Metagenomics 1408929 225913072 2008-07-16T00:00:59Z Thorwald 74279 "genome" -> "genome sequencing" link '''Metagenomics''' (also '''Environmental Genomics''', '''Ecogenomics''' or '''Community Genomics''') is the study of [[genetics|genetic]] material recovered directly from [[Natural environment|environment]]al samples. Traditional [[microbiology]] and microbial [[genome sequencing]] rely upon cultivated [[clone (genetics)|clonal]] [[microbiological culture|cultures]]. This relatively new field of [[genetics|genetic]] research enables studies of organisms that are not easily cultured in a laboratory as well as studies of organisms in their natural environment. An interesting overview of metagenomics is [http://www.newscientist.com/channel/life/mg19325952.100-welcome-to-life-on-the-tiniest-scales.html "Welcome to life on the tiniest scales"] ; written by Henry Nicholls, in March 17th 2007 New Scientist magazine (paid). Early environmental gene sequencing cloned specific genes (often the [[16S ribosomal RNA|16S rRNA]] gene) to produce a profile of diversity in a natural sample. Such work revealed that the vast majority of microbial diversity had been missed by cultivation-based methods. <ref name="Hugenholz1998">{{cite journal | last = Hugenholz | first = P | coauthors = Goebel BM, Pace NR | year = 1998 | title = Impact of culture-independent studies on the emerging phylogenetic view of bacterial diversity | journal = J. Bacteriol | volume = 180 | pages = 4765–4774 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=9733676 | pmid = 9733676}}</ref> Recent studies use "shotgun" Sanger sequencing or chip-based pyrosequencing to get (mostly) unbiased samples of all genes from all members of sampled communities. == History == === Origin of the term === The term "metagenomics" was first used by [[Jo Handelsman]] and others in the University of Wisconsin Department of Plant Pathology, and first appeared in publication in 1998. <ref name="Handelsman1998">{{cite journal | last = Handelsman | first = J | coauthors = Rondon MR, Brady SF, Clardy J, Goodman RM | year = 1998 | title = Molecular biological access to the chemistry of unknown soil microbes: a new frontier for natural products | journal = Chemistry &amp; Biology | volume = 5 | pages = 245&ndash;249 | doi = 10.1016/S1074-5521(98)90108-9}}.</ref> The term '''metagenome''' referenced the idea that a collection of genes sequenced from the environment could be analyzed in way analogous to the study of a single [[genome]]. The exploding interest in environmental genetics, along with the buzzword-like nature of the term, has resulted in the broader use of '''metagenomics''' to describe any sequencing of genetic material from environmental (i.e. uncultured) samples, even work that focuses on one organism or gene. Recently, Kevin Chen and [[Lior Pachter]] (researchers at the [[University of California, Berkeley]]) defined metagenomics as "the application of modern genomics techniques to the study of communities of microbial organisms directly in their natural environments, bypassing the need for isolation and lab cultivation of individual species." <ref name="Chen2005">{{cite journal | last = Chen | first = K | coauthors = Pachter L | year = 2005 | title = Bioinformatics for whole-genome shotgun sequencing of microbial communities | journal = PLoS Comp Biol | volume = 1 | pages = 24 | doi = 10.1371/journal.pcbi.0010024}}.</ref> === Environmental gene surveys === Conventional [[sequencing]] begins with a culture of identical cells as a source of [[DNA]]. However, early metagenomic studies revealed that there are probably large groups of microorganisms in many environments that cannot be cultured and thus cannot be sequenced. These early studies focused on 16S [[ribosomal]] [[RNA]] sequences which are relatively short, often conserved within a species, and generally different between species. Many 16S [[rRNA]] sequences have been found which do not belong to any known cultured species, indicating that there are numerous non-isolated organisms out there. Early molecular work in the field was conducted by [[Norman R. Pace]] and colleagues, who used [[PCR]] to explore the diversity of ribosomal RNA sequences. <ref name="Lane1985">{{cite journal | last = Lane | first = DJ | coauthors = Pace B, Olsen GJ, Stahl DA, Sogin ML, Pace NR | year = 1985 | title = Rapid determination of 16S ribosomal RNA sequences for phylogenetic analyses | journal = [[Proceedings of the National Academy of Sciences]] | volume = 82 | pages = 6955 | doi = 10.1073/pnas.82.20.6955 | pmid = 2413450}}.</ref> The insights gained from these breakthrough studies led Pace to propose the idea of cloning DNA directly from environmental samples as early as 1985. <ref name="Pace1985">{{cite journal | last = Pace | first = NR | coauthors = DA Stahl, DJ Lane, GJ Olsen | year = 1985 | title = Analyzing natural microbial populations by rRNA sequences | journal = ASM News | volume = 51 | pages = 4&ndash;12}}.</ref> This led to the first report of isolating and cloning bulk DNA from an environmental sample, published by Pace and colleagues in 1991 <ref name="Pace1991">{{cite journal | last = Pace | first = NR | authorlink = Norman R. Pace | year = 1991 | title = Analysis of a marine picoplankton community by 16S rRNA gene cloning and sequencing | journal = [[Journal of Bacteriology]] | volume = 173 | pages = 4371&ndash;4378}}.</ref> while Pace was in the Department of Biology at Indiana University. Considerable efforts ensured that these were not PCR false positives and supported the existence of a complex community of unexplored species. Although this methodology was limited to exploring highly conserved, non-protein coding genes, it did support early microbial morphology-based observations that diversity was far more complex than was known by culturing methods. Soon after that, Healy reported the metagenomic isolation of functional genes from "zoolibraries" constructed from a complex culture of environmental organisms grown in the laboratory on dried grasses in 1995. <ref name="Healy1995">{{cite journal | last = Healy | first = FG | coauthors = RM Ray, HC Aldrich, AC Wilkie, LO Ingram, KT Shanmugam | year = 1995 | title = Direct isolation of functional genes encoding cellulases from the microbial consortia in a thermophilic, anaerobic digester maintained on lignocellulose | journal = Appl. Microbiol Biotechnol. | volume = 43 | pages = 667 | doi = 10.1007/BF00164771}}.</ref> After leaving the Pace laboratory, Ed DeLong continued in the field and has published work that has largely laid the groundwork for environmental phylogenies based on signature 16S sequences, beginning with his group's construction of libraries from marine samples. <ref name="Stein1996">{{cite journal | last = Stein | first = JL | coauthors = TL Marsh, KY Wu, H Shizuya, EF DeLong | year = 1996 | title = Characterization of uncultivated prokaryotes: isolation and analysis of a 40-kilobase-pair genome fragment from a planktonic marine archaeon | journal = Journal of Bacteriology | volume = 178 | pages = 591&ndash;599}}.</ref> ===Longer sequences from environmental samples=== Recovery of DNA sequences longer than a few thousand base pairs from environmental samples was very difficult until recent advances in molecular biological techniques, particularly related to constructing libraries in [[bacterial artificial chromosome]]s (BACs), provided better vectors for molecular cloning. <ref name="Beja2000">{{cite journal | last = Beja | first = O | coauthors = Suzuki MT, Koonin EV, Aravind L, Hadd A, Nguyen LP, Villacorta R, Amjadi M, Garrigues C, Jovanovich SB, Feldman RA, Delong EF | title = Construction and analysis of bacterial artificial chromosome libraries from a marine microbial assemblage | year = 2000 | volume = 2 | pages = 516–529}}</ref> ===Shotgun metagenomics=== Advances in [[bioinformatics]], refinements of DNA amplification, and proliferation of computational power have greatly aided the analysis of DNA sequences recovered from environmental samples. These advances have enabled the adaptation of [[shotgun sequencing]] to metagenomic samples. The approach, used to sequence many cultured microorganisms as well as the [[human genome project | human genome]], randomly shears DNA, sequences many short sequences, and reconstructs them into a consensus sequence. In 2002, Mya Breitbart, [[Forest Rohwer]], and colleagues used environmental shotgun sequencing to show that 200 liters of seawater contains over 5000 different viruses. <ref name="Breitbart2002">{{cite journal | last = Breitbart | first = M | coauthors = Salamon P, Andresen B, Mahaffy JM, Segall AM, Mead D, Azam F, Rohwer F | year = 2002 | title = Genomic analysis of uncultured marine viral communities | journal = Proceedings of the National Academy USA | volume = 99 | pages = 14250–14255 | doi = 10.1073/pnas.202488399 | pmid = 12384570}}.</ref> Subsequent studies showed that there are >1000 viral species in human stool and possibly a million different viruses per kilogram of marine sediment, including many [[bacteriophages]]. Essentially all of the viruses in these studies were new species. A 2004 metagenomic study of the [[Sargasso Sea]] found DNA from nearly 2000 different [[species]] including 148 types of [[bacteria]] never seen before. <ref name="Venter2004">{{cite journal | last = Venter | first = JC | coauthors = Remington K, Heidelberg JF, Halpern AL, Rusch D, Eisen JA, Wu D, Paulsen I, Nelson KE, Nelson W, Fouts DE, Levy S, Knap AH, Lomas MW, Nealson K, White O, Peterson J, Hoffman J, Parsons R, Baden-Tillson H, Pfannkoch C, Rogers Y, Smith HO | year = 2004 | title = Environmental Genome Shotgun Sequencing of the Sargasso Sea | journal = Science | volume = 304 | pages = 66–74 | doi = 10.1126/science.1093857 | pmid = 15001713}}.</ref> Also in 2004, Gene Tyson, Jill Banfield, and colleagues at the [[University of California, Berkeley]] and the [[Joint Genome Institute]] sequenced DNA extracted from an [[acid mine drainage]] system. <ref name="Tyson2004">{{cite journal | last = Tyson | first = GW | coauthors = Chapman J, Hugenholtz P, Allen EE, Ram RJ, Richardson PM, Solovyev VV, Rubin EM, Rokhsar DS, Banfield JF | year = 2004 | title = Insights into community structure and metabolism by reconstruction of microbial genomes from the environment | journal = Nature | volume = 428 | pages = 37–43 | url = http://www.nature.com/nature/journal/v428/n6978/full/nature02340.html | doi = 10.1038/nature02340 }}.</ref> This effort resulted in the complete, or nearly complete, genomes for a handful of bacteria and [[archaea]] that had previously resisted attempts to culture them. It was now possible to study entire genomes without the biases associated with laboratory cultures. <ref name="Hugenholz2002">{{cite journal | last = Hugenholz | first = P | year = 2002 | title = Exploring prokaryotic diversity in the genomic era | journal = Genome Biology | volume = 3 | pages = 1–8 | doi = 10.1186/gb-2002-3-2-reviews0003}}.</ref> In 2006 Robert Edwards, [[Forest Rohwer]], and colleagues at [[San Diego State University]] published the first sequences of environmental samples generated with so-called next generation sequencing, in this case chip based [[pyrosequencing]] developed by [[454_Life_Sciences | 454 Life Sciences]]. <ref name="Edwards2006">{{cite journal | last = Edwards | first = RA | coauthors = Rodriguez-Brito B, Wegley L, Haynes M, Breitbart M, Peterson DM, Saar MO, Alexander S, Alexander EC, Rohwer F | year = 2006 | title = Using pyrosequencing to shed light on deep mine microbial ecology | journal = BMC Genomics | volume = 7 | pages = 57 | doi = 10.1186/1471-2164-7-57}}.</ref> This technique for sequencing the DNA generates shorter fragments than the conventional techniques, however this limitation is compensated for by the very large number of sequences generated. In addition, this technique does not require cloning the DNA before sequencing, removing one of the main biases in metagenomics. In 2007, Daniel Huson and Stephan Schuster developed and published the first stand-alone metagenome analysis tool, [[MEGAN]], which can be used to perform a first analysis of a metagenomic shotgun dataset. This tool was originally developed to analyse the metagenome of a mammoth sample <ref>H. N. Poinar, C. Schwarz, Ji Qi, B. Shapiro, R. D. E. MacPhee, B. Buigues, A. Tikhonov, D. H. Huson, L. P. Tomsho, A. Auch, M. Rampp, W. Miller, S. C. Schuster, Metagenomics to Paleogenomics: Large-Scale Sequencing of Mammoth DNA, Science 311:392-394, 2006</ref>. ==Microbial Diversity== Much of the interest in metagenomics comes from the discovery that the vast majority of microorganisms had previously gone unnoticed. Traditional microbiological methods relied upon laboratory cultures of organisms. Surveys of ribosomal RNA (rRNA) genes taken directly from the environment revealed that cultivation based methods find less than 1% of the bacteria and archaea species in a sample. <ref name="Hugenholz1998"/> ==Gene Surveys== Shotgun sequencing and screens of clone libraries reveal genes present in environmental samples. This provides information both on which organisms are present and what metabolic processes are possible in the community. This can be helpful in understanding the ecology of a community, particularly if multiple samples are compared to each other. <ref name="Allen2005">{{cite journal | last = Allen| first = EE | coauthors = Banfield, JF | year = 2005 | title = Community genomics in microbial ecology and evolution | journal = Nature Reviews Microbiology | volume = 3 | pages = 489–498 | doi = 10.1038/nrmicro1157 }}</ref> ==Environmental Genomes== Shotgun metagenomics also is capable of sequencing nearly complete microbial genomes directly from the environment. <ref name="Tyson2004"/> Because the collection of DNA from an environment is largely uncontrolled, the most abundant organisms types in a sample are most highly represented in the resulting sequence data. To achieve the high coverage needed to fully resolve the genomes of underrepresented community members, large samples, often prohibitively so, are needed. On the other hand, the random nature of shotgun sequencing ensures that many of these organisms will be represented by at least some small sequence segments. Due to the limitations of microbial isolation methods, the vast majority of these organisms would go unnoticed using traditional culturing techniques. ==Community metabolism== Many bacterial communities show significant division of labor in metabolism. Waste products of some organisms are metabolites for others. Working together they turn raw resources into fully metabolized waste. Using comparative gene studies and expression experiments with [[microarray]]s or [[proteomics]] researchers can piece together a metabolic network that goes beyond species boundaries. Such studies require detailed knowledge about which versions of which proteins are coded by which species and even by which strains of which species. Therefore, community genomic information is another fundamental part (as metabolomics or proteomics) to be able to estimate how metabolites are possibly transferred and transformed through a community. == References == {{Reflist}} == Additional References == {{linkfarm}} === Review articles === * Edwards RA, & Rohwer F. Viral metagenomics. Nat Rev Microbiol. 2005 3(6):504-10. [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=pubmed&dopt=AbstractPlus&list_uids=15886693 PubMed] * Eisen, J. A. (2007). Environmental shotgun sequencing: its potential and challenges for studying the hidden world of microbes. [http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0050082 ''PLoS Biology 5(3): e82''] * Green, B. D. & Keller, M. (2006). Capturing the uncultivated majority. ''Current Opinion in Biotechnology'' 17[3], 236-240. * Handelsman J. (2004). Metagenomics: application of genomics to uncultured microorganisms. 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(2006) ''RNA viral community in human feces: prevalence of plant pathogenic viruses''. PLoS biology, '''4''', e3. === Ancient DNA=== * [http://www.sciencemag.org/cgi/content/abstract/1123360v1?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=wooly+mammoth&searchid=1135358119618_7589&FIRSTINDEX=0&journalcode=sci H. N. Poinar, C. Schwarz, Ji Qi, B. Shapiro, R. D. E. MacPhee, B. Buigues, A. Tikhonov, D. H. Huson, L. P. Tomsho, A. Auch, M. Rampp, W. Miller, S. C. Schuster, Metagenomics to Paleogenomics: Large-Scale Sequencing of Mammoth DNA, Science 311:392-394, 2006] ==External links== * [http://www-ab.informatik.uni-tuebingen.de/software/megan/ MEGAN] MEtaGenome ANalyzer. A stand-alone metagenome analysis tool. * [http://dels.nas.edu/metagenomics/ Metagenomics and Our Microbial Planet] A website on metagenomics and the vital role of microbes on Earth from the [http://nationalacademies.org National Academies.] * [http://books.nap.edu/catalog.php?record_id=11902 The New Science of Metagenomics: Revealing the Secrets of Our Microbial Planet] A report released by the National Research Council in March 2007. Also, see the [http://dels.nas.edu/dels/rpt_briefs/metagenomics_brief_final.pdf Report In Brief.] * [http://img.jgi.doe.gov/m IMG/M] The Integrated Microbial Genomes system, for metagenome analysis by the DOE-JGI. * [http://camera.calit2.net/index.php CAMERA] Cyberinfrastructure for Metagenomics, data repository and tools for metagenomics research. *[http://www.scq.ubc.ca/?p=509 A good overview of metagenomics from the Science Creative Quarterly] *[http://www.genomesonline.org/gold.cgi?want=Metagenomes list of Metagenome Projects from genomesonline.org] * [http://metagenomics.theseed.org The SEED] publicly available, free, metagenomics annotation pipeline for pyrosequences, Sanger sequences, and other sequence approaches. * [[Human microbiome project]] * [http://www.metahit.eu/ MetaHIT] official website for the EU-funded project : Metagenomics of the Human Intestinal Tract * [http://annotathon.univ-mrs.fr/ Annotathon] Bioinformatics Training Through Metagenomic Sequence Annotation [[Category:Bioinformatics]] [[Category:Genomics]] [[Category:Microbiology]] [[Category:Environmental microbiology]] [[ca:Metagenòmica]] [[de:Metagenomik]] [[ko:범유전체학]] [[it:Metagenomica]] [[hu:Metagenomika]] [[ja:メタジェノミクス]] [[uk:Метагеноміка]]