Evolution of gene and protein function
Since Darwin, the central task of evolutionary biology has been to provide an historical explanation for biodiversity — the great variety of species in nature, each with features remarkably well adapted it to its environment. With the rise of molecular biology, a new level of biodiversity has emerged, which also demands an explanation — the remarkable variety of genes in our genomes, the products of which each have specialized functions within the cell. Our goal is to understand the mechanisms and dynamics by which genes and the proteins they code for evolved their diverse functions. We employ a synthesis of evolutionary and phylogenetic techniques with functional molecular biology and biochemistry. We work on numerous protein families, as long as they are biologically interesting and serve as strong models for key questions in evolutionary biochemistry.

The Functional Synthesis in molecular biology and evolution
We are interested in fundamental questions about the evolutionary processes, such as whether adaptation proceeds by many small steps or a few large ones, whether interactions among mutations limits the pathways and outcomes that evolution can explore, whether the outcomes of evolution are deterministic or contingent upon low-probability chance events, whether evolution is reversible, how complexity evolves, and what the mechanisms are for the evolution of new functions. All of these questions depend upon the map that relates changes in gene sequence to changes in gene function and, ultimately, in phenotype. They remain unresolved because evolutionary biologists have, until recently, ignored the connection between genotype and phenotype by treating genes as mere beans in a bag or long strings of letters. We are advocates of the Functional Synthesis in molecular biology and evolution — a combination of evolutionary approaches for reconstructing history with the experimental strategies of molecular biology and biochemistry to rigorously test hypotheses about the mechanisms of evolution.

Molecular evolution of hormones and their receptors
How did hormones and their diverse functions in humans and other animals evolve? We study the evolution of vertebrate steroid hormones — such as estrogen, testosterone, and the stress hormone cortisol — and the receptor proteins that mediate these hormones’ effects on the body’s cells. Our goal is to reveal the specific molecular events by which hormones and receptors diversified and evolved their specific partnerships during the last 600 million years or so. By combining techniques from statistical phylogenetics, molecular endocrinology, ancestral gene resurrection, structural biology, biophysics, and experimental evolution, we are characterizing receptor biodiversity across the animal kingdom, testing hypotheses about the functions of ancient proteins, and determining the specific mutations and changes in protein structure by which new receptor functions evolved hundreds of millions of years ago. Our goal is to offer a complete mechanistic and historical explanation for a complex, tightly integrated molecular system.

Phylogenetic techniques
We are also evaluating and developing new phylogenetic methods for analyzing gene family evolution, reconstructing ancestral sequences, and making inference about evolutionary forces. We are particularly interested in understanding how heterogeneity in the evolutionary process affects the accuracy of current techniques, and in developing new methods that perform better when sequences evolve differently among sites and lineages.

Environmental health and policy
Many pesticides and industrial chemicals can cause severe effects on reproduction, development, behavior, and immunity, because they mimic or block the actions of our body’s steroid hormones. I have long been interested in how scientific knowledge can be used to support policies that protect both natural systems and democratic principles. Some of our work provides information relevant to efforts to reform environmental policies so that they take better account of the complexity and diversity of animal endocrine systems and contribute to long-term reductions in the production and use of persistent toxic chemicals. This work builds on the argument made in my book Pandora’s Poison.

Cover image for our paper, “Evolutionary Biochemistry,” in Nature Reviews Genetics