[{"type":"journal_article","day":"26","status":"public","intvolume":"        11","file_date_updated":"2022-02-07T07:14:09Z","publication":"eLife","article_type":"original","date_published":"2022-01-26T00:00:00Z","month":"01","language":[{"iso":"eng"}],"scopus_import":"1","publisher":"eLife Sciences Publications","department":[{"_id":"CaGu"},{"_id":"GaTk"},{"_id":"NiBa"}],"has_accepted_license":"1","date_created":"2022-02-06T23:01:32Z","file":[{"success":1,"relation":"main_file","content_type":"application/pdf","creator":"cchlebak","file_id":"10739","file_size":5604343,"file_name":"2022_ELife_Lagator.pdf","checksum":"decdcdf600ff51e9a9703b49ca114170","date_created":"2022-02-07T07:14:09Z","access_level":"open_access","date_updated":"2022-02-07T07:14:09Z"}],"citation":{"chicago":"Lagator, Mato, Srdjan Sarikas, Magdalena Steinrueck, David Toledo-Aparicio, Jonathan P Bollback, Calin C Guet, and Gašper Tkačik. “Predicting Bacterial Promoter Function and Evolution from Random Sequences.” <i>ELife</i>. eLife Sciences Publications, 2022. <a href=\"https://doi.org/10.7554/eLife.64543\">https://doi.org/10.7554/eLife.64543</a>.","ieee":"M. Lagator <i>et al.</i>, “Predicting bacterial promoter function and evolution from random sequences,” <i>eLife</i>, vol. 11. eLife Sciences Publications, 2022.","apa":"Lagator, M., Sarikas, S., Steinrueck, M., Toledo-Aparicio, D., Bollback, J. P., Guet, C. C., &#38; Tkačik, G. (2022). Predicting bacterial promoter function and evolution from random sequences. <i>ELife</i>. eLife Sciences Publications. <a href=\"https://doi.org/10.7554/eLife.64543\">https://doi.org/10.7554/eLife.64543</a>","ista":"Lagator M, Sarikas S, Steinrueck M, Toledo-Aparicio D, Bollback JP, Guet CC, Tkačik G. 2022. Predicting bacterial promoter function and evolution from random sequences. eLife. 11, e64543.","short":"M. Lagator, S. Sarikas, M. Steinrueck, D. Toledo-Aparicio, J.P. Bollback, C.C. Guet, G. Tkačik, ELife 11 (2022).","mla":"Lagator, Mato, et al. “Predicting Bacterial Promoter Function and Evolution from Random Sequences.” <i>ELife</i>, vol. 11, e64543, eLife Sciences Publications, 2022, doi:<a href=\"https://doi.org/10.7554/eLife.64543\">10.7554/eLife.64543</a>.","ama":"Lagator M, Sarikas S, Steinrueck M, et al. Predicting bacterial promoter function and evolution from random sequences. <i>eLife</i>. 2022;11. doi:<a href=\"https://doi.org/10.7554/eLife.64543\">10.7554/eLife.64543</a>"},"publication_status":"published","author":[{"last_name":"Lagator","full_name":"Lagator, Mato","first_name":"Mato","id":"345D25EC-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Srdjan","full_name":"Sarikas, Srdjan","last_name":"Sarikas","id":"35F0286E-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Steinrueck, Magdalena","last_name":"Steinrueck","first_name":"Magdalena"},{"first_name":"David","last_name":"Toledo-Aparicio","full_name":"Toledo-Aparicio, David"},{"id":"2C6FA9CC-F248-11E8-B48F-1D18A9856A87","full_name":"Bollback, Jonathan P","last_name":"Bollback","orcid":"0000-0002-4624-4612","first_name":"Jonathan P"},{"first_name":"Calin C","orcid":"0000-0001-6220-2052","last_name":"Guet","full_name":"Guet, Calin C","id":"47F8433E-F248-11E8-B48F-1D18A9856A87"},{"id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-6699-1455","full_name":"Tkačik, Gašper","last_name":"Tkačik","first_name":"Gašper"}],"abstract":[{"text":"Predicting function from sequence is a central problem of biology. Currently, this is possible only locally in a narrow mutational neighborhood around a wildtype sequence rather than globally from any sequence. Using random mutant libraries, we developed a biophysical model that accounts for multiple features of σ70 binding bacterial promoters to predict constitutive gene expression levels from any sequence. We experimentally and theoretically estimated that 10–20% of random sequences lead to expression and ~80% of non-expressing sequences are one mutation away from a functional promoter. The potential for generating expression from random sequences is so pervasive that selection acts against σ70-RNA polymerase binding sites even within inter-genic, promoter-containing regions. This pervasiveness of σ70-binding sites implies that emergence of promoters is not the limiting step in gene regulatory evolution. Ultimately, the inclusion of novel features of promoter function into a mechanistic model enabled not only more accurate predictions of gene expression levels, but also identified that promoters evolve more rapidly than previously thought.","lang":"eng"}],"article_processing_charge":"No","volume":11,"oa":1,"date_updated":"2023-08-02T14:09:02Z","oa_version":"Published Version","project":[{"_id":"2578D616-B435-11E9-9278-68D0E5697425","name":"Selective Barriers to Horizontal Gene Transfer","call_identifier":"H2020","grant_number":"648440"}],"quality_controlled":"1","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","acknowledgement":"We thank Hande Acar, Nicholas H Barton, Rok Grah, Tiago Paixao, Maros Pleska, Anna Staron, and Murat Tugrul for insightful comments and input on the manuscript. This work was supported by: Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant number 216779/Z/19/Z) to ML; IPC Grant from IST Austria to ML and SS; European Research Council Funding Programme 7 (2007–2013, grant agreement number 648440) to JPB.","publication_identifier":{"eissn":["2050-084X"]},"_id":"10736","pmid":1,"ec_funded":1,"doi":"10.7554/eLife.64543","year":"2022","external_id":{"isi":["000751104400001"],"pmid":["35080492"]},"title":"Predicting bacterial promoter function and evolution from random sequences","isi":1,"article_number":"e64543","tmp":{"image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"ddc":["576"]},{"department":[{"_id":"CaGu"},{"_id":"GaTk"},{"_id":"JoBo"}],"has_accepted_license":"1","date_created":"2018-12-11T11:44:27Z","file":[{"checksum":"383a2e2c944a856e2e821ec8e7bf71b6","date_created":"2020-05-14T11:28:52Z","file_size":1135973,"file_name":"2018_NatureEcology_Igler.pdf","access_level":"open_access","date_updated":"2020-07-14T12:47:37Z","creator":"dernst","file_id":"7830","relation":"main_file","content_type":"application/pdf"}],"date_published":"2018-09-10T00:00:00Z","article_type":"original","month":"09","language":[{"iso":"eng"}],"publisher":"Nature Publishing Group","scopus_import":"1","file_date_updated":"2020-07-14T12:47:37Z","page":"1633 - 1643","issue":"10","publication":"Nature Ecology and Evolution","type":"journal_article","day":"10","status":"public","intvolume":"         2","isi":1,"ddc":["570"],"related_material":{"record":[{"status":"public","id":"5585","relation":"popular_science"},{"relation":"dissertation_contains","id":"6371","status":"public"}]},"ec_funded":1,"doi":"10.1038/s41559-018-0651-y","year":"2018","title":"Evolutionary potential of transcription factors for gene regulatory rewiring","external_id":{"isi":["000447947600021"]},"date_updated":"2024-03-25T23:30:27Z","publist_id":"7987","volume":2,"oa":1,"article_processing_charge":"No","user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","oa_version":"Submitted Version","project":[{"grant_number":"291734","call_identifier":"FP7","name":"International IST Postdoc Fellowship Programme","_id":"25681D80-B435-11E9-9278-68D0E5697425"},{"call_identifier":"H2020","name":"Selective Barriers to Horizontal Gene Transfer","_id":"2578D616-B435-11E9-9278-68D0E5697425","grant_number":"648440"},{"grant_number":"24573","name":"Design principles underlying genetic switch architecture (DOC Fellowship)","_id":"251EE76E-B435-11E9-9278-68D0E5697425"}],"quality_controlled":"1","_id":"67","publication_status":"published","citation":{"ista":"Igler C, Lagator M, Tkačik G, Bollback JP, Guet CC. 2018. Evolutionary potential of transcription factors for gene regulatory rewiring. Nature Ecology and Evolution. 2(10), 1633–1643.","short":"C. Igler, M. Lagator, G. Tkačik, J.P. Bollback, C.C. Guet, Nature Ecology and Evolution 2 (2018) 1633–1643.","ama":"Igler C, Lagator M, Tkačik G, Bollback JP, Guet CC. Evolutionary potential of transcription factors for gene regulatory rewiring. <i>Nature Ecology and Evolution</i>. 2018;2(10):1633-1643. doi:<a href=\"https://doi.org/10.1038/s41559-018-0651-y\">10.1038/s41559-018-0651-y</a>","mla":"Igler, Claudia, et al. “Evolutionary Potential of Transcription Factors for Gene Regulatory Rewiring.” <i>Nature Ecology and Evolution</i>, vol. 2, no. 10, Nature Publishing Group, 2018, pp. 1633–43, doi:<a href=\"https://doi.org/10.1038/s41559-018-0651-y\">10.1038/s41559-018-0651-y</a>.","chicago":"Igler, Claudia, Mato Lagator, Gašper Tkačik, Jonathan P Bollback, and Calin C Guet. “Evolutionary Potential of Transcription Factors for Gene Regulatory Rewiring.” <i>Nature Ecology and Evolution</i>. Nature Publishing Group, 2018. <a href=\"https://doi.org/10.1038/s41559-018-0651-y\">https://doi.org/10.1038/s41559-018-0651-y</a>.","ieee":"C. Igler, M. Lagator, G. Tkačik, J. P. Bollback, and C. C. Guet, “Evolutionary potential of transcription factors for gene regulatory rewiring,” <i>Nature Ecology and Evolution</i>, vol. 2, no. 10. Nature Publishing Group, pp. 1633–1643, 2018.","apa":"Igler, C., Lagator, M., Tkačik, G., Bollback, J. P., &#38; Guet, C. C. (2018). Evolutionary potential of transcription factors for gene regulatory rewiring. <i>Nature Ecology and Evolution</i>. Nature Publishing Group. <a href=\"https://doi.org/10.1038/s41559-018-0651-y\">https://doi.org/10.1038/s41559-018-0651-y</a>"},"author":[{"first_name":"Claudia","last_name":"Igler","full_name":"Igler, Claudia","id":"46613666-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Lagator, Mato","last_name":"Lagator","first_name":"Mato","id":"345D25EC-F248-11E8-B48F-1D18A9856A87"},{"orcid":"0000-0002-6699-1455","last_name":"Tkacik","full_name":"Tkacik, Gasper","first_name":"Gasper","id":"3D494DCA-F248-11E8-B48F-1D18A9856A87"},{"orcid":"0000-0002-4624-4612","last_name":"Bollback","full_name":"Bollback, Jonathan P","first_name":"Jonathan P","id":"2C6FA9CC-F248-11E8-B48F-1D18A9856A87"},{"id":"47F8433E-F248-11E8-B48F-1D18A9856A87","first_name":"Calin C","orcid":"0000-0001-6220-2052","full_name":"Guet, Calin C","last_name":"Guet"}],"abstract":[{"text":"Gene regulatory networks evolve through rewiring of individual components—that is, through changes in regulatory connections. However, the mechanistic basis of regulatory rewiring is poorly understood. Using a canonical gene regulatory system, we quantify the properties of transcription factors that determine the evolutionary potential for rewiring of regulatory connections: robustness, tunability and evolvability. In vivo repression measurements of two repressors at mutated operator sites reveal their contrasting evolutionary potential: while robustness and evolvability were positively correlated, both were in trade-off with tunability. Epistatic interactions between adjacent operators alleviated this trade-off. A thermodynamic model explains how the differences in robustness, tunability and evolvability arise from biophysical characteristics of repressor–DNA binding. The model also uncovers that the energy matrix, which describes how mutations affect repressor–DNA binding, encodes crucial information about the evolutionary potential of a repressor. The biophysical determinants of evolutionary potential for regulatory rewiring constitute a mechanistic framework for understanding network evolution.","lang":"eng"}]},{"related_material":{"record":[{"id":"67","relation":"research_paper","status":"public"},{"status":"public","relation":"research_paper","id":"6371"}]},"date_created":"2018-12-12T12:31:40Z","file":[{"creator":"system","file_id":"5611","relation":"main_file","content_type":"application/vnd.openxmlformats-officedocument.spreadsheetml.sheet","access_level":"open_access","date_updated":"2020-07-14T12:47:07Z","checksum":"1435781526c77413802adee0d4583cce","date_created":"2018-12-12T13:02:45Z","file_size":16507,"file_name":"IST-2018-108-v1+1_data_figures.xlsx"}],"ddc":["576"],"license":"https://creativecommons.org/publicdomain/zero/1.0/","tmp":{"name":"Creative Commons Public Domain Dedication (CC0 1.0)","short":"CC0 (1.0)","image":"/images/cc_0.png","legal_code_url":"https://creativecommons.org/publicdomain/zero/1.0/legalcode"},"has_accepted_license":"1","department":[{"_id":"CaGu"},{"_id":"GaTk"}],"publisher":"Institute of Science and Technology Austria","datarep_id":"108","title":"Data for the paper Evolutionary potential of transcription factors for gene regulatory rewiring","doi":"10.15479/AT:ISTA:108","month":"07","year":"2018","date_published":"2018-07-20T00:00:00Z","ec_funded":1,"_id":"5585","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","project":[{"_id":"25681D80-B435-11E9-9278-68D0E5697425","name":"International IST Postdoc Fellowship Programme","call_identifier":"FP7","grant_number":"291734"},{"call_identifier":"H2020","_id":"2578D616-B435-11E9-9278-68D0E5697425","name":"Selective Barriers to Horizontal Gene Transfer","grant_number":"648440"},{"grant_number":"24573","name":"Design principles underlying genetic switch architecture (DOC Fellowship)","_id":"251EE76E-B435-11E9-9278-68D0E5697425"}],"oa_version":"Published Version","oa":1,"date_updated":"2024-03-25T23:30:27Z","article_processing_charge":"No","file_date_updated":"2020-07-14T12:47:07Z","abstract":[{"lang":"eng","text":"Mean repression values and standard error of the mean are given for all operator mutant libraries."}],"status":"public","author":[{"last_name":"Igler","full_name":"Igler, Claudia","first_name":"Claudia","id":"46613666-F248-11E8-B48F-1D18A9856A87"},{"id":"345D25EC-F248-11E8-B48F-1D18A9856A87","first_name":"Mato","full_name":"Lagator, Mato","last_name":"Lagator"},{"orcid":"0000-0002-6699-1455","last_name":"Tkacik","full_name":"Tkacik, Gasper","first_name":"Gasper","id":"3D494DCA-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Bollback","full_name":"Bollback, Jonathan P","orcid":"0000-0002-4624-4612","first_name":"Jonathan P","id":"2C6FA9CC-F248-11E8-B48F-1D18A9856A87"},{"id":"47F8433E-F248-11E8-B48F-1D18A9856A87","first_name":"Calin C","orcid":"0000-0001-6220-2052","full_name":"Guet, Calin C","last_name":"Guet"}],"citation":{"ama":"Igler C, Lagator M, Tkačik G, Bollback JP, Guet CC. Data for the paper Evolutionary potential of transcription factors for gene regulatory rewiring. 2018. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:108\">10.15479/AT:ISTA:108</a>","mla":"Igler, Claudia, et al. <i>Data for the Paper Evolutionary Potential of Transcription Factors for Gene Regulatory Rewiring</i>. Institute of Science and Technology Austria, 2018, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:108\">10.15479/AT:ISTA:108</a>.","ista":"Igler C, Lagator M, Tkačik G, Bollback JP, Guet CC. 2018. Data for the paper Evolutionary potential of transcription factors for gene regulatory rewiring, Institute of Science and Technology Austria, <a href=\"https://doi.org/10.15479/AT:ISTA:108\">10.15479/AT:ISTA:108</a>.","short":"C. Igler, M. Lagator, G. Tkačik, J.P. Bollback, C.C. Guet, (2018).","ieee":"C. Igler, M. Lagator, G. Tkačik, J. P. Bollback, and C. C. Guet, “Data for the paper Evolutionary potential of transcription factors for gene regulatory rewiring.” Institute of Science and Technology Austria, 2018.","apa":"Igler, C., Lagator, M., Tkačik, G., Bollback, J. P., &#38; Guet, C. C. (2018). Data for the paper Evolutionary potential of transcription factors for gene regulatory rewiring. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:108\">https://doi.org/10.15479/AT:ISTA:108</a>","chicago":"Igler, Claudia, Mato Lagator, Gašper Tkačik, Jonathan P Bollback, and Calin C Guet. “Data for the Paper Evolutionary Potential of Transcription Factors for Gene Regulatory Rewiring.” Institute of Science and Technology Austria, 2018. <a href=\"https://doi.org/10.15479/AT:ISTA:108\">https://doi.org/10.15479/AT:ISTA:108</a>."},"day":"20","type":"research_data"},{"article_processing_charge":"No","publist_id":"7400","oa":1,"volume":7,"date_updated":"2023-09-11T12:49:17Z","project":[{"grant_number":"648440","name":"Selective Barriers to Horizontal Gene Transfer","_id":"2578D616-B435-11E9-9278-68D0E5697425","call_identifier":"H2020"}],"oa_version":"Published Version","quality_controlled":"1","acknowledgement":"We are grateful to Remy Chait for his help and assistance with establishing our experimental setups and to Tobias Bergmiller for valuable insights into some specific experimental details. We thank Luciano Marraffini for donating us the pCas9 plasmid used in this study. We also want to express our gratitude to Seth Barribeau, Andrea Betancourt, Călin Guet, Mato Lagator, Tiago Paixão and Maroš Pleška for valuable discussions on the manuscript. Finally, we would like to thank the \r\neditors and reviewers for their helpful comments and suggestions.","user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","_id":"423","citation":{"ieee":"P. Payne, L. Geyrhofer, N. H. Barton, and J. P. Bollback, “CRISPR-based herd immunity can limit phage epidemics in bacterial populations,” <i>eLife</i>, vol. 7. eLife Sciences Publications, 2018.","apa":"Payne, P., Geyrhofer, L., Barton, N. H., &#38; Bollback, J. P. (2018). CRISPR-based herd immunity can limit phage epidemics in bacterial populations. <i>ELife</i>. eLife Sciences Publications. <a href=\"https://doi.org/10.7554/eLife.32035\">https://doi.org/10.7554/eLife.32035</a>","chicago":"Payne, Pavel, Lukas Geyrhofer, Nicholas H Barton, and Jonathan P Bollback. “CRISPR-Based Herd Immunity Can Limit Phage Epidemics in Bacterial Populations.” <i>ELife</i>. eLife Sciences Publications, 2018. <a href=\"https://doi.org/10.7554/eLife.32035\">https://doi.org/10.7554/eLife.32035</a>.","ama":"Payne P, Geyrhofer L, Barton NH, Bollback JP. CRISPR-based herd immunity can limit phage epidemics in bacterial populations. <i>eLife</i>. 2018;7. doi:<a href=\"https://doi.org/10.7554/eLife.32035\">10.7554/eLife.32035</a>","mla":"Payne, Pavel, et al. “CRISPR-Based Herd Immunity Can Limit Phage Epidemics in Bacterial Populations.” <i>ELife</i>, vol. 7, e32035, eLife Sciences Publications, 2018, doi:<a href=\"https://doi.org/10.7554/eLife.32035\">10.7554/eLife.32035</a>.","short":"P. Payne, L. Geyrhofer, N.H. Barton, J.P. Bollback, ELife 7 (2018).","ista":"Payne P, Geyrhofer L, Barton NH, Bollback JP. 2018. CRISPR-based herd immunity can limit phage epidemics in bacterial populations. eLife. 7, e32035."},"publication_status":"published","author":[{"orcid":"0000-0002-2711-9453","full_name":"Payne, Pavel","last_name":"Payne","first_name":"Pavel","id":"35F78294-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Geyrhofer","full_name":"Geyrhofer, Lukas","first_name":"Lukas"},{"full_name":"Barton, Nicholas H","last_name":"Barton","orcid":"0000-0002-8548-5240","first_name":"Nicholas H","id":"4880FE40-F248-11E8-B48F-1D18A9856A87"},{"orcid":"0000-0002-4624-4612","full_name":"Bollback, Jonathan P","last_name":"Bollback","first_name":"Jonathan P","id":"2C6FA9CC-F248-11E8-B48F-1D18A9856A87"}],"abstract":[{"lang":"eng","text":"Herd immunity, a process in which resistant individuals limit the spread of a pathogen among susceptible hosts has been extensively studied in eukaryotes. Even though bacteria have evolved multiple immune systems against their phage pathogens, herd immunity in bacteria remains unexplored. Here we experimentally demonstrate that herd immunity arises during phage epidemics in structured and unstructured Escherichia coli populations consisting of differing frequencies of susceptible and resistant cells harboring CRISPR immunity. In addition, we develop a mathematical model that quantifies how herd immunity is affected by spatial population structure, bacterial growth rate, and phage replication rate. Using our model we infer a general epidemiological rule describing the relative speed of an epidemic in partially resistant spatially structured populations. Our experimental and theoretical findings indicate that herd immunity may be important in bacterial communities, allowing for stable coexistence of bacteria and their phages and the maintenance of polymorphism in bacterial immunity."}],"article_number":"e32035","isi":1,"tmp":{"image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"ddc":["576"],"related_material":{"record":[{"id":"9840","relation":"research_data","status":"public"}]},"ec_funded":1,"year":"2018","doi":"10.7554/eLife.32035","title":"CRISPR-based herd immunity can limit phage epidemics in bacterial populations","external_id":{"isi":["000431035800001"]},"file_date_updated":"2020-07-14T12:46:25Z","publication":"eLife","type":"journal_article","day":"09","status":"public","intvolume":"         7","department":[{"_id":"NiBa"},{"_id":"JoBo"}],"has_accepted_license":"1","date_created":"2018-12-11T11:46:23Z","file":[{"relation":"main_file","content_type":"application/pdf","file_id":"5689","creator":"dernst","access_level":"open_access","date_updated":"2020-07-14T12:46:25Z","file_size":3533881,"file_name":"2018_eLife_Payne.pdf","checksum":"447cf6e680bdc3c01062a8737d876569","date_created":"2018-12-17T10:36:07Z"}],"date_published":"2018-03-09T00:00:00Z","month":"03","language":[{"iso":"eng"}],"scopus_import":"1","publisher":"eLife Sciences Publications"},{"title":"Evolutionary interplay between structure, energy and epistasis in the coat protein of the ϕX174 phage family","external_id":{"isi":["000393380400001"]},"ec_funded":1,"doi":"10.1098/rsif.2016.0139","year":"2017","ddc":["570"],"related_material":{"record":[{"id":"9864","relation":"research_data","status":"public"}]},"isi":1,"article_number":"20160139","tmp":{"image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"author":[{"id":"409D5C96-F248-11E8-B48F-1D18A9856A87","first_name":"Rodrigo A","full_name":"Fernandes Redondo, Rodrigo A","last_name":"Fernandes Redondo","orcid":"0000-0002-5837-2793"},{"full_name":"Vladar, Harold","last_name":"Vladar","orcid":"0000-0002-5985-7653","first_name":"Harold","id":"2A181218-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Tomasz","full_name":"Włodarski, Tomasz","last_name":"Włodarski"},{"id":"2C6FA9CC-F248-11E8-B48F-1D18A9856A87","first_name":"Jonathan P","full_name":"Bollback, Jonathan P","last_name":"Bollback","orcid":"0000-0002-4624-4612"}],"abstract":[{"lang":"eng","text":"Viral capsids are structurally constrained by interactions among the amino acids (AAs) of their constituent proteins. Therefore, epistasis is expected to evolve among physically interacting sites and to influence the rates of substitution. To study the evolution of epistasis, we focused on the major structural protein of the fX174 phage family by first reconstructing the ancestral protein sequences of 18 species using a Bayesian statistical framework. The inferred ancestral reconstruction differed at eight AAs, for a total of 256 possible ancestral haplotypes. For each ancestral haplotype and the extant species, we estimated, in silico, the distribution of free energies and epistasis of the capsid structure. We found that free energy has not significantly increased but epistasis has. We decomposed epistasis up to fifth order and found that higher-order epistasis sometimes compensates pairwise interactions making the free energy seem additive. The dN/dS ratio is low, suggesting strong purifying selection, and that structure is under stabilizing selection. We synthesized phages carrying ancestral haplotypes of the coat protein gene and measured their fitness experimentally. Our findings indicate that stabilizing mutations can have higher fitness, and that fitness optima do not necessarily coincide with energy minima."}],"publication_status":"published","citation":{"short":"R.A. Fernandes Redondo, H. de Vladar, T. Włodarski, J.P. Bollback, Journal of the Royal Society Interface 14 (2017).","ista":"Fernandes Redondo RA, de Vladar H, Włodarski T, Bollback JP. 2017. Evolutionary interplay between structure, energy and epistasis in the coat protein of the ϕX174 phage family. Journal of the Royal Society Interface. 14(126), 20160139.","mla":"Fernandes Redondo, Rodrigo A., et al. “Evolutionary Interplay between Structure, Energy and Epistasis in the Coat Protein of the ΦX174 Phage Family.” <i>Journal of the Royal Society Interface</i>, vol. 14, no. 126, 20160139, Royal Society of London, 2017, doi:<a href=\"https://doi.org/10.1098/rsif.2016.0139\">10.1098/rsif.2016.0139</a>.","ama":"Fernandes Redondo RA, de Vladar H, Włodarski T, Bollback JP. Evolutionary interplay between structure, energy and epistasis in the coat protein of the ϕX174 phage family. <i>Journal of the Royal Society Interface</i>. 2017;14(126). doi:<a href=\"https://doi.org/10.1098/rsif.2016.0139\">10.1098/rsif.2016.0139</a>","chicago":"Fernandes Redondo, Rodrigo A, Harold de Vladar, Tomasz Włodarski, and Jonathan P Bollback. “Evolutionary Interplay between Structure, Energy and Epistasis in the Coat Protein of the ΦX174 Phage Family.” <i>Journal of the Royal Society Interface</i>. Royal Society of London, 2017. <a href=\"https://doi.org/10.1098/rsif.2016.0139\">https://doi.org/10.1098/rsif.2016.0139</a>.","apa":"Fernandes Redondo, R. A., de Vladar, H., Włodarski, T., &#38; Bollback, J. P. (2017). Evolutionary interplay between structure, energy and epistasis in the coat protein of the ϕX174 phage family. <i>Journal of the Royal Society Interface</i>. Royal Society of London. <a href=\"https://doi.org/10.1098/rsif.2016.0139\">https://doi.org/10.1098/rsif.2016.0139</a>","ieee":"R. A. Fernandes Redondo, H. de Vladar, T. Włodarski, and J. P. Bollback, “Evolutionary interplay between structure, energy and epistasis in the coat protein of the ϕX174 phage family,” <i>Journal of the Royal Society Interface</i>, vol. 14, no. 126. Royal Society of London, 2017."},"user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","project":[{"grant_number":"250152","name":"Limits to selection in biology and in evolutionary computation","_id":"25B07788-B435-11E9-9278-68D0E5697425","call_identifier":"FP7"},{"grant_number":"648440","_id":"2578D616-B435-11E9-9278-68D0E5697425","name":"Selective Barriers to Horizontal Gene Transfer","call_identifier":"H2020"}],"quality_controlled":"1","oa_version":"Published Version","_id":"1077","publication_identifier":{"issn":["17425689"]},"oa":1,"date_updated":"2025-05-28T11:42:51Z","publist_id":"6303","volume":14,"article_processing_charge":"Yes (in subscription journal)","language":[{"iso":"eng"}],"publisher":"Royal Society of London","scopus_import":"1","date_published":"2017-01-04T00:00:00Z","month":"01","file":[{"content_type":"application/pdf","relation":"main_file","creator":"dernst","file_id":"5843","success":1,"date_updated":"2019-01-18T09:14:02Z","access_level":"open_access","file_name":"2017_JRSI_Redondo.pdf","file_size":1092015,"date_created":"2019-01-18T09:14:02Z"}],"date_created":"2018-12-11T11:50:01Z","department":[{"_id":"NiBa"},{"_id":"JoBo"}],"has_accepted_license":"1","status":"public","intvolume":"        14","type":"journal_article","day":"04","file_date_updated":"2019-01-18T09:14:02Z","issue":"126","publication":"Journal of the Royal Society Interface"},{"file_date_updated":"2020-07-14T12:48:10Z","page":"87","supervisor":[{"first_name":"Jonathan P","full_name":"Bollback, Jonathan P","last_name":"Bollback","orcid":"0000-0002-4624-4612","id":"2C6FA9CC-F248-11E8-B48F-1D18A9856A87"}],"status":"public","day":"25","type":"dissertation","date_created":"2018-12-11T11:48:41Z","file":[{"creator":"system","file_id":"5252","relation":"main_file","content_type":"application/pdf","access_level":"open_access","date_updated":"2020-07-14T12:48:10Z","checksum":"c62257a7bff0c5f39e1abffc6bfcca5c","date_created":"2018-12-12T10:17:00Z","file_size":3417773,"file_name":"IST-2017-857-v1+1_thesis_fabienne.pdf"},{"creator":"dernst","file_id":"6212","relation":"source_file","content_type":"application/x-tex","access_level":"closed","date_updated":"2020-07-14T12:48:10Z","checksum":"fc87d7d72fce52824a3ae7dcad0413a8","date_created":"2019-04-05T08:51:59Z","file_size":215899,"file_name":"2017_thesis_Jesse_source.tex"}],"degree_awarded":"PhD","has_accepted_license":"1","department":[{"_id":"JoBo"}],"publisher":"Institute of Science and Technology Austria","language":[{"iso":"eng"}],"month":"08","date_published":"2017-08-25T00:00:00Z","publication_identifier":{"issn":["2663-337X"]},"_id":"820","project":[{"grant_number":"648440","name":"Selective Barriers to Horizontal Gene Transfer","_id":"2578D616-B435-11E9-9278-68D0E5697425","call_identifier":"H2020"}],"oa_version":"Published Version","user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","acknowledgement":"ERC H2020 programme (grant agreement no. 648440)\r\nThanks to Jon Bollback for giving me the chance to do this work, for sharing the ideas that lay at the basis of this work, for his honesty and openness, showing himself to me as a person and not just as a boss. Thanks to Nick Barton for his guidance at the last stage, reading and commenting extensively on several versions of this manuscript, and for his encouragement; thanks to both Jon and Nick for their kindness and patience. Thanks to Erik van Nimwegen and Calin Guet for their time and willingness to be in my thesis committee, and to Erik van Nimwegen especially for agreeing to enter my thesis committee at the last moment, and for his very sharp, helpful and relevant comments during and after the defense. Thanks to my collaborators and discussion partners: Anne Kupczok, for her guidance, ideas and discussions during the construction of the manuscript of Chapter Two, and her comments on the manuscript; Georg Rieckh for making me aware of the issue of parameter identifiability, suggesting how to solve it, and for his unfortunate idea to start the plasmid enterprise in the first place; Murat Tugrul for sharing his model, for his enthusiasm, and his comments on Chapter Three; Srdjan Sarikas for his collaboration on the Monod model fitting, fast forwarding the analysis to turbo speed and making beautiful figures, and making the discussion fun on top of it all; Vanessa Barone for her last minute comments, especially on Chapter Three, providing a sharp and very helpful experimentalist perspective at the last moment; Maros Pleska and Marjon de Vos for their comments on the manuscript of Chapter Two; Gasper Tkacik for his crucial input on the relation between growth rate and lactose concentration; Bor Kavcic for his input on growth rate modeling and error propagation. Thanks to the Bollback, Bollenbach, Barton, Guet and Tkacik group members for both pro- viding an inspiring and supportive scientific environment to work in, as well as a lot of warmth and colour to everyday life. And thanks to the friends I found here, to the people who were there for me and to the people who changed my life, making it stranger and more beautiful than I could have imagined, Maros, Vanessa, Tade, Suzi, Andrej, Peter, Tiago, Kristof, Karin, Irene, Misha, Mato, Guillaume and Zanin. ","article_processing_charge":"No","publist_id":"6829","oa":1,"date_updated":"2023-09-07T12:01:21Z","abstract":[{"lang":"eng","text":"The lac operon is a classic model system for bacterial gene regulation, and has been studied extensively in E. coli, a classic model organism. However, not much is known about E. coli’s ecology and life outside the laboratory, in particular in soil and water environments. The natural diversity of the lac operon outside the laboratory, its role in the ecology of E. coli and the selection pressures it is exposed to, are similarly unknown.\r\nIn Chapter Two of this thesis, I explore the genetic diversity, phylogenetic history and signatures of selection of the lac operon across 20 natural isolates of E. coli and divergent clades of Escherichia. I found that complete lac operons were present in all isolates examined, which in all but one case were functional. The lac operon phylogeny conformed to the whole-genome phylogeny of the divergent Escherichia clades, which excludes horizontal gene transfer as an explanation for the presence of functional lac operons in these clades. All lac operon genes showed a signature of purifying selection; this signature was strongest for the lacY gene. Lac operon genes of human and environmental isolates showed similar signatures of selection, except the lacZ gene, which showed a stronger signature of selection in environmental isolates.\r\nIn Chapter Three, I try to identify the natural genetic variation relevant for phenotype and fitness in the lac operon, comparing growth rate on lactose and LacZ activity of the lac operons of these wild isolates in a common genetic background. Sequence variation in the lac promoter region, upstream of the -10 and -35 RNA polymerase binding motif, predicted variation in LacZ activity at full induction, using a thermodynamic model of polymerase binding (Tugrul, 2016). However, neither variation in LacZ activity, nor RNA polymerase binding predicted by the model correlated with variation in growth rate. Lac operons of human and environmental isolates did not differ systematically in either growth rate on lactose or LacZ protein activity, suggesting that these lac operons have been exposed to similar selection pressures. We thus have no evidence that the phenotypic variation we measured is relevant for fitness.\r\nTo start assessing the effect of genomic background on the growth phenotype conferred by the lac operon, I compared growth on minimal medium with lactose between lac operon constructs and the corresponding original isolates, I found that maximal growth rate was determined by genomic background, with almost all backgrounds conferring higher growth rates than lab strain K12 MG1655. However, I found no evidence that the lactose concentration at which growth was half maximal depended on genomic background."}],"author":[{"last_name":"Jesse","full_name":"Jesse, Fabienne","first_name":"Fabienne","id":"4C8C26A4-F248-11E8-B48F-1D18A9856A87"}],"citation":{"apa":"Jesse, F. (2017). <i>The lac operon in the wild</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:th_857\">https://doi.org/10.15479/AT:ISTA:th_857</a>","ieee":"F. Jesse, “The lac operon in the wild,” Institute of Science and Technology Austria, 2017.","chicago":"Jesse, Fabienne. “The Lac Operon in the Wild.” Institute of Science and Technology Austria, 2017. <a href=\"https://doi.org/10.15479/AT:ISTA:th_857\">https://doi.org/10.15479/AT:ISTA:th_857</a>.","ama":"Jesse F. The lac operon in the wild. 2017. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:th_857\">10.15479/AT:ISTA:th_857</a>","mla":"Jesse, Fabienne. <i>The Lac Operon in the Wild</i>. Institute of Science and Technology Austria, 2017, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:th_857\">10.15479/AT:ISTA:th_857</a>.","short":"F. Jesse, The Lac Operon in the Wild, Institute of Science and Technology Austria, 2017.","ista":"Jesse F. 2017. The lac operon in the wild. Institute of Science and Technology Austria."},"publication_status":"published","ddc":["576","577","579"],"tmp":{"image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"alternative_title":["ISTA Thesis"],"title":"The lac operon in the wild","pubrep_id":"857","doi":"10.15479/AT:ISTA:th_857","year":"2017","ec_funded":1},{"scopus_import":1,"publisher":"eLife Sciences Publications","language":[{"iso":"eng"}],"month":"11","date_published":"2017-11-13T00:00:00Z","date_created":"2018-12-11T11:47:14Z","file":[{"file_size":8453470,"file_name":"IST-2017-918-v1+1_elife-28921-figures-v3.pdf","checksum":"273ab17f33305e4eaafd911ff88e7c5b","date_created":"2018-12-12T10:14:42Z","access_level":"open_access","date_updated":"2020-07-14T12:47:10Z","relation":"main_file","content_type":"application/pdf","file_id":"5096","creator":"system"},{"file_size":1953221,"file_name":"IST-2017-918-v1+2_elife-28921-v3.pdf","checksum":"b433f90576c7be597cd43367946f8e7f","date_created":"2018-12-12T10:14:43Z","access_level":"open_access","date_updated":"2020-07-14T12:47:10Z","relation":"main_file","content_type":"application/pdf","file_id":"5097","creator":"system"}],"has_accepted_license":"1","department":[{"_id":"CaGu"},{"_id":"JoBo"},{"_id":"NiBa"}],"intvolume":"         6","status":"public","day":"13","type":"journal_article","publication":"eLife","file_date_updated":"2020-07-14T12:47:10Z","title":"Regulatory network structure determines patterns of intermolecular epistasis","pubrep_id":"918","doi":"10.7554/eLife.28921","year":"2017","ec_funded":1,"ddc":["576"],"tmp":{"image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"article_number":"e28921","abstract":[{"text":"Most phenotypes are determined by molecular systems composed of specifically interacting molecules. However, unlike for individual components, little is known about the distributions of mutational effects of molecular systems as a whole. We ask how the distribution of mutational effects of a transcriptional regulatory system differs from the distributions of its components, by first independently, and then simultaneously, mutating a transcription factor and the associated promoter it represses. We find that the system distribution exhibits increased phenotypic variation compared to individual component distributions - an effect arising from intermolecular epistasis between the transcription factor and its DNA-binding site. In large part, this epistasis can be qualitatively attributed to the structure of the transcriptional regulatory system and could therefore be a common feature in prokaryotes. Counter-intuitively, intermolecular epistasis can alleviate the constraints of individual components, thereby increasing phenotypic variation that selection could act on and facilitating adaptive evolution. ","lang":"eng"}],"author":[{"last_name":"Lagator","full_name":"Lagator, Mato","first_name":"Mato","id":"345D25EC-F248-11E8-B48F-1D18A9856A87"},{"id":"35F0286E-F248-11E8-B48F-1D18A9856A87","first_name":"Srdjan","last_name":"Sarikas","full_name":"Sarikas, Srdjan"},{"first_name":"Hande","full_name":"Acar, Hande","last_name":"Acar","orcid":"0000-0003-1986-9753","id":"2DDF136A-F248-11E8-B48F-1D18A9856A87"},{"orcid":"0000-0002-4624-4612","last_name":"Bollback","full_name":"Bollback, Jonathan P","first_name":"Jonathan P","id":"2C6FA9CC-F248-11E8-B48F-1D18A9856A87"},{"id":"47F8433E-F248-11E8-B48F-1D18A9856A87","first_name":"Calin C","full_name":"Guet, Calin C","last_name":"Guet","orcid":"0000-0001-6220-2052"}],"citation":{"chicago":"Lagator, Mato, Srdjan Sarikas, Hande Acar, Jonathan P Bollback, and Calin C Guet. “Regulatory Network Structure Determines Patterns of Intermolecular Epistasis.” <i>ELife</i>. eLife Sciences Publications, 2017. <a href=\"https://doi.org/10.7554/eLife.28921\">https://doi.org/10.7554/eLife.28921</a>.","apa":"Lagator, M., Sarikas, S., Acar, H., Bollback, J. P., &#38; Guet, C. C. (2017). Regulatory network structure determines patterns of intermolecular epistasis. <i>ELife</i>. eLife Sciences Publications. <a href=\"https://doi.org/10.7554/eLife.28921\">https://doi.org/10.7554/eLife.28921</a>","ieee":"M. Lagator, S. Sarikas, H. Acar, J. P. Bollback, and C. C. Guet, “Regulatory network structure determines patterns of intermolecular epistasis,” <i>eLife</i>, vol. 6. eLife Sciences Publications, 2017.","short":"M. Lagator, S. Sarikas, H. Acar, J.P. Bollback, C.C. Guet, ELife 6 (2017).","ista":"Lagator M, Sarikas S, Acar H, Bollback JP, Guet CC. 2017. Regulatory network structure determines patterns of intermolecular epistasis. eLife. 6, e28921.","mla":"Lagator, Mato, et al. “Regulatory Network Structure Determines Patterns of Intermolecular Epistasis.” <i>ELife</i>, vol. 6, e28921, eLife Sciences Publications, 2017, doi:<a href=\"https://doi.org/10.7554/eLife.28921\">10.7554/eLife.28921</a>.","ama":"Lagator M, Sarikas S, Acar H, Bollback JP, Guet CC. Regulatory network structure determines patterns of intermolecular epistasis. <i>eLife</i>. 2017;6. doi:<a href=\"https://doi.org/10.7554/eLife.28921\">10.7554/eLife.28921</a>"},"publication_status":"published","publication_identifier":{"issn":["2050084X"]},"_id":"570","oa_version":"Published Version","quality_controlled":"1","project":[{"grant_number":"291734","name":"International IST Postdoc Fellowship Programme","_id":"25681D80-B435-11E9-9278-68D0E5697425","call_identifier":"FP7"},{"grant_number":"648440","call_identifier":"H2020","name":"Selective Barriers to Horizontal Gene Transfer","_id":"2578D616-B435-11E9-9278-68D0E5697425"}],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","oa":1,"volume":6,"date_updated":"2021-01-12T08:03:15Z","publist_id":"7244"},{"intvolume":"         6","status":"public","day":"18","type":"journal_article","publication":"eLife","file_date_updated":"2020-07-14T12:48:16Z","scopus_import":"1","publisher":"eLife Sciences Publications","language":[{"iso":"eng"}],"month":"05","date_published":"2017-05-18T00:00:00Z","file":[{"content_type":"application/pdf","relation":"main_file","creator":"system","file_id":"5306","file_name":"IST-2017-841-v1+1_elife-25192-v2.pdf","file_size":2441529,"date_created":"2018-12-12T10:17:49Z","checksum":"59cdd4400fb41280122d414fea971546","date_updated":"2020-07-14T12:48:16Z","access_level":"open_access"},{"file_id":"5307","creator":"system","relation":"main_file","content_type":"application/pdf","checksum":"b69024880558b858eb8c5d47a92b6377","date_created":"2018-12-12T10:17:50Z","file_size":3752660,"file_name":"IST-2017-841-v1+2_elife-25192-figures-v2.pdf","access_level":"open_access","date_updated":"2020-07-14T12:48:16Z"}],"date_created":"2018-12-11T11:49:23Z","has_accepted_license":"1","department":[{"_id":"CaGu"},{"_id":"NiBa"},{"_id":"JoBo"}],"abstract":[{"lang":"eng","text":"Understanding the relation between genotype and phenotype remains a major challenge. The difficulty of predicting individual mutation effects, and particularly the interactions between them, has prevented the development of a comprehensive theory that links genotypic changes to their phenotypic effects. We show that a general thermodynamic framework for gene regulation, based on a biophysical understanding of protein-DNA binding, accurately predicts the sign of epistasis in a canonical cis-regulatory element consisting of overlapping RNA polymerase and repressor binding sites. Sign and magnitude of individual mutation effects are sufficient to predict the sign of epistasis and its environmental dependence. Thus, the thermodynamic model offers the correct null prediction for epistasis between mutations across DNA-binding sites. Our results indicate that a predictive theory for the effects of cis-regulatory mutations is possible from first principles, as long as the essential molecular mechanisms and the constraints these impose on a biological system are accounted for."}],"author":[{"id":"345D25EC-F248-11E8-B48F-1D18A9856A87","full_name":"Lagator, Mato","last_name":"Lagator","first_name":"Mato"},{"orcid":"0000-0003-2361-3953","full_name":"Paixao, Tiago","last_name":"Paixao","first_name":"Tiago","id":"2C5658E6-F248-11E8-B48F-1D18A9856A87"},{"id":"4880FE40-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-8548-5240","last_name":"Barton","full_name":"Barton, Nicholas H","first_name":"Nicholas H"},{"id":"2C6FA9CC-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-4624-4612","full_name":"Bollback, Jonathan P","last_name":"Bollback","first_name":"Jonathan P"},{"id":"47F8433E-F248-11E8-B48F-1D18A9856A87","first_name":"Calin C","orcid":"0000-0001-6220-2052","last_name":"Guet","full_name":"Guet, Calin C"}],"citation":{"chicago":"Lagator, Mato, Tiago Paixao, Nicholas H Barton, Jonathan P Bollback, and Calin C Guet. “On the Mechanistic Nature of Epistasis in a Canonical Cis-Regulatory Element.” <i>ELife</i>. eLife Sciences Publications, 2017. <a href=\"https://doi.org/10.7554/eLife.25192\">https://doi.org/10.7554/eLife.25192</a>.","apa":"Lagator, M., Paixao, T., Barton, N. H., Bollback, J. P., &#38; Guet, C. C. (2017). On the mechanistic nature of epistasis in a canonical cis-regulatory element. <i>ELife</i>. eLife Sciences Publications. <a href=\"https://doi.org/10.7554/eLife.25192\">https://doi.org/10.7554/eLife.25192</a>","ieee":"M. Lagator, T. Paixao, N. H. Barton, J. P. Bollback, and C. C. Guet, “On the mechanistic nature of epistasis in a canonical cis-regulatory element,” <i>eLife</i>, vol. 6. eLife Sciences Publications, 2017.","ista":"Lagator M, Paixao T, Barton NH, Bollback JP, Guet CC. 2017. On the mechanistic nature of epistasis in a canonical cis-regulatory element. eLife. 6, e25192.","short":"M. Lagator, T. Paixao, N.H. Barton, J.P. Bollback, C.C. Guet, ELife 6 (2017).","ama":"Lagator M, Paixao T, Barton NH, Bollback JP, Guet CC. On the mechanistic nature of epistasis in a canonical cis-regulatory element. <i>eLife</i>. 2017;6. doi:<a href=\"https://doi.org/10.7554/eLife.25192\">10.7554/eLife.25192</a>","mla":"Lagator, Mato, et al. “On the Mechanistic Nature of Epistasis in a Canonical Cis-Regulatory Element.” <i>ELife</i>, vol. 6, e25192, eLife Sciences Publications, 2017, doi:<a href=\"https://doi.org/10.7554/eLife.25192\">10.7554/eLife.25192</a>."},"publication_status":"published","publication_identifier":{"issn":["2050084X"]},"_id":"954","project":[{"grant_number":"618091","call_identifier":"FP7","name":"Speed of Adaptation in Population Genetics and Evolutionary Computation","_id":"25B1EC9E-B435-11E9-9278-68D0E5697425"},{"grant_number":"291734","name":"International IST Postdoc Fellowship Programme","_id":"25681D80-B435-11E9-9278-68D0E5697425","call_identifier":"FP7"},{"_id":"2578D616-B435-11E9-9278-68D0E5697425","name":"Selective Barriers to Horizontal Gene Transfer","call_identifier":"H2020","grant_number":"648440"}],"quality_controlled":"1","oa_version":"Published Version","user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","article_processing_charge":"Yes","volume":6,"publist_id":"6460","date_updated":"2023-09-22T10:01:17Z","oa":1,"external_id":{"isi":["000404024800001"]},"title":"On the mechanistic nature of epistasis in a canonical cis-regulatory element","pubrep_id":"841","doi":"10.7554/eLife.25192","year":"2017","ec_funded":1,"ddc":["576"],"tmp":{"image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"isi":1,"article_number":"e25192"},{"supervisor":[{"first_name":"Jonathan P","full_name":"Bollback, Jonathan P","last_name":"Bollback","orcid":"0000-0002-4624-4612","id":"2C6FA9CC-F248-11E8-B48F-1D18A9856A87"}],"status":"public","day":"01","type":"dissertation","file_date_updated":"2021-02-22T11:51:13Z","page":"75","publisher":"Institute of Science and Technology Austria","language":[{"iso":"eng"}],"month":"12","date_published":"2016-12-01T00:00:00Z","date_created":"2018-12-11T11:50:16Z","file":[{"checksum":"94bbbc754c36115bf37f8fc11fad43c4","date_created":"2019-08-13T11:17:50Z","file_size":3682711,"file_name":"PhDThesis_HandeAcar_1230.pdf","access_level":"closed","date_updated":"2019-08-13T11:17:50Z","creator":"dernst","file_id":"6814","relation":"main_file","content_type":"application/pdf"},{"success":1,"content_type":"application/pdf","relation":"main_file","file_id":"9184","creator":"dernst","file_name":"2016_Thesis_HandeAcar.pdf","file_size":3682711,"date_created":"2021-02-22T11:51:13Z","checksum":"94bbbc754c36115bf37f8fc11fad43c4","date_updated":"2021-02-22T11:51:13Z","access_level":"open_access"}],"has_accepted_license":"1","degree_awarded":"PhD","department":[{"_id":"JoBo"}],"abstract":[{"text":"Horizontal gene transfer (HGT), the lateral acquisition of genes across existing species\r\nboundaries, is a major evolutionary force shaping microbial genomes that facilitates\r\nadaptation to new environments as well as resistance to antimicrobial drugs. As such,\r\nunderstanding the mechanisms and constraints that determine the outcomes of HGT\r\nevents is crucial to understand the dynamics of HGT and to design better strategies to\r\novercome the challenges that originate from it.\r\nFollowing the insertion and expression of a newly transferred gene, the success of an\r\nHGT event will depend on the fitness effect it has on the recipient (host) cell. Therefore,\r\npredicting the impact of HGT on the genetic composition of a population critically\r\ndepends on the distribution of fitness effects (DFE) of horizontally transferred genes.\r\nHowever, to date, we have little knowledge of the DFE of newly transferred genes, and\r\nhence little is known about the shape and scale of this distribution.\r\nIt is particularly important to better understand the selective barriers that determine\r\nthe fitness effects of newly transferred genes. In spite of substantial bioinformatics\r\nefforts to identify horizontally transferred genes and selective barriers, a systematic\r\nexperimental approach to elucidate the roles of different selective barriers in defining\r\nthe fate of a transfer event has largely been absent. Similarly, although the fact that\r\nenvironment might alter the fitness effect of a horizontally transferred gene may seem\r\nobvious, little attention has been given to it in a systematic experimental manner.\r\nIn this study, we developed a systematic experimental approach that consists of\r\ntransferring 44 arbitrarily selected Salmonella typhimurium orthologous genes into an\r\nEscherichia coli host, and estimating the fitness effects of these transferred genes at a\r\nconstant expression level by performing competition assays against the wild type.\r\nIn chapter 2, we performed one-to-one competition assays between a mutant strain\r\ncarrying a transferred gene and the wild type strain. By using flow cytometry we\r\nestimated selection coefficients for the transferred genes with a precision level of 10-3,and obtained the DFE of horizontally transferred genes. We then investigated if these\r\nfitness effects could be predicted by any of the intrinsic properties of the genes, namely,\r\nfunctional category, degree of complexity (protein-protein interactions), GC content,\r\ncodon usage and length. Our analyses revealed that the functional category and length\r\nof the genes act as potential selective barriers. Finally, using the same procedure with\r\nthe endogenous E. coli orthologs of these 44 genes, we demonstrated that gene dosage is\r\nthe most prominent selective barrier to HGT.\r\nIn chapter 3, using the same set of genes we investigated the role of environment on the\r\nsuccess of HGT events. Under six different environments with different levels of stress\r\nwe performed more complex competition assays, where we mixed all 44 mutant strains\r\ncarrying transferred genes with the wild type strain. To estimate the fitness effects of\r\ngenes relative to wild type we used next generation sequencing. We found that the DFEs\r\nof horizontally transferred genes are highly dependent on the environment, with\r\nabundant gene–by-environment interactions. Furthermore, we demonstrated a\r\nrelationship between average fitness effect of a gene across all environments and its\r\nenvironmental variance, and thus its predictability. Finally, in spite of the fitness effects\r\nof genes being highly environment-dependent, we still observed a common shape of\r\nDFEs across all tested environments.","lang":"eng"}],"author":[{"full_name":"Acar, Hande","last_name":"Acar","orcid":"0000-0003-1986-9753","first_name":"Hande","id":"2DDF136A-F248-11E8-B48F-1D18A9856A87"}],"citation":{"chicago":"Acar, Hande. “Selective Barriers to Horizontal Gene Transfer.” Institute of Science and Technology Austria, 2016.","ieee":"H. Acar, “Selective barriers to horizontal gene transfer,” Institute of Science and Technology Austria, 2016.","apa":"Acar, H. (2016). <i>Selective barriers to horizontal gene transfer</i>. Institute of Science and Technology Austria.","ista":"Acar H. 2016. Selective barriers to horizontal gene transfer. Institute of Science and Technology Austria.","short":"H. Acar, Selective Barriers to Horizontal Gene Transfer, Institute of Science and Technology Austria, 2016.","ama":"Acar H. Selective barriers to horizontal gene transfer. 2016.","mla":"Acar, Hande. <i>Selective Barriers to Horizontal Gene Transfer</i>. Institute of Science and Technology Austria, 2016."},"publication_status":"published","publication_identifier":{"issn":["2663-337X"]},"_id":"1121","project":[{"grant_number":"648440","_id":"2578D616-B435-11E9-9278-68D0E5697425","name":"Selective Barriers to Horizontal Gene Transfer","call_identifier":"H2020"}],"oa_version":"Published Version","acknowledgement":"This study was supported by European Research Council ERC CoG 2014 – EVOLHGT,\r\nunder the grant number 648440.\r\n\r\nIt is a pleasure to thank the many people who made this thesis possible.\r\nI would like to first thank my advisor, Jonathan Paul Bollback for providing guidance in\r\nall aspects of my life, encouragement, sound advice, and good teaching over the last six\r\nyears.\r\nI would also like to thank the members of my dissertation committee – Călin C. Guet\r\nand John F. Baines – not only for their time and guidance, but for their intellectual\r\ncontributions to my development as a scientist.\r\nI would like to thank Flavia Gama and Rodrigo Redondo who have taught me all the\r\nskills in the laboratory with their graciousness and friendship. Also special thanks to\r\nBollback group for their support and for providing a stimulating and fun environment:\r\nIsabella Tomanek, Fabienne Jesse, Claudia Igler, and Pavel Payne.\r\nJerneja Beslagic is not only an amazing assistant, she also has a smile brighter and\r\nwarmer than the sunshine, bringing happiness to every moment. Always keep your light\r\nNeja, I will miss our invaluable chatters a lot.","user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","article_processing_charge":"No","publist_id":"6239","oa":1,"date_updated":"2023-09-07T11:42:26Z","title":"Selective barriers to horizontal gene transfer","year":"2016","ec_funded":1,"ddc":["570"],"alternative_title":["ISTA Thesis"]}]