Signal Processing for Metagenomics: Extracting Information from the Soup

Traditionally, studies in microbial genomics have focused on single-genomes from cultured species, thereby limiting their focus to the small percentage of species that can be cultured outside their natural environment. Fortunately, recent advances in high-throughput sequencing and computational analyses have ushered in the new field of metagenomics, which aims to decode the genomes of microbes from natural communities without the need for cultivation. Although metagenomic studies have shed a great deal of insight into bacterial diversity and coding capacity, several computational challenges remain due to the massive size and complexity of metagenomic sequence data. Current tools and techniques are reviewed in this paper which address challenges in 1) genomic fragment annotation, 2) phylogenetic reconstruction, 3) functional classification of samples, and 4) interpreting complementary metaproteomics and metametabolomics data. Also surveyed are important applications of metagenomic studies, including microbial forensics and the roles of microbial communities in shaping human health and soil ecology.

[1]  Rob Knight,et al.  UniFrac – An online tool for comparing microbial community diversity in a phylogenetic context , 2006, BMC Bioinformatics.

[2]  M. Swanson,et al.  Legionella pneumophila pathogesesis: a fateful journey from amoebae to macrophages. , 2000, Annual review of microbiology.

[3]  J. Tamames,et al.  Metagenomics reveals our incomplete knowledge of global diversity , 2008, Bioinform..

[4]  Martin Tompa,et al.  MicroFootPrinter: a tool for phylogenetic footprinting in prokaryotic genomes , 2006, Nucleic Acids Res..

[5]  D. Gevers,et al.  Re-evaluating prokaryotic species , 2005, Nature Reviews Microbiology.

[6]  M. Borodovsky,et al.  GeneMark.hmm: new solutions for gene finding. , 1998, Nucleic acids research.

[7]  J. Banfield,et al.  Community Proteomics of a Natural Microbial Biofilm , 2005, Science.

[8]  Peer Bork,et al.  SMART 4.0: towards genomic data integration , 2004, Nucleic Acids Res..

[9]  Robert R Klevecz,et al.  Signal processing and the design of microarray time-series experiments. , 2007, Methods in molecular biology.

[10]  P. Schenk,et al.  Isolation and analysis of mRNA from environmental microbial communities. , 2008, Journal of microbiological methods.

[11]  F. Bäckhed,et al.  Obesity alters gut microbial ecology. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Xuegong Zhang,et al.  Recursive SVM feature selection and sample classification for mass-spectrometry and microarray data , 2006, BMC Bioinformatics.

[13]  Rudolf Amann,et al.  Optimization Strategies for DNA Microarray-Based Detection of Bacteria with 16S rRNA-Targeting Oligonucleotide Probes , 2003, Applied and Environmental Microbiology.

[14]  N. Pace,et al.  Gastrointestinal microbiology enters the metagenomics era , 2008, Current opinion in gastroenterology.

[15]  Gail Rosen,et al.  An information theoretic method of microarray probe design for genome classification , 2008, 2008 30th Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[16]  R. Knight,et al.  Accurate taxonomy assignments from 16S rRNA sequences produced by highly parallel pyrosequencers , 2008, Nucleic acids research.

[17]  M. Nei,et al.  MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. , 2007, Molecular biology and evolution.

[18]  D. Bessesen,et al.  Human gut microbes associated with obesity , 2007 .

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

[20]  K. Rudi,et al.  Total bacterial and species‐specific 16S rDNA micro‐array quantification of complex samples , 2006, Journal of applied microbiology.

[21]  Jizhong Zhou,et al.  Functional microarray analysis of nitrogen and carbon cycling genes across an Antarctic latitudinal transect , 2007, The ISME Journal.

[22]  Robert M. Hazen,et al.  Genesis: The Scientific Quest for Life's Origin , 2005 .

[23]  P. Turnbaugh,et al.  Microbial ecology: Human gut microbes associated with obesity , 2006, Nature.

[24]  S. Salzberg,et al.  Bioinformatics challenges of new sequencing technology. , 2008, Trends in genetics : TIG.

[25]  Anders F. Andersson,et al.  Comparative Analysis of Human Gut Microbiota by Barcoded Pyrosequencing , 2008, PloS one.

[26]  F. Chen,et al.  Metaproteomic analysis of Chesapeake Bay microbial communities , 2005, Saline systems.

[27]  T. M. Nye Trees of trees: an approach to comparing multiple alternative phylogenies. , 2008, Systematic biology.

[28]  J. A. Aas,et al.  Microbial Risk Indicators of Early Childhood Caries , 2005, Journal of Clinical Microbiology.

[29]  Frank Oliver Glöckner,et al.  TETRA: a web-service and a stand-alone program for the analysis and comparison of tetranucleotide usage patterns in DNA sequences , 2004, BMC Bioinformatics.

[30]  Peter Salamon,et al.  Metagenomic and Small-Subunit rRNA Analyses Reveal the Genetic Diversity of Bacteria, Archaea, Fungi, and Viruses in Soil , 2007, Applied and Environmental Microbiology.

[31]  J. Banfield,et al.  Proteomics-inferred genome typing (PIGT) demonstrates inter-population recombination as a strategy for environmental adaptation. , 2009, Environmental microbiology.

[32]  Paul Wilmes,et al.  Metaproteomics Provides Functional Insight into Activated Sludge Wastewater Treatment , 2008, PloS one.

[33]  A. Hsu,et al.  Using Growing Self-Organising Maps to Improve the Binning Process in Environmental Whole-Genome Shotgun Sequencing , 2007, Journal of biomedicine & biotechnology.

[34]  D. Higgins,et al.  See Blockindiscussions, Blockinstats, Blockinand Blockinauthor Blockinprofiles Blockinfor Blockinthis Blockinpublication Clustal: Blockina Blockinpackage Blockinfor Blockinperforming Multiple Blockinsequence Blockinalignment Blockinon Blockina Minicomputer Article Blockin Blockinin Blockin , 2022 .

[35]  G. Rosen Examining coding structure and redundancy in DNA , 2006, IEEE Engineering in Medicine and Biology Magazine.

[36]  F. Valafar Pattern Recognition Techniques in Microarray Data Analysis : A Survey , 2002 .

[37]  L. Choe,et al.  Metaproteomic analysis of a bacterial community response to cadmium exposure. , 2007, Journal of proteome research.

[38]  I. Rigoutsos,et al.  Accurate phylogenetic classification of variable-length DNA fragments , 2007, Nature Methods.

[39]  J. Thompson,et al.  Multiple sequence alignment with Clustal X. , 1998, Trends in biochemical sciences.

[40]  Frank Oliver Glöckner,et al.  Toward a standards-compliant genomic and metagenomic publication record. , 2008, Omics : a journal of integrative biology.

[41]  Kyle J. Munn,et al.  Development and assessment of whole-genome oligonucleotide microarrays to analyze an anaerobic microbial community and its responses to oxidative stress. , 2007, Biochemical and biophysical research communications.

[42]  L. Eyers,et al.  Environmental genomics: exploring the unmined richness of microbes to degrade xenobiotics , 2004, Applied Microbiology and Biotechnology.

[43]  S. Kravitz,et al.  CAMERA: A Community Resource for Metagenomics , 2007, PLoS biology.

[44]  N. Saitou,et al.  The neighbor-joining method: a new method for reconstructing phylogenetic trees. , 1987, Molecular biology and evolution.

[45]  Cathy H. Wu,et al.  The Universal Protein Resource (UniProt) , 2004, Nucleic Acids Res..

[46]  K. Schleifer,et al.  Phylogenetic identification and in situ detection of individual microbial cells without cultivation. , 1995, Microbiological reviews.

[47]  K. Harris,et al.  Development of broad-range 16S rDNA PCR for use in the routine diagnostic clinical microbiology service. , 2003, Journal of medical microbiology.

[48]  Maureen L. Coleman,et al.  Microbial community gene expression in ocean surface waters , 2008, Proceedings of the National Academy of Sciences.

[49]  M. David,et al.  Evaluation of functional gene enrichment in a soil metagenomic clone library. , 2009, Journal of microbiological methods.

[50]  Jizhong Zhou,et al.  Detection of Genes Involved in Biodegradation and Biotransformation in Microbial Communities by Using 50-Mer Oligonucleotide Microarrays , 2004, Applied and Environmental Microbiology.

[51]  Orly Alter,et al.  Genomic signal processing: from matrix algebra to genetic networks. , 2007, Methods in molecular biology.

[52]  Zhaojun Bai,et al.  CompostBin: A DNA Composition-Based Algorithm for Binning Environmental Shotgun Reads , 2007, RECOMB.

[53]  Mihai Pop,et al.  Microbiome Metagenomic Analysis of the Human Distal Gut , 2009 .

[54]  Jack Sullivan,et al.  Does choice in model selection affect maximum likelihood analysis? , 2008, Systematic biology.

[55]  Minoru Kanehisa,et al.  The KEGG database. , 2002, Novartis Foundation symposium.

[56]  Mahmood Akhtar,et al.  Signal Processing in Sequence Analysis: Advances in Eukaryotic Gene Prediction , 2008, IEEE Journal of Selected Topics in Signal Processing.

[57]  O. Milenkovic,et al.  Designing Compressive Sensing DNA Microarrays , 2007, 2007 2nd IEEE International Workshop on Computational Advances in Multi-Sensor Adaptive Processing.

[58]  M. Blaser,et al.  Evolutionary implications of microbial genome tetranucleotide frequency biases. , 2003, Genome research.

[59]  Paul C. Boutros,et al.  Unsupervised pattern recognition: An introduction to the whys and wherefores of clustering microarray data , 2005, Briefings Bioinform..

[60]  F.C. Harris,et al.  A fuzzy classifier to taxonomically group DNA fragments within a metagenome , 2008, NAFIPS 2008 - 2008 Annual Meeting of the North American Fuzzy Information Processing Society.

[61]  R. Knight,et al.  Global patterns in bacterial diversity , 2007, Proceedings of the National Academy of Sciences.

[62]  Alain Giron,et al.  GENSTYLE: exploration and analysis of DNA sequences with genomic signature , 2005, Nucleic Acids Res..

[63]  Tao Zhang,et al.  The Airborne Metagenome in an Indoor Urban Environment , 2008, PloS one.

[64]  M. Mann,et al.  A proteomic fingerprint of dissolved organic carbon and of soil particles , 2004, Oecologia.

[65]  Ziheng Yang PAML 4: phylogenetic analysis by maximum likelihood. , 2007, Molecular biology and evolution.

[66]  David L. Wheeler,et al.  GenBank , 2015, Nucleic Acids Res..

[67]  S. Allison,et al.  Resistance, resilience, and redundancy in microbial communities , 2008, Proceedings of the National Academy of Sciences.

[68]  Michael Wagner,et al.  16S rRNA Gene-Based Oligonucleotide Microarray for Environmental Monitoring of the Betaproteobacterial Order “Rhodocyclales” , 2005, Applied and Environmental Microbiology.

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

[70]  L. Koski,et al.  The Closest BLAST Hit Is Often Not the Nearest Neighbor , 2001, Journal of Molecular Evolution.

[71]  A. Godzik,et al.  Probing Metagenomics by Rapid Cluster Analysis of Very Large Datasets , 2008, PloS one.

[72]  S. Quake,et al.  Dissecting biological “dark matter” with single-cell genetic analysis of rare and uncultivated TM7 microbes from the human mouth , 2007, Proceedings of the National Academy of Sciences.

[73]  R. B. Jackson,et al.  The diversity and biogeography of soil bacterial communities. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[74]  P. Lewis,et al.  Success of maximum likelihood phylogeny inference in the four-taxon case. , 1995, Molecular biology and evolution.

[75]  Willy Valdivia-Granda The next meta-challenge for Bioinformatics , 2008, Bioinformation.

[76]  Rick Stevens,et al.  Erratum: Functional metagenomic profiling of nine biomes , 2008 .

[77]  T. Takagi,et al.  MetaGene: prokaryotic gene finding from environmental genome shotgun sequences , 2006, Nucleic acids research.

[78]  E. Mardis The impact of next-generation sequencing technology on genetics. , 2008, Trends in genetics : TIG.

[79]  J. V. van Elsas,et al.  A procedure for the metagenomics exploration of disease-suppressive soils. , 2008, Journal of microbiological methods.

[80]  Alexander F. Auch,et al.  MEGAN analysis of metagenomic data. , 2007, Genome research.

[81]  J. Raes,et al.  Quantitative assessment of protein function prediction from metagenomics shotgun sequences , 2007, Proceedings of the National Academy of Sciences.

[82]  Alice C McHardy,et al.  What's in the mix: phylogenetic classification of metagenome sequence samples. , 2007, Current opinion in microbiology.

[83]  Alexander Schliep,et al.  Group testing with DNA chips: generating designs and decoding experiments , 2003, Computational Systems Bioinformatics. CSB2003. Proceedings of the 2003 IEEE Bioinformatics Conference. CSB2003.

[84]  S Karlin,et al.  Compositional biases of bacterial genomes and evolutionary implications , 1997, Journal of bacteriology.

[85]  J. Gilbert,et al.  Detection of Large Numbers of Novel Sequences in the Metatranscriptomes of Complex Marine Microbial Communities , 2008, PloS one.

[86]  S. Tringe,et al.  Comparative Metagenomics of Microbial Communities , 2004, Science.

[87]  Sequencing the microbial soup , 2008, Nature Structural &Molecular Biology.

[88]  Daniela Bartels,et al.  Finding novel genes in bacterial communities isolated from the environment , 2006, ISMB.

[89]  Andreas Wilke,et al.  phylogenetic and functional analysis of metagenomes , 2022 .

[90]  G. Rosen,et al.  A text-mining approach for classification of genomic fragments , 2008, 2008 IEEE International Conference on Bioinformatics and Biomeidcine Workshops.

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

[92]  Colin Hill,et al.  Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome , 2008, Proceedings of the National Academy of Sciences.

[93]  Jaysheel D. Bhavsar,et al.  Metagenomics: Read Length Matters , 2008, Applied and Environmental Microbiology.

[94]  Hiroshi Mori,et al.  Comparative Metagenomics Revealed Commonly Enriched Gene Sets in Human Gut Microbiomes , 2007, DNA research : an international journal for rapid publication of reports on genes and genomes.

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

[96]  Noha H. Youssef,et al.  Novelty and Uniqueness Patterns of Rare Members of the Soil Biosphere , 2008, Applied and Environmental Microbiology.

[97]  S. Karlin,et al.  Dinucleotide relative abundance extremes: a genomic signature. , 1995, Trends in genetics : TIG.

[98]  Baohua Gu,et al.  GeoChip: a comprehensive microarray for investigating biogeochemical, ecological and environmental processes , 2007, The ISME Journal.

[99]  Tao Zhang,et al.  Identification of ancient remains through genomic sequencing. , 2008, Genome research.

[100]  Feng Chen,et al.  Sequencing and Analysis of Neanderthal Genomic DNA , 2006, Science.

[101]  J. Fitch,et al.  Genomic engineering: moving beyond DNA sequence to function , 2000, Proceedings of the IEEE.

[102]  P. Deschavanne,et al.  Genomic signature: characterization and classification of species assessed by chaos game representation of sequences. , 1999, Molecular biology and evolution.

[103]  J. Vorholt,et al.  Quantitative metabolome analysis using liquid chromatography-high-resolution mass spectrometry. , 2008, Analytical biochemistry.

[104]  S. Karlin,et al.  Prediction of complete gene structures in human genomic DNA. , 1997, Journal of molecular biology.

[105]  S. Ho,et al.  Bayesian estimation of sequence damage in ancient DNA. , 2007, Molecular biology and evolution.

[106]  D. Botstein,et al.  Generalized singular value decomposition for comparative analysis of genome-scale expression data sets of two different organisms , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[107]  I-Min A. Chen,et al.  IMG/M: a data management and analysis system for metagenomes , 2007, Nucleic Acids Res..

[108]  Naryttza N. Diaz,et al.  Phylogenetic classification of short environmental DNA fragments , 2008, Nucleic acids research.

[109]  Olivier Poch,et al.  A comprehensive comparison of multiple sequence alignment programs , 1999, Nucleic Acids Res..

[110]  Ilya Levner,et al.  Feature selection and nearest centroid classification for protein mass spectrometry , 2005, BMC Bioinformatics.

[111]  Michael P. Cummings,et al.  MEGA (Molecular Evolutionary Genetics Analysis) , 2004 .

[112]  John Bohannon,et al.  Confusing Kinships , 2008, Science.

[113]  G. Rosen,et al.  An iterative approach to probe-design for compressive sensing microarrays , 2008, 2008 IEEE International Conference on Bioinformatics and Biomeidcine Workshops.

[114]  K. Noordin,et al.  THE EFFECT OF PROBIOTIC MOUTHRINSE ON PLAQUE AND GINGIVAL INFLAMMATION , 2007 .

[115]  Gabriel Renaud,et al.  A diversity profile of the human skin microbiota. , 2008, Genome research.

[116]  Paul Wilmes,et al.  Metaproteomics: studying functional gene expression in microbial ecosystems. , 2006, Trends in microbiology.

[117]  F. James Rohlf,et al.  Biometry: The Principles and Practice of Statistics in Biological Research , 1969 .

[118]  Nathan Kowahl,et al.  Automated Microarray Organism Detection with a Non-Gaussian Maximum Likelihood Model , 2007, 2007 IEEE/SP 14th Workshop on Statistical Signal Processing.

[119]  M. P. Cummings PHYLIP (Phylogeny Inference Package) , 2004 .

[120]  Katharina J. Hoff,et al.  Gene prediction in metagenomic fragments: A large scale machine learning approach , 2008, BMC Bioinformatics.

[121]  A. Salamov,et al.  Use of simulated data sets to evaluate the fidelity of metagenomic processing methods , 2007, Nature Methods.

[122]  F E Dewhirst,et al.  Microbiological diversity of generalized aggressive periodontitis by 16S rRNA clonal analysis. , 2008, Oral microbiology and immunology.

[123]  Cesare Furlanello,et al.  Machine learning methods for predictive proteomics , 2007, Briefings Bioinform..

[124]  E. Myers,et al.  Basic local alignment search tool. , 1990, Journal of molecular biology.

[125]  F. Rohwer,et al.  Use of 16S Ribosomal DNA for Delineation of Marine Bacterioplankton Species , 2002, Applied and Environmental Microbiology.

[126]  K Nishikawa,et al.  Genes from nine genomes are separated into their organisms in the dinucleotide composition space. , 1998, DNA research : an international journal for rapid publication of reports on genes and genomes.

[127]  J. Xuan,et al.  Classification algorithms for phenotype prediction in genomics and proteomics. , 2008, Frontiers in bioscience : a journal and virtual library.

[128]  Halima Bensmail,et al.  A novel approach for clustering proteomics data using Bayesian fast Fourier transform , 2005, Bioinform..

[129]  P. Bork,et al.  Get the most out of your metagenome: computational analysis of environmental sequence data. , 2007, Current opinion in microbiology.

[130]  L. Ranjard,et al.  Metaproteomics: A New Approach for Studying Functional Microbial Ecology , 2007, Microbial Ecology.

[131]  N. Kroer,et al.  Microorganisms as indicators of soil health , 2002 .

[132]  Tom Coenye,et al.  Opinion: Re-evaluating prokaryotic species. , 2005, Nature reviews. Microbiology.

[133]  Alexander F. Auch,et al.  Metagenomics to Paleogenomics: Large-Scale Sequencing of Mammoth DNA , 2006, Science.

[134]  Hideaki Sugawara,et al.  Novel phylogenetic studies of genomic sequence fragments derived from uncultured microbe mixtures in environmental and clinical samples. , 2005, DNA research : an international journal for rapid publication of reports on genes and genomes.

[135]  J. Lindon,et al.  NMR-based metabolic profiling and metabonomic approaches to problems in molecular toxicology. , 2008, Chemical research in toxicology.

[136]  Jonathan A Eisen,et al.  Environmental Shotgun Sequencing: Its Potential and Challenges for Studying the Hidden World of Microbes , 2007, PLoS biology.

[137]  M. Bruns,et al.  Dna Fingerprinting As A Means To Identify Sources Of Soil-Derived Dust: Problems And Potential , 1999, Integrated Assessment of Ecosystem Health.

[138]  Shibu Yooseph,et al.  Gene identification and protein classification in microbial metagenomic sequence data via incremental clustering , 2007, BMC Bioinformatics.

[139]  Ruriko Yoshida,et al.  Maximum likelihood estimation of phylogenetic tree and substitution rates via generalized neighbor-joining and the EM algorithm , 2005 .

[140]  Peter Chung,et al.  Uncultivated Bacteria as Etiologic Agents of Intra-Amniotic Inflammation Leading to Preterm Birth , 2008, Journal of Clinical Microbiology.

[141]  D. Benndorf,et al.  Functional metaproteome analysis of protein extracts from contaminated soil and groundwater , 2007, The ISME Journal.

[142]  J. Fitch,et al.  Technology Challenges in Responding to Biological or Chemical Attacks in the Civilian Sector , 2003, Science.

[143]  F. Rodríguez-Valera,et al.  Use of the 16S--23S ribosomal genes spacer region in studies of prokaryotic diversity. , 1999, Journal of microbiological methods.

[144]  Andrew P. Martin Phylogenetic Approaches for Describing and Comparing the Diversity of Microbial Communities , 2002, Applied and Environmental Microbiology.

[145]  Thomas P. Curtis,et al.  Estimating prokaryotic diversity and its limits , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[146]  Gail L. Rosen,et al.  Metagenome Fragment Classification Using N-Mer Frequency Profiles , 2008, Adv. Bioinformatics.

[147]  Harald Tammen,et al.  Datamining methodology for LC-MALDI-MS based peptide profiling. , 2005, Combinatorial chemistry & high throughput screening.

[148]  Lior Pachter,et al.  Bioinformatics for Whole-Genome Shotgun Sequencing of Microbial Communities , 2005, PLoS Comput. Biol..

[149]  Roderic Guigo,et al.  A comparison of random sequence reads versus 16S rDNA sequences for estimating the biodiversity of a metagenomic library , 2008, Nucleic acids research.

[150]  E. Mardis,et al.  An obesity-associated gut microbiome with increased capacity for energy harvest , 2006, Nature.

[151]  Babak Hassibi,et al.  Recovering Sparse Signals Using Sparse Measurement Matrices in Compressed DNA Microarrays , 2008, IEEE Journal of Selected Topics in Signal Processing.

[152]  E. Delong,et al.  Community Genomics Among Stratified Microbial Assemblages in the Ocean's Interior , 2006, Science.

[153]  Rick L. Stevens,et al.  Functional metagenomic profiling of nine biomes , 2008, Nature.

[154]  S. Salzberg,et al.  Microbial gene identification using interpolated Markov models. , 1998, Nucleic acids research.

[155]  J. Langdale,et al.  A step by step guide to phylogeny reconstruction. , 2006, The Plant journal : for cell and molecular biology.

[156]  J. A. Aas,et al.  Defining the Normal Bacterial Flora of the Oral Cavity , 2005, Journal of Clinical Microbiology.

[157]  R. Sandberg,et al.  Capturing whole-genome characteristics in short sequences using a naïve Bayesian classifier. , 2001, Genome research.

[158]  Edward F. DeLong,et al.  Microbial community genomics in the ocean , 2005, Nature Reviews Microbiology.

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

[160]  Shigehiko Kanaya,et al.  Informatics for unveiling hidden genome signatures. , 2003, Genome research.

[161]  J. Tiedje,et al.  Naïve Bayesian Classifier for Rapid Assignment of rRNA Sequences into the New Bacterial Taxonomy , 2007, Applied and Environmental Microbiology.

[162]  Daniel H. Huson,et al.  MetaSim—A Sequencing Simulator for Genomics and Metagenomics , 2008, PloS one.

[163]  Christian Posse,et al.  Bioinformatic insights from metagenomics through visualization , 2005, 2005 IEEE Computational Systems Bioinformatics Conference (CSB'05).

[164]  David Haussler,et al.  A Generalized Hidden Markov Model for the Recognition of Human Genes in DNA , 1996, ISMB.

[165]  Jan O. Korbel,et al.  Quantifying environmental adaptation of metabolic pathways in metagenomics , 2009, Proceedings of the National Academy of Sciences.

[166]  A. O'donnell,et al.  16S rDNA methods in soil microbiology , 1999, Current opinion in biotechnology.

[167]  Anna Tramontano,et al.  An analysis of the Sargasso Sea resource and the consequences for database composition , 2006, BMC Bioinformatics.

[168]  F. Valafar Pattern Recognition Techniques in Microarray Data Analysis , 2002 .

[169]  S. Batzoglou,et al.  Bacterial flora-typing with targeted, chip-based Pyrosequencing , 2007, BMC Microbiology.

[170]  R. Knight,et al.  The Human Microbiome Project , 2007, Nature.

[171]  W. S. Silver Microbial ecology. , 1967, Science.

[172]  V. Saunders,et al.  Assessing the Potential of Bacterial DNA Profiling for Forensic Soil Comparisons * , 2006, Journal of forensic sciences.

[173]  D. Pearl,et al.  Estimation of Evolutionary Parameters with Phylogenetic Trees , 2002, Journal of Molecular Evolution.

[174]  Bioterrorism. Scientists seek answers, ponder future after anthrax case suicide. , 2008, Science.