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, Silvia G. Acinas, Nathan Ahlgren, Graeme Attwood, Petr Baldrian, Timothy Berry, Jennifer M. Bhatnagar, Devaki BhayaKay D. Bidle, Jeffrey L. Blanchard, Eric S. Boyd, Jennifer L. Bowen, Jeff Bowman, Susan H. Brawley, Eoin L. Brodie, Andreas Brune, Donald A. Bryant, Alison Buchan, Hinsby Cadillo-Quiroz, Barbara J. Campbell, Ricardo Cavicchioli, Peter F. Chuckran, Maureen Coleman, Sean Crowe, Daniel R. Colman, Cameron R. Currie, Jeff Dangl, Nathalie Delherbe, Vincent J. Denef, Paul Dijkstra, Daniel D. Distel, Emiley Eloe-Fadrosh, Kirsten Fisher, Christopher Francis, Aaron Garoutte, Amelie Gaudin, Lena Gerwick, Filipa Godoy-Vitorino, Peter Guerra, Jiarong Guo, Mussie Y. Habteselassie, Steven J. Hallam, Roland Hatzenpichler, Ute Hentschel, Matthias Hess, Ann M. Hirsch, Laura A. Hug, Jenni Hultman, Dana E. Hunt, Marcel Huntemann, William P. Inskeep, Timothy Y. James, Janet Jansson, Eric R. Johnston, Marina Kalyuzhnaya, Charlene N. Kelly, Robert M. Kelly, Jonathan L. Klassen, Klaus Nüsslein, Joel E. Kostka, Steven Lindow, Erik Lilleskov, Mackenzie Lynes, Rachel Mackelprang, Francis M. Martin, Olivia U. Mason, R. Michael McKay, Katherine McMahon, David A. Mead, Monica Medina, Laura K. Meredith, Thomas Mock, William W. Mohn, Mary Ann Moran, Alison Murray, Josh D. Neufeld, Rebecca Neumann, Jeanette M. Norton, Laila P. Partida-Martinez, Nicole Pietrasiak, Dale Pelletier, T. B.K. Reddy, Brandi Kiel Reese, Nicholas J. Reichart, Rebecca Reiss, Mak A. Saito, Daniel P. Schachtman, Rekha Seshadri, Ashley Shade, David Sherman, Rachel Simister, Holly Simon, James Stegen, Ramunas Stepanauskas, Matthew Sullivan, Dawn Y. Sumner, Hanno Teeling, Kimberlee Thamatrakoln, Kathleen Treseder, Susannah Tringe, Parag Vaishampayan, David L. Valentine, Nicholas B. Waldo, Mark P. Waldrop, David A. Walsh, David M. Ward, Michael Wilkins, Thea Whitman, Jamie Woolet, Tanja Woyke, Ioannis Iliopoulos, Konstantinos Konstantinidis, James M. Tiedje, Jennifer Pett-Ridge, David Baker, Axel Visel, Christos A. Ouzounis, Sergey Ovchinnikov, Aydin Buluç, Nikos C. Kyrpides

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)594-602
Number of pages9
JournalNature
Volume622
Issue number7983
DOIs
StatePublished - Oct 19 2023

All Science Journal Classification (ASJC) codes

  • General

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