Functional and evolutionary significance of unknown genes from uncultivated taxa

Álvaro Rodríguez del Río, Joaquín Giner-Lamia, Carlos P. Cantalapiedra, Jorge Botas, Ziqi Deng, Ana Hernández-Plaza, Martí Munar-Palmer, Saray Santamaría-Hernando, José J. Rodríguez-Herva, Hans-Joachim Ruscheweyh, Lucas Paoli, Thomas S. B. Schmidt, Shinichi Sunagawa, Peer Bork, Emilia López-Solanilla, Luis Pedro Coelho and Jaime Huerta-Cepas ()
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Álvaro Rodríguez del Río: Centro de Biotecnología y Genómica de Plantas, Universidad Politécnica de Madrid (UPM) – Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC)
Joaquín Giner-Lamia: Centro de Biotecnología y Genómica de Plantas, Universidad Politécnica de Madrid (UPM) – Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC)
Carlos P. Cantalapiedra: Centro de Biotecnología y Genómica de Plantas, Universidad Politécnica de Madrid (UPM) – Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC)
Jorge Botas: Centro de Biotecnología y Genómica de Plantas, Universidad Politécnica de Madrid (UPM) – Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC)
Ziqi Deng: Centro de Biotecnología y Genómica de Plantas, Universidad Politécnica de Madrid (UPM) – Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC)
Ana Hernández-Plaza: Centro de Biotecnología y Genómica de Plantas, Universidad Politécnica de Madrid (UPM) – Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC)
Martí Munar-Palmer: Centro de Biotecnología y Genómica de Plantas, Universidad Politécnica de Madrid (UPM) – Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC)
Saray Santamaría-Hernando: Centro de Biotecnología y Genómica de Plantas, Universidad Politécnica de Madrid (UPM) – Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC)
José J. Rodríguez-Herva: Centro de Biotecnología y Genómica de Plantas, Universidad Politécnica de Madrid (UPM) – Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC)
Hans-Joachim Ruscheweyh: Institute of Microbiology and Swiss Institute of Bioinformatics, ETH Zürich
Lucas Paoli: Institute of Microbiology and Swiss Institute of Bioinformatics, ETH Zürich
Thomas S. B. Schmidt: Structural and Computational Biology Unit, European Molecular Biology Laboratory
Shinichi Sunagawa: Institute of Microbiology and Swiss Institute of Bioinformatics, ETH Zürich
Peer Bork: Structural and Computational Biology Unit, European Molecular Biology Laboratory
Emilia López-Solanilla: Centro de Biotecnología y Genómica de Plantas, Universidad Politécnica de Madrid (UPM) – Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC)
Luis Pedro Coelho: Fudan University
Jaime Huerta-Cepas: Centro de Biotecnología y Genómica de Plantas, Universidad Politécnica de Madrid (UPM) – Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC)

Nature, 2024, vol. 626, issue 7998, 377-384

Abstract: Abstract Many of the Earth’s microbes remain uncultured and understudied, limiting our understanding of the functional and evolutionary aspects of their genetic material, which remain largely overlooked in most metagenomic studies1. Here we analysed 149,842 environmental genomes from multiple habitats2–6 and compiled a curated catalogue of 404,085 functionally and evolutionarily significant novel (FESNov) gene families exclusive to uncultivated prokaryotic taxa. All FESNov families span multiple species, exhibit strong signals of purifying selection and qualify as new orthologous groups, thus nearly tripling the number of bacterial and archaeal gene families described to date. The FESNov catalogue is enriched in clade-specific traits, including 1,034 novel families that can distinguish entire uncultivated phyla, classes and orders, probably representing synapomorphies that facilitated their evolutionary divergence. Using genomic context analysis and structural alignments we predicted functional associations for 32.4% of FESNov families, including 4,349 high-confidence associations with important biological processes. These predictions provide a valuable hypothesis-driven framework that we used for experimental validatation of a new gene family involved in cell motility and a novel set of antimicrobial peptides. We also demonstrate that the relative abundance profiles of novel families can discriminate between environments and clinical conditions, leading to the discovery of potentially new biomarkers associated with colorectal cancer. We expect this work to enhance future metagenomics studies and expand our knowledge of the genetic repertory of uncultivated organisms.

Date: 2024
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DOI: 10.1038/s41586-023-06955-z

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