---
APC_amount: 5949 EUR
OA_place: publisher
OA_type: hybrid
_id: '19626'
abstract:
- lang: eng
  text: Active regulation of gene expression, orchestrated by complex interactions
    of activators and repressors at promoters, controls the fate of organisms. In
    contrast, basal expression at uninduced promoters is considered to be a dynamically
    inert mode of nonfunctional “promoter leakiness,” merely a byproduct of transcriptional
    regulation. Here, we investigate the basal expression mode of the mar operon,
    the main regulator of intrinsic multiple antibiotic resistance in Escherichia
    coli, and link its dynamic properties to the noncanonical, yet highly conserved
    start codon of marR across Enterobacteriaceae. Real-time, single-cell measurements
    across tens of generations reveal that basal expression consists of rare stochastic
    gene expression pulses, which maximize variability in wildtype and, surprisingly,
    transiently accelerate cellular elongation rates. Competition experiments show
    that basal expression confers fitness advantages to wildtype across several transitions
    between exponential and stationary growth by shortening lag times. The dynamically
    rich basal expression of the mar operon has likely been evolutionarily maintained
    for its role in growth homeostasis of Enterobacteria within the gut environment,
    thereby allowing other ancillary gene regulatory roles to evolve, e.g., control
    of costly-to-induce multidrug efflux pumps. Understanding the complex selection
    forces governing genetic systems involved in intrinsic multidrug resistance is
    crucial for effective public health measures.
acknowledged_ssus:
- _id: Bio
acknowledgement: K.J. thanks B. Wu, I. Tomanek, K. Tomasek for detailed discussions
  on the manuscript, all other members from the Guet laboratory for valuable feedback,
  R. Chait, & Imaging and Optics Facility, Institute of Science and Technology Austria
  for helping with microscopy, Dr. Sudha Rao and Dr. Raja Mugasimangalam, Genotypic
  Technology India for allowing time off to address the revisions. K.J. acknowledges
  Institute of Science and Technology fellowship IC1006FELL02, R.H. was supported
  in part by Chan Zuckerberg Initiative and Donor Advised-Fund grant 2020-225401 (https://doi.org/10.37921/120055ratwvi),
  O.O.B. acknowledges Fonds Zur Förderung der Wissenschaftlichen Forschung (FWF) Grant
  ESP253-B, R.R. acknowledges FWF Grant 10.55776/ESP219, C.C.G. acknowledges FWF I5127-B.
article_number: e2413709122
article_processing_charge: Yes (in subscription journal)
article_type: original
author:
- first_name: Kirti
  full_name: Jain, Kirti
  id: 330F0278-F248-11E8-B48F-1D18A9856A87
  last_name: Jain
  orcid: 0000-0002-3809-0449
- first_name: Robert
  full_name: Hauschild, Robert
  id: 4E01D6B4-F248-11E8-B48F-1D18A9856A87
  last_name: Hauschild
  orcid: 0000-0001-9843-3522
- first_name: Olga
  full_name: Bochkareva, Olga
  id: C4558D3C-6102-11E9-A62E-F418E6697425
  last_name: Bochkareva
  orcid: 0000-0003-1006-6639
- first_name: Roderich
  full_name: Römhild, Roderich
  id: 68E56E44-62B0-11EA-B963-444F3DDC885E
  last_name: Römhild
  orcid: 0000-0001-9480-5261
- 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: Jain K, Hauschild R, Bochkareva O, Römhild R, Tkačik G, Guet CC. Pulsatile
    basal gene expression as a fitness determinant in bacteria. <i>Proceedings of
    the National Academy of Sciences</i>. 2025;122(15). doi:<a href="https://doi.org/10.1073/pnas.2413709122">10.1073/pnas.2413709122</a>
  apa: Jain, K., Hauschild, R., Bochkareva, O., Römhild, R., Tkačik, G., &#38; Guet,
    C. C. (2025). Pulsatile basal gene expression as a fitness determinant in bacteria.
    <i>Proceedings of the National Academy of Sciences</i>. National Academy of Sciences.
    <a href="https://doi.org/10.1073/pnas.2413709122">https://doi.org/10.1073/pnas.2413709122</a>
  chicago: Jain, Kirti, Robert Hauschild, Olga Bochkareva, Roderich Römhild, Gašper
    Tkačik, and Calin C Guet. “Pulsatile Basal Gene Expression as a Fitness Determinant
    in Bacteria.” <i>Proceedings of the National Academy of Sciences</i>. National
    Academy of Sciences, 2025. <a href="https://doi.org/10.1073/pnas.2413709122">https://doi.org/10.1073/pnas.2413709122</a>.
  ieee: K. Jain, R. Hauschild, O. Bochkareva, R. Römhild, G. Tkačik, and C. C. Guet,
    “Pulsatile basal gene expression as a fitness determinant in bacteria,” <i>Proceedings
    of the National Academy of Sciences</i>, vol. 122, no. 15. National Academy of
    Sciences, 2025.
  ista: Jain K, Hauschild R, Bochkareva O, Römhild R, Tkačik G, Guet CC. 2025. Pulsatile
    basal gene expression as a fitness determinant in bacteria. Proceedings of the
    National Academy of Sciences. 122(15), e2413709122.
  mla: Jain, Kirti, et al. “Pulsatile Basal Gene Expression as a Fitness Determinant
    in Bacteria.” <i>Proceedings of the National Academy of Sciences</i>, vol. 122,
    no. 15, e2413709122, National Academy of Sciences, 2025, doi:<a href="https://doi.org/10.1073/pnas.2413709122">10.1073/pnas.2413709122</a>.
  short: K. Jain, R. Hauschild, O. Bochkareva, R. Römhild, G. Tkačik, C.C. Guet, Proceedings
    of the National Academy of Sciences 122 (2025).
corr_author: '1'
date_created: 2025-04-27T22:02:13Z
date_published: 2025-04-15T00:00:00Z
date_updated: 2026-05-20T08:33:08Z
day: '15'
ddc:
- '570'
department:
- _id: CaGu
- _id: Bio
- _id: FyKo
- _id: GaTk
doi: 10.1073/pnas.2413709122
external_id:
  isi:
  - '001471235200001'
  pmid:
  - '40193613'
file:
- access_level: open_access
  checksum: 115a687f40009660eb4b38b4f6559d41
  content_type: application/pdf
  creator: dernst
  date_created: 2025-06-24T07:27:43Z
  date_updated: 2025-06-24T07:27:43Z
  file_id: '19888'
  file_name: 2025_PNAS_Jain.pdf
  file_size: 2949523
  relation: main_file
  success: 1
file_date_updated: 2025-06-24T07:27:43Z
has_accepted_license: '1'
intvolume: '       122'
isi: 1
issue: '15'
language:
- iso: eng
license: https://creativecommons.org/licenses/by/4.0/
month: '04'
oa: 1
oa_version: Published Version
pmid: 1
project:
- _id: c08e9ad1-5a5b-11eb-8a69-9d1cf3b07473
  grant_number: CZI01
  name: Tools for automation and feedback microscopy
- _id: bd6f94d1-d553-11ed-ba76-ae9f07250f74
  grant_number: E219
  name: Non-canonical antibiotic interactions
- _id: 34e076d6-11ca-11ed-8bc3-aec76c41a181
  grant_number: I05127
  name: Evolutionary analysis of gene regulation
publication: Proceedings of the National Academy of Sciences
publication_identifier:
  eissn:
  - 1091-6490
  issn:
  - 0027-8424
publication_status: published
publisher: National Academy of Sciences
quality_controlled: '1'
related_material:
  link:
  - description: News on ISTA website
    relation: press_release
    url: https://ista.ac.at/en/news/clockwork-just-for-antibiotic-resistance/
  record:
  - id: '19294'
    relation: research_data
    status: public
scopus_import: '1'
status: public
title: Pulsatile basal gene expression as a fitness determinant in bacteria
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: 122
year: '2025'
...
---
OA_place: publisher
OA_type: hybrid
_id: '15362'
abstract:
- lang: eng
  text: Constitutional heterozygous pathogenic variants in the exonuclease domain
    of POLE and POLD1, which affect the proofreading activity of the corresponding
    polymerases, cause a cancer predisposition syndrome characterized by increased
    risk of gastrointestinal polyposis, colorectal cancer, endometrial cancer and
    other tumor types. The generally accepted explanation for the connection between
    the disruption of the proofreading activity of polymerases epsilon and delta and
    cancer development is through an increase in the somatic mutation rate. Here we
    studied an extended family with multiple members heterozygous for the pathogenic
    POLD1 variant c.1421T>C p.(Leu474Pro), which segregates with the polyposis and
    cancer phenotypes. Through the analysis of mutational patterns of patient-derived
    fibroblasts colonies and de novo mutations obtained by parent-offspring comparisons,
    we concluded that heterozygous POLD1 L474P just subtly increases the somatic and
    germline mutation burden. In contrast, tumors developed in individuals with a
    heterozygous mutation in the exonuclease domain of POLD1, including L474P, have
    an extremely high mutation rate (>100 mut/Mb) associated with signature SBS10d.
    We solved this contradiction through the observation that tumorigenesis involves
    somatic inactivation of the wildtype POLD1 allele. These results imply that exonuclease
    deficiency of polymerase delta has a recessive effect on mutation rate.
acknowledgement: 'This study was funded by the Spanish Ministry of Science and Innovation
  (Agencia Estatal de Investigación), co-funded by FEDER funds a way to build Europe
  [PID2020-112595RB-I00 (LV)], Instituto de Salud Carlos III [CIBERONC CB16/12/00234
  (LV); ISCIII-AES-2017 PI17/01082 (JLS), PMP22/00064], Government of Catalonia [AGAUR
  2021SGR01112, CERCA Program for institutional support (LV)], Scientific Foundation
  Asociación Española Contra el Cáncer [AECC Investigador (MT)], Austrian Science
  Fund FWF [Grant Agreement # I5127-B (FK)], German Research Foundation DFG [Grant
  Agreement # 429960716 (FK)], and ERC Consolidator [Grant Agreement # 771209 ChrFL
  (FK)].'
article_processing_charge: No
article_type: original
author:
- first_name: Maria A.
  full_name: Andrianova, Maria A.
  last_name: Andrianova
- first_name: Vladimir B.
  full_name: Seplyarskiy, Vladimir B.
  last_name: Seplyarskiy
- first_name: Mariona
  full_name: Terradas, Mariona
  last_name: Terradas
- first_name: Ana Beatriz
  full_name: Sánchez-Heras, Ana Beatriz
  last_name: Sánchez-Heras
- first_name: Pilar
  full_name: Mur, Pilar
  last_name: Mur
- first_name: José Luis
  full_name: Soto, José Luis
  last_name: Soto
- first_name: Gemma
  full_name: Aiza, Gemma
  last_name: Aiza
- first_name: Emma
  full_name: Borràs, Emma
  last_name: Borràs
- first_name: Fyodor
  full_name: Kondrashov, Fyodor
  id: 44FDEF62-F248-11E8-B48F-1D18A9856A87
  last_name: Kondrashov
  orcid: 0000-0001-8243-4694
- first_name: Alexey S.
  full_name: Kondrashov, Alexey S.
  last_name: Kondrashov
- first_name: Georgii A.
  full_name: Bazykin, Georgii A.
  last_name: Bazykin
- first_name: Laura
  full_name: Valle, Laura
  last_name: Valle
citation:
  ama: Andrianova MA, Seplyarskiy VB, Terradas M, et al. Discovery of recessive effect
    of human polymerase δ proofreading deficiency through mutational analysis of POLD1-mutated
    normal and cancer cells. <i>European Journal of Human Genetics</i>. 2024;32:837-845.
    doi:<a href="https://doi.org/10.1038/s41431-024-01598-8">10.1038/s41431-024-01598-8</a>
  apa: Andrianova, M. A., Seplyarskiy, V. B., Terradas, M., Sánchez-Heras, A. B.,
    Mur, P., Soto, J. L., … Valle, L. (2024). Discovery of recessive effect of human
    polymerase δ proofreading deficiency through mutational analysis of POLD1-mutated
    normal and cancer cells. <i>European Journal of Human Genetics</i>. Springer Nature.
    <a href="https://doi.org/10.1038/s41431-024-01598-8">https://doi.org/10.1038/s41431-024-01598-8</a>
  chicago: Andrianova, Maria A., Vladimir B. Seplyarskiy, Mariona Terradas, Ana Beatriz
    Sánchez-Heras, Pilar Mur, José Luis Soto, Gemma Aiza, et al. “Discovery of Recessive
    Effect of Human Polymerase δ Proofreading Deficiency through Mutational Analysis
    of POLD1-Mutated Normal and Cancer Cells.” <i>European Journal of Human Genetics</i>.
    Springer Nature, 2024. <a href="https://doi.org/10.1038/s41431-024-01598-8">https://doi.org/10.1038/s41431-024-01598-8</a>.
  ieee: M. A. Andrianova <i>et al.</i>, “Discovery of recessive effect of human polymerase
    δ proofreading deficiency through mutational analysis of POLD1-mutated normal
    and cancer cells,” <i>European Journal of Human Genetics</i>, vol. 32. Springer
    Nature, pp. 837–845, 2024.
  ista: Andrianova MA, Seplyarskiy VB, Terradas M, Sánchez-Heras AB, Mur P, Soto JL,
    Aiza G, Borràs E, Kondrashov F, Kondrashov AS, Bazykin GA, Valle L. 2024. Discovery
    of recessive effect of human polymerase δ proofreading deficiency through mutational
    analysis of POLD1-mutated normal and cancer cells. European Journal of Human Genetics.
    32, 837–845.
  mla: Andrianova, Maria A., et al. “Discovery of Recessive Effect of Human Polymerase
    δ Proofreading Deficiency through Mutational Analysis of POLD1-Mutated Normal
    and Cancer Cells.” <i>European Journal of Human Genetics</i>, vol. 32, Springer
    Nature, 2024, pp. 837–45, doi:<a href="https://doi.org/10.1038/s41431-024-01598-8">10.1038/s41431-024-01598-8</a>.
  short: M.A. Andrianova, V.B. Seplyarskiy, M. Terradas, A.B. Sánchez-Heras, P. Mur,
    J.L. Soto, G. Aiza, E. Borràs, F. Kondrashov, A.S. Kondrashov, G.A. Bazykin, L.
    Valle, European Journal of Human Genetics 32 (2024) 837–845.
date_created: 2024-05-05T22:01:04Z
date_published: 2024-07-01T00:00:00Z
date_updated: 2026-04-15T08:51:09Z
day: '01'
ddc:
- '570'
department:
- _id: FyKo
doi: 10.1038/s41431-024-01598-8
ec_funded: 1
external_id:
  isi:
  - '001207703200001'
  pmid:
  - '38658779'
file:
- access_level: open_access
  checksum: e45fc987f4e9ebafdd0ec4f0e9027de4
  content_type: application/pdf
  creator: dernst
  date_created: 2025-01-09T09:21:25Z
  date_updated: 2025-01-09T09:21:25Z
  file_id: '18799'
  file_name: 2024_EJHG_Andrianova.pdf
  file_size: 3060724
  relation: main_file
  success: 1
file_date_updated: 2025-01-09T09:21:25Z
has_accepted_license: '1'
intvolume: '        32'
isi: 1
language:
- iso: eng
month: '07'
oa: 1
oa_version: Published Version
page: 837-845
pmid: 1
project:
- _id: 9B767A34-BA93-11EA-9121-9846C619BF3A
  grant_number: '429960716'
  name: Evolution of Sensorimotor Transformation Across Diptera
- _id: 26580278-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '771209'
  name: Characterizing the fitness landscape on population and global scales
- _id: 34e076d6-11ca-11ed-8bc3-aec76c41a181
  grant_number: I05127
  name: Evolutionary analysis of gene regulation
publication: European Journal of Human Genetics
publication_identifier:
  eissn:
  - 1476-5438
  issn:
  - 1018-4813
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
scopus_import: '1'
status: public
title: Discovery of recessive effect of human polymerase δ proofreading deficiency
  through mutational analysis of POLD1-mutated normal and cancer cells
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: 32
year: '2024'
...
---
_id: '11344'
abstract:
- lang: eng
  text: Until recently, Shigella and enteroinvasive Escherichia coli were thought
    to be primate-restricted pathogens. The base of their pathogenicity is the type
    3 secretion system (T3SS) encoded by the pINV virulence plasmid, which facilitates
    host cell invasion and subsequent proliferation. A large family of T3SS effectors,
    E3 ubiquitin-ligases encoded by the ipaH genes, have a key role in the Shigella
    pathogenicity through the modulation of cellular ubiquitination that degrades
    host proteins. However, recent genomic studies identified ipaH genes in the genomes
    of Escherichia marmotae, a potential marmot pathogen, and an E. coli extracted
    from fecal samples of bovine calves, suggesting that non-human hosts may also
    be infected by these strains, potentially pathogenic to humans. We performed a
    comparative genomic study of the functional repertoires in the ipaH gene family
    in Shigella and enteroinvasive Escherichia from human and predicted non-human
    hosts. We found that fewer than half of Shigella genomes had a complete set of
    ipaH genes, with frequent gene losses and duplications that were not consistent
    with the species tree and nomenclature. Non-human host IpaH proteins had a diverse
    set of substrate-binding domains and, in contrast to the Shigella proteins, two
    variants of the NEL C-terminal domain. Inconsistencies between strains phylogeny
    and composition of effectors indicate horizontal gene transfer between E. coli
    adapted to different hosts. These results provide a framework for understanding
    of ipaH-mediated host-pathogens interactions and suggest a need for a genomic
    study of fecal samples from diseased animals.
acknowledgement: 'The project was initiated with Aygul Minnegalieva and Yulia Yakovleva
  at the Summer School of Molecular and Theoretical Biology (SMTB-2020), supported
  by the Zimin Foundation. We thank Inna Shapovalenko, Daria Abuzova, Elizaveta Kaminskaya,
  and Dmitriy Zvezdin for their contribution to the project during SMTB-2020. We also
  thank Peter Vlasov for fruitful discussions.This study was supported by the Russian
  Foundation for Basic Research (RFBR), Grant # 20-54-14005 and Fonds zur Förderung
  der wissenschaftlichen Forschung (FWF), Grant # I5127-B. The work of OB is supported
  by the European Union’s Horizon 2020 Research and Innovation Programme under the
  Marie Skłodowska-Curie Grant Agreement No. 754411. '
article_number: '6868'
article_processing_charge: No
article_type: original
author:
- first_name: NO
  full_name: Dranenko, NO
  last_name: Dranenko
- first_name: MN
  full_name: Tutukina, MN
  last_name: Tutukina
- first_name: MS
  full_name: Gelfand, MS
  last_name: Gelfand
- first_name: Fyodor
  full_name: Kondrashov, Fyodor
  id: 44FDEF62-F248-11E8-B48F-1D18A9856A87
  last_name: Kondrashov
  orcid: 0000-0001-8243-4694
- first_name: Olga
  full_name: Bochkareva, Olga
  id: C4558D3C-6102-11E9-A62E-F418E6697425
  last_name: Bochkareva
  orcid: 0000-0003-1006-6639
citation:
  ama: Dranenko N, Tutukina M, Gelfand M, Kondrashov F, Bochkareva O. Chromosome-encoded
    IpaH ubiquitin ligases indicate non-human enteroinvasive Escherichia. <i>Scientific
    Reports</i>. 2022;12. doi:<a href="https://doi.org/10.1038/s41598-022-10827-3">10.1038/s41598-022-10827-3</a>
  apa: Dranenko, N., Tutukina, M., Gelfand, M., Kondrashov, F., &#38; Bochkareva,
    O. (2022). Chromosome-encoded IpaH ubiquitin ligases indicate non-human enteroinvasive
    Escherichia. <i>Scientific Reports</i>. Springer Nature. <a href="https://doi.org/10.1038/s41598-022-10827-3">https://doi.org/10.1038/s41598-022-10827-3</a>
  chicago: Dranenko, NO, MN Tutukina, MS Gelfand, Fyodor Kondrashov, and Olga Bochkareva.
    “Chromosome-Encoded IpaH Ubiquitin Ligases Indicate Non-Human Enteroinvasive Escherichia.”
    <i>Scientific Reports</i>. Springer Nature, 2022. <a href="https://doi.org/10.1038/s41598-022-10827-3">https://doi.org/10.1038/s41598-022-10827-3</a>.
  ieee: N. Dranenko, M. Tutukina, M. Gelfand, F. Kondrashov, and O. Bochkareva, “Chromosome-encoded
    IpaH ubiquitin ligases indicate non-human enteroinvasive Escherichia,” <i>Scientific
    Reports</i>, vol. 12. Springer Nature, 2022.
  ista: Dranenko N, Tutukina M, Gelfand M, Kondrashov F, Bochkareva O. 2022. Chromosome-encoded
    IpaH ubiquitin ligases indicate non-human enteroinvasive Escherichia. Scientific
    Reports. 12, 6868.
  mla: Dranenko, NO, et al. “Chromosome-Encoded IpaH Ubiquitin Ligases Indicate Non-Human
    Enteroinvasive Escherichia.” <i>Scientific Reports</i>, vol. 12, 6868, Springer
    Nature, 2022, doi:<a href="https://doi.org/10.1038/s41598-022-10827-3">10.1038/s41598-022-10827-3</a>.
  short: N. Dranenko, M. Tutukina, M. Gelfand, F. Kondrashov, O. Bochkareva, Scientific
    Reports 12 (2022).
corr_author: '1'
date_created: 2022-05-02T07:08:42Z
date_published: 2022-04-27T00:00:00Z
date_updated: 2026-04-15T08:51:09Z
day: '27'
ddc:
- '570'
department:
- _id: FyKo
doi: 10.1038/s41598-022-10827-3
ec_funded: 1
external_id:
  isi:
  - '000788639400032'
  pmid:
  - '35477739'
file:
- access_level: open_access
  checksum: 12601b8a5c6b83bb618f92bcb963ecc9
  content_type: application/pdf
  creator: dernst
  date_created: 2022-05-02T09:05:20Z
  date_updated: 2022-05-02T09:05:20Z
  file_id: '11349'
  file_name: 2022_ScientificReports_Dranenko.pdf
  file_size: 3564155
  relation: main_file
  success: 1
file_date_updated: 2022-05-02T09:05:20Z
has_accepted_license: '1'
intvolume: '        12'
isi: 1
language:
- iso: eng
month: '04'
oa: 1
oa_version: Published Version
pmid: 1
project:
- _id: 260C2330-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '754411'
  name: ISTplus - Postdoctoral Fellowships
- _id: 34e076d6-11ca-11ed-8bc3-aec76c41a181
  grant_number: I05127
  name: Evolutionary analysis of gene regulation
publication: Scientific Reports
publication_identifier:
  issn:
  - 2045-2322
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
scopus_import: '1'
status: public
title: Chromosome-encoded IpaH ubiquitin ligases indicate non-human enteroinvasive
  Escherichia
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: 12
year: '2022'
...
---
_id: '11447'
abstract:
- lang: eng
  text: Empirical essays of fitness landscapes suggest that they may be rugged, that
    is having multiple fitness peaks. Such fitness landscapes, those that have multiple
    peaks, necessarily have special local structures, called reciprocal sign epistasis
    (Poelwijk et al. in J Theor Biol 272:141–144, 2011). Here, we investigate the
    quantitative relationship between the number of fitness peaks and the number of
    reciprocal sign epistatic interactions. Previously, it has been shown (Poelwijk
    et al. in J Theor Biol 272:141–144, 2011) that pairwise reciprocal sign epistasis
    is a necessary but not sufficient condition for the existence of multiple peaks.
    Applying discrete Morse theory, which to our knowledge has never been used in
    this context, we extend this result by giving the minimal number of reciprocal
    sign epistatic interactions required to create a given number of peaks.
acknowledgement: We are grateful to Herbert Edelsbrunner and Jeferson Zapata for helpful
  discussions. Open access funding provided by Austrian Science Fund (FWF). Partially
  supported by the ERC Consolidator (771209–CharFL) and the FWF Austrian Science Fund
  (I5127-B) grants to FAK.
article_number: '74'
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Raimundo J
  full_name: Saona Urmeneta, Raimundo J
  id: BD1DF4C4-D767-11E9-B658-BC13E6697425
  last_name: Saona Urmeneta
  orcid: 0000-0001-5103-038X
- first_name: Fyodor
  full_name: Kondrashov, Fyodor
  id: 44FDEF62-F248-11E8-B48F-1D18A9856A87
  last_name: Kondrashov
  orcid: 0000-0001-8243-4694
- first_name: Kseniia
  full_name: Khudiakova, Kseniia
  id: 4E6DC800-AE37-11E9-AC72-31CAE5697425
  last_name: Khudiakova
  orcid: 0000-0002-6246-1465
citation:
  ama: Saona Urmeneta RJ, Kondrashov F, Khudiakova K. Relation between the number
    of peaks and the number of reciprocal sign epistatic interactions. <i>Bulletin
    of Mathematical Biology</i>. 2022;84(8). doi:<a href="https://doi.org/10.1007/s11538-022-01029-z">10.1007/s11538-022-01029-z</a>
  apa: Saona Urmeneta, R. J., Kondrashov, F., &#38; Khudiakova, K. (2022). Relation
    between the number of peaks and the number of reciprocal sign epistatic interactions.
    <i>Bulletin of Mathematical Biology</i>. Springer Nature. <a href="https://doi.org/10.1007/s11538-022-01029-z">https://doi.org/10.1007/s11538-022-01029-z</a>
  chicago: Saona Urmeneta, Raimundo J, Fyodor Kondrashov, and Kseniia Khudiakova.
    “Relation between the Number of Peaks and the Number of Reciprocal Sign Epistatic
    Interactions.” <i>Bulletin of Mathematical Biology</i>. Springer Nature, 2022.
    <a href="https://doi.org/10.1007/s11538-022-01029-z">https://doi.org/10.1007/s11538-022-01029-z</a>.
  ieee: R. J. Saona Urmeneta, F. Kondrashov, and K. Khudiakova, “Relation between
    the number of peaks and the number of reciprocal sign epistatic interactions,”
    <i>Bulletin of Mathematical Biology</i>, vol. 84, no. 8. Springer Nature, 2022.
  ista: Saona Urmeneta RJ, Kondrashov F, Khudiakova K. 2022. Relation between the
    number of peaks and the number of reciprocal sign epistatic interactions. Bulletin
    of Mathematical Biology. 84(8), 74.
  mla: Saona Urmeneta, Raimundo J., et al. “Relation between the Number of Peaks and
    the Number of Reciprocal Sign Epistatic Interactions.” <i>Bulletin of Mathematical
    Biology</i>, vol. 84, no. 8, 74, Springer Nature, 2022, doi:<a href="https://doi.org/10.1007/s11538-022-01029-z">10.1007/s11538-022-01029-z</a>.
  short: R.J. Saona Urmeneta, F. Kondrashov, K. Khudiakova, Bulletin of Mathematical
    Biology 84 (2022).
corr_author: '1'
date_created: 2022-06-17T16:16:15Z
date_published: 2022-06-17T00:00:00Z
date_updated: 2026-05-27T06:26:08Z
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doi: 10.1007/s11538-022-01029-z
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title: Relation between the number of peaks and the number of reciprocal sign epistatic
  interactions
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