---
_id: '8155'
abstract:
- lang: eng
  text: "In the thesis we focus on the interplay of the biophysics and evolution of
    gene regulation. We start by addressing how the type of prokaryotic gene regulation
    – activation and repression – affects spurious binding to DNA, also known as\r\ntranscriptional
    crosstalk. We propose that regulatory interference caused by excess regulatory
    proteins in the dense cellular medium – global crosstalk – could be a factor in
    determining which type of gene regulatory network is evolutionarily preferred.
    Next,we use a normative approach in eukaryotic gene regulation to describe minimal\r\nnon-equilibrium
    enhancer models that optimize so-called regulatory phenotypes. We find a class
    of models that differ from standard thermodynamic equilibrium models by a single
    parameter that notably increases the regulatory performance. Next chapter addresses
    the question of genotype-phenotype-fitness maps of higher dimensional phenotypes.
    We show that our biophysically realistic approach allows us to understand how
    the mechanisms of promoter function constrain genotypephenotype maps, and how
    they affect the evolutionary trajectories of promoters.\r\nIn the last chapter
    we ask whether the intrinsic instability of gene duplication and amplification
    provides a generic alternative to canonical gene regulation. Using mathematical
    modeling, we show that amplifications can tune gene expression in many environments,
    including those where transcription factor-based schemes are\r\nhard to evolve
    or maintain. "
acknowledgement: For the duration of his PhD, Rok was a recipient of a DOC fellowship
  of the Austrian Academy of Sciences.
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Rok
  full_name: Grah, Rok
  id: 483E70DE-F248-11E8-B48F-1D18A9856A87
  last_name: Grah
  orcid: 0000-0003-2539-3560
citation:
  ama: Grah R. Gene regulation across scales – how biophysical constraints shape evolution.
    2020. doi:<a href="https://doi.org/10.15479/AT:ISTA:8155">10.15479/AT:ISTA:8155</a>
  apa: Grah, R. (2020). <i>Gene regulation across scales – how biophysical constraints
    shape evolution</i>. Institute of Science and Technology Austria. <a href="https://doi.org/10.15479/AT:ISTA:8155">https://doi.org/10.15479/AT:ISTA:8155</a>
  chicago: Grah, Rok. “Gene Regulation across Scales – How Biophysical Constraints
    Shape Evolution.” Institute of Science and Technology Austria, 2020. <a href="https://doi.org/10.15479/AT:ISTA:8155">https://doi.org/10.15479/AT:ISTA:8155</a>.
  ieee: R. Grah, “Gene regulation across scales – how biophysical constraints shape
    evolution,” Institute of Science and Technology Austria, 2020.
  ista: Grah R. 2020. Gene regulation across scales – how biophysical constraints
    shape evolution. Institute of Science and Technology Austria.
  mla: Grah, Rok. <i>Gene Regulation across Scales – How Biophysical Constraints Shape
    Evolution</i>. Institute of Science and Technology Austria, 2020, doi:<a href="https://doi.org/10.15479/AT:ISTA:8155">10.15479/AT:ISTA:8155</a>.
  short: R. Grah, Gene Regulation across Scales – How Biophysical Constraints Shape
    Evolution, Institute of Science and Technology Austria, 2020.
date_created: 2020-07-23T09:51:28Z
date_published: 2020-07-24T00:00:00Z
date_updated: 2023-09-07T13:13:27Z
day: '24'
ddc:
- '530'
- '570'
degree_awarded: PhD
department:
- _id: CaGu
- _id: GaTk
doi: 10.15479/AT:ISTA:8155
file:
- access_level: open_access
  content_type: application/pdf
  creator: rgrah
  date_created: 2020-07-27T12:00:07Z
  date_updated: 2020-07-27T12:00:07Z
  file_id: '8176'
  file_name: Thesis_RokGrah_200727_convertedNew.pdf
  file_size: 16638998
  relation: main_file
  success: 1
- access_level: closed
  content_type: application/zip
  creator: rgrah
  date_created: 2020-07-27T12:02:23Z
  date_updated: 2020-07-30T13:04:55Z
  file_id: '8177'
  file_name: Thesis_new.zip
  file_size: 347459978
  relation: main_file
file_date_updated: 2020-07-30T13:04:55Z
has_accepted_license: '1'
language:
- iso: eng
month: '07'
oa: 1
oa_version: Published Version
page: '310'
project:
- _id: 267C84F4-B435-11E9-9278-68D0E5697425
  name: Biophysically realistic genotype-phenotype maps for regulatory networks
publication_identifier:
  issn:
  - 2663-337X
publication_status: published
publisher: Institute of Science and Technology Austria
related_material:
  record:
  - id: '7675'
    relation: part_of_dissertation
    status: public
  - id: '7569'
    relation: part_of_dissertation
    status: public
  - id: '7652'
    relation: part_of_dissertation
    status: public
status: public
supervisor:
- 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
title: Gene regulation across scales – how biophysical constraints shape evolution
type: dissertation
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
year: '2020'
...
---
_id: '9000'
abstract:
- lang: eng
  text: 'In prokaryotes, thermodynamic models of gene regulation provide a highly
    quantitative mapping from promoter sequences to gene-expression levels that is
    compatible with in vivo and in vitro biophysical measurements. Such concordance
    has not been achieved for models of enhancer function in eukaryotes. In equilibrium
    models, it is difficult to reconcile the reported short transcription factor (TF)
    residence times on the DNA with the high specificity of regulation. In nonequilibrium
    models, progress is difficult due to an explosion in the number of parameters.
    Here, we navigate this complexity by looking for minimal nonequilibrium enhancer
    models that yield desired regulatory phenotypes: low TF residence time, high specificity,
    and tunable cooperativity. We find that a single extra parameter, interpretable
    as the “linking rate,” by which bound TFs interact with Mediator components, enables
    our models to escape equilibrium bounds and access optimal regulatory phenotypes,
    while remaining consistent with the reported phenomenology and simple enough to
    be inferred from upcoming experiments. We further find that high specificity in
    nonequilibrium models is in a trade-off with gene-expression noise, predicting
    bursty dynamics—an experimentally observed hallmark of eukaryotic transcription.
    By drastically reducing the vast parameter space of nonequilibrium enhancer models
    to a much smaller subspace that optimally realizes biological function, we deliver
    a rich class of models that could be tractably inferred from data in the near
    future.'
acknowledgement: G.T. was supported by Human Frontiers Science Program Grant RGP0034/2018.
  R.G. was supported by the Austrian Academy of Sciences DOC Fellowship. R.G. thanks
  S. Avvakumov for helpful discussions.
article_processing_charge: No
article_type: original
author:
- first_name: Rok
  full_name: Grah, Rok
  id: 483E70DE-F248-11E8-B48F-1D18A9856A87
  last_name: Grah
  orcid: 0000-0003-2539-3560
- first_name: Benjamin
  full_name: Zoller, Benjamin
  last_name: Zoller
- first_name: Gašper
  full_name: Tkačik, Gašper
  id: 3D494DCA-F248-11E8-B48F-1D18A9856A87
  last_name: Tkačik
  orcid: 0000-0002-6699-1455
citation:
  ama: Grah R, Zoller B, Tkačik G. Nonequilibrium models of optimal enhancer function.
    <i>PNAS</i>. 2020;117(50):31614-31622. doi:<a href="https://doi.org/10.1073/pnas.2006731117">10.1073/pnas.2006731117</a>
  apa: Grah, R., Zoller, B., &#38; Tkačik, G. (2020). Nonequilibrium models of optimal
    enhancer function. <i>PNAS</i>. National Academy of Sciences. <a href="https://doi.org/10.1073/pnas.2006731117">https://doi.org/10.1073/pnas.2006731117</a>
  chicago: Grah, Rok, Benjamin Zoller, and Gašper Tkačik. “Nonequilibrium Models of
    Optimal Enhancer Function.” <i>PNAS</i>. National Academy of Sciences, 2020. <a
    href="https://doi.org/10.1073/pnas.2006731117">https://doi.org/10.1073/pnas.2006731117</a>.
  ieee: R. Grah, B. Zoller, and G. Tkačik, “Nonequilibrium models of optimal enhancer
    function,” <i>PNAS</i>, vol. 117, no. 50. National Academy of Sciences, pp. 31614–31622,
    2020.
  ista: Grah R, Zoller B, Tkačik G. 2020. Nonequilibrium models of optimal enhancer
    function. PNAS. 117(50), 31614–31622.
  mla: Grah, Rok, et al. “Nonequilibrium Models of Optimal Enhancer Function.” <i>PNAS</i>,
    vol. 117, no. 50, National Academy of Sciences, 2020, pp. 31614–22, doi:<a href="https://doi.org/10.1073/pnas.2006731117">10.1073/pnas.2006731117</a>.
  short: R. Grah, B. Zoller, G. Tkačik, PNAS 117 (2020) 31614–31622.
date_created: 2021-01-10T23:01:17Z
date_published: 2020-12-15T00:00:00Z
date_updated: 2023-08-24T11:10:22Z
day: '15'
ddc:
- '570'
department:
- _id: GaTk
doi: 10.1073/pnas.2006731117
external_id:
  isi:
  - '000600608300015'
  pmid:
  - '33268497'
file:
- access_level: open_access
  checksum: 69039cd402a571983aa6cb4815ffa863
  content_type: application/pdf
  creator: dernst
  date_created: 2021-01-11T08:37:31Z
  date_updated: 2021-01-11T08:37:31Z
  file_id: '9004'
  file_name: 2020_PNAS_Grah.pdf
  file_size: 1199247
  relation: main_file
  success: 1
file_date_updated: 2021-01-11T08:37:31Z
has_accepted_license: '1'
intvolume: '       117'
isi: 1
issue: '50'
language:
- iso: eng
license: https://creativecommons.org/licenses/by-nc-nd/4.0/
month: '12'
oa: 1
oa_version: Published Version
page: 31614-31622
pmid: 1
project:
- _id: 2665AAFE-B435-11E9-9278-68D0E5697425
  grant_number: RGP0034/2018
  name: Can evolution minimize spurious signaling crosstalk to reach optimal performance?
- _id: 267C84F4-B435-11E9-9278-68D0E5697425
  name: Biophysically realistic genotype-phenotype maps for regulatory networks
publication: PNAS
publication_identifier:
  eissn:
  - '10916490'
  issn:
  - '00278424'
publication_status: published
publisher: National Academy of Sciences
quality_controlled: '1'
related_material:
  link:
  - description: News on IST Homepage
    relation: press_release
    url: https://ist.ac.at/en/news/new-compact-model-for-gene-regulation-in-higher-organisms/
scopus_import: '1'
status: public
title: Nonequilibrium models of optimal enhancer function
tmp:
  image: /images/cc_by_nc_nd.png
  legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode
  name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
    (CC BY-NC-ND 4.0)
  short: CC BY-NC-ND (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 117
year: '2020'
...
---
_id: '7383'
abstract:
- lang: eng
  text: Organisms cope with change by employing transcriptional regulators. However,
    when faced with rare environments, the evolution of transcriptional regulators
    and their promoters may be too slow. We ask whether the intrinsic instability
    of gene duplication and amplification provides a generic alternative to canonical
    gene regulation. By real-time monitoring of gene copy number mutations in E. coli,
    we show that gene duplications and amplifications enable adaptation to fluctuating
    environments by rapidly generating copy number, and hence expression level, polymorphism.
    This ‘amplification-mediated gene expression tuning’ occurs on timescales similar
    to canonical gene regulation and can deal with rapid environmental changes. Mathematical
    modeling shows that amplifications also tune gene expression in stochastic environments
    where transcription factor-based schemes are hard to evolve or maintain. The fleeting
    nature of gene amplifications gives rise to a generic population-level mechanism
    that relies on genetic heterogeneity to rapidly tune expression of any gene, without
    leaving any genomic signature.
article_processing_charge: No
author:
- first_name: Rok
  full_name: Grah, Rok
  id: 483E70DE-F248-11E8-B48F-1D18A9856A87
  last_name: Grah
  orcid: 0000-0003-2539-3560
citation:
  ama: 'Grah R. Matlab scripts for the Paper: Gene Amplification as a Form of Population-Level
    Gene Expression regulation. 2020. doi:<a href="https://doi.org/10.15479/AT:ISTA:7383">10.15479/AT:ISTA:7383</a>'
  apa: 'Grah, R. (2020). Matlab scripts for the Paper: Gene Amplification as a Form
    of Population-Level Gene Expression regulation. Institute of Science and Technology
    Austria. <a href="https://doi.org/10.15479/AT:ISTA:7383">https://doi.org/10.15479/AT:ISTA:7383</a>'
  chicago: 'Grah, Rok. “Matlab Scripts for the Paper: Gene Amplification as a Form
    of Population-Level Gene Expression Regulation.” Institute of Science and Technology
    Austria, 2020. <a href="https://doi.org/10.15479/AT:ISTA:7383">https://doi.org/10.15479/AT:ISTA:7383</a>.'
  ieee: 'R. Grah, “Matlab scripts for the Paper: Gene Amplification as a Form of Population-Level
    Gene Expression regulation.” Institute of Science and Technology Austria, 2020.'
  ista: 'Grah R. 2020. Matlab scripts for the Paper: Gene Amplification as a Form
    of Population-Level Gene Expression regulation, Institute of Science and Technology
    Austria, <a href="https://doi.org/10.15479/AT:ISTA:7383">10.15479/AT:ISTA:7383</a>.'
  mla: 'Grah, Rok. <i>Matlab Scripts for the Paper: Gene Amplification as a Form of
    Population-Level Gene Expression Regulation</i>. Institute of Science and Technology
    Austria, 2020, doi:<a href="https://doi.org/10.15479/AT:ISTA:7383">10.15479/AT:ISTA:7383</a>.'
  short: R. Grah, (2020).
contributor:
- contributor_type: project_leader
  first_name: Calin C
  id: 47F8433E-F248-11E8-B48F-1D18A9856A87
  last_name: Guet
  orcid: 0000-0001-6220-2052
date_created: 2020-01-28T10:41:49Z
date_published: 2020-01-28T00:00:00Z
date_updated: 2024-02-21T12:42:31Z
day: '28'
department:
- _id: CaGu
- _id: GaTk
doi: 10.15479/AT:ISTA:7383
file:
- access_level: open_access
  checksum: 9d292cf5207b3829225f44c044cdb3fd
  content_type: application/zip
  creator: rgrah
  date_created: 2020-01-28T10:39:40Z
  date_updated: 2020-07-14T12:47:57Z
  file_id: '7384'
  file_name: Scripts.zip
  file_size: 73363365
  relation: main_file
- access_level: open_access
  checksum: 4076ceab32ef588cc233802bab24c1ab
  content_type: text/plain
  creator: rgrah
  date_created: 2020-01-28T10:39:30Z
  date_updated: 2020-07-14T12:47:57Z
  file_id: '7385'
  file_name: READ_ME_MAIN.txt
  file_size: 962
  relation: main_file
file_date_updated: 2020-07-14T12:47:57Z
has_accepted_license: '1'
keyword:
- Matlab scripts
- analysis of microfluidics
- mathematical model
month: '01'
oa: 1
oa_version: Published Version
publisher: Institute of Science and Technology Austria
related_material:
  record:
  - id: '7652'
    relation: used_in_publication
    status: public
status: public
title: 'Matlab scripts for the Paper: Gene Amplification as a Form of Population-Level
  Gene Expression regulation'
type: research_data
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
year: '2020'
...
---
_id: '7569'
abstract:
- lang: eng
  text: 'Genes differ in the frequency at which they are expressed and in the form
    of regulation used to control their activity. In particular, positive or negative
    regulation can lead to activation of a gene in response to an external signal.
    Previous works proposed that the form of regulation of a gene correlates with
    its frequency of usage: positive regulation when the gene is frequently expressed
    and negative regulation when infrequently expressed. Such network design means
    that, in the absence of their regulators, the genes are found in their least required
    activity state, hence regulatory intervention is often necessary. Due to the multitude
    of genes and regulators, spurious binding and unbinding events, called “crosstalk”,
    could occur. To determine how the form of regulation affects the global crosstalk
    in the network, we used a mathematical model that includes multiple regulators
    and multiple target genes. We found that crosstalk depends non-monotonically on
    the availability of regulators. Our analysis showed that excess use of regulation
    entailed by the formerly suggested network design caused high crosstalk levels
    in a large part of the parameter space. We therefore considered the opposite ‘idle’
    design, where the default unregulated state of genes is their frequently required
    activity state. We found, that ‘idle’ design minimized the use of regulation and
    thus minimized crosstalk. In addition, we estimated global crosstalk of S. cerevisiae
    using transcription factors binding data. We demonstrated that even partial network
    data could suffice to estimate its global crosstalk, suggesting its applicability
    to additional organisms. We found that S. cerevisiae estimated crosstalk is lower
    than that of a random network, suggesting that natural selection reduces crosstalk.
    In summary, our study highlights a new type of protein production cost which is
    typically overlooked: that of regulatory interference caused by the presence of
    excess regulators in the cell. It demonstrates the importance of whole-network
    descriptions, which could show effects missed by single-gene models.'
article_number: e1007642
article_processing_charge: No
article_type: original
author:
- first_name: Rok
  full_name: Grah, Rok
  id: 483E70DE-F248-11E8-B48F-1D18A9856A87
  last_name: Grah
  orcid: 0000-0003-2539-3560
- first_name: Tamar
  full_name: Friedlander, Tamar
  last_name: Friedlander
citation:
  ama: Grah R, Friedlander T. The relation between crosstalk and gene regulation form
    revisited. <i>PLOS Computational Biology</i>. 2020;16(2). doi:<a href="https://doi.org/10.1371/journal.pcbi.1007642">10.1371/journal.pcbi.1007642</a>
  apa: Grah, R., &#38; Friedlander, T. (2020). The relation between crosstalk and
    gene regulation form revisited. <i>PLOS Computational Biology</i>. Public Library
    of Science. <a href="https://doi.org/10.1371/journal.pcbi.1007642">https://doi.org/10.1371/journal.pcbi.1007642</a>
  chicago: Grah, Rok, and Tamar Friedlander. “The Relation between Crosstalk and Gene
    Regulation Form Revisited.” <i>PLOS Computational Biology</i>. Public Library
    of Science, 2020. <a href="https://doi.org/10.1371/journal.pcbi.1007642">https://doi.org/10.1371/journal.pcbi.1007642</a>.
  ieee: R. Grah and T. Friedlander, “The relation between crosstalk and gene regulation
    form revisited,” <i>PLOS Computational Biology</i>, vol. 16, no. 2. Public Library
    of Science, 2020.
  ista: Grah R, Friedlander T. 2020. The relation between crosstalk and gene regulation
    form revisited. PLOS Computational Biology. 16(2), e1007642.
  mla: Grah, Rok, and Tamar Friedlander. “The Relation between Crosstalk and Gene
    Regulation Form Revisited.” <i>PLOS Computational Biology</i>, vol. 16, no. 2,
    e1007642, Public Library of Science, 2020, doi:<a href="https://doi.org/10.1371/journal.pcbi.1007642">10.1371/journal.pcbi.1007642</a>.
  short: R. Grah, T. Friedlander, PLOS Computational Biology 16 (2020).
date_created: 2020-03-06T07:39:38Z
date_published: 2020-02-25T00:00:00Z
date_updated: 2023-09-12T11:02:24Z
day: '25'
ddc:
- '000'
- '570'
department:
- _id: CaGu
- _id: GaTk
doi: 10.1371/journal.pcbi.1007642
external_id:
  isi:
  - '000526725200019'
file:
- access_level: open_access
  checksum: 5239dd134dc6e1c71fe7b3ce2953da37
  content_type: application/pdf
  creator: dernst
  date_created: 2020-03-09T15:12:21Z
  date_updated: 2020-07-14T12:48:00Z
  file_id: '7579'
  file_name: 2020_PlosCompBio_Grah.pdf
  file_size: 2209325
  relation: main_file
file_date_updated: 2020-07-14T12:48:00Z
has_accepted_license: '1'
intvolume: '        16'
isi: 1
issue: '2'
language:
- iso: eng
month: '02'
oa: 1
oa_version: Published Version
publication: PLOS Computational Biology
publication_identifier:
  issn:
  - 1553-7358
publication_status: published
publisher: Public Library of Science
quality_controlled: '1'
related_material:
  record:
  - id: '9716'
    relation: research_data
    status: deleted
  - id: '9776'
    relation: research_data
    status: public
  - id: '9779'
    relation: used_in_publication
    status: public
  - id: '8155'
    relation: dissertation_contains
    status: public
  - id: '9777'
    relation: research_data
    status: public
scopus_import: '1'
status: public
title: The relation between crosstalk and gene regulation form revisited
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: 16
year: '2020'
...
---
_id: '7652'
abstract:
- lang: eng
  text: Organisms cope with change by taking advantage of transcriptional regulators.
    However, when faced with rare environments, the evolution of transcriptional regulators
    and their promoters may be too slow. Here, we investigate whether the intrinsic
    instability of gene duplication and amplification provides a generic alternative
    to canonical gene regulation. Using real-time monitoring of gene-copy-number mutations
    in Escherichia coli, we show that gene duplications and amplifications enable
    adaptation to fluctuating environments by rapidly generating copy-number and,
    therefore, expression-level polymorphisms. This amplification-mediated gene expression
    tuning (AMGET) occurs on timescales that are similar to canonical gene regulation
    and can respond to rapid environmental changes. Mathematical modelling shows that
    amplifications also tune gene expression in stochastic environments in which transcription-factor-based
    schemes are hard to evolve or maintain. The fleeting nature of gene amplifications
    gives rise to a generic population-level mechanism that relies on genetic heterogeneity
    to rapidly tune the expression of any gene, without leaving any genomic signature.
acknowledgement: We thank L. Hurst, N. Barton, M. Pleska, M. Steinrück, B. Kavcic
  and A. Staron for input on the manuscript, and To. Bergmiller and R. Chait for help
  with microfluidics experiments. I.T. is a recipient the OMV fellowship. R.G. is
  a recipient of a DOC (Doctoral Fellowship Programme of the Austrian Academy of Sciences)
  Fellowship of the Austrian Academy of Sciences.
article_processing_charge: No
article_type: original
author:
- first_name: Isabella
  full_name: Tomanek, Isabella
  id: 3981F020-F248-11E8-B48F-1D18A9856A87
  last_name: Tomanek
  orcid: 0000-0001-6197-363X
- first_name: Rok
  full_name: Grah, Rok
  id: 483E70DE-F248-11E8-B48F-1D18A9856A87
  last_name: Grah
  orcid: 0000-0003-2539-3560
- first_name: M.
  full_name: Lagator, M.
  last_name: Lagator
- first_name: A. M. C.
  full_name: Andersson, A. M. C.
  last_name: Andersson
- 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: Gašper
  full_name: Tkačik, Gašper
  id: 3D494DCA-F248-11E8-B48F-1D18A9856A87
  last_name: Tkačik
  orcid: 0000-0002-6699-1455
- 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: Tomanek I, Grah R, Lagator M, et al. Gene amplification as a form of population-level
    gene expression regulation. <i>Nature Ecology &#38; Evolution</i>. 2020;4(4):612-625.
    doi:<a href="https://doi.org/10.1038/s41559-020-1132-7">10.1038/s41559-020-1132-7</a>
  apa: Tomanek, I., Grah, R., Lagator, M., Andersson, A. M. C., Bollback, J. P., Tkačik,
    G., &#38; Guet, C. C. (2020). Gene amplification as a form of population-level
    gene expression regulation. <i>Nature Ecology &#38; Evolution</i>. Springer Nature.
    <a href="https://doi.org/10.1038/s41559-020-1132-7">https://doi.org/10.1038/s41559-020-1132-7</a>
  chicago: Tomanek, Isabella, Rok Grah, M. Lagator, A. M. C. Andersson, Jonathan P
    Bollback, Gašper Tkačik, and Calin C Guet. “Gene Amplification as a Form of Population-Level
    Gene Expression Regulation.” <i>Nature Ecology &#38; Evolution</i>. Springer Nature,
    2020. <a href="https://doi.org/10.1038/s41559-020-1132-7">https://doi.org/10.1038/s41559-020-1132-7</a>.
  ieee: I. Tomanek <i>et al.</i>, “Gene amplification as a form of population-level
    gene expression regulation,” <i>Nature Ecology &#38; Evolution</i>, vol. 4, no.
    4. Springer Nature, pp. 612–625, 2020.
  ista: Tomanek I, Grah R, Lagator M, Andersson AMC, Bollback JP, Tkačik G, Guet CC.
    2020. Gene amplification as a form of population-level gene expression regulation.
    Nature Ecology &#38; Evolution. 4(4), 612–625.
  mla: Tomanek, Isabella, et al. “Gene Amplification as a Form of Population-Level
    Gene Expression Regulation.” <i>Nature Ecology &#38; Evolution</i>, vol. 4, no.
    4, Springer Nature, 2020, pp. 612–25, doi:<a href="https://doi.org/10.1038/s41559-020-1132-7">10.1038/s41559-020-1132-7</a>.
  short: I. Tomanek, R. Grah, M. Lagator, A.M.C. Andersson, J.P. Bollback, G. Tkačik,
    C.C. Guet, Nature Ecology &#38; Evolution 4 (2020) 612–625.
date_created: 2020-04-08T15:20:53Z
date_published: 2020-04-01T00:00:00Z
date_updated: 2024-03-25T23:30:20Z
day: '01'
ddc:
- '570'
department:
- _id: GaTk
- _id: CaGu
doi: 10.1038/s41559-020-1132-7
external_id:
  isi:
  - '000519008300005'
file:
- access_level: open_access
  checksum: ef3bbf42023e30b2c24a6278025d2040
  content_type: application/pdf
  creator: dernst
  date_created: 2020-10-09T09:56:01Z
  date_updated: 2020-10-09T09:56:01Z
  file_id: '8640'
  file_name: 2020_NatureEcolEvo_Tomanek.pdf
  file_size: 745242
  relation: main_file
  success: 1
file_date_updated: 2020-10-09T09:56:01Z
has_accepted_license: '1'
intvolume: '         4'
isi: 1
issue: '4'
language:
- iso: eng
month: '04'
oa: 1
oa_version: Submitted Version
page: 612-625
project:
- _id: 267C84F4-B435-11E9-9278-68D0E5697425
  name: Biophysically realistic genotype-phenotype maps for regulatory networks
publication: Nature Ecology & Evolution
publication_identifier:
  issn:
  - 2397-334X
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
related_material:
  link:
  - description: News on IST Homepage
    relation: press_release
    url: https://ist.ac.at/en/news/how-to-thrive-without-gene-regulation/
  record:
  - id: '8155'
    relation: dissertation_contains
    status: public
  - id: '7383'
    relation: research_data
    status: public
  - id: '7016'
    relation: research_data
    status: public
  - id: '8653'
    relation: used_in_publication
    status: public
scopus_import: '1'
status: public
title: Gene amplification as a form of population-level gene expression regulation
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 4
year: '2020'
...
---
_id: '7675'
abstract:
- lang: eng
  text: 'In prokaryotes, thermodynamic models of gene regulation provide a highly
    quantitative mapping from promoter sequences to gene expression levels that is
    compatible with in vivo and in vitro bio-physical measurements. Such concordance
    has not been achieved for models of enhancer function in eukaryotes. In equilibrium
    models, it is difficult to reconcile the reported short transcription factor (TF)
    residence times on the DNA with the high specificity of regulation. In non-equilibrium
    models, progress is difficult due to an explosion in the number of parameters.
    Here, we navigate this complexity by looking for minimal non-equilibrium enhancer
    models that yield desired regulatory phenotypes: low TF residence time, high specificity
    and tunable cooperativity. We find that a single extra parameter, interpretable
    as the “linking rate” by which bound TFs interact with Mediator components, enables
    our models to escape equilibrium bounds and access optimal regulatory phenotypes,
    while remaining consistent with the reported phenomenology and simple enough to
    be inferred from upcoming experiments. We further find that high specificity in
    non-equilibrium models is in a tradeoff with gene expression noise, predicting
    bursty dynamics — an experimentally-observed hallmark of eukaryotic transcription.
    By drastically reducing the vast parameter space to a much smaller subspace that
    optimally realizes biological function prior to inference from data, our normative
    approach holds promise for mathematical models in systems biology.'
article_processing_charge: No
author:
- first_name: Rok
  full_name: Grah, Rok
  id: 483E70DE-F248-11E8-B48F-1D18A9856A87
  last_name: Grah
  orcid: 0000-0003-2539-3560
- first_name: Benjamin
  full_name: Zoller, Benjamin
  last_name: Zoller
- first_name: Gašper
  full_name: Tkačik, Gašper
  id: 3D494DCA-F248-11E8-B48F-1D18A9856A87
  last_name: Tkačik
  orcid: 0000-0002-6699-1455
citation:
  ama: Grah R, Zoller B, Tkačik G. Normative models of enhancer function. <i>bioRxiv</i>.
    2020. doi:<a href="https://doi.org/10.1101/2020.04.08.029405">10.1101/2020.04.08.029405</a>
  apa: Grah, R., Zoller, B., &#38; Tkačik, G. (2020). Normative models of enhancer
    function. <i>bioRxiv</i>. Cold Spring Harbor Laboratory. <a href="https://doi.org/10.1101/2020.04.08.029405">https://doi.org/10.1101/2020.04.08.029405</a>
  chicago: Grah, Rok, Benjamin Zoller, and Gašper Tkačik. “Normative Models of Enhancer
    Function.” <i>BioRxiv</i>. Cold Spring Harbor Laboratory, 2020. <a href="https://doi.org/10.1101/2020.04.08.029405">https://doi.org/10.1101/2020.04.08.029405</a>.
  ieee: R. Grah, B. Zoller, and G. Tkačik, “Normative models of enhancer function,”
    <i>bioRxiv</i>. Cold Spring Harbor Laboratory, 2020.
  ista: Grah R, Zoller B, Tkačik G. 2020. Normative models of enhancer function. bioRxiv,
    <a href="https://doi.org/10.1101/2020.04.08.029405">10.1101/2020.04.08.029405</a>.
  mla: Grah, Rok, et al. “Normative Models of Enhancer Function.” <i>BioRxiv</i>,
    Cold Spring Harbor Laboratory, 2020, doi:<a href="https://doi.org/10.1101/2020.04.08.029405">10.1101/2020.04.08.029405</a>.
  short: R. Grah, B. Zoller, G. Tkačik, BioRxiv (2020).
date_created: 2020-04-23T10:12:51Z
date_published: 2020-04-09T00:00:00Z
date_updated: 2023-09-07T13:13:26Z
day: '09'
department:
- _id: CaGu
- _id: GaTk
doi: 10.1101/2020.04.08.029405
language:
- iso: eng
main_file_link:
- open_access: '1'
  url: 'https://doi.org/10.1101/2020.04.08.029405 '
month: '04'
oa: 1
oa_version: Preprint
project:
- _id: 2665AAFE-B435-11E9-9278-68D0E5697425
  grant_number: RGP0034/2018
  name: Can evolution minimize spurious signaling crosstalk to reach optimal performance?
- _id: 267C84F4-B435-11E9-9278-68D0E5697425
  name: Biophysically realistic genotype-phenotype maps for regulatory networks
publication: bioRxiv
publication_status: published
publisher: Cold Spring Harbor Laboratory
related_material:
  record:
  - id: '8155'
    relation: dissertation_contains
    status: public
status: public
title: Normative models of enhancer function
type: preprint
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
year: '2020'
...
---
_id: '9776'
article_processing_charge: No
author:
- first_name: Rok
  full_name: Grah, Rok
  id: 483E70DE-F248-11E8-B48F-1D18A9856A87
  last_name: Grah
  orcid: 0000-0003-2539-3560
- first_name: Tamar
  full_name: Friedlander, Tamar
  last_name: Friedlander
citation:
  ama: Grah R, Friedlander T. Supporting information. 2020. doi:<a href="https://doi.org/10.1371/journal.pcbi.1007642.s001">10.1371/journal.pcbi.1007642.s001</a>
  apa: Grah, R., &#38; Friedlander, T. (2020). Supporting information. Public Library
    of Science. <a href="https://doi.org/10.1371/journal.pcbi.1007642.s001">https://doi.org/10.1371/journal.pcbi.1007642.s001</a>
  chicago: Grah, Rok, and Tamar Friedlander. “Supporting Information.” Public Library
    of Science, 2020. <a href="https://doi.org/10.1371/journal.pcbi.1007642.s001">https://doi.org/10.1371/journal.pcbi.1007642.s001</a>.
  ieee: R. Grah and T. Friedlander, “Supporting information.” Public Library of Science,
    2020.
  ista: Grah R, Friedlander T. 2020. Supporting information, Public Library of Science,
    <a href="https://doi.org/10.1371/journal.pcbi.1007642.s001">10.1371/journal.pcbi.1007642.s001</a>.
  mla: Grah, Rok, and Tamar Friedlander. <i>Supporting Information</i>. Public Library
    of Science, 2020, doi:<a href="https://doi.org/10.1371/journal.pcbi.1007642.s001">10.1371/journal.pcbi.1007642.s001</a>.
  short: R. Grah, T. Friedlander, (2020).
date_created: 2021-08-06T07:15:04Z
date_published: 2020-02-25T00:00:00Z
date_updated: 2023-08-18T06:47:47Z
day: '25'
department:
- _id: GaTk
doi: 10.1371/journal.pcbi.1007642.s001
month: '02'
oa_version: Published Version
publisher: Public Library of Science
related_material:
  record:
  - id: '7569'
    relation: used_in_publication
    status: public
status: public
title: Supporting information
type: research_data_reference
user_id: 6785fbc1-c503-11eb-8a32-93094b40e1cf
year: '2020'
...
---
_id: '9777'
article_processing_charge: No
author:
- first_name: Rok
  full_name: Grah, Rok
  id: 483E70DE-F248-11E8-B48F-1D18A9856A87
  last_name: Grah
  orcid: 0000-0003-2539-3560
- first_name: Tamar
  full_name: Friedlander, Tamar
  last_name: Friedlander
citation:
  ama: Grah R, Friedlander T. Maximizing crosstalk. 2020. doi:<a href="https://doi.org/10.1371/journal.pcbi.1007642.s002">10.1371/journal.pcbi.1007642.s002</a>
  apa: Grah, R., &#38; Friedlander, T. (2020). Maximizing crosstalk. Public Library
    of Science. <a href="https://doi.org/10.1371/journal.pcbi.1007642.s002">https://doi.org/10.1371/journal.pcbi.1007642.s002</a>
  chicago: Grah, Rok, and Tamar Friedlander. “Maximizing Crosstalk.” Public Library
    of Science, 2020. <a href="https://doi.org/10.1371/journal.pcbi.1007642.s002">https://doi.org/10.1371/journal.pcbi.1007642.s002</a>.
  ieee: R. Grah and T. Friedlander, “Maximizing crosstalk.” Public Library of Science,
    2020.
  ista: Grah R, Friedlander T. 2020. Maximizing crosstalk, Public Library of Science,
    <a href="https://doi.org/10.1371/journal.pcbi.1007642.s002">10.1371/journal.pcbi.1007642.s002</a>.
  mla: Grah, Rok, and Tamar Friedlander. <i>Maximizing Crosstalk</i>. Public Library
    of Science, 2020, doi:<a href="https://doi.org/10.1371/journal.pcbi.1007642.s002">10.1371/journal.pcbi.1007642.s002</a>.
  short: R. Grah, T. Friedlander, (2020).
date_created: 2021-08-06T07:21:51Z
date_published: 2020-02-25T00:00:00Z
date_updated: 2023-09-12T11:02:25Z
day: '25'
department:
- _id: GaTk
doi: 10.1371/journal.pcbi.1007642.s002
main_file_link:
- open_access: '1'
  url: https://doi.org/10.1371/journal.pcbi.1007642.s002
month: '02'
oa: 1
oa_version: None
publisher: Public Library of Science
related_material:
  record:
  - id: '7569'
    relation: used_in_publication
    status: public
status: public
title: Maximizing crosstalk
type: research_data_reference
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
year: '2020'
...
---
_id: '9779'
article_processing_charge: No
author:
- first_name: Rok
  full_name: Grah, Rok
  id: 483E70DE-F248-11E8-B48F-1D18A9856A87
  last_name: Grah
  orcid: 0000-0003-2539-3560
- first_name: Tamar
  full_name: Friedlander, Tamar
  last_name: Friedlander
citation:
  ama: Grah R, Friedlander T. Distribution of crosstalk values. 2020. doi:<a href="https://doi.org/10.1371/journal.pcbi.1007642.s003">10.1371/journal.pcbi.1007642.s003</a>
  apa: Grah, R., &#38; Friedlander, T. (2020). Distribution of crosstalk values. Public
    Library of Science. <a href="https://doi.org/10.1371/journal.pcbi.1007642.s003">https://doi.org/10.1371/journal.pcbi.1007642.s003</a>
  chicago: Grah, Rok, and Tamar Friedlander. “Distribution of Crosstalk Values.” Public
    Library of Science, 2020. <a href="https://doi.org/10.1371/journal.pcbi.1007642.s003">https://doi.org/10.1371/journal.pcbi.1007642.s003</a>.
  ieee: R. Grah and T. Friedlander, “Distribution of crosstalk values.” Public Library
    of Science, 2020.
  ista: Grah R, Friedlander T. 2020. Distribution of crosstalk values, Public Library
    of Science, <a href="https://doi.org/10.1371/journal.pcbi.1007642.s003">10.1371/journal.pcbi.1007642.s003</a>.
  mla: Grah, Rok, and Tamar Friedlander. <i>Distribution of Crosstalk Values</i>.
    Public Library of Science, 2020, doi:<a href="https://doi.org/10.1371/journal.pcbi.1007642.s003">10.1371/journal.pcbi.1007642.s003</a>.
  short: R. Grah, T. Friedlander, (2020).
date_created: 2021-08-06T07:24:37Z
date_published: 2020-02-25T00:00:00Z
date_updated: 2023-08-18T06:47:47Z
day: '25'
department:
- _id: GaTk
doi: 10.1371/journal.pcbi.1007642.s003
month: '02'
oa_version: Published Version
publisher: Public Library of Science
related_material:
  record:
  - id: '7569'
    relation: research_data
    status: public
status: public
title: Distribution of crosstalk values
type: research_data_reference
user_id: 6785fbc1-c503-11eb-8a32-93094b40e1cf
year: '2020'
...
---
_id: '1220'
abstract:
- lang: eng
  text: Theoretical and numerical aspects of aerodynamic efficiency of propulsion
    systems coupled to the boundary layer of a fuselage are studied. We discuss the
    effects of local flow fields, which are affected both by conservative flow acceleration
    as well as total pressure losses, on the efficiency of boundary layer immersed
    propulsion devices. We introduce the concept of a boundary layer retardation turbine
    that helps reduce skin friction over the fuselage. We numerically investigate
    efficiency gains offered by boundary layer and wake interacting devices. We discuss
    the results in terms of a total energy consumption framework and show that efficiency
    gains of any device depend on all the other elements of the propulsion system.
author:
- first_name: Gregor
  full_name: Mikić, Gregor
  last_name: Mikić
- first_name: Alex
  full_name: Stoll, Alex
  last_name: Stoll
- first_name: Joe
  full_name: Bevirt, Joe
  last_name: Bevirt
- first_name: Rok
  full_name: Grah, Rok
  id: 483E70DE-F248-11E8-B48F-1D18A9856A87
  last_name: Grah
  orcid: 0000-0003-2539-3560
- first_name: Mark
  full_name: Moore, Mark
  last_name: Moore
citation:
  ama: 'Mikić G, Stoll A, Bevirt J, Grah R, Moore M. Fuselage boundary layer ingestion
    propulsion applied to a thin haul commuter aircraft for optimal efficiency. In:
    AIAA; 2016:1-19. doi:<a href="https://doi.org/10.2514/6.2016-3764">10.2514/6.2016-3764</a>'
  apa: 'Mikić, G., Stoll, A., Bevirt, J., Grah, R., &#38; Moore, M. (2016). Fuselage
    boundary layer ingestion propulsion applied to a thin haul commuter aircraft for
    optimal efficiency (pp. 1–19). Presented at the AIAA: Aviation Technology, Integration,
    and Operations Conference, Washington, D.C., USA: AIAA. <a href="https://doi.org/10.2514/6.2016-3764">https://doi.org/10.2514/6.2016-3764</a>'
  chicago: Mikić, Gregor, Alex Stoll, Joe Bevirt, Rok Grah, and Mark Moore. “Fuselage
    Boundary Layer Ingestion Propulsion Applied to a Thin Haul Commuter Aircraft for
    Optimal Efficiency,” 1–19. AIAA, 2016. <a href="https://doi.org/10.2514/6.2016-3764">https://doi.org/10.2514/6.2016-3764</a>.
  ieee: 'G. Mikić, A. Stoll, J. Bevirt, R. Grah, and M. Moore, “Fuselage boundary
    layer ingestion propulsion applied to a thin haul commuter aircraft for optimal
    efficiency,” presented at the AIAA: Aviation Technology, Integration, and Operations
    Conference, Washington, D.C., USA, 2016, pp. 1–19.'
  ista: 'Mikić G, Stoll A, Bevirt J, Grah R, Moore M. 2016. Fuselage boundary layer
    ingestion propulsion applied to a thin haul commuter aircraft for optimal efficiency.
    AIAA: Aviation Technology, Integration, and Operations Conference, 1–19.'
  mla: Mikić, Gregor, et al. <i>Fuselage Boundary Layer Ingestion Propulsion Applied
    to a Thin Haul Commuter Aircraft for Optimal Efficiency</i>. AIAA, 2016, pp. 1–19,
    doi:<a href="https://doi.org/10.2514/6.2016-3764">10.2514/6.2016-3764</a>.
  short: G. Mikić, A. Stoll, J. Bevirt, R. Grah, M. Moore, in:, AIAA, 2016, pp. 1–19.
conference:
  end_date: 2016-06-17
  location: Washington, D.C., USA
  name: 'AIAA: Aviation Technology, Integration, and Operations Conference'
  start_date: 2016-06-13
date_created: 2018-12-11T11:50:47Z
date_published: 2016-06-01T00:00:00Z
date_updated: 2023-02-21T10:17:50Z
day: '01'
department:
- _id: CaGu
- _id: GaTk
doi: 10.2514/6.2016-3764
language:
- iso: eng
main_file_link:
- open_access: '1'
  url: https://ntrs.nasa.gov/search.jsp?R=20160010167&amp;hterms=Fuselage+boundary+layer+ingestion+propulsion+applied+thin+haul+commuter+aircraft+optimal+efficiency&amp;qs=N%3D0%26Ntk%3DAll%26Ntt%3DFuselage%2520boundary%2520layer%2520ingestion%2520propulsion%2520applied%2520to%2520a%2520thin%2520haul%2520commuter%2520aircraft%2520for%2520optimal%2520efficiency%26Ntx%3Dmode%2520matchallpartial%26Nm%3D123%7CCollection%7CNASA%2520STI%7C%7C17%7CCollection%7CNACA
month: '06'
oa: 1
oa_version: Preprint
page: 1 - 19
publication_status: published
publisher: AIAA
publist_id: '6114'
quality_controlled: '1'
scopus_import: 1
status: public
title: Fuselage boundary layer ingestion propulsion applied to a thin haul commuter
  aircraft for optimal efficiency
type: conference
user_id: 3E5EF7F0-F248-11E8-B48F-1D18A9856A87
year: '2016'
...
