Drosophila suggests that adaptive evolution is quite common, although the individual selective effects associated with adaptive change are extremely small.