[{"publication":"Current Opinion in Genetics and Development","date_published":"2026-04-15T00:00:00Z","abstract":[{"text":"Promoters and enhancers are cis-regulatory elements (CREs), DNA sequences that bind transcription factor (TF) proteins to up- or down-regulate target genes. Decades-long efforts yielded TF-DNA interaction models that predict how strongly an individual TF binds arbitrary DNA sequences and how individual binding events on the CRE combine to affect gene expression. These insights can be synthesized into a global, biophysically realistic, and quantitative genotype-phenotype (GP) map for gene regulation, a ‘holy grail’ for the application of evolutionary theory. A global map provides a rare opportunity to simulate the long-term evolution of regulatory sequences and pose several fundamental questions: How long does it take to evolve CREs de novo? How many non-trivial regulatory functions exist in sequence space? How connected are they? For which regulatory architecture is CRE evolution most rapid and evolvable? In this article, the second of a two-part series, we review the application of evolutionary concepts — epistasis, robustness, evolvability, tunability, plasticity, and bet-hedging — to the evolution of gene regulatory sequences. We then evaluate the potential for a unifying theory for the evolution of regulatory sequences and identify key open challenges.","lang":"eng"}],"oa_version":"Published Version","main_file_link":[{"url":"https://doi.org/10.1016/j.gde.2026.102472","open_access":"1"}],"author":[{"last_name":"Mascolo","full_name":"Mascolo, Elia","id":"776a6ed0-a053-11f0-8635-80b95e0e0d53","first_name":"Elia","orcid":"0000-0003-2977-7844"},{"last_name":"Körei","full_name":"Körei, Reka E","id":"50FDE43E-AA30-11E9-A72B-8A12E6697425","first_name":"Reka E"},{"first_name":"Noa O.","last_name":"Borst","full_name":"Borst, Noa O."},{"first_name":"Nicholas H","id":"4880FE40-F248-11E8-B48F-1D18A9856A87","full_name":"Barton, Nicholas H","last_name":"Barton","orcid":"0000-0002-8548-5240"},{"full_name":"Crocker, Justin","last_name":"Crocker","first_name":"Justin"},{"id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","first_name":"Gašper","last_name":"Tkačik","full_name":"Tkačik, Gašper","orcid":"0000-0002-6699-1455"}],"day":"15","publication_status":"epub_ahead","article_type":"review","project":[{"grant_number":"101055327","name":"Understanding the evolution of continuous genomes","_id":"bd6958e0-d553-11ed-ba76-86eba6a76c00"}],"title":"Long-term evolution of regulatory DNA sequences. Part 2: Theory and future challenges","type":"journal_article","language":[{"iso":"eng"}],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","date_created":"2026-04-26T22:01:46Z","acknowledgement":"We thank Calin Guet and Santiago Herrera-Álvarez for essential contributions to this manuscript.\r\nE.M. acknowledges support from the APART-USA fellowship, jointly funded by the Austrian Academy of Sciences (ÖAW) and the Institute of Science and Technology Austria (ISTA). N.B. acknowledges funding from the ERC Advanced Grant 101055327 “HaplotypeStructure”.\r\nThis study was also supported by the European Molecular Biology Laboratory (N.O.B., J.C.).","doi":"10.1016/j.gde.2026.102472","article_number":"102472","year":"2026","publication_identifier":{"issn":["0959-437X"],"eissn":["1879-0380"]},"OA_place":"publisher","month":"04","intvolume":"        98","publisher":"Elsevier","OA_type":"hybrid","quality_controlled":"1","volume":98,"citation":{"ieee":"E. Mascolo, R. E. Körei, N. O. Borst, N. H. Barton, J. Crocker, and G. Tkačik, “Long-term evolution of regulatory DNA sequences. Part 2: Theory and future challenges,” <i>Current Opinion in Genetics and Development</i>, vol. 98. Elsevier, 2026.","ama":"Mascolo E, Körei RE, Borst NO, Barton NH, Crocker J, Tkačik G. Long-term evolution of regulatory DNA sequences. Part 2: Theory and future challenges. <i>Current Opinion in Genetics and Development</i>. 2026;98. doi:<a href=\"https://doi.org/10.1016/j.gde.2026.102472\">10.1016/j.gde.2026.102472</a>","chicago":"Mascolo, Elia, Reka E Körei, Noa O. Borst, Nicholas H Barton, Justin Crocker, and Gašper Tkačik. “Long-Term Evolution of Regulatory DNA Sequences. Part 2: Theory and Future Challenges.” <i>Current Opinion in Genetics and Development</i>. Elsevier, 2026. <a href=\"https://doi.org/10.1016/j.gde.2026.102472\">https://doi.org/10.1016/j.gde.2026.102472</a>.","short":"E. Mascolo, R.E. Körei, N.O. Borst, N.H. Barton, J. Crocker, G. Tkačik, Current Opinion in Genetics and Development 98 (2026).","ista":"Mascolo E, Körei RE, Borst NO, Barton NH, Crocker J, Tkačik G. 2026. Long-term evolution of regulatory DNA sequences. Part 2: Theory and future challenges. Current Opinion in Genetics and Development. 98, 102472.","apa":"Mascolo, E., Körei, R. E., Borst, N. O., Barton, N. H., Crocker, J., &#38; Tkačik, G. (2026). Long-term evolution of regulatory DNA sequences. Part 2: Theory and future challenges. <i>Current Opinion in Genetics and Development</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.gde.2026.102472\">https://doi.org/10.1016/j.gde.2026.102472</a>","mla":"Mascolo, Elia, et al. “Long-Term Evolution of Regulatory DNA Sequences. Part 2: Theory and Future Challenges.” <i>Current Opinion in Genetics and Development</i>, vol. 98, 102472, Elsevier, 2026, doi:<a href=\"https://doi.org/10.1016/j.gde.2026.102472\">10.1016/j.gde.2026.102472</a>."},"article_processing_charge":"Yes (via OA deal)","status":"public","_id":"21759","corr_author":"1","scopus_import":"1","ddc":["570"],"department":[{"_id":"GaTk"},{"_id":"NiBa"}],"oa":1,"date_updated":"2026-06-18T08:34:09Z"},{"corr_author":"1","_id":"21983","status":"public","ddc":["570"],"department":[{"_id":"GradSch"},{"_id":"CaGu"},{"_id":"GaTk"}],"arxiv":1,"scopus_import":"1","oa":1,"date_updated":"2026-06-16T12:37:02Z","OA_place":"publisher","month":"05","publisher":"Elsevier","intvolume":"        99","has_accepted_license":"1","citation":{"mla":"Mascolo, Elia, et al. “Long-Term Evolution of Regulatory DNA Sequences. Part 1: Simulations on Global, Biophysically-Realistic Genotype–Phenotype Maps.” <i>Current Opinion in Genetics &#38; Development</i>, vol. 99, 102483, Elsevier, 2026, doi:<a href=\"https://doi.org/10.1016/j.gde.2026.102483\">10.1016/j.gde.2026.102483</a>.","apa":"Mascolo, E., Körei, R. E., Herrera-Álvarez, S., Guet, C. C., Crocker, J., &#38; Tkačik, G. (2026). Long-term evolution of regulatory DNA sequences. Part 1: Simulations on global, biophysically-realistic genotype–phenotype maps. <i>Current Opinion in Genetics &#38; Development</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.gde.2026.102483\">https://doi.org/10.1016/j.gde.2026.102483</a>","ista":"Mascolo E, Körei RE, Herrera-Álvarez S, Guet CC, Crocker J, Tkačik G. 2026. Long-term evolution of regulatory DNA sequences. Part 1: Simulations on global, biophysically-realistic genotype–phenotype maps. Current Opinion in Genetics &#38; Development. 99, 102483.","short":"E. Mascolo, R.E. Körei, S. Herrera-Álvarez, C.C. Guet, J. Crocker, G. Tkačik, Current Opinion in Genetics &#38; Development 99 (2026).","ama":"Mascolo E, Körei RE, Herrera-Álvarez S, Guet CC, Crocker J, Tkačik G. Long-term evolution of regulatory DNA sequences. Part 1: Simulations on global, biophysically-realistic genotype–phenotype maps. <i>Current Opinion in Genetics &#38; Development</i>. 2026;99. doi:<a href=\"https://doi.org/10.1016/j.gde.2026.102483\">10.1016/j.gde.2026.102483</a>","chicago":"Mascolo, Elia, Reka E Körei, Santiago Herrera-Álvarez, Calin C Guet, Justin Crocker, and Gašper Tkačik. “Long-Term Evolution of Regulatory DNA Sequences. Part 1: Simulations on Global, Biophysically-Realistic Genotype–Phenotype Maps.” <i>Current Opinion in Genetics &#38; Development</i>. Elsevier, 2026. <a href=\"https://doi.org/10.1016/j.gde.2026.102483\">https://doi.org/10.1016/j.gde.2026.102483</a>.","ieee":"E. Mascolo, R. E. Körei, S. Herrera-Álvarez, C. C. Guet, J. Crocker, and G. Tkačik, “Long-term evolution of regulatory DNA sequences. Part 1: Simulations on global, biophysically-realistic genotype–phenotype maps,” <i>Current Opinion in Genetics &#38; Development</i>, vol. 99. Elsevier, 2026."},"quality_controlled":"1","OA_type":"hybrid","volume":99,"article_processing_charge":"Yes (via OA deal)","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","short":"CC BY (4.0)"},"article_type":"original","publication_status":"published","language":[{"iso":"eng"}],"type":"journal_article","title":"Long-term evolution of regulatory DNA sequences. Part 1: Simulations on global, biophysically-realistic genotype–phenotype maps","date_created":"2026-06-10T07:37:12Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","article_number":"102483","publication_identifier":{"issn":["0959-437X"],"eissn":["1879-0380"]},"year":"2026","doi":"10.1016/j.gde.2026.102483","acknowledgement":"We thank Nick Barton and Noa Ottilie Borst for essential contributions to this manuscript.\r\nE.M. acknowledges support from the APART-USA fellowship, jointly funded by the Austrian Academy of Sciences (ÖAW) and the Institute of Science and Technology Austria (ISTA).\r\nThis study was supported by the European Molecular Biology Laboratory (J.C.); the European Molecular Biology Laboratory Interdisciplinary Postdoc Programme (EIPOD) under the Marie Skłodowska-Curie Actions cofund (S.H.A.).","date_published":"2026-05-09T00:00:00Z","external_id":{"arxiv":["2601.19681"]},"publication":"Current Opinion in Genetics & Development","abstract":[{"text":"Promoters and enhancers are cis-regulatory elements (CREs), DNA sequences that bind transcription factor (TF) proteins to up- or down-regulate target genes. Decades-long efforts yielded TF-DNA interaction models that predict how strongly an individual TF binds arbitrary DNA sequences and how individual binding events on the CRE combine to affect gene expression. These insights can be synthesized into a global, biophysically realistic, and quantitative genotype–phenotype map for gene regulation, a ‘holy grail’ for the application of evolutionary theory. A global map provides a rare opportunity to simulate the long-term evolution of regulatory sequences and pose several fundamental questions: How long does it take to evolve CREs de novo? How many non-trivial regulatory functions exist in sequence space? How connected are they? For which regulatory architecture is CRE evolution most rapid and evolvable? In this article, the first of a two-part series, we briefly review the pertinent modeling and simulation efforts for a unique system that enables close, quantitative, and mechanistic links between biophysics, as well as systems, synthetic, and evolutionary biology.","lang":"eng"}],"main_file_link":[{"open_access":"1","url":"https://doi.org/10.1016/j.gde.2026.102483"}],"oa_version":"Published Version","PlanS_conform":"1","day":"09","author":[{"orcid":"0000-0003-2977-7844","id":"776a6ed0-a053-11f0-8635-80b95e0e0d53","first_name":"Elia","last_name":"Mascolo","full_name":"Mascolo, Elia"},{"first_name":"Reka E","id":"50FDE43E-AA30-11E9-A72B-8A12E6697425","full_name":"Körei, Reka E","last_name":"Körei"},{"first_name":"Santiago","last_name":"Herrera-Álvarez","full_name":"Herrera-Álvarez, Santiago"},{"orcid":"0000-0001-6220-2052","first_name":"Calin C","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","full_name":"Guet, Calin C","last_name":"Guet"},{"first_name":"Justin","full_name":"Crocker, Justin","last_name":"Crocker"},{"id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","first_name":"Gašper","last_name":"Tkačik","full_name":"Tkačik, Gašper","orcid":"0000-0002-6699-1455"}]}]