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April 11, 2024
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Article
Hybrid Gold

Functional and evolutionary significance of unknown genes from uncultivated taxa

Publicated to: NATURE. 626 (7998): 377-384 - 2024-02-08 626(7998), DOI: 10.1038/s41586-023-06955-z

Authors:

Rodriguez del Rio, Alvaro; Giner-Lamia, Joaquin; Cantalapiedra, Carlos P; Cantalapiedra, Carlos P; Botas, Jorge; Deng, Ziqi; Hernandez-Plaza, Ana; Munar-Palmer, Marti; Santamaria-Hernando, Saray; Rodriguez-Herva, Jose J; Rodriguez-Herva, Jose J; Ruscheweyh, Hans-Joachim; Paoli, Lucas; Schmidt, Thomas S B; Schmidt, Thomas S B; Sunagawa, Shinichi; Bork, Peer; Lopez-Solanilla, Emilia; Coelho, Luis Pedro; Huerta-Cepas, Jaime
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Affiliations

European Mol Biol Lab, Struct & Computat Biol Unit - Author
Queensland Univ Technol, Translat Res Inst, Ctr Microbiome Res, Sch Biomed Sci, Woolloongabba - Author
Swiss Fed Inst Technol, Swiss Inst Bioinformat - Author
Univ Politecn Madrid UPM, Ctr Biotecnol & Genom Plantas, Inst Nacl Invest & Tecnol Agr & Alimentaria INIA C - Author
Univ Politecn Madrid UPM, Escuela Tecn Super Ingn Agron Alimentaria & Biosis, Dept Biotecnol Biol Vegetal - Author
Univ Sevilla CSIC, Fac Biol, Dept Bioquim Vegetal & Biol Mol, Inst Bioquim Vegetal & Fotosintesis IBVF - Author
Univ Wurzburg, Dept Bioinformat, Bioctr - Author
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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. We analysed 149,842 environmental genomes from multiple habitats and compiled a curated catalogue of 404,085 functionally and evolutionarily significant novel gene families exclusive to uncultivated prokaryotic taxa spanning multiple species.
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Keywords

AlignmentAntimicrobial peptidesArchaeaBacteriaBacterialBiologyBiomarkersCell movementCohortColorectal neoplasmsDatabaseEcosystemEvolution, molecularGenes, archaealGenes, bacterialGenomicsKnowledgeMetagenomicsMicrobiomeMultigene familyPhylogenyProtein-structureReduced inequalitiesReproducibility of results

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal NATURE due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2024 there are still no calculated indicators, but in 2023, it was in position 2/136, thus managing to position itself as a Q1 (Primer Cuartil), in the category Multidisciplinary Sciences. Notably, the journal is positioned above the 90th percentile.

This publication has been distinguished as a “Highly Cited Paper” by the agencies WoS (ESI, Clarivate) and ESI (Clarivate), meaning that it ranks within the top 1% of the most cited articles in its thematic field during the year of its publication. In terms of the observed impact of the contribution, this work is considered one of the most influential worldwide, as it is recognized as highly cited. (source consulted: ESI Nov 13, 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2026-04-09, the following number of citations:

  • WoS: 56
  • Scopus: 55
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Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2026-04-09:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 183.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 181 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 152.
  • The number of mentions on the social network X (formerly Twitter): 215 (Altmetric).
  • The number of mentions on Wikipedia: 2 (Altmetric).
  • The number of mentions in news outlets: 1 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
  • Assignment of a Handle/URN as an identifier within the deposit in the Institutional Repository: https://oa.upm.es/92728/

As a result of the publication of the work in the institutional repository, statistical usage data has been obtained that reflects its impact. In terms of dissemination, we can state that, as of

  • Views: 52
  • Downloads: 6
Continuing with the social impact of the work, it is important to emphasize that, due to its content, it can be assigned to the area of interest of ODS 10 - Reduce inequality within and among countries, with a probability of 68% according to the mBERT algorithm developed by Aurora University.
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Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Australia; China; Germany; Switzerland.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (RODRIGUEZ DEL RIO, ALVARO) and Last Author (HUERTA CEPAS, JAIME).

the author responsible for correspondence tasks has been HUERTA CEPAS, JAIME.

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Project objectives

La aportación persigue los siguientes objetivos: analizar 149,842 genomas ambientales procedentes de múltiples hábitats para identificar genes exclusivos de taxones procariotas no cultivados; compilar un catálogo curado de 404,085 familias génicas novedosas con significación funcional y evolutiva; caracterizar las familias génicas en términos de selección purificadora y agrupación en nuevos grupos ortólogos; predecir asociaciones funcionales mediante análisis genómico y alineamientos estructurales; validar experimentalmente funciones biológicas de nuevas familias génicas, incluyendo motilidad celular y péptidos antimicrobianos; y evaluar la capacidad de las familias génicas novedosas para discriminar ambientes y condiciones clínicas, identificando posibles biomarcadores asociados al cáncer colorrectal.
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Most relevant results

El estudio aborda la caracterización funcional y evolutiva de genes desconocidos en taxones no cultivados mediante el análisis de 149,842 genomas ambientales. Se identificaron 404,085 familias génicas novedosas exclusivas de procariotas no cultivados, triplicando las familias bacterianas y arqueales descritas hasta la fecha. Estas familias muestran señales de selección purificadora y constituyen nuevos grupos ortólogos. Se detectaron 1,034 familias específicas de clados que distinguen filos, clases y órdenes, sugiriendo sinapomorfías evolutivas. Además, se predijeron asociaciones funcionales para el 32.4% de las familias, incluyendo 4,349 vinculadas a procesos biológicos clave, lo que permitió validar experimentalmente una familia génica relacionada con la motilidad celular y nuevos péptidos antimicrobianos. Finalmente, los perfiles de abundancia relativa de estas familias permitieron discriminar ambientes y condiciones clínicas, identificando posibles biomarcadores para cáncer colorrectal.
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