Measuring shifts in function and evolutionary opportunity using variability profiles: A case study of the globins

Variability profiles measured over a set of aligned sequences can be used t o estimate evolutionary freedom to vary. Differences in variability profile s between clades can be used to identify shifts in function at the molecula r level. We demonstrate such a shift between the alpha and beta subunits of hemoglobin. We also show that the variability profiles for myoglobin are d ifferent between whales and primates and speculate that the differences bet ween the two clades may reflect a shift associated with the novel oxygen st orage demands in the lineage leading to whales. We discuss the relationship between sequence variability and "evolutionary opportunity" and explore th e utility of Maynard Smith's multidimensional evolutionary opportunity spac e metaphor for exploring functional constraints, genetic redundancy, and th e context dependency of the genotype-phenotype map. This work has implicati ons for quantitatively defining and comparing protein function. Supplementa ry data is available from bioinfo.mbb.yale.edu/align.