Unraveling the functional dark matter through global metagenomics

Georgios A. Pavlopoulos (), Fotis A. Baltoumas, Sirui Liu, Oguz Selvitopi, Antonio Pedro Camargo, Stephen Nayfach, Ariful Azad, Simon Roux, Lee Call, Natalia N. Ivanova, I. Min Chen, David Paez-Espino, Evangelos Karatzas, Ioannis Iliopoulos, Konstantinos Konstantinidis, James M. Tiedje, Jennifer Pett-Ridge, David Baker, Axel Visel, Christos A. Ouzounis, Sergey Ovchinnikov, Aydin Buluç and Nikos C. Kyrpides ()
Additional contact information
Georgios A. Pavlopoulos: Institute for Fundamental Biomedical Research, Biomedical Science Research Center Alexander Fleming
Fotis A. Baltoumas: Institute for Fundamental Biomedical Research, Biomedical Science Research Center Alexander Fleming
Sirui Liu: Harvard University
Oguz Selvitopi: Lawrence Berkeley National Laboratory
Antonio Pedro Camargo: DOE Joint Genome Institute, Lawrence Berkeley National Laboratory
Stephen Nayfach: DOE Joint Genome Institute, Lawrence Berkeley National Laboratory
Ariful Azad: Indiana University Bloomington
Simon Roux: DOE Joint Genome Institute, Lawrence Berkeley National Laboratory
Lee Call: DOE Joint Genome Institute, Lawrence Berkeley National Laboratory
Natalia N. Ivanova: DOE Joint Genome Institute, Lawrence Berkeley National Laboratory
I. Min Chen: DOE Joint Genome Institute, Lawrence Berkeley National Laboratory
David Paez-Espino: DOE Joint Genome Institute, Lawrence Berkeley National Laboratory
Evangelos Karatzas: Institute for Fundamental Biomedical Research, Biomedical Science Research Center Alexander Fleming
Ioannis Iliopoulos: University of Crete
Konstantinos Konstantinidis: Georgia Institute of Technology
James M. Tiedje: Michigan State University
Jennifer Pett-Ridge: Lawrence Livermore National Laboratory
David Baker: University of Washington
Axel Visel: DOE Joint Genome Institute, Lawrence Berkeley National Laboratory
Christos A. Ouzounis: DOE Joint Genome Institute, Lawrence Berkeley National Laboratory
Sergey Ovchinnikov: Harvard University
Aydin Buluç: Lawrence Berkeley National Laboratory
Nikos C. Kyrpides: DOE Joint Genome Institute, Lawrence Berkeley National Laboratory

Nature, 2023, vol. 622, issue 7983, 594-602

Abstract: Abstract Metagenomes encode an enormous diversity of proteins, reflecting a multiplicity of functions and activities1,2. Exploration of this vast sequence space has been limited to a comparative analysis against reference microbial genomes and protein families derived from those genomes. Here, to examine the scale of yet untapped functional diversity beyond what is currently possible through the lens of reference genomes, we develop a computational approach to generate reference-free protein families from the sequence space in metagenomes. We analyse 26,931 metagenomes and identify 1.17 billion protein sequences longer than 35 amino acids with no similarity to any sequences from 102,491 reference genomes or the Pfam database3. Using massively parallel graph-based clustering, we group these proteins into 106,198 novel sequence clusters with more than 100 members, doubling the number of protein families obtained from the reference genomes clustered using the same approach. We annotate these families on the basis of their taxonomic, habitat, geographical and gene neighbourhood distributions and, where sufficient sequence diversity is available, predict protein three-dimensional models, revealing novel structures. Overall, our results uncover an enormously diverse functional space, highlighting the importance of further exploring the microbial functional dark matter.

Date: 2023
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DOI: 10.1038/s41586-023-06583-7

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