---
OA_place: publisher
OA_type: hybrid
_id: '21759'
abstract:
- lang: eng
  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.'
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.)."
article_number: '102472'
article_processing_charge: Yes (via OA deal)
article_type: review
author:
- first_name: Elia
  full_name: Mascolo, Elia
  id: 776a6ed0-a053-11f0-8635-80b95e0e0d53
  last_name: Mascolo
  orcid: 0000-0003-2977-7844
- first_name: Reka E
  full_name: Körei, Reka E
  id: 50FDE43E-AA30-11E9-A72B-8A12E6697425
  last_name: Körei
- first_name: Noa O.
  full_name: Borst, Noa O.
  last_name: Borst
- first_name: Nicholas H
  full_name: Barton, Nicholas H
  id: 4880FE40-F248-11E8-B48F-1D18A9856A87
  last_name: Barton
  orcid: 0000-0002-8548-5240
- first_name: Justin
  full_name: Crocker, Justin
  last_name: Crocker
- first_name: Gašper
  full_name: Tkačik, Gašper
  id: 3D494DCA-F248-11E8-B48F-1D18A9856A87
  last_name: Tkačik
  orcid: 0000-0002-6699-1455
citation:
  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>'
  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>'
  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>.'
  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.'
  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.'
  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>.'
  short: E. Mascolo, R.E. Körei, N.O. Borst, N.H. Barton, J. Crocker, G. Tkačik, Current
    Opinion in Genetics and Development 98 (2026).
corr_author: '1'
date_created: 2026-04-26T22:01:46Z
date_published: 2026-04-15T00:00:00Z
date_updated: 2026-04-28T12:41:00Z
day: '15'
department:
- _id: GaTk
- _id: NiBa
doi: 10.1016/j.gde.2026.102472
intvolume: '        98'
language:
- iso: eng
main_file_link:
- open_access: '1'
  url: https://doi.org/10.1016/j.gde.2026.102472
month: '04'
oa: 1
oa_version: Published Version
project:
- _id: bd6958e0-d553-11ed-ba76-86eba6a76c00
  grant_number: '101055327'
  name: Understanding the evolution of continuous genomes
publication: Current Opinion in Genetics and Development
publication_identifier:
  eissn:
  - 1879-0380
  issn:
  - 0959-437X
publication_status: epub_ahead
publisher: Elsevier
quality_controlled: '1'
scopus_import: '1'
status: public
title: 'Long-term evolution of regulatory DNA sequences. Part 2: Theory and future
  challenges'
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 98
year: '2026'
...
---
OA_place: publisher
OA_type: hybrid
PlanS_conform: '1'
_id: '21983'
abstract:
- lang: eng
  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.'
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.)."
article_number: '102483'
article_processing_charge: Yes (via OA deal)
article_type: original
arxiv: 1
author:
- first_name: Elia
  full_name: Mascolo, Elia
  id: 776a6ed0-a053-11f0-8635-80b95e0e0d53
  last_name: Mascolo
  orcid: 0000-0003-2977-7844
- first_name: Reka E
  full_name: Körei, Reka E
  id: 50FDE43E-AA30-11E9-A72B-8A12E6697425
  last_name: Körei
- first_name: Santiago
  full_name: Herrera-Álvarez, Santiago
  last_name: Herrera-Álvarez
- first_name: Calin C
  full_name: Guet, Calin C
  id: 47F8433E-F248-11E8-B48F-1D18A9856A87
  last_name: Guet
  orcid: 0000-0001-6220-2052
- first_name: Justin
  full_name: Crocker, Justin
  last_name: Crocker
- first_name: Gašper
  full_name: Tkačik, Gašper
  id: 3D494DCA-F248-11E8-B48F-1D18A9856A87
  last_name: Tkačik
  orcid: 0000-0002-6699-1455
citation:
  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>'
  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>'
  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.'
  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.'
  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>.'
  short: E. Mascolo, R.E. Körei, S. Herrera-Álvarez, C.C. Guet, J. Crocker, G. Tkačik,
    Current Opinion in Genetics &#38; Development 99 (2026).
corr_author: '1'
date_created: 2026-06-10T07:37:12Z
date_published: 2026-05-09T00:00:00Z
date_updated: 2026-06-16T12:37:02Z
day: '09'
ddc:
- '570'
department:
- _id: GradSch
- _id: CaGu
- _id: GaTk
doi: 10.1016/j.gde.2026.102483
external_id:
  arxiv:
  - '2601.19681'
has_accepted_license: '1'
intvolume: '        99'
language:
- iso: eng
main_file_link:
- open_access: '1'
  url: https://doi.org/10.1016/j.gde.2026.102483
month: '05'
oa: 1
oa_version: Published Version
publication: Current Opinion in Genetics & Development
publication_identifier:
  eissn:
  - 1879-0380
  issn:
  - 0959-437X
publication_status: published
publisher: Elsevier
quality_controlled: '1'
scopus_import: '1'
status: public
title: 'Long-term evolution of regulatory DNA sequences. Part 1: Simulations on global,
  biophysically-realistic genotype–phenotype maps'
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)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 99
year: '2026'
...