Beyond cells – The virome in the human holobiont

Viromics, or viral metagenomics, is a relatively new and burgeoning field of research that studies the complete collection of viruses forming part of the microbiota in any given niche. It has strong foundations rooted in over a century of discoveries in the field of virology and recent advances in molecular biology and sequencing technologies. Historically, most studies have deconstructed the concept of viruses into a simplified perception of viral agents as mere pathogens, which demerits the scope of large-scale viromic analyses. Viruses are, in fact, much more than regular parasites. They are by far the most dynamic and abundant entity and the greatest killers on the planet, as well as the most effective geo-transforming genetic engineers and resource recyclers, acting on all life strata in any habitat. Yet, most of this uncanny viral world remains vastly unexplored to date, greatly hindered by the bewildering complexity inherent to such studies and the methodological and conceptual limitations. Viromic studies are just starting to address some of these issues but they still lag behind microbial metagenomics. In recent years, however, higher-throughput analysis and resequencing have rekindled interest in a field that is just starting to show its true potential. In this review, we take a look at the scientific and technological developments that led to the advent of viral and bacterial metagenomics with a particular, but not exclusive, focus on human viromics from an ecological perspective. We also address some of the most relevant challenges that current viral studies face and ponder on the future directions of the field.

[1]  F. Twort AN INVESTIGATION ON THE NATURE OF ULTRA-MICROSCOPIC VIRUSES. , 1915 .

[2]  M. Delbrück,et al.  Electron Microscope Studies of Bacterial Viruses , 1943, Journal of bacteriology.

[3]  T. H. Weller,et al.  Production of Hemagglutinin by Mumps and Influenza A Viruses in Suspended Cell Tissue Cultures.∗ , 1948, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[4]  A. Lwoff The concept of virus. , 1957, Journal of general microbiology.

[5]  A. Lwoff,et al.  A system of viruses. , 1962, Cold Spring Harbor symposia on quantitative biology.

[6]  A. Lwoff,et al.  The classification of viruses. , 1966, Annual review of microbiology.

[7]  T. Dobzhansky Genetics of the Evolutionary Process , 1970 .

[8]  W. J. Hadden,et al.  A Comparison of , 1971 .

[9]  D. Baltimore Expression of animal virus genomes. , 1971, Bacteriological reviews.

[10]  F. Fenner The nomenclature and classification of viruses the International Committee on Nomenclature of Viruses. , 1971, Virology.

[11]  R. Symons,et al.  Biochemical method for inserting new genetic information into DNA of Simian Virus 40: circular SV40 DNA molecules containing lambda phage genes and the galactose operon of Escherichia coli. , 1972, Proceedings of the National Academy of Sciences of the United States of America.

[12]  A. C. Chang,et al.  Construction of biologically functional bacterial plasmids in vitro. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[13]  L. V. Valen,et al.  A new evolutionary law , 1973 .

[14]  R. Contreras,et al.  Complete nucleotide sequence of bacteriophage MS2 RNA: primary and secondary structure of the replicase gene , 1976, Nature.

[15]  F. Sanger,et al.  Nucleotide sequence of bacteriophage φX174 DNA , 1977, Nature.

[16]  C. Woese,et al.  Phylogenetic structure of the prokaryotic domain: The primary kingdoms , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[17]  F. Sanger,et al.  Nucleotide sequence of bacteriophage phi X174 DNA. , 1977, Nature.

[18]  F. Sanger,et al.  DNA sequencing with chain-terminating inhibitors. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[19]  S. Anderson,et al.  Shotgun DNA sequencing using cloned DNase I-generated fragments , 1981, Nucleic Acids Res..

[20]  Diagnostic virology: from animals to automation. , 1984 .

[21]  Hsiung Gd,et al.  Diagnostic virology: from animals to automation. , 1984, The Yale journal of biology and medicine.

[22]  R. Holmes,et al.  Shiga-like toxin-converting phages from Escherichia coli strains that cause hemorrhagic colitis or infantile diarrhea. , 1984, Science.

[23]  P. Nyrén,et al.  Enzymatic method for continuous monitoring of inorganic pyrophosphate synthesis. , 1985, Analytical biochemistry.

[24]  T. Macke,et al.  A phylogenetic definition of the major eubacterial taxa. , 1985, Systematic and applied microbiology.

[25]  W. Ansorge,et al.  A non-radioactive automated method for DNA sequence determination. , 1986, Journal of biochemical and biophysical methods.

[26]  K. Mullis,et al.  Specific enzymatic amplification of DNA in vitro: the polymerase chain reaction. , 1986, Cold Spring Harbor symposia on quantitative biology.

[27]  N. Pace,et al.  Microbial ecology and evolution: a ribosomal RNA approach. , 1986, Annual review of microbiology.

[28]  Lloyd M. Smith,et al.  Fluorescence detection in automated DNA sequence analysis , 1986, Nature.

[29]  F. Young DNA probes. Fruits of the new biotechnology. , 1987, JAMA.

[30]  K. Makino,et al.  Nucleotide sequence of the iap gene, responsible for alkaline phosphatase isozyme conversion in Escherichia coli, and identification of the gene product , 1987, Journal of bacteriology.

[31]  M. Houghton,et al.  Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. , 1989, Science.

[32]  H. Swerdlow,et al.  Capillary gel electrophoresis for rapid, high resolution DNA sequencing. , 1990, Nucleic acids research.

[33]  S. Giovannoni,et al.  Genetic diversity in Sargasso Sea bacterioplankton , 1990, Nature.

[34]  D. M. Ward,et al.  16S rRNA sequences of uncultivated hot spring cyanobacterial mat inhabitants retrieved as randomly primed cDNA , 1991, Applied and environmental microbiology.

[35]  L. Hood,et al.  Large-scale and automated DNA sequence determination. , 1991, Science.

[36]  G. Reyes,et al.  Sequence-independent, single-primer amplification (SISPA) of complex DNA populations. , 1991, Molecular and cellular probes.

[37]  F. Rodríguez-Valera,et al.  Transcription at different salinities of Haloferax mediterranei sequences adjacent to partially modified PstI sites , 1993, Molecular microbiology.

[38]  K. Wilson,et al.  Human colonic biota studied by ribosomal DNA sequence analysis , 1996, Applied and environmental microbiology.

[39]  R. Herwig,et al.  Phylogenetic analysis of the bacterial communities in marine sediments , 1996, Applied and environmental microbiology.

[40]  W. Whitman,et al.  Prokaryotes: the unseen majority. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[41]  J. Handelsman,et al.  Molecular biological access to the chemistry of unknown soil microbes: a new frontier for natural products. , 1998, Chemistry & biology.

[42]  Dan S. Tawfik,et al.  Man-made cell-like compartments for molecular evolution , 1998, Nature Biotechnology.

[43]  K. Wommack,et al.  Virioplankton: Viruses in Aquatic Ecosystems , 2000, Microbiology and Molecular Biology Reviews.

[44]  L. Bos,et al.  100 years of virology: from vitalism via molecular biology to genetic engineering. , 2000, Trends in microbiology.

[45]  T. Thingstad Elements of a theory for the mechanisms controlling abundance, diversity, and biogeochemical role of lytic bacterial viruses in aquatic systems , 2000 .

[46]  J. Handelsman,et al.  Cloning the Soil Metagenome: a Strategy for Accessing the Genetic and Functional Diversity of Uncultured Microorganisms , 2000, Applied and Environmental Microbiology.

[47]  F. Dean,et al.  Rapid amplification of plasmid and phage DNA using Phi 29 DNA polymerase and multiply-primed rolling circle amplification. , 2001, Genome research.

[48]  J. Gordon,et al.  Commensal Host-Bacterial Relationships in the Gut , 2001, Science.

[49]  S. Emerson,et al.  A virus discovery method incorporating DNase treatment and its application to the identification of two bovine parvovirus species , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[50]  L. Schouls,et al.  Identification of genes that are associated with DNA repeats in prokaryotes , 2002, Molecular microbiology.

[51]  R. Simons,et al.  Reverse Transcriptase-Mediated Tropism Switching in Bordetella Bacteriophage , 2002, Science.

[52]  A. Hüttenhofer,et al.  Identification of 86 candidates for small non-messenger RNAs from the archaeon Archaeoglobus fulgidus , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[53]  B. Andresen,et al.  Genomic analysis of uncultured marine viral communities , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[54]  F. Rohwer,et al.  Marine phage genomics. , 2002, Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology.

[55]  R. Edwards,et al.  The Phage Proteomic Tree: a Genome-Based Taxonomy for Phage , 2002, Journal of bacteriology.

[56]  P. Salamon,et al.  Metagenomic Analyses of an Uncultured Viral Community from Human Feces , 2003, Journal of bacteriology.

[57]  C. Suttle,et al.  High diversity of unknown picorna-like viruses in the sea , 2003, Nature.

[58]  A. Gibbs Viral nomenclature, where next? , 2003, Archives of Virology.

[59]  O. White,et al.  Environmental Genome Shotgun Sequencing of the Sargasso Sea , 2004, Science.

[60]  P. Wilmes,et al.  The application of two-dimensional polyacrylamide gel electrophoresis and downstream analyses to a mixed community of prokaryotic microorganisms. , 2004, Environmental microbiology.

[61]  J. García-Martínez,et al.  Intervening Sequences of Regularly Spaced Prokaryotic Repeats Derive from Foreign Genetic Elements , 2005, Journal of Molecular Evolution.

[62]  J. Banfield,et al.  Community structure and metabolism through reconstruction of microbial genomes from the environment , 2004, Nature.

[63]  R. Simons,et al.  Tropism switching in Bordetella bacteriophage defines a family of diversity-generating retroelements , 2004, Nature.

[64]  M. Bergeron,et al.  Multiplex Real-Time PCR Assay for Detection of Influenza and Human Respiratory Syncytial Viruses , 2004, Journal of Clinical Microbiology.

[65]  R. Stanier,et al.  The concept of a bacterium , 2004, Archiv für Mikrobiologie.

[66]  Samson S. Y. Wong,et al.  Characterization and Complete Genome Sequence of a Novel Coronavirus, Coronavirus HKU1, from Patients with Pneumonia , 2005, Journal of Virology.

[67]  G. Vergnaud,et al.  CRISPR elements in Yersinia pestis acquire new repeats by preferential uptake of bacteriophage DNA, and provide additional tools for evolutionary studies. , 2005, Microbiology.

[68]  F. Bäckhed,et al.  Host-Bacterial Mutualism in the Human Intestine , 2005, Science.

[69]  Jaideep P. Sundaram,et al.  Genome analysis of multiple pathogenic isolates of Streptococcus agalactiae: implications for the microbial "pan-genome". , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[70]  M. Tammi,et al.  Cloning of a human parvovirus by molecular screening of respiratory tract samples. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[71]  M. V. Regenmortel,et al.  Applying the species concept to plant viruses , 2005, Archives of Virology.

[72]  James R. Knight,et al.  Genome sequencing in microfabricated high-density picolitre reactors , 2005, Nature.

[73]  M. Breitbart,et al.  Using pyrosequencing to shed light on deep mine microbial ecology , 2006, BMC Genomics.

[74]  R. Friedman,et al.  Mechanisms of persistent infections by cytopathic viruses in tissue culture , 2005, Archives of Virology.

[75]  R. Edwards,et al.  Viral metagenomics , 2005, Nature Reviews Microbiology.

[76]  M. Moran,et al.  Analysis of Microbial Gene Transcripts in Environmental Samples , 2005, Applied and Environmental Microbiology.

[77]  F. Shanahan,et al.  The gut flora as a forgotten organ , 2006, EMBO reports.

[78]  R. Ley,et al.  Ecological and Evolutionary Forces Shaping Microbial Diversity in the Human Intestine , 2006, Cell.

[79]  Florent E. Angly,et al.  The Marine Viromes of Four Oceanic Regions , 2006, PLoS biology.

[80]  M. Pop,et al.  Metagenomic Analysis of the Human Distal Gut Microbiome , 2006, Science.

[81]  V. Kunin,et al.  Evolutionary conservation of sequence and secondary structures in CRISPR repeats , 2007, Genome Biology.

[82]  Daniel B. DiGiulio,et al.  Development of the Human Infant Intestinal Microbiota , 2007, PLoS biology.

[83]  R. Barrangou,et al.  CRISPR Provides Acquired Resistance Against Viruses in Prokaryotes , 2007, Science.

[84]  A. Halpern,et al.  The Sorcerer II Global Ocean Sampling Expedition: Northwest Atlantic through Eastern Tropical Pacific , 2007, PLoS biology.

[85]  P. Forterre,et al.  Redefining viruses: lessons from Mimivirus , 2008, Nature Reviews Microbiology.

[86]  P. Turnbaugh,et al.  An Invitation to the Marriage of Metagenomics and Metabolomics , 2008, Cell.

[87]  Nancy F. Hansen,et al.  Accurate Whole Human Genome Sequencing using Reversible Terminator Chemistry , 2008, Nature.

[88]  J. Xaus,et al.  Is meconium from healthy newborns actually sterile? , 2008, Research in microbiology.

[89]  E. Sintes,et al.  Dynamics and diversity of newly produced virioplankton in the North Sea , 2008, The ISME Journal.

[90]  V. Kunin,et al.  A bacterial metapopulation adapts locally to phage predation despite global dispersal. , 2008, Genome research.

[91]  T. Mockler,et al.  Multiplex sequencing of plant chloroplast genomes using Solexa sequencing-by-synthesis technology , 2008, Nucleic acids research.

[92]  Vincent J. Denef,et al.  Population Genomic Analysis of Strain Variation in Leptospirillum Group II Bacteria Involved in Acid Mine Drainage Formation , 2008, PLoS biology.

[93]  F. Rohwer,et al.  Explaining microbial population genomics through phage predation , 2009, Nature Reviews Microbiology.

[94]  Florent E. Angly,et al.  Genomic analysis of multiple Roseophage SIO1 strains. , 2009, Environmental microbiology.

[95]  R. Knight,et al.  The Effect of Diet on the Human Gut Microbiome: A Metagenomic Analysis in Humanized Gnotobiotic Mice , 2009, Science Translational Medicine.

[96]  D. Moreira,et al.  Ten reasons to exclude viruses from the tree of life , 2009, Nature Reviews Microbiology.

[97]  C. Desnues,et al.  Pepper Mild Mottle Virus, a Plant Virus Associated with Specific Immune Responses, Fever, Abdominal Pains, and Pruritus in Humans , 2010, PloS one.

[98]  R. Knight,et al.  Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns , 2010, Proceedings of the National Academy of Sciences.

[99]  B. Haas,et al.  A Catalog of Reference Genomes from the Human Microbiome , 2010, Science.

[100]  P. Bork,et al.  A human gut microbial gene catalogue established by metagenomic sequencing , 2010, Nature.

[101]  Peter Chung,et al.  Transmission of Diverse Oral Bacteria to Murine Placenta: Evidence for the Oral Microbiome as a Potential Source of Intrauterine Infection , 2010, Infection and Immunity.

[102]  J. F. Atkins,et al.  Recoding : expansion of decoding rules enriches gene expression , 2010 .

[103]  S. Valverde,et al.  Statistical structure of host–phage interactions , 2011, Proceedings of the National Academy of Sciences.

[104]  C. García-Aljaro,et al.  Bacteriophage-Encoding Cytolethal Distending Toxin Type V Gene Induced from Nonclinical Escherichia coli Isolates , 2011, Infection and Immunity.

[105]  R. Knight,et al.  Supervised classification of human microbiota. , 2011, FEMS microbiology reviews.

[106]  Martha R. J. Clokie,et al.  Phages in nature , 2011, Bacteriophage.

[107]  David S. Wishart,et al.  PHAST: A Fast Phage Search Tool , 2011, Nucleic Acids Res..

[108]  Nicole Rusk Torrents of sequence , 2011, Nature Methods.

[109]  Stan J. J. Brouns,et al.  Evolution and classification of the CRISPR–Cas systems , 2011, Nature Reviews Microbiology.

[110]  F. Bushman,et al.  The human gut virome: inter-individual variation and dynamic response to diet. , 2011, Genome research.

[111]  P. Bork,et al.  Enterotypes of the human gut microbiome , 2011, Nature.

[112]  G. Cochrane,et al.  The International Nucleotide Sequence Database Collaboration , 2011, Nucleic Acids Res..

[113]  Katherine H. Huang,et al.  Structure, Function and Diversity of the Healthy Human Microbiome , 2012, Nature.

[114]  H. Swerdlow,et al.  A tale of three next generation sequencing platforms: comparison of Ion Torrent, Pacific Biosciences and Illumina MiSeq sequencers , 2012, BMC Genomics.

[115]  Katherine H. Huang,et al.  The Human Microbiome Project: A Community Resource for the Healthy Human Microbiome , 2012, PLoS biology.

[116]  D. Sinderen,et al.  Gut microbiota composition correlates with diet and health in the elderly , 2012, Nature.

[117]  S. Weaver,et al.  Virus species polemics: 14 senior virologists oppose a proposed change to the ICTV definition of virus species , 2012, Archives of Virology.

[118]  David C. Smith,et al.  Global distribution of microbial abundance and biomass in subseafloor sediment , 2012, Proceedings of the National Academy of Sciences.

[119]  J. Clemente,et al.  Human gut microbiome viewed across age and geography , 2012, Nature.

[120]  Guy Cochrane,et al.  The International Nucleotide Sequence Database Collaboration , 2011, Nucleic Acids Res..

[121]  Katherine H. Huang,et al.  A framework for human microbiome research , 2012, Nature.

[122]  Daniel B. DiGiulio Diversity of microbes in amniotic fluid. , 2012, Seminars in fetal & neonatal medicine.

[123]  G. Weinstock,et al.  Emerging view of the human virome , 2012, Translational Research.

[124]  D. Raoult,et al.  Tobacco mosaic virus in cigarettes and saliva of smokers. , 2012, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[125]  E. Boyd,et al.  Bacteriophage-encoded bacterial virulence factors and phage-pathogenicity island interactions. , 2012, Advances in virus research.

[126]  K. Foster,et al.  Competition, Not Cooperation, Dominates Interactions among Culturable Microbial Species , 2012, Current Biology.

[127]  Timothy L. Tickle,et al.  Computational meta'omics for microbial community studies , 2013, Molecular systems biology.

[128]  M. Pignatelli,et al.  Comparison of different assembly and annotation tools on analysis of simulated viral metagenomic communities in the gut , 2014, BMC Genomics.

[129]  C. Robert,et al.  Marseillevirus-like virus recovered from blood donated by asymptomatic humans. , 2013, The Journal of infectious diseases.

[130]  P. Salamon,et al.  Bacteriophage adhering to mucus provide a non–host-derived immunity , 2013, Proceedings of the National Academy of Sciences.

[131]  J. Jofre,et al.  Antibiotic Resistance Genes in the Bacteriophage DNA Fraction of Human Fecal Samples , 2013, Antimicrobial Agents and Chemotherapy.

[132]  A. Latorre,et al.  Study of the Viral and Microbial Communities Associated With Crohn's Disease: A Metagenomic Approach , 2013, Clinical and Translational Gastroenterology.

[133]  A. Gibbs Viral taxonomy needs a spring clean; its exploration era is over , 2013, Virology Journal.

[134]  J. Collins,et al.  Antibiotic Treatment Expands the Resistance Reservoir and Ecological Network of the Phage Metagenome , 2013, Nature.

[135]  Anders F. Andersson,et al.  Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by Caesarean section , 2013, Gut.

[136]  H. Makino,et al.  Mother-to-Infant Transmission of Intestinal Bifidobacterial Strains Has an Impact on the Early Development of Vaginally Delivered Infant's Microbiota , 2013, PloS one.

[137]  E. Cheek,et al.  Genome signature-based dissection of human gut metagenomes to extract subliminal viral sequences , 2013, Nature Communications.

[138]  M. Sullivan,et al.  The global virome: not as big as we thought? , 2013, Current opinion in virology.

[139]  K. Foster,et al.  Evolutionary limits to cooperation in microbial communities , 2014, Proceedings of the National Academy of Sciences.

[140]  Julia E. Storesund,et al.  A theoretical analysis of how strain-specific viruses can control microbial species diversity , 2014, Proceedings of the National Academy of Sciences.

[141]  A. Sidow,et al.  The future of sequencing: convergence of intelligent design and market Darwinism , 2014, Genome Biology.

[142]  W. D. de Vos,et al.  The first 1000 cultured species of the human gastrointestinal microbiota , 2014, FEMS microbiology reviews.

[143]  Austin G. Davis-Richardson,et al.  Meconium Microbiome Analysis Identifies Bacteria Correlated with Premature Birth , 2014, PloS one.

[144]  G. Weinstock,et al.  Metagenomic analysis of double-stranded DNA viruses in healthy adults , 2014, BMC Biology.

[145]  Daniel J. Nasko,et al.  Caught in the middle with multiple displacement amplification: the myth of pooling for avoiding multiple displacement amplification bias in a metagenome , 2014, Microbiome.

[146]  J. Harrow,et al.  Multiple evidence strands suggest that there may be as few as 19 000 human protein-coding genes , 2014, Human molecular genetics.

[147]  D. DiMaio Is Virology Dead? , 2014, mBio.

[148]  R. Edwards,et al.  A highly abundant bacteriophage discovered in the unknown sequences of human faecal metagenomes , 2014, Nature Communications.

[149]  J. Petrosino,et al.  The Placenta Harbors a Unique Microbiome , 2014, Science Translational Medicine.

[150]  Christopher E. McKinlay,et al.  Rethinking "enterotypes". , 2014, Cell host & microbe.

[151]  M. Schatz Biological data sciences in genome research , 2015, Genome research.

[152]  G. Weinstock,et al.  Making the Leap from Research Laboratory to Clinic: Challenges and Opportunities for Next-Generation Sequencing in Infectious Disease Diagnostics , 2015, mBio.

[153]  V. Tremaroli,et al.  Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life. , 2015, Cell host & microbe.

[154]  K. Foster,et al.  The ecology of the microbiome: Networks, competition, and stability , 2015, Science.

[155]  T Laver,et al.  Assessing the performance of the Oxford Nanopore Technologies MinION , 2015, Biomolecular detection and quantification.

[156]  M. Carabotti,et al.  The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems , 2015, Annals of gastroenterology.

[157]  G. Mihăescu,et al.  Human anelloviruses: an update of molecular, epidemiological and clinical aspects , 2015, Archives of Virology.

[158]  Melissa Ly,et al.  The human urine virome in association with urinary tract infections , 2014, Front. Microbiol..

[159]  Yanjiao Zhou,et al.  Early life dynamics of the human gut virome and bacterial microbiome in infants , 2015, Nature Medicine.

[160]  Eric C Keen,et al.  A century of phage research: Bacteriophages and the shaping of modern biology , 2015, BioEssays : news and reviews in molecular, cellular and developmental biology.

[161]  M. Schatz,et al.  Big Data: Astronomical or Genomical? , 2015, PLoS biology.

[162]  F. Bushman,et al.  Comparison of placenta samples with contamination controls does not provide evidence for a distinct placenta microbiota , 2016, Microbiome.

[163]  S. Salminen,et al.  Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid , 2016, Scientific Reports.

[164]  C. Huttenhower,et al.  The healthy human microbiome , 2016, Genome Medicine.

[165]  L. Villarreal Viruses and the placenta: the essential virus first view , 2016, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[166]  R. Milo,et al.  Revised Estimates for the Number of Human and Bacteria Cells in the Body , 2016, bioRxiv.

[167]  G. Gloor,et al.  Human milk microbiota profiles in relation to birthing method, gestation and infant gender , 2016, Microbiome.

[168]  R. L. Harrison,et al.  50 years of the International Committee on Taxonomy of Viruses: progress and prospects , 2017, Archives of Virology.

[169]  Ralf Schweizer Symbiosis As A Source Of Evolutionary Innovation Speciation And Morphogenesis , 2016 .

[170]  Gregory J. Morgan What is a virus species? Radical pluralism in viral taxonomy. , 2016, Studies in history and philosophy of biological and biomedical sciences.

[171]  Michael Y. Galperin,et al.  The 2016 database issue of Nucleic Acids Research and an updated molecular biology database collection , 2015, Nucleic Acids Res..

[172]  The taxonomy of viruses should include viruses , 2016, Archives of Virology.

[173]  Georgios A. Pavlopoulos,et al.  Uncovering Earth’s virome , 2016, Nature.

[174]  P. Hyman,et al.  More Is Better: Selecting for Broad Host Range Bacteriophages , 2016, Front. Microbiol..

[175]  Barbara A. Bailey,et al.  Lytic to temperate switching of viral communities , 2016, Nature.

[176]  K. Aagaard,et al.  Maturation of the Infant Microbiome Community Structure and Function Across Multiple Body Sites and in Relation to Mode of Delivery , 2017, Nature Medicine.

[177]  M. Muniesa,et al.  Phages in the Human Body , 2017, Front. Microbiol..

[178]  Michael Y. Galperin,et al.  The 24th annual Nucleic Acids Research database issue: a look back and upcoming changes , 2017, Nucleic acids research.

[179]  Brian C. Thomas,et al.  Retroelement guided protein diversification abounds in vast lineages of bacteria and archaea , 2017, Nature Microbiology.

[180]  Ahmed Halioui,et al.  A machine learning approach for viral genome classification , 2017, BMC Bioinformatics.

[181]  J. Walter,et al.  A critical assessment of the “sterile womb” and “in utero colonization” hypotheses: implications for research on the pioneer infant microbiome , 2017, Microbiome.

[182]  S. Giovannoni SAR11 Bacteria: The Most Abundant Plankton in the Oceans. , 2017, Annual review of marine science.

[183]  I-Min A. Chen,et al.  IMG/M: integrated genome and metagenome comparative data analysis system , 2016, Nucleic Acids Res..

[184]  J. Lehtimäki,et al.  The ecology of human microbiota: dynamics and diversity in health and disease , 2017, Annals of the New York Academy of Sciences.

[185]  Jie Ren,et al.  Prediction of virus-host infectious association by supervised learning methods , 2017, BMC Bioinformatics.

[186]  I-Min A. Chen,et al.  IMG/VR: a database of cultured and uncultured DNA Viruses and retroviruses , 2016, Nucleic Acids Res..

[187]  Robert D. Finn,et al.  EBI Metagenomics in 2017: enriching the analysis of microbial communities, from sequence reads to assemblies , 2017, Nucleic Acids Res..

[188]  Xosé M. Fernández-Suárez,et al.  The 2018 Nucleic Acids Research database issue and the online molecular biology database collection , 2017, Nucleic Acids Res..

[189]  Lenwood S. Heath,et al.  DeepARG: a deep learning approach for predicting antibiotic resistance genes from metagenomic data , 2017, bioRxiv.

[190]  E. Koonin,et al.  Origins and Evolution of the Global RNA Virome , 2018, mBio.

[191]  A. Greninger A decade of RNA virus metagenomics is (not) enough , 2017, Virus Research.

[192]  P. Daszak,et al.  The Global Virome Project , 2018, Science.

[193]  R. Edwards,et al.  A diversity-generating retroelement encoded by a globally ubiquitous Bacteroides phage , 2018, Microbiome.

[194]  Cynthia Rodriguez,et al.  Amniotic fluid from healthy term pregnancies does not harbor a detectable microbial community , 2018, Microbiome.

[195]  M. Shi,et al.  The evolutionary history of vertebrate RNA viruses , 2018, Nature.

[196]  E. Chuong The placenta goes viral: Retroviruses control gene expression in pregnancy , 2018, PLoS biology.

[197]  Jeff F. Miller,et al.  Template-assisted synthesis of adenine-mutagenized cDNA by a retroelement protein complex , 2018, bioRxiv.

[198]  M. V. Van Regenmortel,et al.  The Species Problem in Virology. , 2018, Advances in virus research.

[199]  Kevin M. Johnson,et al.  Shared and Distinct Features of Human Milk and Infant Stool Viromes , 2018, Front. Microbiol..

[200]  Andreas Wilke,et al.  MG-RAST version 4 - lessons learned from a decade of low-budget ultra-high-throughput metagenome analysis , 2019, Briefings Bioinform..

[201]  Y. Smulders,et al.  1,8 , 2019, Huisarts en wetenschap.