{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T08:51:50Z","timestamp":1784796710518,"version":"3.55.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Syst Biol"],"published-print":{"date-parts":[[2011,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>How transcriptionally regulated gene expression evolves under natural selection is an open question. The cost and benefit of gene expression are the driving factors. While the former can be determined by gratuitous induction, the latter is difficult to measure directly.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We addressed this problem by decoupling the regulatory and metabolic function of the <jats:italic>Escherichia coli lac<\/jats:italic> system, using an inducer that cannot be metabolized and a carbon source that does not induce. Growth rate measurements directly identified the induced expression level that maximizes the metabolism benefits minus the protein production costs, without relying on models. Using these results, we established a controlled mismatch between sensing and metabolism, resulting in sub-optimal transcriptional regulation with the potential to improve by evolution. Next, we tested the evolutionary response by serial transfer. Constant environments showed cells evolving to the predicted expression optimum. Phenotypes with decreased expression emerged several hundred generations later than phenotypes with increased expression, indicating a higher genetic accessibility of the latter. Environments alternating between low and high expression demands resulted in overall rather than differential changes in expression, which is explained by the concave shape of the cross-environmental tradeoff curve that limits the selective advantage of altering the regulatory response.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>This work indicates that the decoupling of regulatory and metabolic functions allows one to directly measure the costs and benefits that underlie the natural selection of gene regulation. Regulated gene expression is shown to evolve within several hundreds of generations to optima that are predicted by these costs and benefits. The results provide a step towards a quantitative understanding of the adaptive origins of regulatory systems.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1752-0509-5-128","type":"journal-article","created":{"date-parts":[[2011,8,16]],"date-time":"2011-08-16T18:33:43Z","timestamp":1313519623000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Optimality and evolution of transcriptionally regulated gene expression"],"prefix":"10.1186","volume":"5","author":[{"given":"Frank J","family":"Poelwijk","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip D","family":"Heyning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjon GJ","family":"de Vos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J","family":"Kiviet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sander J","family":"Tans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2011,8,16]]},"reference":[{"issue":"1","key":"747_CR1","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1146\/annurev.es.09.110178.000335","volume":"9","author":"J Maynard Smith","year":"1978","unstructured":"Maynard Smith J: Optimization theory in evolution. Annu Rev Ecol Syst. 1978, 9 (1): 31-56. 10.1146\/annurev.es.09.110178.000335.","journal-title":"Annu Rev Ecol Syst"},{"key":"747_CR2","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1038\/nrg1523","volume":"6","author":"HA Orr","year":"2005","unstructured":"Orr HA: The genetic theory of adaptation: a brief history. Nat Rev Genet. 2005, 6: 119-27.","journal-title":"Nat Rev Genet"},{"key":"747_CR3","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1038\/nature01149","volume":"420","author":"RU Ibarra","year":"2002","unstructured":"Ibarra RU, Edwards JS, Palsson BO: Escherichia coli K-12 undergoes adaptive evolution to achieve in silico predicted optimal growth. Nature. 2002, 420: 186-9. 10.1038\/nature01149","journal-title":"Nature"},{"issue":"7050","key":"747_CR4","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1038\/nature03842","volume":"436","author":"E Dekel","year":"2005","unstructured":"Dekel E, Alon U: Optimality and evolutionary tuning of the expression level of a protein. Nature. 2005, 436 (7050): 588-92. 10.1038\/nature03842","journal-title":"Nature"},{"key":"747_CR5","doi-asserted-by":"publisher","first-page":"2453","DOI":"10.1073\/pnas.71.6.2453","volume":"71","author":"MA Savageau","year":"1974","unstructured":"Savageau MA: Genetic regulatory mechanisms and the ecological niche of Escherichia coli. Proc Natl Acad Sci USA. 1974, 71: 2453-5. 10.1073\/pnas.71.6.2453","journal-title":"Proc Natl Acad Sci USA"},{"key":"747_CR6","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1086\/285289","volume":"138","author":"RE Lenski","year":"1991","unstructured":"Lenski RE, et al.: Long-term experimental evolution in Escherichia coli. I. Adaptation and divergence during 2, 000 generations. Am Nat. 1991, 138: 1315-1341. 10.1086\/285289.","journal-title":"Am Nat"},{"key":"747_CR7","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/nrg1088","volume":"4","author":"SF Elena","year":"2003","unstructured":"Elena SF, Lenski RE: Evolution experiments with microorganisms: the dynamics and genetic bases of adaptation. Nat Rev Genet. 2003, 4: 457-69.","journal-title":"Nat Rev Genet"},{"key":"747_CR8","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1093\/genetics\/115.1.25","volume":"115","author":"DE Dykhuizen","year":"1987","unstructured":"Dykhuizen DE, Dean AM, Hartl DL: Metabolic flux and fitness. Genetics. 1987, 115: 25-31.","journal-title":"Genetics"},{"key":"747_CR9","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1098\/rspb.1979.0086","volume":"205","author":"SJ Gould","year":"1979","unstructured":"Gould SJ, Lewontin RC: The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme. Proc R Soc Lond, B, Biol Sci. 1979, 205: 581-98. 10.1098\/rspb.1979.0086","journal-title":"Proc R Soc Lond, B, Biol Sci"},{"issue":"5","key":"747_CR10","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/0169-5347(91)90059-7","volume":"6","author":"J Antonovics","year":"1991","unstructured":"Antonovics J, van Tienderen PH: Ontoecogenophyloconstraints? The chaos of constraint terminology. Trends Ecol Evol. 1991, 6 (5): 166-168. 10.1016\/0169-5347(91)90059-7","journal-title":"Trends Ecol Evol"},{"key":"747_CR11","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1007\/BF02102321","volume":"19","author":"AL Koch","year":"1983","unstructured":"Koch AL: The protein burden of lac operon products. J Mol Evol. 1983, 19: 455-62. 10.1007\/BF02102321","journal-title":"J Mol Evol"},{"issue":"3","key":"747_CR12","doi-asserted-by":"publisher","first-page":"1653","DOI":"10.1534\/genetics.107.085399","volume":"178","author":"DM Stoebel","year":"2008","unstructured":"Stoebel DM, Dean AM, Dykhuizen DE: The cost of expression of Escherichia coli lac operon proteins is in the process, not in the products. Genetics. 2008, 178 (3): 1653-60. 10.1534\/genetics.107.085399","journal-title":"Genetics"},{"key":"747_CR13","doi-asserted-by":"publisher","DOI":"10.1515\/9783110879476","volume-title":"The lac Operon","author":"B M\u00fcller-Hill","year":"1996","unstructured":"M\u00fcller-Hill B: The lac Operon. 1996, Berlin: Walter de Gruyter,"},{"key":"747_CR14","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1016\/S0022-2836(02)00994-4","volume":"323","author":"N Rosenfeld","year":"2002","unstructured":"Rosenfeld N, Elowitz MB, Alon U: Negative autoregulation speeds the response times of transcription networks. J Mol Biol. 2002, 323: 785-93. 10.1016\/S0022-2836(02)00994-4","journal-title":"J Mol Biol"},{"issue":"4","key":"747_CR15","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1016\/S0092-8674(02)00900-5","volume":"110","author":"JG Lawrence","year":"2002","unstructured":"Lawrence JG: Shared strategies in gene organization among prokaryotes and eukaryotes. Cell. 2002, 110 (4): 407-13. 10.1016\/S0092-8674(02)00900-5","journal-title":"Cell"},{"key":"747_CR16","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1038\/35085569","volume":"412","author":"CO Wilke","year":"2001","unstructured":"Wilke CO, et al.: Evolution of digital organisms at high mutation rates leads to survival of the flattest. Nature. 2001, 412: 331-3. 10.1038\/35085569","journal-title":"Nature"},{"issue":"4","key":"747_CR17","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1088\/1478-3975\/4\/4\/001","volume":"4","author":"T Kalisky","year":"2007","unstructured":"Kalisky T, Dekel E, Alon U: Cost-benefit theory and optimal design of gene regulation functions. Phys Biol. 2007, 4 (4): 229-45. 10.1088\/1478-3975\/4\/4\/001","journal-title":"Phys Biol"},{"issue":"8","key":"747_CR18","doi-asserted-by":"publisher","first-page":"e1000125","DOI":"10.1371\/journal.pcbi.1000125","volume":"4","author":"S T\u0103nase-Nicola","year":"2008","unstructured":"T\u0103nase-Nicola S, ten Wolde PR: Regulatory control and the costs and benefits of biochemical noise. PLoS Comput Biol. 2008, 4 (8): e1000125- 10.1371\/journal.pcbi.1000125","journal-title":"PLoS Comput Biol"},{"key":"747_CR19","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.1126\/science.277.5331.1453","volume":"277","author":"FR Blattner","year":"1997","unstructured":"Blattner FR, et al.: The complete genome sequence of Escherichia coli K-12. Science. 1997, 277: 1453-74. 10.1126\/science.277.5331.1453","journal-title":"Science"},{"key":"747_CR20","volume-title":"The Operon","author":"JH Miller","year":"1978","unstructured":"Miller JH, Reznikoff WS: The Operon. 1978, New York: Cold Spring Harbor Laboratory Press,"},{"key":"747_CR21","volume-title":"Principles of population genetics","author":"DL Hartl","year":"2007","unstructured":"Hartl DL, Clark AG: Principles of population genetics. 2007, Sunderland: Sinauer Associates, 4,","edition":"4"},{"key":"747_CR22","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/0022-2836(86)90509-7","volume":"189","author":"RM Schaaper","year":"1986","unstructured":"Schaaper RM, Danforth BN, Glickman BW: Mechanisms of spontaneous mutagenesis: an analysis of the spectrum of spontaneous mutation in the Escherichia coli lacI gene. J Mol Biol. 1986, 189: 273-84. 10.1016\/0022-2836(86)90509-7","journal-title":"J Mol Biol"},{"key":"747_CR23","doi-asserted-by":"publisher","first-page":"1891","DOI":"10.1073\/pnas.56.6.1891","volume":"56","author":"W Gilbert","year":"1966","unstructured":"Gilbert W, M\u00fcller-Hill B: Isolation of the lac repressor. Proc Natl Acad Sci USA. 1966, 56: 1891-1898. 10.1073\/pnas.56.6.1891","journal-title":"Proc Natl Acad Sci USA"},{"key":"747_CR24","volume-title":"The Lactose Operon","author":"JR Beckwith","year":"1970","unstructured":"Beckwith JR, Zipser D: The Lactose Operon. 1970, New York: Cold Spring Harbor Laboratory Press,"},{"key":"747_CR25","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1038\/nature04599","volume":"440","author":"L Cai","year":"2006","unstructured":"Cai L, Friedman N, Xie XS: Stochastic protein expression in individual cells at the single molecule level. Nature. 2006, 440: 358-62. 10.1038\/nature04599","journal-title":"Nature"},{"key":"747_CR26","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1093\/genetics\/56.1.163","volume":"56","author":"R Levins","year":"1967","unstructured":"Levins R: Theory of fitness in a heterogeneous environment. VI. The adaptive significance of mutation. Genetics. 1967, 56: 163-78.","journal-title":"Genetics"},{"key":"747_CR27","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1073\/pnas.43.7.553","volume":"43","author":"A Novick","year":"1957","unstructured":"Novick A, Weiner M: Enzyme induction as an all-or-none phenomenon. Proc Natl Acad Sci USA. 1957, 43: 553-66. 10.1073\/pnas.43.7.553","journal-title":"Proc Natl Acad Sci USA"},{"key":"747_CR28","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1093\/genetics\/148.4.1667","volume":"148","author":"JW Drake","year":"1998","unstructured":"Drake JW, Charlesworth B, Charlesworth D, Crow JF: Rates of spontaneous mutation. Genetics. 1998, 148: 1667-1686.","journal-title":"Genetics"},{"key":"747_CR29","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/0022-2836(90)90126-7","volume":"212","author":"LG Kleina","year":"1990","unstructured":"Kleina LG, Miller JH: Genetic studies of the lac repressor. XIII. Extensive amino acid replacements generated by the use of natural and synthetic nonsense suppressors. J Mol Biol. 1990, 212: 295-318. 10.1016\/0022-2836(90)90126-7","journal-title":"J Mol Biol"},{"key":"747_CR30","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1111\/j.1365-2958.2004.04076.x","volume":"52","author":"C Beloin","year":"2004","unstructured":"Beloin C, et al.: Encoded errors: mutations and rearrangements mediated by misalignment at repetitive DNA sequences. Mol Microbiol. 2004, 52: 1243-53. 10.1111\/j.1365-2958.2004.04076.x","journal-title":"Mol Microbiol"}],"container-title":["BMC Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1752-0509-5-128.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T16:32:45Z","timestamp":1630513965000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcsystbiol.biomedcentral.com\/articles\/10.1186\/1752-0509-5-128"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,8,16]]},"references-count":30,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2011,12]]}},"alternative-id":["747"],"URL":"https:\/\/doi.org\/10.1186\/1752-0509-5-128","relation":{},"ISSN":["1752-0509"],"issn-type":[{"value":"1752-0509","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,8,16]]},"assertion":[{"value":"2 December 2010","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 August 2011","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 August 2011","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"128"}}