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Joseph Thornton

TitlePROFESSOR
InstitutionUniversity of Chicago
DepartmentEcology & Evolution
AddressChicago IL 60637
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    Collapse Overview 
    Collapse overview
    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.


    Collapse Biography 
    Collapse education and training
    Columbia University/ American Museum of Natural HistoryPh.D06/2000Biological Sciences
    Columbia University, New YorkPostdoc08/2012
    Collapse awards and honors
    2016Steenbock Distinguished Lecturer in Biochemistry, University of Wisconsin
    2016Distinguished Alumni Lectureship, University of Queensland School of Biochemistry
    2014Guggenheim Foundation Fellowship
    2014Hans Falk Award, National Institute for Environmental Health Sciences
    2010Richard Jones Investigator Award, Oregon Medical Research Foundation
    2009Early Career Investigator, Howard Hughes Medical Institute
    2007U.S. Presidential Early Career Award for Scientists and Engineers
    2006Alfred P. Sloan Foundation Research Fellow
    2006CAREER Award, National Science Foundation
    2002Distinguished University Lecturer in Environmental Sustainability, Carnegie-Mellon University

    Collapse ORNG Applications 
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    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    List All   |   Timeline
    1. Siddiq MA, Thornton JW. Fitness effects but no temperature-mediated balancing selection at the polymorphic Adh gene of Drosophila melanogaster. Proc Natl Acad Sci U S A. 2019 Oct 22; 116(43):21634-21640. PMID: 31594844.
      View in: PubMed
    2. 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.
      View in: PubMed
    3. 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.
      View in: PubMed
    4. 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.
      View in: PubMed
    5. 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.
      View in: PubMed
    6. 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.
      View in: PubMed
    7. 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.
      View in: PubMed
    8. 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.
      View in: PubMed
    9. Starr TN, Thornton JW. Exploring protein sequence-function landscapes. Nat Biotechnol. 2017 02 08; 35(2):125-126. PMID: 28178247.
      View in: PubMed
    10. 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.
      View in: PubMed
    11. 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.
      View in: PubMed
    12. Katsu Y, Cziko PA, Chandsawangbhuwana C, Thornton JW, Sato R, Oka K, Takei Y, Baker ME, Iguchi T. A second estrogen receptor from Japanese lamprey (Lethenteron japonicum) does not have activities for estrogen binding and transcription. Gen Comp Endocrinol. 2016 09 15; 236:105-114. PMID: 27432813.
      View in: PubMed
    13. Starr TN, Thornton JW. Epistasis in protein evolution. Protein Sci. 2016 07; 25(7):1204-18. PMID: 26833806.
      View in: PubMed
    14. Anderson DP, Whitney DS, Hanson-Smith V, Woznica A, Campodonico-Burnett W, Volkman BF, King N, Thornton JW, Prehoda KE. Correction: Evolution of an ancient protein function involved in organized multicellularity in animals. Elife. 2016 Jan 21; 5:e14311. PMID: 26790885.
      View in: PubMed
    15. Anderson DP, Whitney DS, Hanson-Smith V, Woznica A, Campodonico-Burnett W, Volkman BF, King N, Thornton JW, Prehoda KE. Evolution of an ancient protein function involved in organized multicellularity in animals. Elife. 2016 Jan 07; 5:e10147. PMID: 26740169.
      View in: PubMed
    16. Hudson WH, Kossmann BR, de Vera IM, Chuo SW, Weikum ER, Eick GN, Thornton JW, Ivanov IN, Kojetin DJ, Ortlund EA. Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space. Proc Natl Acad Sci U S A. 2016 Jan 12; 113(2):326-31. PMID: 26715749.
      View in: PubMed
    17. Anderson DW, McKeown AN, Thornton JW. Intermolecular epistasis shaped the function and evolution of an ancient transcription factor and its DNA binding sites. Elife. 2015 Jun 15; 4:e07864. PMID: 26076233.
      View in: PubMed
    18. Hart KM, Harms MJ, Schmidt BH, Elya C, Thornton JW, Marqusee S. Thermodynamic system drift in protein evolution. PLoS Biol. 2014 Nov; 12(11):e1001994. PMID: 25386647.
      View in: PubMed
    19. McKeown AN, Bridgham JT, Anderson DW, Murphy MN, Ortlund EA, Thornton JW. Evolution of DNA specificity in a transcription factor family produced a new gene regulatory module. Cell. 2014 Sep 25; 159(1):58-68. PMID: 25259920.
      View in: PubMed
    20. Harms MJ, Thornton JW. Historical contingency and its biophysical basis in glucocorticoid receptor evolution. Nature. 2014 Aug 14; 512(7513):203-7. PMID: 24930765.
      View in: PubMed
    21. Bridgham JT, Keay J, Ortlund EA, Thornton JW. Vestigialization of an allosteric switch: genetic and structural mechanisms for the evolution of constitutive activity in a steroid hormone receptor. PLoS Genet. 2014 Jan; 10(1):e1004058. PMID: 24415950.
      View in: PubMed
    22. Harms MJ, Thornton JW. Evolutionary biochemistry: revealing the historical and physical causes of protein properties. Nat Rev Genet. 2013 Aug; 14(8):559-71. PMID: 23864121.
      View in: PubMed
    23. Harms MJ, Eick GN, Goswami D, Colucci JK, Griffin PR, Ortlund EA, Thornton JW. Biophysical mechanisms for large-effect mutations in the evolution of steroid hormone receptors. Proc Natl Acad Sci U S A. 2013 Jul 09; 110(28):11475-80. PMID: 23798447.
      View in: PubMed
    24. Eick GN, Colucci JK, Harms MJ, Ortlund EA, Thornton JW. Evolution of minimal specificity and promiscuity in steroid hormone receptors. PLoS Genet. 2012; 8(11):e1003072. PMID: 23166518.
      View in: PubMed
    25. Liberles DA, Teichmann SA, Bahar I, Bastolla U, Bloom J, Bornberg-Bauer E, Colwell LJ, de Koning AP, Dokholyan NV, Echave J, Elofsson A, Gerloff DL, Goldstein RA, Grahnen JA, Holder MT, Lakner C, Lartillot N, Lovell SC, Naylor G, Perica T, Pollock DD, Pupko T, Regan L, Roger A, Rubinstein N, Shakhnovich E, Sjölander K, Sunyaev S, Teufel AI, Thorne JL, Thornton JW, Weinreich DM, Whelan S. The interface of protein structure, protein biophysics, and molecular evolution. Protein Sci. 2012 Jun; 21(6):769-85. PMID: 22528593.
      View in: PubMed
    26. Finnigan GC, Hanson-Smith V, Stevens TH, Thornton JW. Evolution of increased complexity in a molecular machine. Nature. 2012 Jan 09; 481(7381):360-4. PMID: 22230956.
      View in: PubMed
    27. Carroll SM, Ortlund EA, Thornton JW. Mechanisms for the evolution of a derived function in the ancestral glucocorticoid receptor. PLoS Genet. 2011 Jun; 7(6):e1002117. PMID: 21698144.
      View in: PubMed
    28. Thornton JW, Carroll SM. Lamprey endocrinology is not ancestral. Proc Natl Acad Sci U S A. 2011 Jan 11; 108(2):E5; author reply E6. PMID: 21209326.
      View in: PubMed
    29. Bridgham JT, Eick GN, Larroux C, Deshpande K, Harms MJ, Gauthier ME, Ortlund EA, Degnan BM, Thornton JW. Protein evolution by molecular tinkering: diversification of the nuclear receptor superfamily from a ligand-dependent ancestor. PLoS Biol. 2010 Oct 05; 8(10). PMID: 20957188.
      View in: PubMed
    30. Eick GN, Thornton JW. Evolution of steroid receptors from an estrogen-sensitive ancestral receptor. Mol Cell Endocrinol. 2011 Mar 01; 334(1-2):31-8. PMID: 20837101.
      View in: PubMed
    31. Harms MJ, Thornton JW. Analyzing protein structure and function using ancestral gene reconstruction. Curr Opin Struct Biol. 2010 Jun; 20(3):360-6. PMID: 20413295.
      View in: PubMed
    32. Hanson-Smith V, Kolaczkowski B, Thornton JW. Robustness of ancestral sequence reconstruction to phylogenetic uncertainty. Mol Biol Evol. 2010 Sep; 27(9):1988-99. PMID: 20368266.
      View in: PubMed
    33. Kolaczkowski B, Thornton JW. Long-branch attraction bias and inconsistency in Bayesian phylogenetics. PLoS One. 2009 Dec 09; 4(12):e7891. PMID: 20011052.
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    34. Bridgham JT, Ortlund EA, Thornton JW. An epistatic ratchet constrains the direction of glucocorticoid receptor evolution. Nature. 2009 Sep 24; 461(7263):515-9. PMID: 19779450.
      View in: PubMed
    35. Keay J, Thornton JW. Hormone-activated estrogen receptors in annelid invertebrates: implications for evolution and endocrine disruption. Endocrinology. 2009 Apr; 150(4):1731-8. PMID: 19036877.
      View in: PubMed
    36. Carroll SM, Bridgham JT, Thornton JW. Evolution of hormone signaling in elasmobranchs by exploitation of promiscuous receptors. Mol Biol Evol. 2008 Dec; 25(12):2643-52. PMID: 18799714.
      View in: PubMed
    37. Bridgham JT, Brown JE, Rodríguez-Marí A, Catchen JM, Thornton JW. Evolution of a new function by degenerative mutation in cephalochordate steroid receptors. PLoS Genet. 2008 Sep 12; 4(9):e1000191. PMID: 18787702.
      View in: PubMed
    38. Kolaczkowski B, Thornton JW. A mixed branch length model of heterotachy improves phylogenetic accuracy. Mol Biol Evol. 2008 Jun; 25(6):1054-66. PMID: 18319244.
      View in: PubMed
    39. Dean AM, Thornton JW. Mechanistic approaches to the study of evolution: the functional synthesis. Nat Rev Genet. 2007 Sep; 8(9):675-88. PMID: 17703238.
      View in: PubMed
    40. Ortlund EA, Bridgham JT, Redinbo MR, Thornton JW. Crystal structure of an ancient protein: evolution by conformational epistasis. Science. 2007 Sep 14; 317(5844):1544-8. PMID: 17702911.
      View in: PubMed
    41. Kolaczkowski B, Thornton JW. Effects of branch length uncertainty on Bayesian posterior probabilities for phylogenetic hypotheses. Mol Biol Evol. 2007 Sep; 24(9):2108-18. PMID: 17636043.
      View in: PubMed
    42. Fox JE, Bridgham JT, Bovee TF, Thornton JW. An evolvable oestrogen receptor activity sensor: development of a modular system for integrating multiple genes into the yeast genome. Yeast. 2007 May; 24(5):379-90. PMID: 17345582.
      View in: PubMed
    43. Kolaczkowski B, Thornton JW. Is there a star tree paradox? Mol Biol Evol. 2006 Oct; 23(10):1819-23. PMID: 16837562.
      View in: PubMed
    44. Keay J, Bridgham JT, Thornton JW. The Octopus vulgaris estrogen receptor is a constitutive transcriptional activator: evolutionary and functional implications. Endocrinology. 2006 Aug; 147(8):3861-9. PMID: 16690796.
      View in: PubMed
    45. Bridgham JT, Carroll SM, Thornton JW. Evolution of hormone-receptor complexity by molecular exploitation. Science. 2006 Apr 07; 312(5770):97-101. PMID: 16601189.
      View in: PubMed
    46. Thornton JW, Kolaczkowski B. No magic pill for phylogenetic error. Trends Genet. 2005 Jun; 21(6):310-1. PMID: 15922825.
      View in: PubMed
    47. Krylova IN, Sablin EP, Moore J, Xu RX, Waitt GM, MacKay JA, Juzumiene D, Bynum JM, Madauss K, Montana V, Lebedeva L, Suzawa M, Williams JD, Williams SP, Guy RK, Thornton JW, Fletterick RJ, Willson TM, Ingraham HA. Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1. Cell. 2005 Feb 11; 120(3):343-55. PMID: 15707893.
      View in: PubMed
    48. Kolaczkowski B, Thornton JW. Performance of maximum parsimony and likelihood phylogenetics when evolution is heterogeneous. Nature. 2004 Oct 21; 431(7011):980-4. PMID: 15496922.
      View in: PubMed
    49. Thornton JW. Resurrecting ancient genes: experimental analysis of extinct molecules. Nat Rev Genet. 2004 May; 5(5):366-75. PMID: 15143319.
      View in: PubMed
    50. Thornton JW, Need E, Crews D. Resurrecting the ancestral steroid receptor: ancient origin of estrogen signaling. Science. 2003 Sep 19; 301(5640):1714-7. PMID: 14500980.
      View in: PubMed
    51. Wu KH, Tobias ML, Thornton JW, Kelley DB. Estrogen receptors in Xenopus: duplicate genes, splice variants, and tissue-specific expression. Gen Comp Endocrinol. 2003 Aug; 133(1):38-49. PMID: 12899845.
      View in: PubMed
    52. Sarkar IN, Thornton JW, Planet PJ, Figurski DH, Schierwater B, DeSalle R. An automated phylogenetic key for classifying homeoboxes. Mol Phylogenet Evol. 2002 Sep; 24(3):388-99. PMID: 12220982.
      View in: PubMed
    53. Thornton JW, McCally M, Houlihan J. Biomonitoring of industrial pollutants: health and policy implications of the chemical body burden. Public Health Rep. 2002 Jul-Aug; 117(4):315-23. PMID: 12477912.
      View in: PubMed
    54. Thornton JW. Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. Proc Natl Acad Sci U S A. 2001 May 08; 98(10):5671-6. PMID: 11331759.
      View in: PubMed
    55. Hawkins MB, Thornton JW, Crews D, Skipper JK, Dotte A, Thomas P. Identification of a third distinct estrogen receptor and reclassification of estrogen receptors in teleosts. Proc Natl Acad Sci U S A. 2000 Sep 26; 97(20):10751-6. PMID: 11005855.
      View in: PubMed
    56. Thornton JW, DeSalle R. A new method to localize and test the significance of incongruence: detecting domain shuffling in the nuclear receptor superfamily. Syst Biol. 2000 Jun; 49(2):183-201. PMID: 12118404.
      View in: PubMed
    57. Thornton JW, DeSalle R. Gene family evolution and homology: genomics meets phylogenetics. Annu Rev Genomics Hum Genet. 2000; 1:41-73. PMID: 11701624.
      View in: PubMed
    58. Thornton JW, Kelley DB. Evolution of the androgen receptor: structure-function implications. Bioessays. 1998 Oct; 20(10):860-9. PMID: 9819573.
      View in: PubMed
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