The genomics of emerging pathogens.

Globalization and industrialization have dramatically altered the vulnerability of human and animal populations to emerging and reemerging infectious diseases while shifting both the scale and pace of disease outbreaks. Fortunately, the advent of high-throughput DNA sequencing platforms has also increased the speed with which such pathogens can be detected and characterized as part of an outbreak response effort. It is now possible to sequence the genome of a pathogen rapidly, inexpensively, and with high sensitivity, transforming the fields of diagnostics, surveillance, forensic analysis, and pathogenesis. Here, we review advances in methods for microbial discovery and characterization, as well as strategies for testing the clinical and public health significance of microbe-disease associations. Finally, we discuss how genetic data can inform our understanding of the general process of pathogen emergence.

[1]  Thijs Kuiken,et al.  H5N1 Virus Attachment to Lower Respiratory Tract , 2006, Science.

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

[3]  P. Froussard.  A random-PCR method (rPCR) to construct whole cDNA library from low amounts of RNA. , 1992, Nucleic acids research.

[4]  Rachel L. Marine,et al.  High Variety of Known and New RNA and DNA Viruses of Diverse Origins in Untreated Sewage , 2012, Journal of Virology.

[5]  R. Koch.  Über bakteriologische Forschung , 2010 .

[6]  Yuriy Fofanov,et al.  PIQA: pipeline for Illumina G1 genome analyzer data quality assessment , 2009, Bioinform..

[7]  E. Holmes,et al.  A single positively selected West Nile viral mutation confers increased virogenesis in American crows , 2007, Nature Genetics.

[8]  S Falkow,et al.  Molecular Koch's postulates applied to microbial pathogenicity. , 1988, Reviews of infectious diseases.

[9]  M. Suchard,et al.  Molecular dating of human-to-bovid host jumps by Staphylococcus aureus reveals an association with the spread of domestication , 2012, Biology Letters.

[10]  M. Dunowska,et al.  Identification of a novel nidovirus associated with a neurological disease of the Australian brushtail possum (Trichosurus vulpecula) , 2011, Veterinary Microbiology.

[11]  M. Van Ranst,et al.  A Sequence-Independent Strategy for Detection and Cloning of Circular DNA Virus Genomes by Using Multiply Primed Rolling-Circle Amplification , 2004, Journal of Virology.

[12]  P. Kellam,et al.  Metagenomics and the molecular identification of novel viruses , 2010, The Veterinary Journal.

[13]  Corrie Brown,et al.  Emerging infections in animals—potential new zoonoses? , 2004, Clinics in Laboratory Medicine.

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

[15]  W. Lipkin,et al.  Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances , 2011, PloS one.

[16]  Theo M Bestebroer,et al.  A previously undescribed coronavirus associated with respiratory disease in humans. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[17]  R. Sharp,et al.  The role of patient advocacy organizations in shaping genomic science. , 2013, Annual review of genomics and human genetics.

[18]  Mark A. Miller,et al.  The genesis and spread of reassortment human influenza A/H3N2 viruses conferring adamantane resistance. , 2007, Molecular biology and evolution.

[19]  David P. Mindell,et al.  Molecular evidence of HIV-1 transmission in a criminal case , 2002, Proceedings of the National Academy of Sciences of the United States of America.

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

[21]  L. Heyndrickx,et al.  Isolation and partial characterization of an unusual human immunodeficiency retrovirus from two persons of west-central African origin , 1990, Journal of virology.

[22]  S. Tringe,et al.  Validation of two ribosomal RNA removal methods for microbial metatranscriptomics , 2010, Nature Methods.

[23]  Z. Stamataki,et al.  In Vitro Systems for the Study of Hepatitis C Virus Infection , 2012, International journal of hepatology.

[24]  Robert A. Edwards,et al.  Quality control and preprocessing of metagenomic datasets , 2011, Bioinform..

[25]  A. Rambaut,et al.  Episodic Sexual Transmission of HIV Revealed by Molecular Phylodynamics , 2008, PLoS medicine.

[26]  B. Eaton,et al.  Bats, Civets and the Emergence of SARS , 2007, Current topics in microbiology and immunology.

[27]  B. Hanson,et al.  Emerging swine zoonoses. , 2011, Vector borne and zoonotic diseases.

[28]  K. Kupferschmidt.  Infectious diseases. As E. coli outbreak recedes, new questions come to the fore. , 2011, Science.

[29]  M. Woldemeskel,et al.  An Outbreak of Marek's Disease in Chickens in Central Ethiopia , 2004, Tropical Animal Health and Production.

[30]  P. Daszak,et al.  Henipaviruses: Emerging Paramyxoviruses Associated with Fruit Bats , 2007, Current topics in microbiology and immunology.

[31]  S. Higgs,et al.  A Single Mutation in Chikungunya Virus Affects Vector Specificity and Epidemic Potential , 2007, PLoS pathogens.

[32]  H. Okamoto.  History of discoveries and pathogenicity of TT viruses. , 2009, Current topics in microbiology and immunology.

[33]  Kate E. Jones,et al.  Global trends in emerging infectious diseases , 2008, Nature.

[34]  Kenneth D. Mandl,et al.  HealthMap: Global Infectious Disease Monitoring through Automated Classification and Visualization of Internet Media Reports , 2008, Journal of the American Medical Informatics Association.

[35]  Atila Iamarino,et al.  Phylogeographic Analysis of HIV-1 Subtype C Dissemination in Southern Brazil , 2012, PloS one.

[36]  Christopher H Wade,et al.  Growing up in the genomic era: implications of whole-genome sequencing for children, families, and pediatric practice. , 2013, Annual review of genomics and human genetics.

[37]  J. Simons,et al.  A new arenavirus in a cluster of fatal transplant-associated diseases. , 2008, The New England journal of medicine.

[38]  J. Derisi,et al.  Identification of a Novel Gammaretrovirus in Prostate Tumors of Patients Homozygous for R462Q RNASEL Variant , 2006, PLoS pathogens.

[39]  Robert Schlaberg,et al.  Absence of echovirus sequences in brain and spinal cord of amyotrophic lateral sclerosis patients , 2001, Annals of neurology.

[40]  H. Margolis,et al.  Molecular Cloning and Disease Association of Hepatitis G Virus: A Transfusion-Transmissible Agent , 1996, Science.

[41]  J. Rothberg,et al.  Prospective Genomic Characterization of the German Enterohemorrhagic Escherichia coli O104:H4 Outbreak by Rapid Next Generation Sequencing Technology , 2011, PloS one.

[42]  J. Derisi,et al.  In-Depth Investigation of Archival and Prospectively Collected Samples Reveals No Evidence for XMRV Infection in Prostate Cancer , 2012, PloS one.

[43]  Lin Liu,et al.  Comparison of Next-Generation Sequencing Systems , 2012, Journal of biomedicine & biotechnology.

[44]  M. Milinkovitch,et al.  Phylogenetic Analyses Indicate an Atypical Nurse-to-Patient Transmission of Human Immunodeficiency Virus Type 1 , 2000, Journal of Virology.

[45]  E. Domingo,et al.  Cell Recognition by Foot-and-Mouth Disease Virus That Lacks the RGD Integrin-Binding Motif: Flexibility in Aphthovirus Receptor Usage , 2000, Journal of Virology.

[46]  T. Dallman,et al.  Performance comparison of benchtop high-throughput sequencing platforms , 2012, Nature Biotechnology.

[47]  E. Holmes,et al.  The Role of Evolutionary Intermediates in the Host Adaptation of Canine Parvovirus , 2011, Journal of Virology.

[48]  Jan Berka,et al.  A massively parallel PicoTiterPlate™ based platform for discrete picoliter‐scale polymerase chain reactions , 2003, Electrophoresis.

[49]  Jeffrey A Sparks,et al.  Communicating genetic risk information for common disorders in the era of genomic medicine. , 2013, Annual review of genomics and human genetics.

[50]  R. Edwards,et al.  Fast Identification and Removal of Sequence Contamination from Genomic and Metagenomic Datasets , 2011, PloS one.

[51]  E. Holmes,et al.  The molecular epidemiology of human immunodeficiency virus type 1 in Edinburgh. , 1995, The Journal of infectious diseases.

[52]  H. Bayley,et al.  Continuous base identification for single-molecule nanopore DNA sequencing. , 2009, Nature nanotechnology.

[53]  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.

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

[55]  Jeffery K. Taubenberger,et al.  Initial Genetic Characterization of the 1918 “Spanish” Influenza Virus , 1997, Science.

[56]  D. Bradley,et al.  Isolation of a cDNA from the virus responsible for enterically transmitted non-A, non-B hepatitis. , 1990, Science.

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

[58]  Jeremy M. Brown,et al.  Source identification in two criminal cases using phylogenetic analysis of HIV-1 DNA sequences , 2010, Proceedings of the National Academy of Sciences.

[59]  Simon Wessely,et al.  Comment on “Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome” , 2010 .

[60]  S. Weaver,et al.  Venezuelan encephalitis emergence mediated by a phylogenetically predicted viral mutation. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[61]  M E Woolhouse,et al.  Risk factors for human disease emergence. , 2001, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[62]  C. Chiu,et al.  Metagenomics for the discovery of novel human viruses. , 2010, Future microbiology.

[63]  N. Patel,et al.  Infection and Propagation of Human Rhinovirus C in Human Airway Epithelial Cells , 2012, Journal of Virology.

[64]  W. Lipkin.  Microbe Hunting , 2010, Microbiology and Molecular Biology Reviews.

[65]  Tulio de Oliveira,et al.  Molecular Epidemiology: HIV-1 and HCV sequences from Libyan outbreak , 2006, Nature.

[66]  Curtis A Suttle,et al.  Metagenomic Analysis of Coastal RNA Virus Communities , 2006, Science.

[67]  E. Holmes,et al.  Role of Multiple Hosts in the Cross-Species Transmission and Emergence of a Pandemic Parvovirus , 2011, Journal of Virology.

[68]  Calvin M. Johnson,et al.  Transmission of Equine Influenza Virus to Dogs , 2005, Science.

[69]  Per Magnus,et al.  THE AUTISM BIRTH COHORT (ABC): A PARADIGM FOR GENE-ENVIRONMENT-TIMING RESEARCH , 2010, Molecular Psychiatry.

[70]  Guy Boivin,et al.  Generation and characterization of recombinant pandemic influenza A(H1N1) viruses resistant to neuraminidase inhibitors. , 2011, The Journal of infectious diseases.

[71]  P. Simmonds,et al.  New DNA Viruses Identified in Patients with Acute Viral Infection Syndrome , 2005, Journal of Virology.

[72]  J. Mullins,et al.  Molecular Epidemiology of HIV Transmission in a Dental Practice , 1992, Science.

[73]  Fang Li,et al.  Structural Analysis of Major Species Barriers between Humans and Palm Civets for Severe Acute Respiratory Syndrome Coronavirus Infections , 2008, Journal of Virology.

[74]  Yoshihiro Kawaoka,et al.  Molecular Basis for High Virulence of Hong Kong H5N1 Influenza A Viruses , 2001, Science.

[75]  C. Viboud,et al.  Explorer The genomic and epidemiological dynamics of human influenza A virus , 2016 .

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

[77]  F. Rohwer,et al.  Metagenomics and future perspectives in virus discovery , 2012, Current Opinion in Virology.

[78]  L. Wain,et al.  Chimpanzee Reservoirs of Pandemic and Nonpandemic HIV-1 , 2006, Science.

[79]  John C. Wooley,et al.  A Primer on Metagenomics , 2010, PLoS Comput. Biol..

[80]  R. Baric,et al.  Mechanisms of Zoonotic Severe Acute Respiratory Syndrome Coronavirus Host Range Expansion in Human Airway Epithelium , 2007, Journal of Virology.

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

[82]  F. Robbins,et al.  Cultivation of the Lansing Strain of Poliomyelitis Virus in Cultures of Various Human Embryonic Tissues. , 1949, Science.

[83]  P. Simmonds,et al.  Analysis of the entire genomes of torque teno midi virus variants in chimpanzees: infrequent cross-species infection between humans and chimpanzees. , 2009, The Journal of general virology.

[84]  Huldrych F. Günthard,et al.  Inferring Epidemic Contact Structure from Phylogenetic Trees , 2012, PLoS Comput. Biol..

[85]  H. Ambrose,et al.  Virus discovery by sequence‐independent genome amplification , 2006, Reviews in medical virology.

[86]  Louise V Wain,et al.  Adaptation of HIV-1 to its human host. , 2007, Molecular biology and evolution.

[87]  G. Tabor,et al.  Global Factors Driving Emerging Infectious Diseases , 2008, Annals of the New York Academy of Sciences.

[88]  M. Egholm,et al.  Human Metapneumovirus Infection in Wild Mountain Gorillas, Rwanda , 2011, Emerging infectious diseases.

[89]  F. Brun-Vézinet,et al.  Identification of a new human immunodeficiency virus type 1 distinct from group M and group O , 1998, Nature Medicine.

[90]  P. Zhou,et al.  Metagenomic Analysis of Viruses from Bat Fecal Samples Reveals Many Novel Viruses in Insectivorous Bats in China , 2012, Journal of Virology.

[91]  E. Wimmer,et al.  Synthetic viruses: a new opportunity to understand and prevent viral disease , 2009, Nature Biotechnology.

[92]  Andrew Rambaut,et al.  Reconstructing the initial global spread of a human influenza pandemic , 2017 .

[93]  S. Ikegawa.  The genetics of common degenerative skeletal disorders: osteoarthritis and degenerative disc disease. , 2013, Annual review of genomics and human genetics.

[94]  W. Ian Lipkin,et al.  Genetic Detection and Characterization of Lujo Virus, a New Hemorrhagic Fever–Associated Arenavirus from Southern Africa , 2009, PLoS pathogens.

[95]  E. Domingo,et al.  RNA virus mutations and fitness for survival. , 1997, Annual review of microbiology.

[96]  B. Thiers,et al.  Clonal Integration of a Polyomavirus in Human Merkel Cell Carcinoma , 2009 .

[97]  Andreas Nitsche,et al.  Pandemic Human Viruses Cause Decline of Endangered Great Apes , 2008, Current Biology.

[98]  Yi Guan,et al.  Temporally structured metapopulation dynamics and persistence of influenza A H3N2 virus in humans , 2011, Proceedings of the National Academy of Sciences.

[99]  L. H. Taylor,et al.  Diseases of humans and their domestic mammals: pathogen characteristics, host range and the risk of emergence. , 2001, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[100]  M. Feltkamp,et al.  Discovery of a New Human Polyomavirus Associated with Trichodysplasia Spinulosa in an Immunocompromized Patient , 2010, PLoS pathogens.

[101]  J. A. Comer,et al.  A novel coronavirus associated with severe acute respiratory syndrome. , 2003, The New England journal of medicine.

[102]  Theo M Bestebroer,et al.  Airborne Transmission of Influenza A/H5N1 Virus Between Ferrets , 2012, Science.

[103]  D. Relman,et al.  Sequence-based identification of microbial pathogens: a reconsideration of Koch's postulates , 1996, Clinical microbiology reviews.

[104]  N. Howard-Jones,et al.  Robert Koch and the cholera vibrio: a centenary. , 1984, British medical journal.

[105]  Yasuhiro Yoshikawa,et al.  Bat Coronaviruses and Experimental Infection of Bats, the Philippines , 2010, Emerging infectious diseases.

[106]  A. Rambaut,et al.  The emergence of HIV/AIDS in the Americas and beyond , 2007, Proceedings of the National Academy of Sciences.

[107]  Kamil Khanipov,et al.  Slim-Filter: an interactive windows-based application for illumina genome analyzer data assessment and manipulation , 2012, BMC Bioinformatics.

[108]  Guo-Ping Zhao,et al.  Cross-host evolution of severe acute respiratory syndrome coronavirus in palm civet and human. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[109]  T. Rose,et al.  Detection and analysis of diverse herpesviral species by consensus primer PCR , 1996, Journal of clinical microbiology.

[110]  M. Kieny,et al.  The 2009 A (H1N1) influenza virus pandemic: A review. , 2010, Vaccine.

[111]  M. Mazzocchi,et al.  Impact of Bovine Spongiform Encephalopathy on Agribusiness in the United Kingdom: Results of an Event Study of Equity Prices , 2002 .

[112]  K. Holmes,et al.  Blinded Case‐Control Study of the Relationship between Human Coronavirus NL63 and Kawasaki Syndrome , 2006, The Journal of infectious diseases.

[113]  Junhua Li,et al.  Open-source genomic analysis of Shiga-toxin-producing E. coli O104:H4. , 2011, The New England journal of medicine.

[114]  Rithy K. Roth,et al.  Gene expression analysis by massively parallel signature sequencing (MPSS) on microbead arrays , 2000, Nature Biotechnology.

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

[116]  Mark E.J. Woolhouse,et al.  Host Range and Emerging and Reemerging Pathogens , 2005, Emerging infectious diseases.

[117]  M. Metzker.  Sequencing technologies — the next generation , 2010, Nature Reviews Genetics.

[118]  K. Kupferschmidt.  Germany. Scientists rush to study genome of lethal E. coli. , 2011, Science.

[119]  T. Sittler,et al.  A Novel Rhabdovirus Associated with Acute Hemorrhagic Fever in Central Africa , 2012, PLoS pathogens.

[120]  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.

[121]  T. Briese,et al.  Identification of a Kunjin/West Nile-like flavivirus in brains of patients with New York encephalitis , 1999, The Lancet.

[122]  Eric Mykhalovskiy,et al.  The Global Public Health Intelligence Network and early warning outbreak detection: a Canadian contribution to global public health. , 2006, Canadian journal of public health = Revue canadienne de sante publique.

[123]  M. Woolhouse,et al.  Emerging pathogens: the epidemiology and evolution of species jumps , 2005, Trends in Ecology & Evolution.

[124]  H. Kraemer,et al.  Absence of evidence for bornavirus infection in schizophrenia, bipolar disorder and major depressive disorder , 2012, Molecular Psychiatry.

[125]  C. Rice,et al.  Characterization of a canine homolog of hepatitis C virus , 2011, Proceedings of the National Academy of Sciences.

[126]  M. Gottschling,et al.  Genomic characterization of ten novel cutaneous human papillomaviruses from keratotic lesions of immunosuppressed patients. , 2011, The Journal of general virology.

[127]  Alain Blanchard,et al.  Molecular Evidence for Nosocomial Transmission of Human Immunodeficiency Virus from a Surgeon to One of His Patients , 1998, Journal of Virology.

[128]  P. Eckburg,et al.  Human monkeypox: an emerging zoonosis , 2004, The Lancet. Infectious diseases.

[129]  J. Huelsenbeck,et al.  Support for dental HIV transmission , 1994, Nature.

[130]  S. Ritchie,et al.  Ecology and geographical expansion of Japanese encephalitis virus. , 2009, Annual review of entomology.

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

[132]  I. Clarke,et al.  Cloning of noncultivatable human rotavirus by single primer amplification , 1992, Journal of virology.

[133]  John P A Ioannidis,et al.  The power of meta-analysis in genome-wide association studies. , 2013, Annual review of genomics and human genetics.

[134]  Hideaki Tanaka,et al.  MetaVelvet: an extension of Velvet assembler to de novo metagenome assembly from short sequence reads , 2011, BCB '11.

[135]  E. Delwart,et al.  From orphan virus to pathogen: the path to the clinical lab. , 2011, Current opinion in virology.

[136]  N. W. Davis,et al.  The complete genome sequence of Escherichia coli K-12. , 1997, Science.

[137]  W. Heneine,et al.  A Multicenter Blinded Analysis Indicates No Association between Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and either Xenotropic Murine Leukemia Virus-Related Virus or Polytropic Murine Leukemia Virus , 2012, mBio.

[138]  L. H. Taylor,et al.  Overviews of Pathogen Emergence: Which Pathogens Emerge, When and Why? , 2007, Current topics in microbiology and immunology.

[139]  L. Finelli,et al.  Emergence of a novel swine-origin influenza A (H1N1) virus in humans. , 2009, The New England journal of medicine.

[140]  Forest Rohwer,et al.  Laboratory procedures to generate viral metagenomes , 2009, Nature Protocols.

[141]  E. Delwart,et al.  Rapidly expanding genetic diversity and host range of the Circoviridae viral family and other Rep encoding small circular ssDNA genomes. , 2012, Virus research.

[142]  L. Madoff.  ProMED-mail: an early warning system for emerging diseases. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[143]  X. de Lamballerie,et al.  A real-time RT-PCR method for the universal detection and identification of flaviviruses. , 2007, Vector borne and zoonotic diseases.

[144]  Timothy B. Stockwell,et al.  Migratory flyway and geographical distance are barriers to the gene flow of influenza virus among North American birds. , 2012, Ecology letters.

[145]  B. Mahy,et al.  The Evolution and Emergence of RNA Viruses , 2010, Emerging Infectious Diseases.

[146]  A. Evans.  Causation and Disease: The Henle-Koch Postulates Revisited 1 , 1976, The Yale journal of biology and medicine.

[147]  P. Sharp,et al.  AIDS as a zoonosis: scientific and public health implications. , 2000, Science.

[148]  Jian Ye,et al.  BLAST: improvements for better sequence analysis , 2006, Nucleic Acids Res..

[149]  F. Collins,et al.  Benefits and Risks of Influenza Research: Lessons Learned , 2012, Science.

[150]  Forrest W. Crawford,et al.  Unifying the spatial epidemiology and molecular evolution of emerging epidemics , 2012, Proceedings of the National Academy of Sciences.

[151]  J. Derisi,et al.  Recovery of divergent avian bornaviruses from cases of proventricular dilatation disease: Identification of a candidate etiologic agent , 2008, Virology Journal.

[152]  P. Lemey,et al.  Molecular testing of multiple HIV-1 transmissions in a criminal case , 2005, AIDS (London).

[153]  Evan S Snitkin,et al.  Tracking a Hospital Outbreak of Carbapenem-Resistant Klebsiella pneumoniae with Whole-Genome Sequencing , 2012, Science Translational Medicine.

[154]  S. Turner,et al.  Real-time DNA sequencing from single polymerase molecules. , 2010, Methods in enzymology.

[155]  J. Mikovits,et al.  Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome , 2009, Science.

[156]  James M. Eldred,et al.  Viral Discovery and Sequence Recovery Using DNA Microarrays , 2003, PLoS biology.

[157]  Charles H. Calisher,et al.  Cross-Species Virus Transmission and the Emergence of New Epidemic Diseases , 2008, Microbiology and Molecular Biology Reviews.

[158]  Gavin J. D. Smith,et al.  Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic , 2009, Nature.

[159]  M. Rowland,et al.  Economic costs of the foot and mouth disease outbreak in the United Kingdom in 2001. , 2002, Revue scientifique et technique.

[160]  Z. Fu,et al.  Rabies virus quasispecies: implications for pathogenesis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[161]  Y. Guan,et al.  Prevalence and Genetic Diversity of Coronaviruses in Bats from China , 2006, Journal of Virology.

[162]  Ronald W. Davis,et al.  Quantitative Monitoring of Gene Expression Patterns with a Complementary DNA Microarray , 1995, Science.

[163]  David Baltimore,et al.  Permissive Secondary Mutations Enable the Evolution of Influenza Oseltamivir Resistance , 2010, Science.

[164]  M. Uhlén,et al.  Accurate reconstruction of a known HIV-1 transmission history by phylogenetic tree analysis. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[165]  T. Rivers.  Viruses and Koch's Postulates , 1937, Journal of bacteriology.