---
_id: '10736'
abstract:
- lang: eng
  text: Predicting function from sequence is a central problem of biology. Currently,
    this is possible only locally in a narrow mutational neighborhood around a wildtype
    sequence rather than globally from any sequence. Using random mutant libraries,
    we developed a biophysical model that accounts for multiple features of σ70 binding
    bacterial promoters to predict constitutive gene expression levels from any sequence.
    We experimentally and theoretically estimated that 10–20% of random sequences
    lead to expression and ~80% of non-expressing sequences are one mutation away
    from a functional promoter. The potential for generating expression from random
    sequences is so pervasive that selection acts against σ70-RNA polymerase binding
    sites even within inter-genic, promoter-containing regions. This pervasiveness
    of σ70-binding sites implies that emergence of promoters is not the limiting step
    in gene regulatory evolution. Ultimately, the inclusion of novel features of promoter
    function into a mechanistic model enabled not only more accurate predictions of
    gene expression levels, but also identified that promoters evolve more rapidly
    than previously thought.
acknowledgement: 'We thank Hande Acar, Nicholas H Barton, Rok Grah, Tiago Paixao,
  Maros Pleska, Anna Staron, and Murat Tugrul for insightful comments and input on
  the manuscript. This work was supported by: Sir Henry Dale Fellowship jointly funded
  by the Wellcome Trust and the Royal Society (grant number 216779/Z/19/Z) to ML;
  IPC Grant from IST Austria to ML and SS; European Research Council Funding Programme
  7 (2007–2013, grant agreement number 648440) to JPB.'
article_number: e64543
article_processing_charge: No
article_type: original
author:
- first_name: Mato
  full_name: Lagator, Mato
  id: 345D25EC-F248-11E8-B48F-1D18A9856A87
  last_name: Lagator
- first_name: Srdjan
  full_name: Sarikas, Srdjan
  id: 35F0286E-F248-11E8-B48F-1D18A9856A87
  last_name: Sarikas
- first_name: Magdalena
  full_name: Steinrueck, Magdalena
  last_name: Steinrueck
- first_name: David
  full_name: Toledo-Aparicio, David
  last_name: Toledo-Aparicio
- first_name: Jonathan P
  full_name: Bollback, Jonathan P
  id: 2C6FA9CC-F248-11E8-B48F-1D18A9856A87
  last_name: Bollback
  orcid: 0000-0002-4624-4612
- 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: Gašper
  full_name: Tkačik, Gašper
  id: 3D494DCA-F248-11E8-B48F-1D18A9856A87
  last_name: Tkačik
  orcid: 0000-0002-6699-1455
citation:
  ama: Lagator M, Sarikas S, Steinrueck M, et al. Predicting bacterial promoter function
    and evolution from random sequences. <i>eLife</i>. 2022;11. doi:<a href="https://doi.org/10.7554/eLife.64543">10.7554/eLife.64543</a>
  apa: Lagator, M., Sarikas, S., Steinrueck, M., Toledo-Aparicio, D., Bollback, J.
    P., Guet, C. C., &#38; Tkačik, G. (2022). Predicting bacterial promoter function
    and evolution from random sequences. <i>ELife</i>. eLife Sciences Publications.
    <a href="https://doi.org/10.7554/eLife.64543">https://doi.org/10.7554/eLife.64543</a>
  chicago: Lagator, Mato, Srdjan Sarikas, Magdalena Steinrueck, David Toledo-Aparicio,
    Jonathan P Bollback, Calin C Guet, and Gašper Tkačik. “Predicting Bacterial Promoter
    Function and Evolution from Random Sequences.” <i>ELife</i>. eLife Sciences Publications,
    2022. <a href="https://doi.org/10.7554/eLife.64543">https://doi.org/10.7554/eLife.64543</a>.
  ieee: M. Lagator <i>et al.</i>, “Predicting bacterial promoter function and evolution
    from random sequences,” <i>eLife</i>, vol. 11. eLife Sciences Publications, 2022.
  ista: Lagator M, Sarikas S, Steinrueck M, Toledo-Aparicio D, Bollback JP, Guet CC,
    Tkačik G. 2022. Predicting bacterial promoter function and evolution from random
    sequences. eLife. 11, e64543.
  mla: Lagator, Mato, et al. “Predicting Bacterial Promoter Function and Evolution
    from Random Sequences.” <i>ELife</i>, vol. 11, e64543, eLife Sciences Publications,
    2022, doi:<a href="https://doi.org/10.7554/eLife.64543">10.7554/eLife.64543</a>.
  short: M. Lagator, S. Sarikas, M. Steinrueck, D. Toledo-Aparicio, J.P. Bollback,
    C.C. Guet, G. Tkačik, ELife 11 (2022).
date_created: 2022-02-06T23:01:32Z
date_published: 2022-01-26T00:00:00Z
date_updated: 2023-08-02T14:09:02Z
day: '26'
ddc:
- '576'
department:
- _id: CaGu
- _id: GaTk
- _id: NiBa
doi: 10.7554/eLife.64543
ec_funded: 1
external_id:
  isi:
  - '000751104400001'
  pmid:
  - '35080492'
file:
- access_level: open_access
  checksum: decdcdf600ff51e9a9703b49ca114170
  content_type: application/pdf
  creator: cchlebak
  date_created: 2022-02-07T07:14:09Z
  date_updated: 2022-02-07T07:14:09Z
  file_id: '10739'
  file_name: 2022_ELife_Lagator.pdf
  file_size: 5604343
  relation: main_file
  success: 1
file_date_updated: 2022-02-07T07:14:09Z
has_accepted_license: '1'
intvolume: '        11'
isi: 1
language:
- iso: eng
month: '01'
oa: 1
oa_version: Published Version
pmid: 1
project:
- _id: 2578D616-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '648440'
  name: Selective Barriers to Horizontal Gene Transfer
publication: eLife
publication_identifier:
  eissn:
  - 2050-084X
publication_status: published
publisher: eLife Sciences Publications
quality_controlled: '1'
scopus_import: '1'
status: public
title: Predicting bacterial promoter function and evolution from random sequences
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: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 11
year: '2022'
...
---
_id: '570'
abstract:
- lang: eng
  text: 'Most phenotypes are determined by molecular systems composed of specifically
    interacting molecules. However, unlike for individual components, little is known
    about the distributions of mutational effects of molecular systems as a whole.
    We ask how the distribution of mutational effects of a transcriptional regulatory
    system differs from the distributions of its components, by first independently,
    and then simultaneously, mutating a transcription factor and the associated promoter
    it represses. We find that the system distribution exhibits increased phenotypic
    variation compared to individual component distributions - an effect arising from
    intermolecular epistasis between the transcription factor and its DNA-binding
    site. In large part, this epistasis can be qualitatively attributed to the structure
    of the transcriptional regulatory system and could therefore be a common feature
    in prokaryotes. Counter-intuitively, intermolecular epistasis can alleviate the
    constraints of individual components, thereby increasing phenotypic variation
    that selection could act on and facilitating adaptive evolution. '
article_number: e28921
author:
- first_name: Mato
  full_name: Lagator, Mato
  id: 345D25EC-F248-11E8-B48F-1D18A9856A87
  last_name: Lagator
- first_name: Srdjan
  full_name: Sarikas, Srdjan
  id: 35F0286E-F248-11E8-B48F-1D18A9856A87
  last_name: Sarikas
- first_name: Hande
  full_name: Acar, Hande
  id: 2DDF136A-F248-11E8-B48F-1D18A9856A87
  last_name: Acar
  orcid: 0000-0003-1986-9753
- first_name: Jonathan P
  full_name: Bollback, Jonathan P
  id: 2C6FA9CC-F248-11E8-B48F-1D18A9856A87
  last_name: Bollback
  orcid: 0000-0002-4624-4612
- first_name: Calin C
  full_name: Guet, Calin C
  id: 47F8433E-F248-11E8-B48F-1D18A9856A87
  last_name: Guet
  orcid: 0000-0001-6220-2052
citation:
  ama: Lagator M, Sarikas S, Acar H, Bollback JP, Guet CC. Regulatory network structure
    determines patterns of intermolecular epistasis. <i>eLife</i>. 2017;6. doi:<a
    href="https://doi.org/10.7554/eLife.28921">10.7554/eLife.28921</a>
  apa: Lagator, M., Sarikas, S., Acar, H., Bollback, J. P., &#38; Guet, C. C. (2017).
    Regulatory network structure determines patterns of intermolecular epistasis.
    <i>ELife</i>. eLife Sciences Publications. <a href="https://doi.org/10.7554/eLife.28921">https://doi.org/10.7554/eLife.28921</a>
  chicago: Lagator, Mato, Srdjan Sarikas, Hande Acar, Jonathan P Bollback, and Calin
    C Guet. “Regulatory Network Structure Determines Patterns of Intermolecular Epistasis.”
    <i>ELife</i>. eLife Sciences Publications, 2017. <a href="https://doi.org/10.7554/eLife.28921">https://doi.org/10.7554/eLife.28921</a>.
  ieee: M. Lagator, S. Sarikas, H. Acar, J. P. Bollback, and C. C. Guet, “Regulatory
    network structure determines patterns of intermolecular epistasis,” <i>eLife</i>,
    vol. 6. eLife Sciences Publications, 2017.
  ista: Lagator M, Sarikas S, Acar H, Bollback JP, Guet CC. 2017. Regulatory network
    structure determines patterns of intermolecular epistasis. eLife. 6, e28921.
  mla: Lagator, Mato, et al. “Regulatory Network Structure Determines Patterns of
    Intermolecular Epistasis.” <i>ELife</i>, vol. 6, e28921, eLife Sciences Publications,
    2017, doi:<a href="https://doi.org/10.7554/eLife.28921">10.7554/eLife.28921</a>.
  short: M. Lagator, S. Sarikas, H. Acar, J.P. Bollback, C.C. Guet, ELife 6 (2017).
date_created: 2018-12-11T11:47:14Z
date_published: 2017-11-13T00:00:00Z
date_updated: 2021-01-12T08:03:15Z
day: '13'
ddc:
- '576'
department:
- _id: CaGu
- _id: JoBo
- _id: NiBa
doi: 10.7554/eLife.28921
ec_funded: 1
file:
- access_level: open_access
  checksum: 273ab17f33305e4eaafd911ff88e7c5b
  content_type: application/pdf
  creator: system
  date_created: 2018-12-12T10:14:42Z
  date_updated: 2020-07-14T12:47:10Z
  file_id: '5096'
  file_name: IST-2017-918-v1+1_elife-28921-figures-v3.pdf
  file_size: 8453470
  relation: main_file
- access_level: open_access
  checksum: b433f90576c7be597cd43367946f8e7f
  content_type: application/pdf
  creator: system
  date_created: 2018-12-12T10:14:43Z
  date_updated: 2020-07-14T12:47:10Z
  file_id: '5097'
  file_name: IST-2017-918-v1+2_elife-28921-v3.pdf
  file_size: 1953221
  relation: main_file
file_date_updated: 2020-07-14T12:47:10Z
has_accepted_license: '1'
intvolume: '         6'
language:
- iso: eng
month: '11'
oa: 1
oa_version: Published Version
project:
- _id: 25681D80-B435-11E9-9278-68D0E5697425
  call_identifier: FP7
  grant_number: '291734'
  name: International IST Postdoc Fellowship Programme
- _id: 2578D616-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '648440'
  name: Selective Barriers to Horizontal Gene Transfer
publication: eLife
publication_identifier:
  issn:
  - 2050084X
publication_status: published
publisher: eLife Sciences Publications
publist_id: '7244'
pubrep_id: '918'
quality_controlled: '1'
scopus_import: 1
status: public
title: Regulatory network structure determines patterns of intermolecular epistasis
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: 6
year: '2017'
...