Departments of Human Genetics and Ecology and Evolution, University of Chicago, Chicago, IL 60637 USA
We would all like to understand how a protein's sequence determines its structure and function – and why it has each of these properties – but a protein is such a complex physical object with so many degrees of freedom that this is a very hard problem to solve. I contend that evolutionary analysis of a protein's history through time is the only effective way to answer these questions. In this talk, I show how we have retraced in detail the mechanisms by which an essential family of ligand-regulated transcription factors evolved its diverse functions by using ancestral protein reconstruction – phylogenetic inference, synthesis, and expression of ancient protein sequences followed by experimental characterization of their structures and functions and the effects of historical mutations upon them. These studies reveal how just a handful of sequence changes hundreds of millions of years ago – driven by blind chance, natural selection, and the physical architecture of biochemical function – triggered the evolution of biological functions that are now essential to the biology of all vertebrates.