Abstract
Since the last decade of the twentieth century, systems biology has gained the ability to study the structure and function of genome-scale metabolic networks. These are systems of hundreds to thousands of chemical reactions that sustain life. Most of these reactions are catalyzed by enzymes which are encoded by genes. A metabolic network extracts chemical elements and energy from the environment, and converts them into forms that the organism can use. The function of a whole metabolic network constrains evolutionary changes in its parts. I will discuss here three classes of such changes, and how they are constrained by the function of the whole. These are the accumulation of amino acid changes in enzyme-coding genes, duplication of enzyme-coding genes, and changes in the regulation of enzymes. Conversely, evolutionary change in network parts can alter the function of the whole network. I will discuss here two such changes, namely the elimination of reactions from a metabolic network through loss of function mutations in enzyme-coding genes, and the addition of metabolic reactions, for example through mechanisms such as horizontal gene transfer. Reaction addition also provides a window into the evolution of metabolic innovations, the ability of a metabolism to sustain life on new sources of energy and of chemical elements.
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References
Feist AM, Henry CS, Reed JL, Krummenacker M, Joyce AR, Karp PD, Broadbelt LJ, Hatzimanikatis V, Palsson BO (2007) A genome-scale metabolic reconstruction for Escherichia coli K-12 MG1655 that accounts for 1260 ORFs and thermodynamic information. Mol Syst Biol 3. doi:121.10.1038/msb4100155
Feist AM, Herrgard MJ, Thiele I, Reed JL, Palsson BO (2009) Reconstruction of biochemical networks in microorganisms. Nat Rev Microbiol 7(2):129–143. doi:10.1038/nrmicro1949
Holms WH (1986) The central metabolic pathways of Escherischia coli: relationship between flux and control at a branch point, efficiency of conversion to biomass and excretion of acetate. Current Topics Cell Regul 28:69–105
Dykhuizen DE, Dean AM, Hartl DL (1987) Metabolic flux and fitness. Genetics 115(#1):25–31
Keightley PD, Kacser H (1987) Dominance, pleiotropy and metabolic structure. Genetics 117(#2):319–329
Joshi A, Palsson BO (1989) Metabolic dynamics in the human red-cell.1. A comprehensive kinetic model. J Theor Biol 141(4):515–528
Hofmeyr J-HS (1991) Control pattern analysis of metabolic pathways: flux and concentration control in linear pathways. Eur J Biochem 275:253–258
Varma A, Palsson BO (1993) Metabolic capabilities of Escherichia coli. Synthesis of biosynthetic precursors and cofactors. J Theor Biol 165:477–502
Veech RL, Fell DA (1996) Distribution control of metabolic flux. Cell Biochem Funct 14(#4):229–236
Bonarius HPJ, Schmid G, Tramper J (1997) Flux analysis of underdetermined metabolic networks: the quest for the missing constraints. Trends Biotechnol 15(8):308–314
Thomas S, Fell DA (1998) A control analysis exploration of the role of ATP utilisation in glycolytic-flux control and glycolytic-metabolite-concentration regulation. Eur J Biochem 258(#3):956–967
Fell D (1997) Understanding the control of metabolism. Portland Press, Miami
Fischer E, Sauer U (2005) Large-scale in vivo flux analysis shows rigidity and suboptimal performance of Bacillus subtilis metabolism. Nat Genet 37(6):636–640
Blank LM, Lehmbeck F, Sauer U (2005) Metabolic-flux and network analysis in fourteen hemiascomycetous yeasts. Fems Yeast Res 5(6–7):545–558
Blank LM, Kuepfer L, Sauer U (2005) Large-scale C-13-flux analysis reveals mechanistic principles of metabolic network robustness to null mutations in yeast. Genome Biol 6(6):R49
Price N, Reed J, Palsson B (2004) Genome-scale models of microbial cells: evaluating the consequences of constraints. Nat Rev Microbiol 2:886–897
Becker SA, Feist AM, Mo ML, Hannum G, Palsson BO, Herrgard MJ (2007) Quantitative prediction of cellular metabolism with constraint-based models: the COBRA Toolbox. Nat Protoc 2(3):727–738. doi:10.1038/nprot.2007.99
Heinrich R, Schuster S (1996) The regulation of cellular systems. Chapman and Hall, New York
Cormen TH, Leiserson CE, Rivest RL, Stein C (2005) Introduction to algorithms. 2nd edn. MIT Press, Cambridge, MA
Forster J, Famili I, Fu P, Palsson B, Nielsen J (2003) Genome-scale reconstruction of the Saccharomyces cerevisiae metabolic network. Genome Res 13:244–253
Edwards JS, Palsson BO (2000) The Escherichia coli MG1655 in silico metabolic genotype: Its definition, characteristics, and capabilities. Proc Natal Acad Sci USA 97(10):5528–5533
Schuetz R, Kuepfer L, Sauer U (2007) Systematic evaluation of objective functions for predicting intracellular fluxes in Escherichia coli. Mol Syst Biol 3. doi:119.10.1038/msb4100162
Savinell JM, Palsson BO (1992) Network analysis of intermediary metabolism using linear optimization.1. development of mathematical formalism. J Theor Biol 154(4):421–454
Fell DA, Small JR (1986) Fat synthesis in adipose-tissue - an examination of stoichiometric constraints. Biochem J 238(3):781–786
Segre D, Vitkup D, Church G (2002) Analysis of optimality in natural and perturbed metabolic networks. Proc Natl Acad Sci USA 99:15112–15117
Papin JA, Stelling J, Price ND, Klamt S, Schuster S, Palsson BO (2004) Comparison of network-based pathway analysis methods. Trends in Biotechnology 22(8):400–405. doi:10.1016/j.tibtech.2004.06.010
Palsson BO, Price ND, Papin JA (2003) Development of network-based pathway definitions: the need to analyze real metabolic networks. Trends Biotechnol 21 (5):195–198. doi:10.1016/s0167–7799(03)00080–5
Papin JA, Price ND, Palsson BO (2002) Extreme pathway lengths and reaction participation in genome-scale metabolic networks. Genome Res 12(12):1889–1900. doi:10.1101/gr.327702
Stelling J, Klamt S, Bettenbrock K, Schuster S, Gilles ED (2002) Metabolic network structure determines key aspects of functionality and regulation. Nature 420(6912):190–193
Schuster S, Fell DA, Dandekar T (2000) A general definition of metabolic pathways useful for systematic organization and analysis of complex metabolic networks. Nat Biotechnol 18(3):326–332
Klamt S, Stelling J (2003) Two approaches for metabolic pathway analysis? Trends Biotechnol 21(2):64–69
Larhlimi A, Bockmayr A (2006) A new constraint-based description of the steady-state flux cone of metabolic networks. In: Workshop on Networks in Computational Biology, Ankara, TURKEY, Sep 10–12 2006. pp. 2257–2266. doi:10.1016/j.dam.2008.06.039
Becker SA, Palsson BO (2008) Context-specific metabolic networks are consistent with experiments. Plos Comput Biol 4(5). doi:e1000082.10.1371/journal.pcbi.1000082
Herrgard MJ, Fong SS, Palsson BO (2006) Identification of genome-scale metabolic network models using experimentally measured flux profiles. Plos Comput Biol 2(7):676–686. doi:e72q.10.1371/journal.pcbi.0020072
Covert MW, Knight EM, Reed JL, Herrgard MJ, Palsson BO (2004) Integrating high-throughput and computational data elucidates bacterial networks. Nature 429(6987):92–96
Herrgard MJ, Lee BS, Portnoy V, Palsson BO (2006) Integrated analysis of regulatory and metabolic networks reveals novel regulatory mechanisms in Saccharomyces cerevisiae. Genome Res 16(5):627–635. doi:10.1101/gr.4083206
Forster J, Famili I, Palsson BO, Nielsen J (2003) Large-scale evaluation of in-silico gene deletions in Saccharomyces cerevisiae. Omics 7:193–202
Fong SS, Palsson BO (2004) Metabolic gene-deletion strains of Escherichia coli evolve to computationally predicted growth phenotypes. Nat Genet 36(10):1056–1058
Feist AM, Palsson BO (2008) The growing scope of applications of genome-scale metabolic reconstructions using Escherichia coli. Nat Biotechnol 26(6):659–667. doi:10.1038/nbt1401
Henry CS, Broadbelt LJ, Hatzimanikatis V (2007) Thermodynamics-based metabolic flux analysis. Biophys J 92(5):1792–1805. doi:10.1529/biophysj.106.093138
Mavrovouniotis ML (1991) Estimation of standard Gibbs energy changes of biotransformations. J Biol Chem 266(22):14440–14445
Li W-H (1997) Molecular evolution. Sinauer, Massachusetts
Parmley JL, Hurst LD (2007) How do synonymous mutations affect fitness? Bioessays 29(6):515–519. doi:10.1002/bies.20592
Wagner A, Fell D (2001) The small world inside large metabolic networks. Proc Roy Soc London Ser B 280:1803–1810
Newman MEJ (2003) The structure and function of complex networks. Siam Review 45(2):167–256
Vitkup D, Kharchenko P, Wagner A (2006) Influence of metabolic network structure and function on enzyme evolution. Genome Biol 7(5). doi:R3910.1186/gb-2006–7–5-r39
Greenberg AJ, Stockwell SR, Clark AG (2008) Evolutionary constraint and adaptation in the metabolic network of Drosophila. Mol Biol Evol 25(12):2537–2546. doi:10.1093/molbev/msn205
Hudson CM, Conant GC (2011) Expression level, cellular compartment and metabolic network position all influence the average selective constraint on mammalian enzymes. BMC Evolutionary Biol 11. doi:89.10.1186/1471-2148-11-89
Hahn M, Conant GC, Wagner A (2004) Molecular evolution in large genetic networks: does connectivity equal importance? J Mol Evol 58:203–211
Low WY, Ng HL, Morton CJ, Parker MW, Batterham P, Robin C (2007) Molecular evolution of glutathione S-transferases in the genus drosophila. Genetics 177(3):1363–1375. doi:10.1534/genetics.107.075838
Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, Yandell M, Evans CA, Holt RA, Gocayne JD, Amanatides P, Ballew RM, Huson DH, Wortman JR, Zhang Q, Kodira CD, Zheng XQH, Chen L, Skupski M, Subramanian G, Thomas PD, Zhang JH, Miklos GLG, Nelson C, Broder S, Clark AG, Nadeau C, McKusick VA, Zinder N, Levine AJ, Roberts RJ, Simon M, Slayman C, Hunkapiller M, Bolanos R, Delcher A, Dew I, Fasulo D, Flanigan M, Florea L, Halpern A, Hannenhalli S, Kravitz S, Levy S, Mobarry C, Reinert K, Remington K, Abu-Threideh J, Beasley E, Biddick K, Bonazzi V, Brandon R, Cargill M, Chandramouliswaran I, Charlab R, Chaturvedi K, Deng ZM, Di Francesco V, Dunn P, Eilbeck K, Evangelista C, Gabrielian AE, Gan W, Ge WM, Gong FC, Gu ZP, Guan P, Heiman TJ, Higgins ME, Ji RR, Ke ZX, Ketchum KA, Lai ZW, Lei YD, Li ZY, Li JY, Liang Y, Lin XY, Lu F, Merkulov GV, Milshina N, Moore HM, Naik AK, Narayan VA, Neelam B, Nusskern D, Rusch DB, Salzberg S, Shao W, Shue BX, Sun JT, Wang ZY, Wang AH, Wang X, Wang J, Wei MH, Wides R, Xiao CL, Yan CH, Yao A, Ye J, Zhan M, Zhang WQ, Zhang HY, Zhao Q, Zheng LS, Zhong F, Zhong WY, Zhu SPC, Zhao SY, Gilbert D, Baumhueter S, Spier G, Carter C, Cravchik A, Woodage T, Ali F, An HJ, Awe A, Baldwin D, Baden H, Barnstead M, Barrow I, Beeson K, Busam D, Carver A, Center A, Cheng ML, Curry L, Danaher S, Davenport L, Desilets R, Dietz S, Dodson K, Doup L, Ferriera S, Garg N, Gluecksmann A, Hart B, Haynes J, Haynes C, Heiner C, Hladun S, Hostin D, Houck J, Howland T, Ibegwam C, Johnson J, Kalush F, Kline L, Koduru S, Love A, Mann F, May D, McCawley S, McIntosh T, McMullen I, Moy M, Moy L, Murphy B, Nelson K, Pfannkoch C, Pratts E, Puri V, Qureshi H, Reardon M, Rodriguez R, Rogers YH, Romblad D, Ruhfel B, Scott R, Sitter C, Smallwood M, Stewart E, Strong R, Suh E, Thomas R, Tint NN, Tse S, Vech C, Wang G, Wetter J, Williams S, Williams M, Windsor S, Winn-Deen E, Wolfe K, Zaveri J, Zaveri K, Abril JF, Guigo R, Campbell MJ, Sjolander KV, Karlak B, Kejariwal A, Mi HY, Lazareva B, Hatton T, Narechania A, Diemer K, Muruganujan A, Guo N, Sato S, Bafna V, Istrail S, Lippert R, Schwartz R, Walenz B, Yooseph S, Allen D, Basu A, Baxendale J, Blick L, Caminha M, Carnes-Stine J, Caulk P, Chiang YH, Coyne M, Dahlke C, Mays AD, Dombroski M, Donnelly M, Ely D, Esparham S, Fosler C, Gire H, Glanowski S, Glasser K, Glodek A, Gorokhov M, Graham K, Gropman B, Harris M, Heil J, Henderson S, Hoover J, Jennings D, Jordan C, Jordan J, Kasha J, Kagan L, Kraft C, Levitsky A, Lewis M, Liu XJ, Lopez J, Ma D, Majoros W, McDaniel J, Murphy S, Newman M, Nguyen T, Nguyen N, Nodell M, Pan S, Peck J, Peterson M, Rowe W, Sanders R, Scott J, Simpson M, Smith T, Sprague A, Stockwell T, Turner R, Venter E, Wang M, Wen MY, Wu D, Wu M, Xia A, Zandieh A, Zhu XH (2001) The sequence of the human genome. Science 291(5507):1304–1351
Lynch M, Conery JS (2000) The evolutionary fate and consequences of duplicate genes. Science 290(5494):1151–1155
Taylor JS, Raes J (2004) Duplication and divergence: the evolution of new genes and old ideas. Ann Rev Genet 38:615–643
Conant GC, Wolfe KH (2008) Turning a hobby into a job: how duplicated genes find new functions. Nat Rev Genet 9(12):938–950. doi:10.1038/nrg2482
Bekaert M, Conant GC (2011) Copy number alterations among mammalian enzymes cluster in the metabolic network. Molecular Biology and Evolution 28(2):1111–1121. doi:10.1093/molbev/msq296
Dunham MJ, Badrane H, Ferea T, Adams J, Brown PO, Rosenzweig F, Botstein D (2002) Characteristic genome rearrangements in experimental evolution of Saccharomyces cerevisiae. Proc Natal Acad Sci USA 99(25):16144–16149
van Hoek MJA, Hogeweg P (2009) Metabolic adaptation after whole genome duplication. Mol Biol Evol 26(11):2441–2453. doi:10.1093/molbev/msp160
Fong SS, Joyce AR, Palsson BO (2005) Parallel adaptive evolution cultures of Escherichia coli lead to convergent growth phenotypes with different gene expression states. Genome Res 15(10):1365–1372. doi:10.1101/gr.3832305
McAlister-Henn L, Small W (1997) Molecular genetics of yeast TCA cycle isozymes. Prog Nucleic Acid Res Mol Biol 57:317–339
Wagner A (2009) Evolutionary constraints permeate large metabolic networks. BMC Evolutionary Biol 9. doi:231.10.1186/1471-2148-9-231
Vieira G, Sabarly V, Bourguignon PY, Durot M, Le Fevre F, Mornico D, Vallenet D, Bouvet O, Denamur E, Schachter V, Medigue C (2011) Core and panmetabolism in Escherichia coli. J Bacteriol 193(6):1461–1472. doi:10.1128/jb.01192–10
Noor E, Eden E, Milo R, Alon U (2010) Central carbon metabolism as a minimal biochemical walk between precursors for biomass and energy. Mol Cell 39(5):809–820. doi:10.1016/j.molcel.2010.08.031
Melendez-Hevia E, Waddell TG, Cascante M (1996) The puzzle of the Krebs citric-acid cycle: assembling the pieces of chemically feasible reactions; and opportunism in the design of metabolic pathways during evolution. J Mol Evol 43(#3):293–303
Huynen MA, Dandekar T, Bork P (1999) Variation and evolution of the citric acid cycle: a genomic perspective. Trends Microbiol 7(7):281–291
Moran NA, Wernegreen JJ (2000) Lifestyle evolution in symbiotic bacteria: insights from genomics. Trends Ecol Evol 15(8):321–326
Moran NA, McCutcheon JP, Nakabachi A (2008) Genomics and evolution of heritable bacterial symbionts. Ann Rev Genet 42:165–190. doi:10.1146/annurev.genet.41.110306.130119
Thomas GH, Zucker J, MacDonald SJ, Sorokin A, Goryanin I, Douglas AE (2009) A fragile metabolic network adapted for cooperation in the symbiotic bacterium Buchnera aphidicola. BMC Sys Biol 3:24. doi:10.1186/1752–0509–3–24
Reed JL, Vo TD, Schilling CH, Palsson BO (2003) An expanded genome-scale model of Escherichia coli K-12 (iJR904 GSM/GPR). Genome Biol 4(9):R54
Yus E, Maier T, Michalodimitrakis K, van Noort V, Yamada T, Chen WH, Wodke JAH, Guell M, Martinez S, Bourgeois R, Kuhner S, Raineri E, Letunic I, Kalinina OV, Rode M, Herrmann R, Gutierrez-Gallego R, Russell RB, Gavin AC, Bork P, Serrano L (2009) Impact of genome reduction on bacterial metabolism and its regulation. Science 326(5957):1263–1268. doi:10.1126/science.1177263
Soyer OS, Pfeiffer T (2010) Evolution under fluctuating environments explains observed robustness in metabolic networks. PLoS Comp Biol 6(8). doi:e1000907.10.1371/journal.pcbi.1000907
Rodrigues JF, Wagner A (2011) Genotype networks in sulfur metabolism. BMC Sys Biol 5:39. doi:10.1186/1752–0509–5–39
Yizhak K, Tuller T, Papp B, Ruppin E (2011) Metabolic modeling of endosymbiont genome reduction on a temporal scale. Mol Syst Biol 7. doi:479.10.1038/msb.2011.11
Pal C, Papp B, Lercher MJ, Csermely P, Oliver SG, Hurst LD (2006) Chance and necessity in the evolution of minimal metabolic networks. Nature 440(7084):667–670
Pal C, Papp B, Lercher MJ (2005) Horizontal gene transfer depends on gene content of the host. In: Joint meeting of the 4th european conference on computational biology/6th meeting of the spanish-bioinformatics-network, Madrid, SPAIN, Sep 28-Oct 01 2005. pp 222–223. doi:10.1093/bioinformatics/bti1136
Pal C, Papp B, Lercher MJ (2005) Adaptive evolution of bacterial metabolic networks by horizontal gene transfer. Nat Genet 37(12):1372–1375. doi:10.1038/ng1686
Nelson KE, Clayton RA, Gill SR, Gwinn ML, Dodson RJ, Haft DH, Hickey EK, Peterson LD, Nelson WC, Ketchum KA, McDonald L, Utterback TR, Malek JA, Linher KD, Garrett MM, Stewart AM, Cotton MD, Pratt MS, Phillips CA, Richardson D, Heidelberg J, Sutton GG, Fleischmann RD, Eisen JA, White O, Salzberg SL, Smith HO, Venter JC, Fraser CM (1999) Evidence for lateral gene transfer between Archaea and Bacteria from genome sequence of Thermotoga maritima. Nature 399(6734):323–329
Ochman H, Lawrence J, Groisman E (2000) Lateral gene transfer and the nature of bacterial innovation. Nature 405:299–304
Lerat E, Daubin V, Ochman H, Moran NA (2005) Evolutionary origins of genomic repertoires in bacteria. PLoS Biol 3(5):e130
Ochman H, Lerat E, Daubin V (2005) Examining bacterial species under the specter of gene transfer and exchange. Proc Natl Acad Sci USA 102:6595–6599
Choi IG, Kim SH (2007) Global extent of horizontal gene transfer. Proc Natl Acad Sci USA 104(11):4489–4494
Koonin EV, Makarova KS, Aravind L (2001) Horizontal gene transfer in prokaryotes: quantification and classification. Ann Rev Microbiol 55:709–742
Daubin V, Ochman H (2004) Quartet mapping and the extent of lateral transfer in bacterial genomes. Mol Biol Evol 21(1):86–89
Lawrence JG, Ochman H (1998) Molecular archaeology of the Escherichia coli genome. Proc Natl Acad Sci USA 95(16):9413–9417
Blattner FR, Plunkett G, Bloch CA, Perna NT, Burland V, Riley M, Colladovides J, Glasner JD, Rode CK, Mayhew GF, Gregor J, Davis NW, Kirkpatrick HA, Goeden MA, Rose DJ, Mau B, Shao Y (1997) The complete genome sequence of Escherichia-Coli K-12. Science 277(#5331):1453–1462
Postgate JR (1994) The outer reaches of life. Cambridge University Press, Cambridge, UK
Dantas G, Sommer MOA, Oluwasegun RD, Church GM (2008) Bacteria subsisting on antibiotics. Science 320(5872):100–103. doi:10.1126/science.1155157
Rehmann L, Daugulis AJ (2008) Enhancement of PCB degradation by Burkholderia xenovorans LB400 in biphasic systems by manipulating culture conditions. Biotechnol Bioeng 99(3):521–528. doi:10.1002/bit.21610
van der Meer JR, Werlen C, Nishino SF, Spain JC (1998) Evolution of a pathway for chlorobenzene metabolism leads to natural attenuation in contaminated groundwater. Appl Environ Microbiol 64(11):4185–4193
van der Meer JR Evolution of novel metabolic pathways for the degradation of chloroaromatic compounds. In: Beijerinck centennial symposium on microbial physiology and gene regulation - emerging principles and applications, The Hague, Netherlands, Dec 1995. pp 159–178
Copley SD (2000) Evolution of a metabolic pathway for degradation of a toxic xenobiotic: the patchwork approach. Trends Biochem Sci 25(6):261–265
Cline RE, Hill RH, Phillips DL, Needham LL (1989) Pentachlorophenol measurements in body-fluids of people in log homes and workplaces. Arch Environ Contam Toxicol 18(4):475–481
Dobzhansky T (1964) Biology, molecular and organismic. Am Zool 4:443–452
Benfey PN, Mitchell-Olds T (2008) Perspective - From genotype to phenotype: Systems biology meets natural variation. Science 320(5875):495–497. doi:10.1126/science.1153716
Wagner A (2011) The origins of evolutionary innovations. A theory of transformative change in living systems. Oxford University Press, Oxford, UK
Rodrigues JF, Wagner A (2009) Evolutionary plasticity and innovations in complex metabolic reaction networks. PLoS Comp Biol 5(12):e1000613
Samal A, Rodrigues JFM, Jost J, Martin OC, Wagner A (2010) Genotype networks in metabolic reaction spaces. BMC Sys Biol 4:30
Gavrilets S, Gravner J (1997) Percolation on the fitness hypercube and the evolution of reproductive isolation. J Theor Biol 184(#1):51–64
Reidys CM, Stadler PF (2002) Combinatorial landscapes. SIAM Rev 44:3–54
Ndifon W, Plotkin JB, Dushoff J (2009) On the accessibility of adaptive phenotypes of a bacterial metabolic network. Plos Comput Biol 5(8). doi:e1000472.10.1371/journal.pcbi.1000472
Meiklejohn C, Hartl D (2002) A single mode of canalization. Trends Ecol Evol 17(10):468–473
Wagner A (2005) Robustness and evolvability in living systems. Princeton University Press, Princeton, NJ
Wagner GP, Booth G, Bagherichaichian H (1997) A population genetic theory of canalization. Evolution 51(#2):329–347
Papp B, Teusink B, Notebaart RA (2009) A critical view of metabolic network adaptations. HFSP J 3(1):24–35. doi:10.2976/1.3020599
Wang Z, Zhang J (2009) Abundant indispensable redundancies in cellular metabolic networks. Genome Biol Evol 1:23–33
Freilich S, Kreimer A, Borenstein E, Gophna U, Sharan R, Ruppin E (2010) Decoupling environment-dependent and independent genetic robustness across bacterial species. PLoS Comp Biol 6(2). doi:e1000690.10.1371/journal.pcbi.1000690
Ciliberti S, Martin OC, Wagner A (2007) Innovation and robustness in complex regulatory gene networks. Proc Natal Acad Sci USA 104:13591–13596
Ferrada E, Wagner A (2008) Protein robustness promotes evolutionary innovations on large evolutionary time scales. Proc Roy Soc Lond B Biol Sci 275:1595–1602
Schuster P, Fontana W, Stadler P, Hofacker I (1994) From sequences to shapes and back - a case-study in RNA secondary structures. Proc Roy Soc Lond B 255(1344):279–284
Lipman D, Wilbur W (1991) Modeling neutral and selective evolution of protein folding. Proc Roy Soc Lond B 245(1312):7–11
Raman K, Wagner A (2011) Evolvability and robustness in a complex signaling circuit. Mol BioSyst 7:1081–1092
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Wagner, A. (2012). Metabolic Networks and Their Evolution. In: Soyer, O. (eds) Evolutionary Systems Biology. Advances in Experimental Medicine and Biology, vol 751. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3567-9_2
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