Joseph Thornton, PhD

My lab studies the mechanisms by which protein functions evolve. We do this by phylogenetically reconstructing the histories of ancient proteins and then synthesizing, manipulating, and experimentally characterizing their biological functions and physical properties.



This kind of work is powerful and fun — and possible at all — because we are a diverse group of evolutionary biologists, biochemists, biophysicists, computational biologists, geneticists, and molecular biologists, all working together and freely mingling our expertise, techniques, and ideas.



We address classical and recent questions about the nature of evolutionary processes, such as: How do complex molecular systems evolve? Does evolution proceed by a few large-effect or many small-effect mutations? Does epistasis shape the evolutionary process and make the pathways and outcomes of evolution contingent on chance events? Is evolution reversible? How does the architecture of biological systems shape the evolutionary process? How did evolution produce those architectures in the first place?



Evolutionary analysis can also help address core questions in biochemistry, biophysics, and molecular biology. Why do proteins have the particular architectures that they do? How does that architecture itself evolve? What structural and genetic mechanisms cause functions to differ between members of protein families? How do molecular machines, allostery, and molecular interfaces evolve? Are proteins’ physical properties always optimized for their functions, and if not, why not? Can history explain why particular proteins are subject to interference by particular drugs and pollutants? We have found that detailed reconstruction of proteins’ histories helps us to understand why and how their present-day descendants work as they do today.

Columbia University/ American Museum of Natural History
Ph.D - Biological Sciences
06/2000

Columbia University
New York
Postdoc
08/2012

Ancient mechanisms for the evolution of the bicoid homeodomain's function in fly development.
Liu Q, Onal P, Datta RR, Rogers JM, Schmidt-Ott U, Bulyk ML, Small S, Thornton JW. Ancient mechanisms for the evolution of the bicoid homeodomain's function in fly development. Elife. 2018 10 09; 7.
PMID: 30298815

Family of neural wiring receptors in bilaterians defined by phylogenetic, biochemical, and structural evidence.
Cheng S, Park Y, Kurleto JD, Jeon M, Zinn K, Thornton JW, Özkan E. Family of neural wiring receptors in bilaterians defined by phylogenetic, biochemical, and structural evidence. Proc Natl Acad Sci U S A. 2019 May 14; 116(20):9837-9842.
PMID: 31043568

Multinucleotide mutations cause false inferences of lineage-specific positive selection.
Venkat A, Hahn MW, Thornton JW. Multinucleotide mutations cause false inferences of lineage-specific positive selection. Nat Ecol Evol. 2018 08; 2(8):1280-1288.
PMID: 29967485

Pervasive contingency and entrenchment in a billion years of Hsp90 evolution.
Starr TN, Flynn JM, Mishra P, Bolon DNA, Thornton JW. Pervasive contingency and entrenchment in a billion years of Hsp90 evolution. Proc Natl Acad Sci U S A. 2018 04 24; 115(17):4453-4458.
PMID: 29626131

Alternative evolutionary histories in the sequence space of an ancient protein.
Starr TN, Picton LK, Thornton JW. Alternative evolutionary histories in the sequence space of an ancient protein. Nature. 2017 09 21; 549(7672):409-413.
PMID: 28902834

Evolution of protein specificity: insights from ancestral protein reconstruction.
Siddiq MA, Hochberg GK, Thornton JW. Evolution of protein specificity: insights from ancestral protein reconstruction. Curr Opin Struct Biol. 2017 12; 47:113-122.
PMID: 28841430

Reconstructing Ancient Proteins to Understand the Causes of Structure and Function.
Hochberg GKA, Thornton JW. Reconstructing Ancient Proteins to Understand the Causes of Structure and Function. Annu Rev Biophys. 2017 05 22; 46:247-269.
PMID: 28301769

Exploring protein sequence-function landscapes.
Starr TN, Thornton JW. Exploring protein sequence-function landscapes. Nat Biotechnol. 2017 02 08; 35(2):125-126.
PMID: 28178247

Robustness of Reconstructed Ancestral Protein Functions to Statistical Uncertainty.
Eick GN, Bridgham JT, Anderson DP, Harms MJ, Thornton JW. Robustness of Reconstructed Ancestral Protein Functions to Statistical Uncertainty. Mol Biol Evol. 2017 02 01; 34(2):247-261.
PMID: 27795231

Experimental test and refutation of a classic case of molecular adaptation in Drosophila melanogaster.
Siddiq MA, Loehlin DW, Montooth KL, Thornton JW. Experimental test and refutation of a classic case of molecular adaptation in Drosophila melanogaster. Nat Ecol Evol. 2017 Jan 13; 1(2):25.
PMID: 28812605

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Steenbock Distinguished Lecturer in Biochemistry
University of Wisconsin
2016

Distinguished Alumni Lectureship
University of Queensland School of Biochemistry
2016

Guggenheim Foundation Fellowship
2014

Hans Falk Award
National Institute for Environmental Health Sciences
2014

Richard Jones Investigator Award
Oregon Medical Research Foundation
2010

Early Career Investigator
Howard Hughes Medical Institute
2009

U.S. Presidential Early Career Award for Scientists and Engineers
2007

Alfred P. Sloan Foundation Research Fellow
2006

CAREER Award
National Science Foundation
2006

Distinguished University Lecturer in Environmental Sustainability
Carnegie-Mellon University
2002