Joe Thornton, Ph.D.


Research Description


We study 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. Our current model system is a gene family of great biological and biomedical importance.

The Functional Synthesis in molecular biology and evolution

We are interested in two kinds of fundamental issues: 1) first, the nature of evolutionary processes, such as how complexity evolves, 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, and whether the outcomes of evolution are deterministic or contingent upon low-probability chance events; and 2) the genetic, biochemical, and biophysical mechanisms by which proteins evolve 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. These issues remain unresolved because evolutionary biologists have, until recently, ignored the connection between genotype and phenotype by treating genes as mere strings of letters. We have helped to develop and articulate 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. This approach is uniquely powerful for elucidating both the proximal and ultimate causes of protein function.

Ancestral gene resurrection

We have played an important role in developing a new strategy for studying protein evolution called ancestral gene resurrection. We use computational phylogenetic methods to infer ancestral sequences, followed by gene synthesis to synthesize them and experimental techniques to characterize them. We use cell biological, biochemical, and biophysical methods, as well as (by collaboration) X-ray crystallography and molecular dynamics approaches, to elucidate the functions, structures, and biophysical properties of ancestral proteins. With ancient proteins in hand, we can also introduce the mutations that occurred during crucial evolutionary periods to test hypotheses about the the specific effects caused by each historical genetic change.

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, receptors, and their DNA targets evolved their specific partnerships during the last 600 million years or so. 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.

Phylogenetic techniques

We are also evaluating and developing new phylogenetic methods for analyzing gene family evolution. We are particularly interested in understanding how uncertainty and heterogeneity in the evolutionary process affects the accuracy of current techniques for reconstructing phylogenies and inferring ancestral sequences. We also develop new methods that perform better when sequences evolve with a high degree of complexity.

Selected Publications

Evolutionary biochemistry: revealing the historical and physical causes of protein properties. Harms MJ, Thornton JW. (2013 Aug) Nat Rev Genet. 2013 Aug;14(8):559-71. doi: 10.1038/nrg3540. 23864121

Biophysical mechanisms for large-effect mutations in the evolution of steroid hormone receptors. Harms MJ, Eick GN, Goswami D, Colucci JK, Griffin PR, Ortlund EA, Thornton JW. (2013 Jul) Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):11475-80. doi: 10.1073/pnas.1303930110. Epub 2013 Jun 24. 23798447 ( Full Text )

Evolution of minimal specificity and promiscuity in steroid hormone receptors. Eick GN, Colucci JK, Harms MJ, Ortlund EA, Thornton JW. (2012) PLoS Genet. 2012;8(11):e1003072. doi: 10.1371/journal.pgen.1003072. Epub 2012 Nov 15.23166518 ( Full Text )

Evolution of increased complexity in a molecular machine. Finnigan GC, Hanson-Smith V, Stevens TH, Thornton JW. (2012 Jan) Nature. 2012 Jan 9;481(7381):360-4. doi: 10.1038/nature10724. 22230956

Robustness of ancestral sequence reconstruction to phylogenetic uncertainty. Hanson-Smith V, Kolaczkowski B, Thornton JW. (2010 Sep) Mol Biol Evol. 2010 Sep;27(9):1988-99. doi: 10.1093/molbev/msq081. Epub 2010 Apr 5.20368266 ( Full Text )

Protein evolution by molecular tinkering: diversification of the nuclear receptor superfamily from a ligand-dependent ancestor. Bridgham JT, Eick GN, Larroux C, Deshpande K, Harms MJ, Gauthier ME, Ortlund EA, Degnan BM, Thornton JW. (2010) PLoS Biol. 2010 Oct 5;8(10). pii: e1000497. doi: 10.1371/journal.pbio.1000497. 20957188 ( Full Text )

Analyzing protein structure and function using ancestral gene reconstruction. Harms MJ, Thornton JW. (2010 Jun) Curr Opin Struct Biol. 2010 Jun;20(3):360-6. doi: 10.1016/ Epub 2010 Apr 21. 20413295 ( Full Text )

An epistatic ratchet constrains the direction of glucocorticoid receptor evolution. Bridgham JT, Ortlund EA, Thornton JW. (2009 Sep) Nature. 2009 Sep 24;461(7263):515-9. doi: 10.1038/nature08249. 19779450

Crystal structure of an ancient protein: evolution by conformational epistasis. Ortlund EA, Bridgham JT, Redinbo MR, Thornton JW. (2007 Sep) Science. 2007 Sep 14;317(5844):1544-8. Epub 2007 Aug 16. 17702911 ( Full Text )

Mechanistic approaches to the study of evolution: the functional synthesis. Dean AM, Thornton JW. (2007 Sep) Nat Rev Genet. 2007 Sep;8(9):675-88. 17703238 ( Full Text )

Evolution of hormone-receptor complexity by molecular exploitation. Bridgham JT, Carroll SM, Thornton JW. (2006 Apr) Science. 2006 Apr 7;312(5770):97-101. 16601189

Performance of maximum parsimony and likelihood phylogenetics when evolution is heterogeneous. Kolaczkowski B, Thornton JW. (2004 Oct) Nature. 2004 Oct 21;431(7011):980-4. 15496922

Resurrecting ancient genes: experimental analysis of extinct molecules. Thornton JW. (2004 May) Nat Rev Genet. 2004 May;5(5):366-75. 15143319

Resurrecting the ancestral steroid receptor: ancient origin of estrogen signaling. Thornton JW, Need E, Crews D. (2003 Sep) Science. 2003 Sep 19;301(5640):1714-7. 14500980