{"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."}],"date_created":"2018-12-11T11:49:23Z","language":[{"iso":"eng"}],"publisher":"eLife Sciences Publications","oa":1,"file":[{"checksum":"59cdd4400fb41280122d414fea971546","access_level":"open_access","relation":"main_file","file_name":"IST-2017-841-v1+1_elife-25192-v2.pdf","content_type":"application/pdf","file_id":"5306","file_size":2441529,"date_created":"2018-12-12T10:17:49Z","date_updated":"2020-07-14T12:48:16Z","creator":"system"},{"creator":"system","date_created":"2018-12-12T10:17:50Z","file_size":3752660,"date_updated":"2020-07-14T12:48:16Z","content_type":"application/pdf","file_name":"IST-2017-841-v1+2_elife-25192-figures-v2.pdf","file_id":"5307","checksum":"b69024880558b858eb8c5d47a92b6377","access_level":"open_access","relation":"main_file"}],"doi":"10.7554/eLife.25192","publist_id":"6460","file_date_updated":"2020-07-14T12:48:16Z","has_accepted_license":"1","day":"18","article_processing_charge":"Yes","article_number":"e25192","isi":1,"date_updated":"2023-09-22T10:01:17Z","date_published":"2017-05-18T00:00:00Z","publication_status":"published","quality_controlled":"1","author":[{"first_name":"Mato","last_name":"Lagator","id":"345D25EC-F248-11E8-B48F-1D18A9856A87","full_name":"Lagator, Mato"},{"full_name":"Paixao, Tiago","orcid":"0000-0003-2361-3953","id":"2C5658E6-F248-11E8-B48F-1D18A9856A87","last_name":"Paixao","first_name":"Tiago"},{"orcid":"0000-0002-8548-5240","full_name":"Barton, Nicholas H","first_name":"Nicholas H","last_name":"Barton","id":"4880FE40-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Bollback, Jonathan P","orcid":"0000-0002-4624-4612","last_name":"Bollback","id":"2C6FA9CC-F248-11E8-B48F-1D18A9856A87","first_name":"Jonathan P"},{"orcid":"0000-0001-6220-2052","full_name":"Guet, Calin C","first_name":"Calin C","last_name":"Guet","id":"47F8433E-F248-11E8-B48F-1D18A9856A87"}],"type":"journal_article","intvolume":"         6","publication_identifier":{"issn":["2050084X"]},"tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"pubrep_id":"841","publication":"eLife","oa_version":"Published Version","ec_funded":1,"status":"public","year":"2017","scopus_import":"1","ddc":["576"],"volume":6,"project":[{"grant_number":"618091","call_identifier":"FP7","name":"Speed of Adaptation in Population Genetics and Evolutionary Computation","_id":"25B1EC9E-B435-11E9-9278-68D0E5697425"},{"_id":"25681D80-B435-11E9-9278-68D0E5697425","name":"International IST Postdoc Fellowship Programme","grant_number":"291734","call_identifier":"FP7"},{"grant_number":"648440","call_identifier":"H2020","name":"Selective Barriers to Horizontal Gene Transfer","_id":"2578D616-B435-11E9-9278-68D0E5697425"}],"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>.","short":"M. Lagator, T. Paixao, N.H. Barton, J.P. Bollback, C.C. Guet, ELife 6 (2017).","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.","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>.","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>"},"_id":"954","month":"05","title":"On the mechanistic nature of epistasis in a canonical cis-regulatory element","user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","department":[{"_id":"CaGu"},{"_id":"NiBa"},{"_id":"JoBo"}],"external_id":{"isi":["000404024800001"]}}