@article{21759,
  abstract     = {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.},
  author       = {Mascolo, Elia and Körei, Reka E and Borst, Noa O. and Barton, Nicholas H and Crocker, Justin and Tkačik, Gašper},
  issn         = {1879-0380},
  journal      = {Current Opinion in Genetics and Development},
  publisher    = {Elsevier},
  title        = {{Long-term evolution of regulatory DNA sequences. Part 2: Theory and future challenges}},
  doi          = {10.1016/j.gde.2026.102472},
  volume       = {98},
  year         = {2026},
}

@article{21983,
  abstract     = {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.},
  author       = {Mascolo, Elia and Körei, Reka E and Herrera-Álvarez, Santiago and Guet, Calin C and Crocker, Justin and Tkačik, Gašper},
  issn         = {1879-0380},
  journal      = {Current Opinion in Genetics & Development},
  publisher    = {Elsevier},
  title        = {{Long-term evolution of regulatory DNA sequences. Part 1: Simulations on global, biophysically-realistic genotype–phenotype maps}},
  doi          = {10.1016/j.gde.2026.102483},
  volume       = {99},
  year         = {2026},
}