Figure 1. Biophysics as a stepping stone between sequence and phenotype.

Closing the genotype-phenotype gap is facilitated by an intermediate projection of organismal fitness to biophysical properties of macromolecules. While the effect of sequence variation (panel a) on molecular traits (e.g. folding stability, binding affinity, catalytic activity, panel b) might be complex, the ensuing relation between variation of the observable biophysical traits (vertical axes in panel b) and their fitness effect on the organism might be simple and predictable in some cases (panel d and Figure 2). The effects of mutations are also modulated by a regulation of biological networks (panel c) that might also have simple integrative effect on fitness. On the level of populations, the probability of fixing a specific mutation is a function of the effect of a mutation (selection coefficient) and an effective population size (N_e). Note a different interpretation of fitness landscape in (panel d) from classical Wright’s where mean fitness of the population vs allele frequencies is usually plotted.