title: Identification and assembly of genomes and genetic elements in complex metagenomic samples without using reference genomes.
abstract: Most current approaches for analyzing metagenomic data rely on comparisons to reference genomes, but the microbial diversity of many environments extends far beyond what is covered by reference databases. De novo segregation of complex metagenomic data into specific biological entities, such as particular bacterial strains or viruses, remains a largely unsolved problem. Here we present a method, based on binning co-abundant genes across a series of metagenomic samples, that enables comprehensive discovery of new microbial organisms, viruses and co-inherited genetic entities and aids assembly of microbial genomes without the need for reference sequences. We demonstrate the method on data from 396 human gut microbiome samples and identify 7,381 co-abundance gene groups (CAGs), including 741 metagenomic species (MGS). We use these to assemble 238 high-quality microbial genomes and identify affiliations between MGS and hundreds of viruses or genetic entities. Our method provides the means for comprehensive profiling of the diversity within complex metagenomic samples.
authors.affiliation: 1] Center for Biological Sequence Analysis, Technical University of Denmark, Kongens Lyngby, Denmark. [2] Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark. [3].
authors.forename: H Bjørn
authors.initials: HB
authors.lastname: Nielsen
authors.affiliation: 1] INRA, Institut National de la Recherche Agronomique, UMR 14121 MICALIS, Jouy en Josas, France. [2] INRA, Institut National de la Recherche Agronomique, US 1367 Metagenopolis, Jouy en Josas, France. [3] Department of Computer Science, Center for Bioinformatics and Computational Biology, University of Maryland, USA. [4].
authors.forename: Mathieu
authors.initials: M
authors.lastname: Almeida
authors.affiliation: 1] Center for Biological Sequence Analysis, Technical University of Denmark, Kongens Lyngby, Denmark. [2] Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark.
authors.forename: Agnieszka Sierakowska
authors.initials: AS
authors.lastname: Juncker
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Kongens Lyngby, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Rasmussen
authors.affiliation: 1] BGI Hong Kong Research Institute, Hong Kong, China. [2] BGI-Shenzhen, Shenzhen, China. [3] School of Bioscience and Biotechnology, South China University of Technology, Guangzhou, China.
authors.forename: Junhua
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authors.lastname: Li
authors.affiliation: European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sunagawa
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Kongens Lyngby, Denmark.
authors.forename: Damian R
authors.initials: DR
authors.lastname: Plichta
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Kongens Lyngby, Denmark.
authors.forename: Laurent
authors.initials: L
authors.lastname: Gautier
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Kongens Lyngby, Denmark.
authors.forename: Anders G
authors.initials: AG
authors.lastname: Pedersen
authors.affiliation: 1] INRA, Institut National de la Recherche Agronomique, UMR 14121 MICALIS, Jouy en Josas, France. [2] INRA, Institut National de la Recherche Agronomique, US 1367 Metagenopolis, Jouy en Josas, France.
authors.forename: Emmanuelle
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authors.lastname: Le Chatelier
authors.affiliation: 1] Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Institut de Génomique, Évry, France. [2] Centre National de la Recherche Scientifique, Évry, France. [3] Université d'Évry Val d'Essonne, Évry, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Pelletier
authors.affiliation: 1] Center for Biological Sequence Analysis, Technical University of Denmark, Kongens Lyngby, Denmark. [2] Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark.
authors.forename: Ida
authors.initials: I
authors.lastname: Bonde
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Trine
authors.initials: T
authors.lastname: Nielsen
authors.affiliation: Digestive System Research Unit, University Hospital Vall d'Hebron, Ciberehd, Barcelona, Spain.
authors.forename: Chaysavanh
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authors.affiliation: 1] BGI-Shenzhen, Shenzhen, China. [2] European Molecular Biology Laboratory, Heidelberg, Germany. [3] The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Manimozhiyan
authors.identifier: 0000000208869101
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authors.lastname: Arumugam
authors.affiliation: 1] INRA, Institut National de la Recherche Agronomique, UMR 14121 MICALIS, Jouy en Josas, France. [2] INRA, Institut National de la Recherche Agronomique, US 1367 Metagenopolis, Jouy en Josas, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Batto
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Kongens Lyngby, Denmark.
authors.forename: Marcelo B
authors.initials: MB
authors.lastname: Quintanilha Dos Santos
authors.affiliation: Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark.
authors.forename: Nikolaj
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authors.lastname: Blom
authors.affiliation: Digestive System Research Unit, University Hospital Vall d'Hebron, Ciberehd, Barcelona, Spain.
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authors.lastname: Borruel
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kristoffer S
authors.initials: KS
authors.lastname: Burgdorf
authors.affiliation: 1] INRA, Institut National de la Recherche Agronomique, UMR 14121 MICALIS, Jouy en Josas, France. [2] INRA, Institut National de la Recherche Agronomique, US 1367 Metagenopolis, Jouy en Josas, France.
authors.forename: Fouad
authors.initials: F
authors.lastname: Boumezbeur
authors.affiliation: Digestive System Research Unit, University Hospital Vall d'Hebron, Ciberehd, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Casellas
authors.affiliation: 1] INRA, Institut National de la Recherche Agronomique, UMR 14121 MICALIS, Jouy en Josas, France. [2] INRA, Institut National de la Recherche Agronomique, US 1367 Metagenopolis, Jouy en Josas, France.
authors.forename: Joël
authors.initials: J
authors.lastname: Doré
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Kongens Lyngby, Denmark.
authors.forename: Piotr
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authors.lastname: Dworzynski
authors.affiliation: Digestive System Research Unit, University Hospital Vall d'Hebron, Ciberehd, Barcelona, Spain.
authors.forename: Francisco
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authors.affiliation: 1] The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. [2] Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
authors.forename: Torben
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authors.lastname: Hansen
authors.affiliation: 1] Department of Structural Biology, VIB, Brussels, Belgium. [2] Department of Bioscience Engineering, Vrije Universiteit, Brussels, Belgium.
authors.forename: Falk
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authors.lastname: Hildebrand
authors.affiliation: National Food Institute, Division for Epidemiology and Microbial Genomics, Technical University of Denmark, Kongens Lyngby, Denmark.
authors.forename: Rolf S
authors.initials: RS
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authors.affiliation: 1] INRA, Institut National de la Recherche Agronomique, UMR 14121 MICALIS, Jouy en Josas, France. [2] INRA, Institut National de la Recherche Agronomique, US 1367 Metagenopolis, Jouy en Josas, France.
authors.forename: Sean
authors.initials: S
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authors.affiliation: 1] BGI-Shenzhen, Shenzhen, China. [2] Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Karsten
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authors.lastname: Kristiansen
authors.affiliation: European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Jens Roat
authors.initials: JR
authors.lastname: Kultima
authors.affiliation: 1] INRA, Institut National de la Recherche Agronomique, UMR 14121 MICALIS, Jouy en Josas, France. [2] INRA, Institut National de la Recherche Agronomique, US 1367 Metagenopolis, Jouy en Josas, France.
authors.forename: Pierre
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authors.lastname: Léonard
authors.affiliation: 1] INRA, Institut National de la Recherche Agronomique, UMR 14121 MICALIS, Jouy en Josas, France. [2] INRA, Institut National de la Recherche Agronomique, US 1367 Metagenopolis, Jouy en Josas, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Levenez
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Kongens Lyngby, Denmark.
authors.forename: Ole
authors.initials: O
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authors.affiliation: 1] INRA, Institut National de la Recherche Agronomique, UMR 14121 MICALIS, Jouy en Josas, France. [2] INRA, Institut National de la Recherche Agronomique, US 1367 Metagenopolis, Jouy en Josas, France.
authors.forename: Bouziane
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authors.lastname: Le Paslier
authors.affiliation: 1] INRA, Institut National de la Recherche Agronomique, UMR 14121 MICALIS, Jouy en Josas, France. [2] INRA, Institut National de la Recherche Agronomique, US 1367 Metagenopolis, Jouy en Josas, France.
authors.forename: Nicolas
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authors.affiliation: 1] The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. [2] Hagedorn Research Institute, Gentofte, Denmark. [3] Institute of Biomedical Science, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [4] Faculty of Health, Aarhus University, Aarhus, Denmark.
authors.forename: Oluf
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authors.affiliation: 1] INRA, Institut National de la Recherche Agronomique, UMR 14121 MICALIS, Jouy en Josas, France. [2] INRA, Institut National de la Recherche Agronomique, US 1367 Metagenopolis, Jouy en Josas, France.
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authors.forename: Jeroen
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authors.affiliation: Section of Microbiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
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authors.lastname: Sørensen
authors.affiliation: European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Julien
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authors.affiliation: Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands.
authors.forename: Sebastian
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authors.lastname: Tims
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Kongens Lyngby, Denmark.
authors.forename: David W
authors.initials: DW
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authors.affiliation: 1] European Molecular Biology Laboratory, Heidelberg, Germany. [2] Department of Biological Information, Tokyo Institute of Technology, Yokohama, Japan.
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authors.affiliation: INRA, Institut National de la Recherche Agronomique, UMR 14121 MICALIS, Jouy en Josas, France.
authors.forename: Pierre
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authors.lastname: Renault
authors.affiliation: 1] Center for Biological Sequence Analysis, Technical University of Denmark, Kongens Lyngby, Denmark. [2] Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark.
authors.forename: Thomas
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authors.lastname: Sicheritz-Ponten
authors.affiliation: 1] European Molecular Biology Laboratory, Heidelberg, Germany. [2] Max Delbrück Centre for Molecular Medicine, Berlin, Germany.
authors.forename: Peer
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authors.lastname: Bork
authors.affiliation: 1] BGI-Shenzhen, Shenzhen, China. [2] The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. [3] Department of Biology, University of Copenhagen, Copenhagen, Denmark. [4] Princess Al Jawhara Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: 1] Center for Biological Sequence Analysis, Technical University of Denmark, Kongens Lyngby, Denmark. [2] Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark.
authors.forename: Søren
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authors.lastname: Brunak
authors.affiliation: 1] INRA, Institut National de la Recherche Agronomique, UMR 14121 MICALIS, Jouy en Josas, France. [2] INRA, Institut National de la Recherche Agronomique, US 1367 Metagenopolis, Jouy en Josas, France. [3] King's College London, Centre for Host-Microbiome Interactions, Dental Institute Central Office, Guy's Hospital, United Kingdom.
authors.forename: S Dusko
authors.initials: SD
authors.lastname: Ehrlich
mesh_terms: D016000:Cluster Analysis; D030541:Databases, Genetic; D056186:Metagenomics