[{"month":"07","supervisor":[{"last_name":"Guet","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","full_name":"Guet, Calin C","orcid":"0000-0001-6220-2052","first_name":"Calin C"},{"orcid":"0000-0002-6699-1455","first_name":"Gašper","id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","full_name":"Tkačik, Gašper","last_name":"Tkačik"}],"file":[{"file_id":"8176","creator":"rgrah","date_updated":"2020-07-27T12:00:07Z","date_created":"2020-07-27T12:00:07Z","file_size":16638998,"relation":"main_file","content_type":"application/pdf","access_level":"open_access","file_name":"Thesis_RokGrah_200727_convertedNew.pdf","success":1},{"file_size":347459978,"date_created":"2020-07-27T12:02:23Z","date_updated":"2020-07-30T13:04:55Z","creator":"rgrah","file_id":"8177","file_name":"Thesis_new.zip","access_level":"closed","content_type":"application/zip","relation":"main_file"}],"department":[{"_id":"CaGu"},{"_id":"GaTk"}],"language":[{"iso":"eng"}],"oa":1,"user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","citation":{"short":"R. Grah, Gene Regulation across Scales – How Biophysical Constraints Shape Evolution, Institute of Science and Technology Austria, 2020.","ieee":"R. Grah, “Gene regulation across scales – how biophysical constraints shape evolution,” Institute of Science and Technology Austria, 2020.","ama":"Grah R. Gene regulation across scales – how biophysical constraints shape evolution. 2020. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8155\">10.15479/AT:ISTA:8155</a>","mla":"Grah, Rok. <i>Gene Regulation across Scales – How Biophysical Constraints Shape Evolution</i>. Institute of Science and Technology Austria, 2020, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8155\">10.15479/AT:ISTA:8155</a>.","apa":"Grah, R. (2020). <i>Gene regulation across scales – how biophysical constraints shape evolution</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:8155\">https://doi.org/10.15479/AT:ISTA:8155</a>","ista":"Grah R. 2020. Gene regulation across scales – how biophysical constraints shape evolution. Institute of Science and Technology Austria.","chicago":"Grah, Rok. “Gene Regulation across Scales – How Biophysical Constraints Shape Evolution.” Institute of Science and Technology Austria, 2020. <a href=\"https://doi.org/10.15479/AT:ISTA:8155\">https://doi.org/10.15479/AT:ISTA:8155</a>."},"oa_version":"Published Version","title":"Gene regulation across scales – how biophysical constraints shape evolution","day":"24","author":[{"orcid":"0000-0003-2539-3560","first_name":"Rok","full_name":"Grah, Rok","id":"483E70DE-F248-11E8-B48F-1D18A9856A87","last_name":"Grah"}],"date_created":"2020-07-23T09:51:28Z","abstract":[{"text":"In the thesis we focus on the interplay of the biophysics and evolution of gene regulation. We start by addressing how the type of prokaryotic gene regulation – activation and repression – affects spurious binding to DNA, also known as\r\ntranscriptional crosstalk. We propose that regulatory interference caused by excess regulatory proteins in the dense cellular medium – global crosstalk – could be a factor in determining which type of gene regulatory network is evolutionarily preferred. Next,we use a normative approach in eukaryotic gene regulation to describe minimal\r\nnon-equilibrium enhancer models that optimize so-called regulatory phenotypes. We find a class of models that differ from standard thermodynamic equilibrium models by a single parameter that notably increases the regulatory performance. Next chapter addresses the question of genotype-phenotype-fitness maps of higher dimensional phenotypes. We show that our biophysically realistic approach allows us to understand how the mechanisms of promoter function constrain genotypephenotype maps, and how they affect the evolutionary trajectories of promoters.\r\nIn the last chapter we ask whether the intrinsic instability of gene duplication and amplification provides a generic alternative to canonical gene regulation. Using mathematical modeling, we show that amplifications can tune gene expression in many environments, including those where transcription factor-based schemes are\r\nhard to evolve or maintain. ","lang":"eng"}],"has_accepted_license":"1","file_date_updated":"2020-07-30T13:04:55Z","publication_identifier":{"issn":["2663-337X"]},"publication_status":"published","related_material":{"record":[{"id":"7675","relation":"part_of_dissertation","status":"public"},{"id":"7569","relation":"part_of_dissertation","status":"public"},{"relation":"part_of_dissertation","status":"public","id":"7652"}]},"year":"2020","status":"public","project":[{"name":"Biophysically realistic genotype-phenotype maps for regulatory networks","_id":"267C84F4-B435-11E9-9278-68D0E5697425"}],"degree_awarded":"PhD","acknowledgement":"For the duration of his PhD, Rok was a recipient of a DOC fellowship of the Austrian Academy of Sciences.","date_published":"2020-07-24T00:00:00Z","publisher":"Institute of Science and Technology Austria","article_processing_charge":"No","alternative_title":["ISTA Thesis"],"doi":"10.15479/AT:ISTA:8155","type":"dissertation","_id":"8155","date_updated":"2023-09-07T13:13:27Z","ddc":["530","570"],"page":"310"},{"year":"2020","isi":1,"related_material":{"link":[{"relation":"press_release","url":"https://ist.ac.at/en/news/new-compact-model-for-gene-regulation-in-higher-organisms/","description":"News on IST Homepage"}]},"external_id":{"isi":["000600608300015"],"pmid":["33268497"]},"pmid":1,"acknowledgement":"G.T. was supported by Human Frontiers Science Program Grant RGP0034/2018. R.G. was supported by the Austrian Academy of Sciences DOC Fellowship. R.G. thanks S. Avvakumov for helpful discussions.","date_published":"2020-12-15T00:00:00Z","status":"public","publication":"PNAS","project":[{"grant_number":"RGP0034/2018","name":"Can evolution minimize spurious signaling crosstalk to reach optimal performance?","_id":"2665AAFE-B435-11E9-9278-68D0E5697425"},{"name":"Biophysically realistic genotype-phenotype maps for regulatory networks","_id":"267C84F4-B435-11E9-9278-68D0E5697425"}],"_id":"9000","date_updated":"2023-08-24T11:10:22Z","type":"journal_article","article_processing_charge":"No","doi":"10.1073/pnas.2006731117","publisher":"National Academy of Sciences","quality_controlled":"1","page":"31614-31622","ddc":["570"],"department":[{"_id":"GaTk"}],"file":[{"checksum":"69039cd402a571983aa6cb4815ffa863","relation":"main_file","content_type":"application/pdf","access_level":"open_access","file_name":"2020_PNAS_Grah.pdf","success":1,"file_id":"9004","date_updated":"2021-01-11T08:37:31Z","creator":"dernst","date_created":"2021-01-11T08:37:31Z","file_size":1199247}],"month":"12","citation":{"ista":"Grah R, Zoller B, Tkačik G. 2020. Nonequilibrium models of optimal enhancer function. PNAS. 117(50), 31614–31622.","chicago":"Grah, Rok, Benjamin Zoller, and Gašper Tkačik. “Nonequilibrium Models of Optimal Enhancer Function.” <i>PNAS</i>. National Academy of Sciences, 2020. <a href=\"https://doi.org/10.1073/pnas.2006731117\">https://doi.org/10.1073/pnas.2006731117</a>.","mla":"Grah, Rok, et al. “Nonequilibrium Models of Optimal Enhancer Function.” <i>PNAS</i>, vol. 117, no. 50, National Academy of Sciences, 2020, pp. 31614–22, doi:<a href=\"https://doi.org/10.1073/pnas.2006731117\">10.1073/pnas.2006731117</a>.","apa":"Grah, R., Zoller, B., &#38; Tkačik, G. (2020). Nonequilibrium models of optimal enhancer function. <i>PNAS</i>. National Academy of Sciences. <a href=\"https://doi.org/10.1073/pnas.2006731117\">https://doi.org/10.1073/pnas.2006731117</a>","ama":"Grah R, Zoller B, Tkačik G. Nonequilibrium models of optimal enhancer function. <i>PNAS</i>. 2020;117(50):31614-31622. doi:<a href=\"https://doi.org/10.1073/pnas.2006731117\">10.1073/pnas.2006731117</a>","short":"R. Grah, B. Zoller, G. Tkačik, PNAS 117 (2020) 31614–31622.","ieee":"R. Grah, B. Zoller, and G. Tkačik, “Nonequilibrium models of optimal enhancer function,” <i>PNAS</i>, vol. 117, no. 50. National Academy of Sciences, pp. 31614–31622, 2020."},"issue":"50","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","oa":1,"language":[{"iso":"eng"}],"volume":117,"date_created":"2021-01-10T23:01:17Z","article_type":"original","scopus_import":"1","day":"15","author":[{"orcid":"0000-0003-2539-3560","first_name":"Rok","id":"483E70DE-F248-11E8-B48F-1D18A9856A87","full_name":"Grah, Rok","last_name":"Grah"},{"first_name":"Benjamin","full_name":"Zoller, Benjamin","last_name":"Zoller"},{"last_name":"Tkačik","full_name":"Tkačik, Gašper","id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-6699-1455","first_name":"Gašper"}],"title":"Nonequilibrium models of optimal enhancer function","oa_version":"Published Version","file_date_updated":"2021-01-11T08:37:31Z","publication_status":"published","publication_identifier":{"eissn":["10916490"],"issn":["00278424"]},"has_accepted_license":"1","tmp":{"image":"/images/cc_by_nc_nd.png","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","short":"CC BY-NC-ND (4.0)"},"abstract":[{"lang":"eng","text":"In prokaryotes, thermodynamic models of gene regulation provide a highly quantitative mapping from promoter sequences to gene-expression levels that is compatible with in vivo and in vitro biophysical measurements. Such concordance has not been achieved for models of enhancer function in eukaryotes. In equilibrium models, it is difficult to reconcile the reported short transcription factor (TF) residence times on the DNA with the high specificity of regulation. In nonequilibrium models, progress is difficult due to an explosion in the number of parameters. Here, we navigate this complexity by looking for minimal nonequilibrium enhancer models that yield desired regulatory phenotypes: low TF residence time, high specificity, and tunable cooperativity. We find that a single extra parameter, interpretable as the “linking rate,” by which bound TFs interact with Mediator components, enables our models to escape equilibrium bounds and access optimal regulatory phenotypes, while remaining consistent with the reported phenomenology and simple enough to be inferred from upcoming experiments. We further find that high specificity in nonequilibrium models is in a trade-off with gene-expression noise, predicting bursty dynamics—an experimentally observed hallmark of eukaryotic transcription. By drastically reducing the vast parameter space of nonequilibrium enhancer models to a much smaller subspace that optimally realizes biological function, we deliver a rich class of models that could be tractably inferred from data in the near future."}],"intvolume":"       117"},{"department":[{"_id":"CaGu"},{"_id":"GaTk"}],"keyword":["Matlab scripts","analysis of microfluidics","mathematical model"],"file":[{"date_created":"2020-01-28T10:39:40Z","file_size":73363365,"creator":"rgrah","date_updated":"2020-07-14T12:47:57Z","file_id":"7384","file_name":"Scripts.zip","access_level":"open_access","content_type":"application/zip","relation":"main_file","checksum":"9d292cf5207b3829225f44c044cdb3fd"},{"file_id":"7385","file_size":962,"date_created":"2020-01-28T10:39:30Z","date_updated":"2020-07-14T12:47:57Z","creator":"rgrah","relation":"main_file","checksum":"4076ceab32ef588cc233802bab24c1ab","file_name":"READ_ME_MAIN.txt","content_type":"text/plain","access_level":"open_access"}],"year":"2020","related_material":{"record":[{"relation":"used_in_publication","status":"public","id":"7652"}]},"month":"01","citation":{"ista":"Grah R. 2020. Matlab scripts for the Paper: Gene Amplification as a Form of Population-Level Gene Expression regulation, Institute of Science and Technology Austria, <a href=\"https://doi.org/10.15479/AT:ISTA:7383\">10.15479/AT:ISTA:7383</a>.","chicago":"Grah, Rok. “Matlab Scripts for the Paper: Gene Amplification as a Form of Population-Level Gene Expression Regulation.” Institute of Science and Technology Austria, 2020. <a href=\"https://doi.org/10.15479/AT:ISTA:7383\">https://doi.org/10.15479/AT:ISTA:7383</a>.","mla":"Grah, Rok. <i>Matlab Scripts for the Paper: Gene Amplification as a Form of Population-Level Gene Expression Regulation</i>. Institute of Science and Technology Austria, 2020, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:7383\">10.15479/AT:ISTA:7383</a>.","apa":"Grah, R. (2020). Matlab scripts for the Paper: Gene Amplification as a Form of Population-Level Gene Expression regulation. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:7383\">https://doi.org/10.15479/AT:ISTA:7383</a>","ama":"Grah R. Matlab scripts for the Paper: Gene Amplification as a Form of Population-Level Gene Expression regulation. 2020. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:7383\">10.15479/AT:ISTA:7383</a>","short":"R. Grah, (2020).","ieee":"R. Grah, “Matlab scripts for the Paper: Gene Amplification as a Form of Population-Level Gene Expression regulation.” Institute of Science and Technology Austria, 2020."},"date_published":"2020-01-28T00:00:00Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","oa":1,"status":"public","date_updated":"2024-02-21T12:42:31Z","_id":"7383","type":"research_data","date_created":"2020-01-28T10:41:49Z","doi":"10.15479/AT:ISTA:7383","author":[{"last_name":"Grah","full_name":"Grah, Rok","id":"483E70DE-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-2539-3560","first_name":"Rok"}],"contributor":[{"last_name":"Guet","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","first_name":"Calin C","orcid":"0000-0001-6220-2052","contributor_type":"project_leader"}],"article_processing_charge":"No","day":"28","publisher":"Institute of Science and Technology Austria","title":"Matlab scripts for the Paper: Gene Amplification as a Form of Population-Level Gene Expression regulation","oa_version":"Published Version","file_date_updated":"2020-07-14T12:47:57Z","has_accepted_license":"1","abstract":[{"lang":"eng","text":"Organisms cope with change by employing transcriptional regulators. However, when faced with rare environments, the evolution of transcriptional regulators and their promoters may be too slow. We ask whether the intrinsic instability of gene duplication and amplification provides a generic alternative to canonical gene regulation. By real-time monitoring of gene copy number mutations in E. coli, we show that gene duplications and amplifications enable adaptation to fluctuating environments by rapidly generating copy number, and hence expression level, polymorphism. This ‘amplification-mediated gene expression tuning’ occurs on timescales similar to canonical gene regulation and can deal with rapid environmental changes. Mathematical modeling shows that amplifications also tune gene expression in stochastic environments where transcription factor-based schemes are hard to evolve or maintain. The fleeting nature of gene amplifications gives rise to a generic population-level mechanism that relies on genetic heterogeneity to rapidly tune expression of any gene, without leaving any genomic signature."}]},{"publisher":"Public Library of Science","doi":"10.1371/journal.pcbi.1007642","article_processing_charge":"No","type":"journal_article","date_updated":"2023-09-12T11:02:24Z","_id":"7569","ddc":["000","570"],"quality_controlled":"1","external_id":{"isi":["000526725200019"]},"related_material":{"record":[{"status":"deleted","relation":"research_data","id":"9716"},{"id":"9776","status":"public","relation":"research_data"},{"id":"9779","status":"public","relation":"used_in_publication"},{"id":"8155","relation":"dissertation_contains","status":"public"},{"relation":"research_data","status":"public","id":"9777"}]},"year":"2020","isi":1,"status":"public","publication":"PLOS Computational Biology","date_published":"2020-02-25T00:00:00Z","title":"The relation between crosstalk and gene regulation form revisited","oa_version":"Published Version","author":[{"full_name":"Grah, Rok","id":"483E70DE-F248-11E8-B48F-1D18A9856A87","last_name":"Grah","orcid":"0000-0003-2539-3560","first_name":"Rok"},{"first_name":"Tamar","full_name":"Friedlander, Tamar","last_name":"Friedlander"}],"scopus_import":"1","day":"25","article_type":"original","date_created":"2020-03-06T07:39:38Z","volume":16,"abstract":[{"text":"Genes differ in the frequency at which they are expressed and in the form of regulation used to control their activity. In particular, positive or negative regulation can lead to activation of a gene in response to an external signal. Previous works proposed that the form of regulation of a gene correlates with its frequency of usage: positive regulation when the gene is frequently expressed and negative regulation when infrequently expressed. Such network design means that, in the absence of their regulators, the genes are found in their least required activity state, hence regulatory intervention is often necessary. Due to the multitude of genes and regulators, spurious binding and unbinding events, called “crosstalk”, could occur. To determine how the form of regulation affects the global crosstalk in the network, we used a mathematical model that includes multiple regulators and multiple target genes. We found that crosstalk depends non-monotonically on the availability of regulators. Our analysis showed that excess use of regulation entailed by the formerly suggested network design caused high crosstalk levels in a large part of the parameter space. We therefore considered the opposite ‘idle’ design, where the default unregulated state of genes is their frequently required activity state. We found, that ‘idle’ design minimized the use of regulation and thus minimized crosstalk. In addition, we estimated global crosstalk of S. cerevisiae using transcription factors binding data. We demonstrated that even partial network data could suffice to estimate its global crosstalk, suggesting its applicability to additional organisms. We found that S. cerevisiae estimated crosstalk is lower than that of a random network, suggesting that natural selection reduces crosstalk. In summary, our study highlights a new type of protein production cost which is typically overlooked: that of regulatory interference caused by the presence of excess regulators in the cell. It demonstrates the importance of whole-network descriptions, which could show effects missed by single-gene models.","lang":"eng"}],"tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","short":"CC BY (4.0)"},"intvolume":"        16","has_accepted_license":"1","publication_identifier":{"issn":["1553-7358"]},"publication_status":"published","file_date_updated":"2020-07-14T12:48:00Z","month":"02","article_number":"e1007642","file":[{"file_id":"7579","creator":"dernst","date_updated":"2020-07-14T12:48:00Z","file_size":2209325,"date_created":"2020-03-09T15:12:21Z","checksum":"5239dd134dc6e1c71fe7b3ce2953da37","relation":"main_file","access_level":"open_access","content_type":"application/pdf","file_name":"2020_PlosCompBio_Grah.pdf"}],"department":[{"_id":"CaGu"},{"_id":"GaTk"}],"language":[{"iso":"eng"}],"oa":1,"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","issue":"2","citation":{"apa":"Grah, R., &#38; Friedlander, T. (2020). The relation between crosstalk and gene regulation form revisited. <i>PLOS Computational Biology</i>. Public Library of Science. <a href=\"https://doi.org/10.1371/journal.pcbi.1007642\">https://doi.org/10.1371/journal.pcbi.1007642</a>","mla":"Grah, Rok, and Tamar Friedlander. “The Relation between Crosstalk and Gene Regulation Form Revisited.” <i>PLOS Computational Biology</i>, vol. 16, no. 2, e1007642, Public Library of Science, 2020, doi:<a href=\"https://doi.org/10.1371/journal.pcbi.1007642\">10.1371/journal.pcbi.1007642</a>.","chicago":"Grah, Rok, and Tamar Friedlander. “The Relation between Crosstalk and Gene Regulation Form Revisited.” <i>PLOS Computational Biology</i>. Public Library of Science, 2020. <a href=\"https://doi.org/10.1371/journal.pcbi.1007642\">https://doi.org/10.1371/journal.pcbi.1007642</a>.","ista":"Grah R, Friedlander T. 2020. The relation between crosstalk and gene regulation form revisited. PLOS Computational Biology. 16(2), e1007642.","ieee":"R. Grah and T. Friedlander, “The relation between crosstalk and gene regulation form revisited,” <i>PLOS Computational Biology</i>, vol. 16, no. 2. Public Library of Science, 2020.","short":"R. Grah, T. Friedlander, PLOS Computational Biology 16 (2020).","ama":"Grah R, Friedlander T. The relation between crosstalk and gene regulation form revisited. <i>PLOS Computational Biology</i>. 2020;16(2). doi:<a href=\"https://doi.org/10.1371/journal.pcbi.1007642\">10.1371/journal.pcbi.1007642</a>"}},{"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","issue":"4","citation":{"ieee":"I. Tomanek <i>et al.</i>, “Gene amplification as a form of population-level gene expression regulation,” <i>Nature Ecology &#38; Evolution</i>, vol. 4, no. 4. Springer Nature, pp. 612–625, 2020.","short":"I. Tomanek, R. Grah, M. Lagator, A.M.C. Andersson, J.P. Bollback, G. Tkačik, C.C. Guet, Nature Ecology &#38; Evolution 4 (2020) 612–625.","ama":"Tomanek I, Grah R, Lagator M, et al. Gene amplification as a form of population-level gene expression regulation. <i>Nature Ecology &#38; Evolution</i>. 2020;4(4):612-625. doi:<a href=\"https://doi.org/10.1038/s41559-020-1132-7\">10.1038/s41559-020-1132-7</a>","apa":"Tomanek, I., Grah, R., Lagator, M., Andersson, A. M. C., Bollback, J. P., Tkačik, G., &#38; Guet, C. C. (2020). Gene amplification as a form of population-level gene expression regulation. <i>Nature Ecology &#38; Evolution</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41559-020-1132-7\">https://doi.org/10.1038/s41559-020-1132-7</a>","mla":"Tomanek, Isabella, et al. “Gene Amplification as a Form of Population-Level Gene Expression Regulation.” <i>Nature Ecology &#38; Evolution</i>, vol. 4, no. 4, Springer Nature, 2020, pp. 612–25, doi:<a href=\"https://doi.org/10.1038/s41559-020-1132-7\">10.1038/s41559-020-1132-7</a>.","chicago":"Tomanek, Isabella, Rok Grah, M. Lagator, A. M. C. Andersson, Jonathan P Bollback, Gašper Tkačik, and Calin C Guet. “Gene Amplification as a Form of Population-Level Gene Expression Regulation.” <i>Nature Ecology &#38; Evolution</i>. Springer Nature, 2020. <a href=\"https://doi.org/10.1038/s41559-020-1132-7\">https://doi.org/10.1038/s41559-020-1132-7</a>.","ista":"Tomanek I, Grah R, Lagator M, Andersson AMC, Bollback JP, Tkačik G, Guet CC. 2020. Gene amplification as a form of population-level gene expression regulation. Nature Ecology &#38; Evolution. 4(4), 612–625."},"language":[{"iso":"eng"}],"oa":1,"file":[{"access_level":"open_access","content_type":"application/pdf","success":1,"file_name":"2020_NatureEcolEvo_Tomanek.pdf","checksum":"ef3bbf42023e30b2c24a6278025d2040","relation":"main_file","date_updated":"2020-10-09T09:56:01Z","creator":"dernst","date_created":"2020-10-09T09:56:01Z","file_size":745242,"file_id":"8640"}],"department":[{"_id":"GaTk"},{"_id":"CaGu"}],"month":"04","publication_identifier":{"issn":["2397-334X"]},"publication_status":"published","file_date_updated":"2020-10-09T09:56:01Z","abstract":[{"text":"Organisms cope with change by taking advantage of transcriptional regulators. However, when faced with rare environments, the evolution of transcriptional regulators and their promoters may be too slow. Here, we investigate whether the intrinsic instability of gene duplication and amplification provides a generic alternative to canonical gene regulation. Using real-time monitoring of gene-copy-number mutations in Escherichia coli, we show that gene duplications and amplifications enable adaptation to fluctuating environments by rapidly generating copy-number and, therefore, expression-level polymorphisms. This amplification-mediated gene expression tuning (AMGET) occurs on timescales that are similar to canonical gene regulation and can respond to rapid environmental changes. Mathematical modelling shows that amplifications also tune gene expression in stochastic environments in which transcription-factor-based schemes are hard to evolve or maintain. The fleeting nature of gene amplifications gives rise to a generic population-level mechanism that relies on genetic heterogeneity to rapidly tune the expression of any gene, without leaving any genomic signature.","lang":"eng"}],"intvolume":"         4","has_accepted_license":"1","article_type":"original","date_created":"2020-04-08T15:20:53Z","volume":4,"oa_version":"Submitted Version","title":"Gene amplification as a form of population-level gene expression regulation","author":[{"last_name":"Tomanek","full_name":"Tomanek, Isabella","id":"3981F020-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-6197-363X","first_name":"Isabella"},{"orcid":"0000-0003-2539-3560","first_name":"Rok","id":"483E70DE-F248-11E8-B48F-1D18A9856A87","full_name":"Grah, Rok","last_name":"Grah"},{"first_name":"M.","last_name":"Lagator","full_name":"Lagator, M."},{"last_name":"Andersson","full_name":"Andersson, A. M. C.","first_name":"A. M. C."},{"full_name":"Bollback, Jonathan P","id":"2C6FA9CC-F248-11E8-B48F-1D18A9856A87","last_name":"Bollback","first_name":"Jonathan P","orcid":"0000-0002-4624-4612"},{"last_name":"Tkačik","full_name":"Tkačik, Gašper","id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","first_name":"Gašper","orcid":"0000-0002-6699-1455"},{"orcid":"0000-0001-6220-2052","first_name":"Calin C","last_name":"Guet","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","full_name":"Guet, Calin C"}],"day":"01","scopus_import":"1","acknowledgement":"We thank L. Hurst, N. Barton, M. Pleska, M. Steinrück, B. Kavcic and A. Staron for input on the manuscript, and To. Bergmiller and R. Chait for help with microfluidics experiments. I.T. is a recipient the OMV fellowship. R.G. is a recipient of a DOC (Doctoral Fellowship Programme of the Austrian Academy of Sciences) Fellowship of the Austrian Academy of Sciences.","date_published":"2020-04-01T00:00:00Z","project":[{"name":"Biophysically realistic genotype-phenotype maps for regulatory networks","_id":"267C84F4-B435-11E9-9278-68D0E5697425"}],"publication":"Nature Ecology & Evolution","status":"public","external_id":{"isi":["000519008300005"]},"related_material":{"link":[{"relation":"press_release","description":"News on IST Homepage","url":"https://ist.ac.at/en/news/how-to-thrive-without-gene-regulation/"}],"record":[{"id":"8155","status":"public","relation":"dissertation_contains"},{"status":"public","relation":"research_data","id":"7383"},{"id":"7016","relation":"research_data","status":"public"},{"id":"8653","relation":"used_in_publication","status":"public"}]},"year":"2020","isi":1,"quality_controlled":"1","ddc":["570"],"page":"612-625","type":"journal_article","date_updated":"2024-03-25T23:30:20Z","_id":"7652","publisher":"Springer Nature","doi":"10.1038/s41559-020-1132-7","article_processing_charge":"No"},{"abstract":[{"text":"In prokaryotes, thermodynamic models of gene regulation provide a highly quantitative mapping from promoter sequences to gene expression levels that is compatible with in vivo and in vitro bio-physical measurements. Such concordance has not been achieved for models of enhancer function in eukaryotes. In equilibrium models, it is difficult to reconcile the reported short transcription factor (TF) residence times on the DNA with the high specificity of regulation. In non-equilibrium models, progress is difficult due to an explosion in the number of parameters. Here, we navigate this complexity by looking for minimal non-equilibrium enhancer models that yield desired regulatory phenotypes: low TF residence time, high specificity and tunable cooperativity. We find that a single extra parameter, interpretable as the “linking rate” by which bound TFs interact with Mediator components, enables our models to escape equilibrium bounds and access optimal regulatory phenotypes, while remaining consistent with the reported phenomenology and simple enough to be inferred from upcoming experiments. We further find that high specificity in non-equilibrium models is in a tradeoff with gene expression noise, predicting bursty dynamics — an experimentally-observed hallmark of eukaryotic transcription. By drastically reducing the vast parameter space to a much smaller subspace that optimally realizes biological function prior to inference from data, our normative approach holds promise for mathematical models in systems biology.","lang":"eng"}],"publication_status":"published","main_file_link":[{"open_access":"1","url":"https://doi.org/10.1101/2020.04.08.029405 "}],"publisher":"Cold Spring Harbor Laboratory","oa_version":"Preprint","title":"Normative models of enhancer function","author":[{"orcid":"0000-0003-2539-3560","first_name":"Rok","id":"483E70DE-F248-11E8-B48F-1D18A9856A87","full_name":"Grah, Rok","last_name":"Grah"},{"last_name":"Zoller","full_name":"Zoller, Benjamin","first_name":"Benjamin"},{"orcid":"0000-0002-6699-1455","first_name":"Gašper","full_name":"Tkačik, Gašper","id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","last_name":"Tkačik"}],"doi":"10.1101/2020.04.08.029405","day":"09","article_processing_charge":"No","type":"preprint","date_created":"2020-04-23T10:12:51Z","date_updated":"2023-09-07T13:13:26Z","_id":"7675","project":[{"grant_number":"RGP0034/2018","name":"Can evolution minimize spurious signaling crosstalk to reach optimal performance?","_id":"2665AAFE-B435-11E9-9278-68D0E5697425"},{"_id":"267C84F4-B435-11E9-9278-68D0E5697425","name":"Biophysically realistic genotype-phenotype maps for regulatory networks"}],"language":[{"iso":"eng"}],"publication":"bioRxiv","status":"public","oa":1,"date_published":"2020-04-09T00:00:00Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","citation":{"short":"R. Grah, B. Zoller, G. Tkačik, BioRxiv (2020).","ieee":"R. Grah, B. Zoller, and G. Tkačik, “Normative models of enhancer function,” <i>bioRxiv</i>. Cold Spring Harbor Laboratory, 2020.","ama":"Grah R, Zoller B, Tkačik G. Normative models of enhancer function. <i>bioRxiv</i>. 2020. doi:<a href=\"https://doi.org/10.1101/2020.04.08.029405\">10.1101/2020.04.08.029405</a>","mla":"Grah, Rok, et al. “Normative Models of Enhancer Function.” <i>BioRxiv</i>, Cold Spring Harbor Laboratory, 2020, doi:<a href=\"https://doi.org/10.1101/2020.04.08.029405\">10.1101/2020.04.08.029405</a>.","apa":"Grah, R., Zoller, B., &#38; Tkačik, G. (2020). Normative models of enhancer function. <i>bioRxiv</i>. Cold Spring Harbor Laboratory. <a href=\"https://doi.org/10.1101/2020.04.08.029405\">https://doi.org/10.1101/2020.04.08.029405</a>","ista":"Grah R, Zoller B, Tkačik G. 2020. Normative models of enhancer function. bioRxiv, <a href=\"https://doi.org/10.1101/2020.04.08.029405\">10.1101/2020.04.08.029405</a>.","chicago":"Grah, Rok, Benjamin Zoller, and Gašper Tkačik. “Normative Models of Enhancer Function.” <i>BioRxiv</i>. Cold Spring Harbor Laboratory, 2020. <a href=\"https://doi.org/10.1101/2020.04.08.029405\">https://doi.org/10.1101/2020.04.08.029405</a>."},"month":"04","related_material":{"record":[{"relation":"dissertation_contains","status":"public","id":"8155"}]},"year":"2020","department":[{"_id":"CaGu"},{"_id":"GaTk"}]},{"oa_version":"Published Version","publisher":"Public Library of Science","title":"Supporting information","doi":"10.1371/journal.pcbi.1007642.s001","author":[{"last_name":"Grah","full_name":"Grah, Rok","id":"483E70DE-F248-11E8-B48F-1D18A9856A87","first_name":"Rok","orcid":"0000-0003-2539-3560"},{"first_name":"Tamar","last_name":"Friedlander","full_name":"Friedlander, Tamar"}],"article_processing_charge":"No","day":"25","type":"research_data_reference","date_created":"2021-08-06T07:15:04Z","date_updated":"2023-08-18T06:47:47Z","_id":"9776","related_material":{"record":[{"id":"7569","status":"public","relation":"used_in_publication"}]},"month":"02","year":"2020","department":[{"_id":"GaTk"}],"status":"public","date_published":"2020-02-25T00:00:00Z","user_id":"6785fbc1-c503-11eb-8a32-93094b40e1cf","citation":{"ama":"Grah R, Friedlander T. Supporting information. 2020. doi:<a href=\"https://doi.org/10.1371/journal.pcbi.1007642.s001\">10.1371/journal.pcbi.1007642.s001</a>","ieee":"R. Grah and T. Friedlander, “Supporting information.” Public Library of Science, 2020.","short":"R. Grah, T. Friedlander, (2020).","ista":"Grah R, Friedlander T. 2020. Supporting information, Public Library of Science, <a href=\"https://doi.org/10.1371/journal.pcbi.1007642.s001\">10.1371/journal.pcbi.1007642.s001</a>.","chicago":"Grah, Rok, and Tamar Friedlander. “Supporting Information.” Public Library of Science, 2020. <a href=\"https://doi.org/10.1371/journal.pcbi.1007642.s001\">https://doi.org/10.1371/journal.pcbi.1007642.s001</a>.","apa":"Grah, R., &#38; Friedlander, T. (2020). Supporting information. Public Library of Science. <a href=\"https://doi.org/10.1371/journal.pcbi.1007642.s001\">https://doi.org/10.1371/journal.pcbi.1007642.s001</a>","mla":"Grah, Rok, and Tamar Friedlander. <i>Supporting Information</i>. Public Library of Science, 2020, doi:<a href=\"https://doi.org/10.1371/journal.pcbi.1007642.s001\">10.1371/journal.pcbi.1007642.s001</a>."}},{"title":"Maximizing crosstalk","publisher":"Public Library of Science","oa_version":"None","article_processing_charge":"No","day":"25","doi":"10.1371/journal.pcbi.1007642.s002","author":[{"first_name":"Rok","orcid":"0000-0003-2539-3560","last_name":"Grah","full_name":"Grah, Rok","id":"483E70DE-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Tamar","full_name":"Friedlander, Tamar","last_name":"Friedlander"}],"date_created":"2021-08-06T07:21:51Z","type":"research_data_reference","_id":"9777","date_updated":"2023-09-12T11:02:25Z","main_file_link":[{"open_access":"1","url":"https://doi.org/10.1371/journal.pcbi.1007642.s002"}],"month":"02","related_material":{"record":[{"status":"public","relation":"used_in_publication","id":"7569"}]},"year":"2020","department":[{"_id":"GaTk"}],"status":"public","oa":1,"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","date_published":"2020-02-25T00:00:00Z","citation":{"apa":"Grah, R., &#38; Friedlander, T. (2020). Maximizing crosstalk. Public Library of Science. <a href=\"https://doi.org/10.1371/journal.pcbi.1007642.s002\">https://doi.org/10.1371/journal.pcbi.1007642.s002</a>","mla":"Grah, Rok, and Tamar Friedlander. <i>Maximizing Crosstalk</i>. Public Library of Science, 2020, doi:<a href=\"https://doi.org/10.1371/journal.pcbi.1007642.s002\">10.1371/journal.pcbi.1007642.s002</a>.","chicago":"Grah, Rok, and Tamar Friedlander. “Maximizing Crosstalk.” Public Library of Science, 2020. <a href=\"https://doi.org/10.1371/journal.pcbi.1007642.s002\">https://doi.org/10.1371/journal.pcbi.1007642.s002</a>.","ista":"Grah R, Friedlander T. 2020. Maximizing crosstalk, Public Library of Science, <a href=\"https://doi.org/10.1371/journal.pcbi.1007642.s002\">10.1371/journal.pcbi.1007642.s002</a>.","ieee":"R. Grah and T. Friedlander, “Maximizing crosstalk.” Public Library of Science, 2020.","short":"R. Grah, T. Friedlander, (2020).","ama":"Grah R, Friedlander T. Maximizing crosstalk. 2020. doi:<a href=\"https://doi.org/10.1371/journal.pcbi.1007642.s002\">10.1371/journal.pcbi.1007642.s002</a>"}},{"department":[{"_id":"GaTk"}],"month":"02","related_material":{"record":[{"id":"7569","status":"public","relation":"research_data"}]},"year":"2020","user_id":"6785fbc1-c503-11eb-8a32-93094b40e1cf","date_published":"2020-02-25T00:00:00Z","citation":{"mla":"Grah, Rok, and Tamar Friedlander. <i>Distribution of Crosstalk Values</i>. Public Library of Science, 2020, doi:<a href=\"https://doi.org/10.1371/journal.pcbi.1007642.s003\">10.1371/journal.pcbi.1007642.s003</a>.","apa":"Grah, R., &#38; Friedlander, T. (2020). Distribution of crosstalk values. Public Library of Science. <a href=\"https://doi.org/10.1371/journal.pcbi.1007642.s003\">https://doi.org/10.1371/journal.pcbi.1007642.s003</a>","chicago":"Grah, Rok, and Tamar Friedlander. “Distribution of Crosstalk Values.” Public Library of Science, 2020. <a href=\"https://doi.org/10.1371/journal.pcbi.1007642.s003\">https://doi.org/10.1371/journal.pcbi.1007642.s003</a>.","ista":"Grah R, Friedlander T. 2020. Distribution of crosstalk values, Public Library of Science, <a href=\"https://doi.org/10.1371/journal.pcbi.1007642.s003\">10.1371/journal.pcbi.1007642.s003</a>.","short":"R. Grah, T. Friedlander, (2020).","ieee":"R. Grah and T. Friedlander, “Distribution of crosstalk values.” Public Library of Science, 2020.","ama":"Grah R, Friedlander T. Distribution of crosstalk values. 2020. doi:<a href=\"https://doi.org/10.1371/journal.pcbi.1007642.s003\">10.1371/journal.pcbi.1007642.s003</a>"},"status":"public","date_created":"2021-08-06T07:24:37Z","type":"research_data_reference","_id":"9779","date_updated":"2023-08-18T06:47:47Z","title":"Distribution of crosstalk values","publisher":"Public Library of Science","oa_version":"Published Version","day":"25","article_processing_charge":"No","doi":"10.1371/journal.pcbi.1007642.s003","author":[{"orcid":"0000-0003-2539-3560","first_name":"Rok","full_name":"Grah, Rok","id":"483E70DE-F248-11E8-B48F-1D18A9856A87","last_name":"Grah"},{"first_name":"Tamar","full_name":"Friedlander, Tamar","last_name":"Friedlander"}]},{"month":"06","year":"2016","publist_id":"6114","department":[{"_id":"CaGu"},{"_id":"GaTk"}],"status":"public","language":[{"iso":"eng"}],"oa":1,"date_published":"2016-06-01T00:00:00Z","conference":{"name":"AIAA: Aviation Technology, Integration, and Operations Conference","end_date":"2016-06-17","start_date":"2016-06-13","location":"Washington, D.C., USA"},"user_id":"3E5EF7F0-F248-11E8-B48F-1D18A9856A87","citation":{"mla":"Mikić, Gregor, et al. <i>Fuselage Boundary Layer Ingestion Propulsion Applied to a Thin Haul Commuter Aircraft for Optimal Efficiency</i>. AIAA, 2016, pp. 1–19, doi:<a href=\"https://doi.org/10.2514/6.2016-3764\">10.2514/6.2016-3764</a>.","apa":"Mikić, G., Stoll, A., Bevirt, J., Grah, R., &#38; Moore, M. (2016). Fuselage boundary layer ingestion propulsion applied to a thin haul commuter aircraft for optimal efficiency (pp. 1–19). Presented at the AIAA: Aviation Technology, Integration, and Operations Conference, Washington, D.C., USA: AIAA. <a href=\"https://doi.org/10.2514/6.2016-3764\">https://doi.org/10.2514/6.2016-3764</a>","chicago":"Mikić, Gregor, Alex Stoll, Joe Bevirt, Rok Grah, and Mark Moore. “Fuselage Boundary Layer Ingestion Propulsion Applied to a Thin Haul Commuter Aircraft for Optimal Efficiency,” 1–19. AIAA, 2016. <a href=\"https://doi.org/10.2514/6.2016-3764\">https://doi.org/10.2514/6.2016-3764</a>.","ista":"Mikić G, Stoll A, Bevirt J, Grah R, Moore M. 2016. Fuselage boundary layer ingestion propulsion applied to a thin haul commuter aircraft for optimal efficiency. AIAA: Aviation Technology, Integration, and Operations Conference, 1–19.","short":"G. Mikić, A. Stoll, J. Bevirt, R. Grah, M. Moore, in:, AIAA, 2016, pp. 1–19.","ieee":"G. Mikić, A. Stoll, J. Bevirt, R. Grah, and M. Moore, “Fuselage boundary layer ingestion propulsion applied to a thin haul commuter aircraft for optimal efficiency,” presented at the AIAA: Aviation Technology, Integration, and Operations Conference, Washington, D.C., USA, 2016, pp. 1–19.","ama":"Mikić G, Stoll A, Bevirt J, Grah R, Moore M. Fuselage boundary layer ingestion propulsion applied to a thin haul commuter aircraft for optimal efficiency. In: AIAA; 2016:1-19. doi:<a href=\"https://doi.org/10.2514/6.2016-3764\">10.2514/6.2016-3764</a>"},"oa_version":"Preprint","title":"Fuselage boundary layer ingestion propulsion applied to a thin haul commuter aircraft for optimal efficiency","publisher":"AIAA","doi":"10.2514/6.2016-3764","author":[{"full_name":"Mikić, Gregor","last_name":"Mikić","first_name":"Gregor"},{"first_name":"Alex","last_name":"Stoll","full_name":"Stoll, Alex"},{"first_name":"Joe","last_name":"Bevirt","full_name":"Bevirt, Joe"},{"orcid":"0000-0003-2539-3560","first_name":"Rok","id":"483E70DE-F248-11E8-B48F-1D18A9856A87","full_name":"Grah, Rok","last_name":"Grah"},{"last_name":"Moore","full_name":"Moore, Mark","first_name":"Mark"}],"day":"01","scopus_import":1,"type":"conference","date_created":"2018-12-11T11:50:47Z","date_updated":"2023-02-21T10:17:50Z","_id":"1220","abstract":[{"text":"Theoretical and numerical aspects of aerodynamic efficiency of propulsion systems coupled to the boundary layer of a fuselage are studied. We discuss the effects of local flow fields, which are affected both by conservative flow acceleration as well as total pressure losses, on the efficiency of boundary layer immersed propulsion devices. We introduce the concept of a boundary layer retardation turbine that helps reduce skin friction over the fuselage. We numerically investigate efficiency gains offered by boundary layer and wake interacting devices. We discuss the results in terms of a total energy consumption framework and show that efficiency gains of any device depend on all the other elements of the propulsion system.","lang":"eng"}],"page":"1 - 19","publication_status":"published","quality_controlled":"1","main_file_link":[{"url":"https://ntrs.nasa.gov/search.jsp?R=20160010167&amp;hterms=Fuselage+boundary+layer+ingestion+propulsion+applied+thin+haul+commuter+aircraft+optimal+efficiency&amp;qs=N%3D0%26Ntk%3DAll%26Ntt%3DFuselage%2520boundary%2520layer%2520ingestion%2520propulsion%2520applied%2520to%2520a%2520thin%2520haul%2520commuter%2520aircraft%2520for%2520optimal%2520efficiency%26Ntx%3Dmode%2520matchallpartial%26Nm%3D123%7CCollection%7CNASA%2520STI%7C%7C17%7CCollection%7CNACA","open_access":"1"}]}]