article published yes Elia Mascolo author 776a6ed0-a053-11f0-8635-80b95e0e0d530000-0003-2977-7844 Reka E Körei author 50FDE43E-AA30-11E9-A72B-8A12E6697425 Santiago Herrera-Álvarez author Calin C Guet author 47F8433E-F248-11E8-B48F-1D18A9856A870000-0001-6220-2052 Justin Crocker author Gašper Tkačik author 3D494DCA-F248-11E8-B48F-1D18A9856A870000-0002-6699-1455 GradSch department CaGu department GaTk department 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. https://creativecommons.org/licenses/by/4.0/ Elsevier2026 eng 0959-437X 1879-0380 2601.1968110.1016/j.gde.2026.102483 99 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. 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>. E. Mascolo, R.E. Körei, S. Herrera-Álvarez, C.C. Guet, J. Crocker, G. Tkačik, Current Opinion in Genetics &#38; Development 99 (2026). 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. 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> 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> 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>. 219832026-06-10T07:37:12Z2026-06-16T12:37:02Z