There is a growing awareness that recent advances in developmental genetics and in complex systems theory, both, will fundamentally change how we think about the evolution of higher organisms. This is also the focus of the research in my lab. The lab consists of a group of theorists, who use mathematical modeling to understand complex adaptations, and a group of molecular and developmental biologists, using comparative sequencing and transgenic techniques to understand the evolution of developmental control genes. The emphasis of the molecular group is on the molecular evolution of Hox genes and their role in the origin and early evolution of tetrapod limbs. Tetrapod limbs are both an important complex adaptation of terrestrial vertebrates and as well as one of the best known developmental model systems from vertebrates. The focus of our mathematical work is on the dynamics of complex adaptations and the evolution of the so-called genotype-phenotype map, i.e. the way how genetic changes relate to phenotypic changes. This requires us to develop new modeling techniques, like the theory of recombination landscapes and the modeling of gene interactions. Another goal is to understand the mechanisms causing the evolution of a modular representation of the phenotype.
Extensive Research Description
Evolution of gene regulation in endometrial stromal cells:
We study the gene regulatory network of endometrial stomal cells and how it evolved. In particular we are interested in the role of transposable elements in providing novel cis-regulatory elements and in the role of transcription factor protein changes to allow the regulation of novel target genes.
Evolution of human parturition and spontaneous decidualization (menstruation):
Humans and higher primates are distinct from most other mammals in that 1) the endometrium differentiates each reproductive cycle even in the absence of a conceptus, and 2) parturition is initiated without systemic progesterone withdrawal. Interestingly these two characteristics are taxonomically co-extensive, i.e. are only found in humans and higher primates. In my lab we try to understand the genetic changes underlying both phenomena. This research is in collaboration with the NIH Perinatology Research Branch at Wayne State University, Detroit, MI.
Evolution of digit identity in birds:
The identity of the three definite digits in the bird wing is a longstanding problem in comparative anatomy. The problem is that these digits have the structure of digits 1, 2, and 3, but develop from embryonic positions 2, 3, and 4. In 1999 my colleague Jacques Gauthier and I proposed that this occurred because of a homeotic digit identity frameshift during the evolution of dinosaurs. Gene expression evidence supports this hypothesis and now we are working towards identifying the genetic changes which gave rise to the digit identity frame shift.
The developmental genetics of homology.
Wagner, G.P. (2007). The developmental genetics of homology. Nat. Rev. Genet. (6):473-9.
Adaptive changes in the transcription factor HoxA-11 are essential for the evolution of pregnancy in mammals.
Lynch, V. J., A. Tanzer, Y. Wang, F. C. Leung, B. Gellersen, and G. P. Wagner 2008 Adaptive changes in the transcription factor HoxA-11 are essential for the evolution of pregnancy in mammals. Proc. Natl. Acad. Sci. USA, 105:14928-14933.
Pleiotropic scaling of gene effects an the “cost of complexity.”
Wagner, G. P., J. P. Kenny-Hunt, M. Pavlicev, J. R. Peck, D. Waxman and J. Cheverund 2008. Pleiotropic scaling of gene effects an the “cost of complexity.” Nature, 452: 470-472.
Measuring transcription factor binding site turnover: a maximum likelihood approach using phylogenies.
Otto, W., P. F. Stader, F. López-Gialdéz, J. P. Townsend, V. J. Lynch, and G. P. Wagner 2009. Measuring transcription factor binding site turnover: a maximum likelihood approach using phylogenies. Genome Biology and Evolution, 1:85-98.
Cartilage formation and digit identity in bird evolution and Cyclopamine-treated wings.
Vargas, A. O. and G. P. Wagner 2009. Cartilage formation and digit identity in bird evolution and Cyclopamine-treated wings. Evolution and Development, 11:163-169.
The Gene regulatory logic of transcription factor evolution. Trends in Ecology and Evolution
Wagner, G. P., and V. J. Lynch 2008 The Gene regulatory logic of transcription factor evolution. Trends in Ecology and Evolution, 23: 377-385.
The road to modularity.
Wagner, G. P., M. Pavlicev and J. Cheverud 2007. The road to modularity. Nature Reviews Genetics, 8:921-931.
A stochastic model for transcription factor binding site abundance.
Wagner, GP, W. Otto, V. Lynch, and PF Stadler 2007. A stochastic model for transcription factor binding site abundance. J. theor, Biol., 247:544-553.
Evidence for the reversibility of digit loss: a phylogenetic study of limb evolution in the genus Bachia (Gymnophthalmidae: Squamata).
Kohlsdorf, T and G. P. Wagner 2006 Evidence for the reversibility of digit loss: a phylogenetic study of limb evolution in the genus Bachia (Gymnophthalmidae: Squamata). Evolution 60: 1896-1912.
The “fish specific” Hox cluster duplication is coincidental with the origin of teleosts.
Crow K. D., Stadler PF, Lynch V, Amemiya C, Wagner GP (2006) The “fish specific” Hox cluster duplication is coincidental with the origin of teleosts. Mol Biol. & Evol, 23:121-136.
1,2,3 = 2,3,4: a solution to the problem of the homology of the digits in the avian hand
Wagner, G. P., and J. Gauthier 1999. 1,2,3 = 2,3,4: a solution to the problem of the homology of the digits in the avian hand. Proc. Natl. Acad. Sci. USA, 96, 5111-5116.
Full List of PubMed Publications
- Wagner GP, Pavličev M: Origin, Function, and Effects of Female Orgasm: All Three are Different. J Exp Zool B Mol Dev Evol. 2017 Jun; 2017 Apr 3. PMID: 28371416
- Pavličev M, Wagner GP, Chavan AR, Owens K, Maziarz J, Dunn-Fletcher C, Kallapur SG, Muglia L, Jones H: Single-cell transcriptomics of the human placenta: inferring the cell communication network of the maternal-fetal interface. Genome Res. 2017 Mar; 2017 Feb 7. PMID: 28174237
- Park Y, Nnamani MC, Maziarz J, Wagner GP: Cis-Regulatory Evolution of Forkhead Box O1 (FOXO1), a Terminal Selector Gene for Decidual Stromal Cell Identity. Mol Biol Evol. 2016 Dec; 2016 Sep 15. PMID: 27634871
- Arendt D, Musser JM, Baker CV, Bergman A, Cepko C, Erwin DH, Pavlicev M, Schlosser G, Widder S, Laubichler MD, Wagner GP: The origin and evolution of cell types. Nat Rev Genet. 2016 Dec; 2016 Nov 7. PMID: 27818507
- Wagner GP, Pavličev M: What the Evolution of Female Orgasm Teaches Us. J Exp Zool B Mol Dev Evol. 2016 Sep. PMID: 27700007
- Kin K, Maziarz J, Chavan AR, Kamat M, Vasudevan S, Birt A, Emera D, Lynch VJ, Ott TL, Pavlicev M, Wagner GP: The Transcriptomic Evolution of Mammalian Pregnancy: Gene Expression Innovations in Endometrial Stromal Fibroblasts. Genome Biol Evol. 2016 Aug 25; 2016 Aug 25. PMID: 27401177
- Chavan AR, Wagner GP: The fetal-maternal interface of the nine-banded armadillo: endothelial cells of maternal sinus are partially replaced by trophoblast. Zoological Lett. 2016; 2016 Jun 8. PMID: 27284459
- Nnamani MC, Ganguly S, Erkenbrack EM, Lynch VJ, Mizoue LS, Tong Y, Darling HL, Fuxreiter M, Meiler J, Wagner GP: A Derived Allosteric Switch Underlies the Evolution of Conditional Cooperativity between HOXA11 and FOXO1. Cell Rep. 2016 Jun 7; 2016 May 26. PMID: 27239043
- Chavan AR, Bhullar BA, Wagner GP: What was the ancestral function of decidual stromal cells? A model for the evolution of eutherian pregnancy. Placenta. 2016 Apr; 2016 Feb 23. PMID: 27016782
- Stopper GF, Richards-Hrdlicka KL, Wagner GP: Hedgehog inhibition causes complete loss of limb outgrowth and transformation of digit identity in Xenopus tropicalis. J Exp Zool B Mol Dev Evol. 2016 Mar; 2016 Feb 26. PMID: 26918681
- Wagner GP: What is "homology thinking" and what is it for? J Exp Zool B Mol Dev Evol. 2016 Jan; 2015 Oct 21. PMID: 26486321
- Musser JM, Wagner GP: Character trees from transcriptome data: Origin and individuation of morphological characters and the so-called "species signal". J Exp Zool B Mol Dev Evol. 2015 Nov; 2015 Jul 14. PMID: 26175303
- Singarete ME, Grizante MB, Milograna SR, Nery MF, Kin K, Wagner GP, Kohlsdorf T: Molecular evolution of HoxA13 and the multiple origins of limbless morphologies in amphibians and reptiles. Genet Mol Biol. 2015 Jul-Sep; 2015 Aug 21. PMID: 26500429
- Musser JM, Wagner GP, Prum RO: Nuclear β-catenin localization supports homology of feathers, avian scutate scales, and alligator scales in early development. Evol Dev. 2015 May-Jun. PMID: 25963196
- Kin K, Nnamani MC, Lynch VJ, Michaelides E, Wagner GP: Cell-type phylogenetics and the origin of endometrial stromal cells. Cell Rep. 2015 Mar 3; 2015 Feb 26. PMID: 25732829
- Lynch VJ, Nnamani MC, Kapusta A, Brayer K, Plaza SL, Mazur EC, Emera D, Sheikh SZ, Grützner F, Bauersachs S, Graf A, Young SL, Lieb JD, DeMayo FJ, Feschotte C, Wagner GP: Ancient transposable elements transformed the uterine regulatory landscape and transcriptome during the evolution of mammalian pregnancy. Cell Rep. 2015 Feb 3; 2015 Jan 29. PMID: 25640180
- Liang C, FANTOM Consortium., Forrest AR, Wagner GP: The statistical geometry of transcriptome divergence in cell-type evolution and cancer. Nat Commun. 2015 Jan 14; 2015 Jan 14. PMID: 25585899
- Wagner GP: Two rules for the detection and quantification of epistasis and other interaction effects. Methods Mol Biol. 2015. PMID: 25403531
- D'Souza AW, Wagner GP: Malignant cancer and invasive placentation: A case for positive pleiotropy between endometrial and malignancy phenotypes. Evol Med Public Health. 2014 Oct 15; 2014 Oct 15. PMID: 25324490
- Kin K, Maziarz J, Wagner GP: Immunohistological study of the endometrial stromal fibroblasts in the opossum, Monodelphis domestica: evidence for homology with eutherian stromal fibroblasts. Biol Reprod. 2014 May; 2014 Apr 16. PMID: 24740599
- Wagner GP, Kin K, Muglia L, Pavlicev M: Evolution of mammalian pregnancy and the origin of the decidual stromal cell. Int J Dev Biol. 2014. PMID: 25023677
- Nnamani MC, Plaza S, Romero R, Wagner GP: Evidence for independent evolution of functional progesterone withdrawal in primates and guinea pigs. Evol Med Public Health. 2013 Jan; 2013 Dec 3. PMID: 24481205
- Wagner GP, Kin K, Lynch VJ: Measurement of mRNA abundance using RNA-seq data: RPKM measure is inconsistent among samples. Theory Biosci. 2012 Dec; 2012 Aug 8. PMID: 22872506
- Wagner GP: Next Gen Devo-Evo. J Exp Zool B Mol Dev Evol. 2012 Nov; 2012 Jul 12. PMID: 22791647
- Emera D, Wagner GP: Transformation of a transposon into a derived prolactin promoter with function during human pregnancy. Proc Natl Acad Sci U S A. 2012 Jul 10; 2012 Jun 25. PMID: 22733751
- Emera D, Wagner GP: Transposable element recruitments in the mammalian placenta: impacts and mechanisms. Brief Funct Genomics. 2012 Jul; 2012 Jun 28. PMID: 22753775
- Wagner GP, Tong Y, Emera D, Romero R: An evolutionary test of the isoform switching hypothesis of functional progesterone withdrawal for parturition: humans have a weaker repressive effect of PR-A than mice. J Perinat Med. 2012 Mar 27; 2012 Mar 27. PMID: 22752763
- Brandley MC, Young RL, Warren DL, Thompson MB, Wagner GP: Uterine gene expression in the live-bearing lizard, Chalcides ocellatus, reveals convergence of squamate reptile and mammalian pregnancy mechanisms. Genome Biol Evol. 2012; 2012 Feb 14. PMID: 22333490
- Emera D, Casola C, Lynch VJ, Wildman DE, Agnew D, Wagner GP: Convergent evolution of endometrial prolactin expression in primates, mice, and elephants through the independent recruitment of transposable elements. Mol Biol Evol. 2012 Jan; 2011 Aug 2. PMID: 21813467
- Lynch VJ, May G, Wagner GP: Regulatory evolution through divergence of a phosphoswitch in the transcription factor CEBPB. Nature. 2011 Nov 13; 2011 Nov 13. PMID: 22080951
- Lynch VJ, Leclerc RD, May G, Wagner GP: Transposon-mediated rewiring of gene regulatory networks contributed to the evolution of pregnancy in mammals. Nat Genet. 2011 Sep 25; 2011 Sep 25. PMID: 21946353
- Wang Z, Young RL, Xue H, Wagner GP: Transcriptomic analysis of avian digits reveals conserved and derived digit identities in birds. Nature. 2011 Sep 4; 2011 Sep 4. PMID: 21892187
- Brayer KJ, Lynch VJ, Wagner GP: Evolution of a derived protein-protein interaction between HoxA11 and Foxo1a in mammals caused by changes in intramolecular regulation. Proc Natl Acad Sci U S A. 2011 Aug 9; 2011 Jul 25. PMID: 21788518
- Young RL, Wagner GP: Why ontogenetic homology criteria can be misleading: lessons from digit identity transformations. J Exp Zool B Mol Dev Evol. 2011 May 15; 2011 Jan 11. PMID: 21462311
- Young RL, Bever GS, Wang Z, Wagner GP: Identity of the avian wing digits: problems resolved and unsolved. Dev Dyn. 2011 May; 2011 Mar 15. PMID: 21412936
- Bever GS, Gauthier JA, Wagner GP: Finding the frame shift: digit loss, developmental variability, and the origin of the avian hand. Evol Dev. 2011 May-Jun. PMID: 21535465
- Lynch VJ, Wagner GP: Revisiting a classic example of transcription factor functional equivalence: are Eyeless and Pax6 functionally equivalent or divergent? J Exp Zool B Mol Dev Evol. 2011 Mar 15; 2010 Sep 17. PMID: 20853421
- Wagner GP, Zhang J: The pleiotropic structure of the genotype-phenotype map: the evolvability of complex organisms. Nat Rev Genet. 2011 Mar. PMID: 21331091
- Rorick MM, Wagner GP: Protein structural modularity and robustness are associated with evolvability. Genome Biol Evol. 2011; 2011 May 21. PMID: 21602570
- Wagner GP: The measurement theory of fitness. Evolution. 2010 May; 2009 Nov 26. PMID: 20002165
- Wagner GP, Lynch VJ: Evolutionary novelties. Curr Biol. 2010 Jan 26. PMID: 20129035
- Lynch VJ, Wagner GP: Did egg-laying boas break Dollo's law? Phylogenetic evidence for reversal to oviparity in sand boas (Eryx: Boidae). Evolution. 2010 Jan; 2009 Jul 30. PMID: 19659599
- Rorick MM, Wagner GP: The origin of conserved protein domains and amino acid repeats via adaptive competition for control over amino acid residues. J Mol Evol. 2010 Jan; 2009 Dec 19. PMID: 20024539
- Young RL, Caputo V, Giovannotti M, Kohlsdorf T, Vargas AO, May GE, Wagner GP: Evolution of digit identity in the three-toed Italian skink Chalcides chalcides: a new case of digit identity frame shift. Evol Dev. 2009 Nov-Dec. PMID: 19878286
- Lynch VJ, Brayer K, Gellersen B, Wagner GP: HoxA-11 and FOXO1A cooperate to regulate decidual prolactin expression: towards inferring the core transcriptional regulators of decidual genes. PLoS One. 2009 Sep 3; 2009 Sep 3. PMID: 19727442
- Vargas AO, Wagner GP: Frame-shifts of digit identity in bird evolution and Cyclopamine-treated wings. Evol Dev. 2009 Mar-Apr. PMID: 19245548
- Lynch VJ, Wagner GP: Multiple chromosomal rearrangements structured the ancestral vertebrate Hox-bearing protochromosomes. PLoS Genet. 2009 Jan; 2009 Jan 23. PMID: 19165336
- Kohlsdorf T, Cummings MP, Lynch VJ, Stopper GF, Takahashi K, Wagner GP: A molecular footprint of limb loss: sequence variation of the autopodial identity gene Hoxa-13. J Mol Evol. 2008 Dec. PMID: 18855040
- Vargas AO, Kohlsdorf T, Fallon JF, Vandenbrooks J, Wagner GP: The evolution of HoxD-11 expression in the bird wing: insights from Alligator mississippiensis. PLoS One. 2008 Oct 3; 2008 Oct 3. PMID: 18833328
- Lynch VJ, Tanzer A, Wang Y, Leung FC, Gellersen B, Emera D, Wagner GP: Adaptive changes in the transcription factor HoxA-11 are essential for the evolution of pregnancy in mammals. Proc Natl Acad Sci U S A. 2008 Sep 30; 2008 Sep 22. PMID: 18809929
- Lynch VJ, Wagner GP: Resurrecting the role of transcription factor change in developmental evolution. Evolution. 2008 Sep; 2008 Jun 28. PMID: 18564379
- Wagner GP, Lynch VJ: The gene regulatory logic of transcription factor evolution. Trends Ecol Evol. 2008 Jul; 2008 May 22. PMID: 18501470
- Wagner GP, Kenney-Hunt JP, Pavlicev M, Peck JR, Waxman D, Cheverud JM: Pleiotropic scaling of gene effects and the 'cost of complexity'. Nature. 2008 Mar 27. PMID: 18368117
- Draghi J, Wagner GP: Evolution of evolvability in a developmental model. Evolution. 2008 Feb; 2007 Nov 19. PMID: 18031304
- Wagner GP, Vargas AO: On the nature of thumbs. Genome Biol. 2008; 2008 Mar 4. PMID: 18341703
- Wagner GP, Pavlicev M, Cheverud JM: The road to modularity. Nat Rev Genet. 2007 Dec. PMID: 18007649
- Wagner GP, Otto W, Lynch V, Stadler PF: A stochastic model for the evolution of transcription factor binding site abundance. J Theor Biol. 2007 Aug 7; 2007 Mar 7. PMID: 17475285
- Wagner GP: The developmental genetics of homology. Nat Rev Genet. 2007 Jun; 2007 May 8. PMID: 17486120
- Stopper GF, Wagner GP: Inhibition of Sonic hedgehog signaling leads to posterior digit loss in Ambystoma mexicanum: parallels to natural digit reduction in urodeles. Dev Dyn. 2007 Jan. PMID: 17117438
- Wagner GP, Pyle AM: Tinkering with transcription factor proteins: the role of transcription factor adaptation in developmental evolution. Novartis Found Symp. 2007. PMID: 17710850
- Lynch VJ, Roth JJ, Wagner GP: Adaptive evolution of Hox-gene homeodomains after cluster duplications. BMC Evol Biol. 2006 Nov 1; 2006 Nov 1. PMID: 17078881
- Kohlsdorf T, Wagner GP: Evidence for the reversibility of digit loss: a phylogenetic study of limb evolution in Bachia (Gymnophthalmidae: Squamata). Evolution. 2006 Sep. PMID: 17089974
- Crow KD, Wagner GP, SMBE Tri-National Young Investigators.: Proceedings of the SMBE Tri-National Young Investigators' Workshop 2005. What is the role of genome duplication in the evolution of complexity and diversity? Mol Biol Evol. 2006 May; 2005 Dec 20. PMID: 16368775
- Crow KD, Stadler PF, Lynch VJ, Amemiya C, Wagner GP: The "fish-specific" Hox cluster duplication is coincident with the origin of teleosts. Mol Biol Evol. 2006 Jan; 2005 Sep 14. PMID: 16162861
- Stopper GF, Wagner GP: Of chicken wings and frog legs: a smorgasbord of evolutionary variation in mechanisms of tetrapod limb development. Dev Biol. 2005 Dec 1; 2005 Oct 24. PMID: 16246321
- Wagner GP, Lynch VJ: Molecular evolution of evolutionary novelties: the vagina and uterus of therian mammals. J Exp Zool B Mol Dev Evol. 2005 Nov 15. PMID: 16252266
- Wagner GP: The developmental evolution of avian digit homology: an update. Theory Biosci. 2005 Nov; 2005 Sep 12. PMID: 17046354
- Wagner GP, Takahashi K, Lynch V, Prohaska SJ, Fried C, Stadler PF, Amemiya C: Molecular evolution of duplicated ray finned fish HoxA clusters: increased synonymous substitution rate and asymmetrical co-divergence of coding and non-coding sequences. J Mol Evol. 2005 May. PMID: 15983874
- Lynch VJ, Roth JJ, Takahashi K, Dunn CW, Nonaka DF, Stopper GF, Wagner GP: Adaptive evolution of HoxA-11 and HoxA-13 at the origin of the uterus in mammals. Proc Biol Sci. 2004 Nov 7. PMID: 15539344
- Wagner GP, Fried C, Prohaska SJ, Stadler PF: Divergence of conserved non-coding sequences: rate estimates and relative rate tests. Mol Biol Evol. 2004 Nov; 2004 Jul 28. PMID: 15282332
- Wagner GP, Laubichler MD: Rupert Riedl and the re-synthesis of evolutionary and developmental biology: body plans and evolvability. J Exp Zool B Mol Dev Evol. 2004 Jan 15. PMID: 14760655
- Wagner GP: Evolutionary genetics: the nature of hidden genetic variation unveiled. Curr Biol. 2003 Dec 16. PMID: 14680653
- Wagner GP, Larsson HC: What is the promise of developmental evolution? III. The crucible of developmental evolution. J Exp Zool B Mol Dev Evol. 2003 Dec 15. PMID: 14984030
- Hermisson J, Hansen TF, Wagner GP: Epistasis in polygenic traits and the evolution of genetic architecture under stabilizing selection. Am Nat. 2003 May; 2003 May 2. PMID: 12858280
- Wagner GP, Stadler PF: Quasi-independence, homology and the unity of type: a topological theory of characters. J Theor Biol. 2003 Feb 21. PMID: 12623283
- Carter AJ, Wagner GP: Evolution of functionally conserved enhancers can be accelerated in large populations: a population-genetic model. Proc Biol Sci. 2002 May 7. PMID: 12028779
- Chiu CH, Amemiya C, Dewar K, Kim CB, Ruddle FH, Wagner GP: Molecular evolution of the HoxA cluster in the three major gnathostome lineages. Proc Natl Acad Sci U S A. 2002 Apr 16; 2002 Apr 9. PMID: 11943847
- Wagner GP, Müller GB: Evolutionary innovations overcome ancestral constraints: a re-examination of character evolution in male sepsid flies (Diptera: Sepsidae). Evol Dev. 2002 Jan-Feb. PMID: 11868655