Unifying the known and unknown microbial coding sequence space

  1. Chiara Vanni
  2. Matthew S Schechter
  3. Silvia G Acinas
  4. Albert Barberán
  5. Pier Luigi Buttigieg
  6. Emilio O Casamayor
  7. Tom O Delmont
  8. Carlos M Duarte
  9. A Murat Eren
  10. Robert D Finn
  11. Renzo Kottmann
  12. Alex Mitchell
  13. Pablo Sánchez
  14. Kimmo Siren
  15. Martin Steinegger
  16. Frank Oliver Gloeckner
  17. Antonio Fernàndez-Guerra  Is a corresponding author
  1. Max Planck Institute for Marine Microbiology, Germany
  2. University of Chicago, United States
  3. Institut de Ciències del Mar-CMIMA (CSIC), Spain
  4. University of Arizona, United States
  5. Alfred Wegener Institute, Germany
  6. Spanish Council for Research, Spain
  7. Genoscope, Institut François Jacob, CEA, CNRS, France
  8. King Abdullah University of Science and Technology, Saudi Arabia
  9. European Molecular Biology Laboratory, United Kingdom
  10. University of Copenhagen, Denmark
  11. Seoul National University, Republic of Korea
  12. University of Bremen, Germany

Abstract

Genes of unknown function are among the biggest challenges in molecular biology, especially in microbial systems, where 40%-60% of the predicted genes are unknown. Despite previous attempts, systematic approaches to include the unknown fraction into analytical workflows are still lacking. Here, we present a conceptual framework, its translation into the computational workflow AGNOSTOS and a demonstration on how we can bridge the known-unknown gap in genomes and metagenomes. By analyzing 415,971,742 genes predicted from 1,749 metagenomes and 28,941 bacterial and archaeal genomes, we quantify the extent of the unknown fraction, its diversity, and its relevance across multiple organisms and environments. The unknown sequence space is exceptionally diverse, phylogenetically more conserved than the known fraction and predominantly taxonomically restricted at the species level. From the 71M genes identified to be of unknown function, we compiled a collection of 283,874 lineage-specific genes of unknown function for Cand. Patescibacteria (also known as Candidate Phyla Radiation, CPR), which provides a significant resource to expand our understanding of their unusual biology. Finally, by identifying a target gene of unknown function for antibiotic resistance, we demonstrate how we can enable the generation of hypotheses that can be used to augment experimental data.

Data availability

We used public data as described in the Methods section and Appendix 1-table 5.The code used for the analyses in the manuscript is available at https://github.com/functional-dark-side/functional-dark-side.github.io/tree/master/scripts. A list with the program versions can be found in https://github.com/functional-dark-side/functional-dark-side.github.io/blob/master/programs_and_versions.txt.The code to create the figures is available at https://github.com/functional-dark-side/vanni_et_al-figures, and the data for the figure can be downloaded from https://doi.org/10.6084/m9.figshare.12738476.v2. A reproducible version of the workflow is available at https://github.com/functional-dark-side/agnostos-wf.The data is publicly available at https://doi.org/10.6084/m9.figshare.12459056.

The following data sets were generated
The following previously published data sets were used
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    5. Ivaylo Kostadinov
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    11. Antje Wichels
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    28. Viggo Marteinsson
    29. Eyjolfur Reynisson
    30. Clara Magalhães Loureiro
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    32. Grazia Marina Quero
    33. Carolin R Löscher
    34. Anke Kremp
    35. Marie E DeLorenzo
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    41. Timothy Davis
    42. Barker Katherine
    43. Christopher P Meyer
    44. Sandra Ramos
    45. Catarina Magalhães
    46. Florence Jude-Lemeilleur
    47. Ma Leopoldina Aguirre-Macedo
    48. Shiao Wang
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    66. Klaas Deneudt
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    83. Veronique Berteaux-Lecellier
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    94. Abderrahim Bouali
    95. Rajaa Chahboune
    96. Said Barrijal
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    98. Fatima El Otmani
    99. Mohamed Bennani
    100. Marianna Mea
    101. Nadezhda Todorova
    102. Ventzislav Karamfilov
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    106. Kemal Can Bizsel
    107. Alessandro Vezzi
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Article and author information

Author details

  1. Chiara Vanni

    Microbial Genomics and Bioinformatics Research G, Max Planck Institute for Marine Microbiology, Bremen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Matthew S Schechter

    Department of Medicine, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8435-3203
  3. Silvia G Acinas

    Department of Marine Biology and Oceanography, Institut de Ciències del Mar-CMIMA (CSIC), Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  4. Albert Barberán

    Department of Environmental Science, University of Arizona, Tucson, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Pier Luigi Buttigieg

    Helmholtz Centre for Polar and Marine Research, Alfred Wegener Institute, Bremerhaven, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Emilio O Casamayor

    Center for Advanced Studies of Blanes CEAB-CSIC, Spanish Council for Research, Blanes, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7074-3318
  7. Tom O Delmont

    Génomique Métabolique, Genoscope, Institut François Jacob, CEA, CNRS, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7053-7848
  8. Carlos M Duarte

    Computational Bioscience Research Center, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
    Competing interests
    The authors declare that no competing interests exist.
  9. A Murat Eren

    Department of Medicine, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9013-4827
  10. Robert D Finn

    European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Renzo Kottmann

    Microbial Genomics and Bioinformatics Research G, Max Planck Institute for Marine Microbiology, Bremen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Alex Mitchell

    European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Pablo Sánchez

    Department of Marine Biology and Oceanography, Institut de Ciències del Mar-CMIMA (CSIC), Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2787-822X
  14. Kimmo Siren

    Section for Evolutionary Genomics, The GLOBE Institute, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  15. Martin Steinegger

    School of Biological Sciences, Seoul National University, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  16. Frank Oliver Gloeckner

    MARUM, Helmholtz Center for Polar and Marine Research, University of Bremen, Bremen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  17. Antonio Fernàndez-Guerra

    Lundbeck Foundation GeoGenetics Centre, GLOBE Institute, University of Copenhagen, Copenhagen, Denmark
    For correspondence
    antonio.fernandez-guerra@sund.ku.dk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8679-490X

Funding

Max Planck Society

  • Chiara Vanni

European Union's Horizon 2020 (INMARE)

  • Antonio Fernàndez-Guerra

Biotechnology and Biological Sciences Research Council

  • Alex Mitchell

European Molecular Biology Laboratory

  • Robert D Finn

Spanish Agency of Science MICIU/AEI (INTERACTOMA RTI2018-101205-B-I00)

  • Emilio O Casamayor

Spanish Ministry of Economy and Competitiveness (MAGGY (CTM2017-87736-R))

  • Silvia G Acinas
  • Pablo Sánchez

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. C Titus Brown, University of California, Davis, United States

Publication history

  1. Preprint posted: July 1, 2020 (view preprint)
  2. Received: February 18, 2021
  3. Accepted: March 30, 2022
  4. Accepted Manuscript published: March 31, 2022 (version 1)

Copyright

© 2022, Vanni et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Chiara Vanni
  2. Matthew S Schechter
  3. Silvia G Acinas
  4. Albert Barberán
  5. Pier Luigi Buttigieg
  6. Emilio O Casamayor
  7. Tom O Delmont
  8. Carlos M Duarte
  9. A Murat Eren
  10. Robert D Finn
  11. Renzo Kottmann
  12. Alex Mitchell
  13. Pablo Sánchez
  14. Kimmo Siren
  15. Martin Steinegger
  16. Frank Oliver Gloeckner
  17. Antonio Fernàndez-Guerra
(2022)
Unifying the known and unknown microbial coding sequence space
eLife 11:e67667.
https://doi.org/10.7554/eLife.67667

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