Detecting Signatures of Positive Selection against a Backdrop of Compensatory Processes.

There are known limitations in methods of detecting positive selection. Common methods do not enable differentiation between positive selection and compensatory covariation, a major limitation. Further, the traditional method of calculating the ratio of nonsynonymous to synonymous substitutions (dN/dS) does not take into account the 3D structure of biomacromolecules nor differences between amino acids. It also does not account for saturation of synonymous mutations (dS) over long evolutionary time that renders codon-based methods ineffective for older divergences. This work aims to address these shortcomings for detecting positive selection through the development of a statistical model that examines clusters of substitutions in clusters of variable radii. Additionally, it uses a parametric bootstrapping approach to differentiate positive selection from compensatory processes. A previously reported case of positive selection in the leptin protein of primates was reexamined using this methodology.

Evolutionary Processes and Biophysical Mechanisms: Revisiting Why Evolved Proteins Are Marginally Stable.

Evolved proteins observed in natural organisms are found to be only marginally stable. Several mechanistic hypotheses have been presented to date to explain this observation. One idea that has been put forward is that active selection prevents proteins from becoming too stable to enable proper function. A second idea is that marginal stability reflects the point of mutation-selection-drift balance, where it is mutational pressure that generates marginal stability. A third idea explored in this issue of Journal of Molecular Evolution is that a physical limit prevents the evolution of more stable proteins rather than an evolutionary process. While the first two notions are based upon specific evolutionary processes, discussion here is aimed at reconciling evolutionary processes with the physics of protein folding, drawing upon the ideas that have been presented.