Title Comparative genomics of the major fungal agents of human and animal Sporotrichosis : Sporothrix schenckii and Sporothrix brasiliensis Permalink

Background: The fungal genus Sporothrix includes at least four human pathogenic species. One of these species, S. brasiliensis, is the causal agent of a major ongoing zoonotic outbreak of sporotrichosis in Brazil. Elsewhere, sapronoses are caused by S. schenckii and S. globosa. The major aims on this comparative genomic study are: 1) to explore the presence of virulence factors in S. schenckii and S. brasiliensis; 2) to compare S. brasiliensis, which is cat-transmitted and infects both humans and cats with S. schenckii, mainly a human pathogen; 3) to compare these two species to other human pathogens (Onygenales) with similar thermo-dimorphic behavior and to other plant-associated Sordariomycetes. Results: The genomes of S. schenckii and S. brasiliensis were pyrosequenced to 17x and 20x coverage comprising a total of 32.3 Mb and 33.2 Mb, respectively. Pair-wise genome alignments revealed that the two species are highly syntenic showing 97.5% average sequence identity. Phylogenomic analysis reveals that both species diverged about 3.8-4.9 MYA suggesting a recent event of speciation. Transposable elements comprise respectively 0.34% and 0.62% of the S. schenckii and S. brasiliensis genomes and expansions of Gypsy-like elements was observed reflecting the accumulation of repetitive elements in the S. brasiliensis genome. Mitochondrial genomic comparisons showed the presence of group-I intron encoding homing endonucleases (HE’s) exclusively in S. brasiliensis. Analysis of protein family expansions and contractions in the Sporothrix lineage revealed expansion of LysM domain-containing proteins, small GTPases, PKS type1 and leucin-rich proteins. In contrast, a lack of polysaccharide lyase genes that are associated with decay of plants was observed when compared to other Sordariomycetes and dimorphic fungal pathogens, suggesting evolutionary adaptations from a plant pathogenic or saprobic to an animal pathogenic life style. (Continued on next page) * Correspondence: msueliunb@gmail.com Departamento de Biologia Celular, Universidade de Brasília, Brasília, DF, Brazil Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília, DF, Brazil Full list of author information is available at the end of the article © 2014 Teixeira et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Teixeira et al. BMC Genomics 2014, 15:943 Page 2 of 22 http://www.biomedcentral.com/1471-2164/15/943 (Continued from previous page) Conclusions: Comparative genomic data suggest a unique ecological shift in the Sporothrix lineage from plantassociation to mammalian parasitism, which contributes to the understanding of how environmental interactions may shape fungal virulence. . Moreover, the striking differences found in comparison with other dimorphic fungi revealed that dimorphism in these close relatives of plant-associated Sordariomycetes is a case of convergent evolution, stressing the importance of this morphogenetic change in fungal pathogenesis.

[1]  W. de Souza,et al.  Differences in Cell Morphometry, Cell Wall Topography and Gp70 Expression Correlate with the Virulence of Sporothrix brasiliensis Clinical Isolates , 2013, PloS one.

[2]  S. de Hoog,et al.  Emergence of pathogenicity in the Sporothrix schenckii complex. , 2013, Medical mycology.

[3]  P. Mieczkowski,et al.  Global analyses of Ceratocystis cacaofunesta mitochondria: from genome to proteome , 2013, BMC Genomics.

[4]  C. Gil,et al.  Differential proteomic analysis of Aspergillus fumigatus morphotypes reveals putative drug targets. , 2013, Journal of proteomics.

[5]  C. Specht,et al.  Innate Sensing of Chitin and Chitosan , 2013, PLoS pathogens.

[6]  J. Heitman,et al.  Evolution of fungal sexual reproduction , 2013, Mycologia.

[7]  W. Nierman,et al.  Sequencing of mitochondrial genomes of nine Aspergillus and Penicillium species identifies mobile introns and accessory genes as main sources of genome size variability , 2012, BMC Genomics.

[8]  Robert D. Finn,et al.  Dfam: a database of repetitive DNA based on profile hidden Markov models , 2012, Nucleic Acids Res..

[9]  J. Nosanchuk,et al.  Biosynthesis and Functions of a Melanoid Pigment Produced by Species of the Sporothrix Complex in the Presence of l-Tyrosine , 2012, Applied and Environmental Microbiology.

[10]  Christina A. Cuomo,et al.  Comparative Genome Analysis of Trichophyton rubrum and Related Dermatophytes Reveals Candidate Genes Involved in Infection , 2012, mBio.

[11]  Liyuan Liu,et al.  Comparative Analysis of the Genomes of Two Field Isolates of the Rice Blast Fungus Magnaporthe oryzae , 2012, PLoS genetics.

[12]  P. de Knijff,et al.  Transposon proliferation in an asexual parasitoid. , 2012, Molecular ecology.

[13]  C. Munro,et al.  Isolation and functional characterization of Sporothrix schenckii ROT2, the encoding gene for the endoplasmic reticulum glucosidase II. , 2012, Fungal biology.

[14]  Gagandeep Singh,et al.  Sporotrichosis in Sub-Himalayan India , 2012, PLoS neglected tropical diseases.

[15]  M. Felipe,et al.  Genus Paracoccidioides: Species Recognition and Biogeographic Aspects , 2012, PloS one.

[16]  A. Ralph,et al.  Sporotrichosis (Sporothrix schenckii infection) in the New South Wales mid‐north coast, 2000–2010 , 2012, The Medical journal of Australia.

[17]  K. Ferreira-Paim,et al.  Disseminated Sporothrix brasiliensis infection with endocardial and ocular involvement in an HIV-infected patient. , 2012, The American journal of tropical medicine and hygiene.

[18]  B. Brandt,et al.  ProFASTA: a pipeline web server for fungal protein scanning with integration of cell surface prediction software. , 2012, Fungal genetics and biology : FG & B.

[19]  Alexander D. Johnson,et al.  A Conserved Transcriptional Regulator Governs Fungal Morphology in Widely Diverged Species , 2012, Genetics.

[20]  A. Casadevall,et al.  Synthesis and assembly of fungal melanin , 2012, Applied Microbiology and Biotechnology.

[21]  A. Valencia,et al.  The Ras protein superfamily: Evolutionary tree and role of conserved amino acids , 2012, The Journal of cell biology.

[22]  M. Hood,et al.  Patterns of Repeat-Induced Point Mutation in Transposable Elements of Basidiomycete Fungi , 2012, Genome biology and evolution.

[23]  J. Glushka,et al.  Biosynthesis of UDP-4-keto-6-deoxyglucose and UDP-rhamnose in Pathogenic Fungi Magnaporthe grisea and Botryotinia fuckeliana* , 2011, The Journal of Biological Chemistry.

[24]  Leila M. Lopes-Bezerra Sporothrix schenckii Cell Wall Peptidorhamnomannans , 2011, Front. Microbio..

[25]  Christina A. Cuomo,et al.  Comparative Genomic Analysis of Human Fungal Pathogens Causing Paracoccidioidomycosis , 2011, PLoS genetics.

[26]  Bernard Henrissat,et al.  Genomic Analysis of the Necrotrophic Fungal Pathogens Sclerotinia sclerotiorum and Botrytis cinerea , 2011, PLoS genetics.

[27]  R. Zancopé-Oliveira,et al.  Phenotypic and Molecular Identification of Sporothrix Isolates from an Epidemic Area of Sporotrichosis in Brazil , 2011, Mycopathologia.

[28]  Shanshan Li,et al.  Infant sporotrichosis in northeast China: a report of 15 cases , 2011, International journal of dermatology.

[29]  A. Salamov,et al.  Comparative genome sequence analysis underscores mycoparasitism as the ancestral life style of Trichoderma , 2011, Genome Biology.

[30]  Srinivasan Ramachandran,et al.  FungalRV: adhesin prediction and immunoinformatics portal for human fungal pathogens , 2011, BMC Genomics.

[31]  M. Netea,et al.  Recognition and Blocking of Innate Immunity Cells by Candida albicans Chitin , 2011, Infection and Immunity.

[32]  R. Rupec,et al.  Chitin Modulates Innate Immune Responses of Keratinocytes , 2011, PloS one.

[33]  B. Ma,et al.  Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury. , 2011, Annual review of physiology.

[34]  Steven J. M. Jones,et al.  Genome and transcriptome analyses of the mountain pine beetle-fungal symbiont Grosmannia clavigera, a lodgepole pine pathogen , 2011, Proceedings of the National Academy of Sciences.

[35]  Narmada Thanki,et al.  CDD: a Conserved Domain Database for the functional annotation of proteins , 2010, Nucleic Acids Res..

[36]  José M. Sempere,et al.  The Gypsy Database (GyDB) of mobile genetic elements: release 2.0 , 2010, Nucleic Acids Res..

[37]  N. Talbot,et al.  Comparative Genome Analysis Reveals an Absence of Leucine-Rich Repeat Pattern-Recognition Receptor Proteins in the Kingdom Fungi , 2010, PloS one.

[38]  J. Régnière,et al.  Climate Change and Bark Beetles of the Western United States and Canada: Direct and Indirect Effects , 2010 .

[39]  J. Vederas,et al.  Biosynthesis of lovastatin and related metabolites formed by fungal iterative PKS enzymes. , 2010, Biopolymers.

[40]  Bart P. H. J. Thomma,et al.  Conserved Fungal LysM Effector Ecp6 Prevents Chitin-Triggered Immunity in Plants , 2010, Science.

[41]  N. Gow,et al.  Chitin synthesis and fungal pathogenesis , 2010, Current opinion in microbiology.

[42]  S. Rozental,et al.  L-DOPA accessibility in culture medium increases melanin expression and virulence of Sporothrix schenckii yeast cells. , 2010, Medical mycology.

[43]  J. Latgé Tasting the fungal cell wall , 2010, Cellular microbiology.

[44]  H. Mora-Montes,et al.  Biochemical characterization of Candida albicans α-glucosidase I heterologously expressed in Escherichia coli , 2010, Antonie van Leeuwenhoek.

[45]  H. Mora-Montes,et al.  Purification and biochemical characterisation of endoplasmic reticulum alpha1,2-mannosidase from Sporothrix schenckiil. , 2010, Memorias do Instituto Oswaldo Cruz.

[46]  R. Lücking,et al.  Fungi evolved right on track , 2009, Mycologia.

[47]  S. R. de Almeida,et al.  Cell surface expression of adhesins for fibronectin correlates with virulence in Sporothrix schenckii. , 2009, Microbiology.

[48]  G. Hausner,et al.  Genes within genes: multiple LAGLIDADG homing endonucleases target the ribosomal protein S3 gene encoded within an rnl group I intron of Ophiostoma and related taxa. , 2009, Molecular biology and evolution.

[49]  Jason E Stajich,et al.  Comparative genomic analyses of the human fungal pathogens Coccidioides and their relatives. , 2009, Genome research.

[50]  G. Niño-Vega,et al.  Transcription levels of CHS5 and CHS4 genes in Paracoccidioides brasiliensis mycelial phase, respond to alterations in external osmolarity, oxidative stress and glucose concentration. , 2009, Mycological research.

[51]  Marie-Adèle Rajandream,et al.  Comparative genomics of the fungal pathogens Candida dubliniensis and Candida albicans. , 2009, Genome research.

[52]  J. Stringer,et al.  Common strategies for antigenic variation by bacterial, fungal and protozoan pathogens , 2009, Nature Reviews Microbiology.

[53]  Toni Gabaldón,et al.  trimAl: a tool for automated alignment trimming in large-scale phylogenetic analyses , 2009, Bioinform..

[54]  J. Nosanchuk,et al.  Growth conditions influence melanization of Brazilian clinical Sporothrix schenckii isolates. , 2009, Microbes and infection.

[55]  E. López-Romero,et al.  Isolation and some properties of a glycoprotein of 70 kDa (Gp70) from the cell wall of Sporothrix schenckii involved in fungal adherence to dermal extracellular matrix. , 2009, Medical mycology.

[56]  D. Sanders,et al.  Aspergillus nidulans UDP-galactopyranose mutase, encoded by ugmA plays key roles in colony growth, hyphal morphogenesis, and conidiation. , 2008, Fungal genetics and biology : FG & B.

[57]  Brandi L. Cantarel,et al.  The Carbohydrate-Active EnZymes database (CAZy): an expert resource for Glycogenomics , 2008, Nucleic Acids Res..

[58]  A. Casadevall,et al.  Vesicular transport in Histoplasma capsulatum: an effective mechanism for trans‐cell wall transfer of proteins and lipids in ascomycetes , 2008, Cellular microbiology.

[59]  M. Wingfield,et al.  Taxonomy and phylogeny of new wood- and soil-inhabiting Sporothrix species in the Ophiostoma stenoceras-Sporothrix schenckii complex , 2008, Mycologia.

[60]  A. Sil,et al.  Temperature-induced switch to the pathogenic yeast form of Histoplasma capsulatum requires Ryp1, a conserved transcriptional regulator , 2008, Proceedings of the National Academy of Sciences.

[61]  Jonathan E. Allen,et al.  Automated eukaryotic gene structure annotation using EVidenceModeler and the Program to Assemble Spliced Alignments , 2007, Genome Biology.

[62]  J. Bennetzen,et al.  A unified classification system for eukaryotic transposable elements , 2007, Nature Reviews Genetics.

[63]  A. Casadevall,et al.  Extracellular Vesicles Produced by Cryptococcus neoformans Contain Protein Components Associated with Virulence , 2007, Eukaryotic Cell.

[64]  M. Roncero,et al.  ChsVb, a Class VII Chitin Synthase Involved in Septation, Is Critical for Pathogenicity in Fusarium oxysporum , 2007, Eukaryotic Cell.

[65]  J. Latgé The cell wall: a carbohydrate armour for the fungal cell , 2007, Molecular microbiology.

[66]  Christina A. Cuomo,et al.  The Fusarium graminearum Genome Reveals a Link Between Localized Polymorphism and Pathogen Specialization , 2007, Science.

[67]  J. Guarro,et al.  Sporothrix brasiliensis, S. globosa, and S. mexicana, Three New Sporothrix Species of Clinical Interest , 2007, Journal of Clinical Microbiology.

[68]  B. Klein,et al.  Dimorphism and virulence in fungi. , 2007, Current opinion in microbiology.

[69]  D. Speers,et al.  Outbreak of Sporotrichosis, Western Australia , 2007, Emerging infectious diseases.

[70]  Y. Ohsumi,et al.  Molecular machinery of autophagosome formation in yeast, Saccharomyces cerevisiae , 2007, FEBS letters.

[71]  S. Kroken,et al.  Coccidioides posadasii contains single chitin synthase genes corresponding to classes I to VII. , 2006, Fungal genetics and biology : FG & B.

[72]  A. Casadevall,et al.  Impact of Melanin on Microbial Virulence and Clinical Resistance to Antimicrobial Compounds , 2006, Antimicrobial Agents and Chemotherapy.

[73]  M. Berbee,et al.  Dating divergences in the Fungal Tree of Life: review and new analyses. , 2006, Mycologia.

[74]  B. Charlesworth,et al.  The Fate of Transposable Elements in Asexual Populations , 2006, Genetics.

[75]  W. Goldman,et al.  Defining virulence genes in the dimorphic fungi. , 2006, Annual review of microbiology.

[76]  M. Wüthrich,et al.  Global Control of Dimorphism and Virulence in Fungi , 2006, Science.

[77]  Dannie Durand,et al.  A hybrid micro-macroevolutionary approach to gene tree reconstruction. , 2006 .

[78]  A. Ohta,et al.  Aspergillus nidulans class V and VI chitin synthases CsmA and CsmB, each with a myosin motor‐like domain, perform compensatory functions that are essential for hyphal tip growth , 2006, Molecular microbiology.

[79]  L. Lopes-Bezerra,et al.  Sporothrix schenckii and sporotrichosis. , 2006, Anais da Academia Brasileira de Ciencias.

[80]  J. Bennett,et al.  Fungal secondary metabolism — from biochemistry to genomics , 2005, Nature Reviews Microbiology.

[81]  David M. A. Martin,et al.  The Genome of the African Trypanosome Trypanosoma brucei , 2005, Science.

[82]  J. Jurka,et al.  Repbase Update, a database of eukaryotic repetitive elements , 2005, Cytogenetic and Genome Research.

[83]  David Posada,et al.  ProtTest: selection of best-fit models of protein evolution , 2005, Bioinform..

[84]  Thomas Ludwig,et al.  RAxML-III: a fast program for maximum likelihood-based inference of large phylogenetic trees , 2005, Bioinform..

[85]  Ewan Birney,et al.  Automated generation of heuristics for biological sequence comparison , 2005, BMC Bioinformatics.

[86]  Ana Tereza Ribeiro de Vasconcelos,et al.  A System for Automated Bacterial (genome) Integrated Annotation - SABIA , 2004, Bioinform..

[87]  C. Nombela,et al.  Fungal cell wall biogenesis: building a dynamic interface with the environment. , 2004, Microbiology.

[88]  F. Blattner,et al.  Mauve: multiple alignment of conserved genomic sequence with rearrangements. , 2004, Genome research.

[89]  Ian Korf,et al.  Gene finding in novel genomes , 2004, BMC Bioinformatics.

[90]  M. Bar-Peled,et al.  A Bifunctional 3,5-Epimerase/4-Keto Reductase for Nucleotide-Rhamnose Synthesis in Arabidopsis1 , 2004, Plant Physiology.

[91]  F. Eisenhaber,et al.  A sensitive predictor for potential GPI lipid modification sites in fungal protein sequences and its application to genome-wide studies for Aspergillus nidulans, Candida albicans, Neurospora crassa, Saccharomyces cerevisiae and Schizosaccharomyces pombe. , 2004, Journal of molecular biology.

[92]  S. Kroken,et al.  Phylogenomic analysis of type I polyketide synthase genes in pathogenic and saprobic ascomycetes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[93]  P. Capy,et al.  Transposable elements in filamentous fungi. , 2003, Annual review of microbiology.

[94]  Mario Stanke,et al.  Gene prediction with a hidden Markov model and a new intron submodel , 2003, ECCB.

[95]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[96]  R. Hay,et al.  Synthesis of Melanin-Like Pigments by Sporothrix schenckii In Vitro and during Mammalian Infection , 2003, Infection and Immunity.

[97]  D. S. Reiner,et al.  Mining the Giardia lamblia Genome for New Cyst Wall Proteins* , 2003, Journal of Biological Chemistry.

[98]  M. Wingfield,et al.  Phylogeny of the Ophiostoma stenoceras–Sporothrix schenckii complex , 2003, Mycologia.

[99]  E. Mauceli,et al.  The genome sequence of the filamentous fungus Neurospora crassa , 2003, Nature.

[100]  Michael J. Sanderson,et al.  R8s: Inferring Absolute Rates of Molecular Evolution, Divergence times in the Absence of a Molecular Clock , 2003, Bioinform..

[101]  A. Ohta,et al.  csmA, a gene encoding a class V chitin synthase with a myosin motor-like domain of Aspergillus nidulans, is translated as a single polypeptide and regulated in response to osmotic conditions. , 2002, Biochemical and biophysical research communications.

[102]  K. Katoh,et al.  MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform. , 2002, Nucleic acids research.

[103]  E. Selker,et al.  A cytosine methyltransferase homologue is essential for repeat-induced point mutation in Neurospora crassa , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[104]  P. Stanley,et al.  Antibodies that recognize bisected complex N-glycans on cell surface glycoproteins can be made in mice lacking N-acetylglucosaminyltransferase III , 2002, Glycoconjugate Journal.

[105]  K. Madduri,et al.  Rhamnose Biosynthesis Pathway Supplies Precursors for Primary and Secondary Metabolism in Saccharopolyspora spinosa , 2001, Journal of bacteriology.

[106]  J. Browse,et al.  Production of Polyunsaturated Fatty Acids by Polyketide Synthases in Both Prokaryotes and Eukaryotes , 2001, Science.

[107]  C. Barja-Fidalgo,et al.  Virulence of Sporothrix schenckii conidia and yeast cells, and their susceptibility to nitric oxide , 2000, Immunology.

[108]  Kim Rutherford,et al.  Artemis: sequence visualization and annotation , 2000, Bioinform..

[109]  M. Wheeler,et al.  Biosynthesis and Functions of Melanin inSporothrix schenckii , 2000, Infection and Immunity.

[110]  J. Heitman,et al.  RAS1 regulates filamentation, mating and growth at high temperature of Cryptococcus neoformans , 2000, Molecular microbiology.

[111]  S. McCormick,et al.  TRI12, a trichothecene efflux pump from Fusarium sporotrichioides: gene isolation and expression in yeast , 1999, Molecular and General Genetics MGG.

[112]  K. Langfelder,et al.  Identification of a polyketide synthase gene (pksP) of Aspergillus fumigatus involved in conidial pigment biosynthesis and virulence , 1998, Medical Microbiology and Immunology.

[113]  J Schultz,et al.  SMART, a simple modular architecture research tool: identification of signaling domains. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[114]  R. Durbin,et al.  Pfam: A comprehensive database of protein domain families based on seed alignments , 1997, Proteins.

[115]  A. Yasui,et al.  Characterization of the alternative excision repair pathway of UV-damaged DNA in Schizosaccharomyces pombe. , 1997, Nucleic acids research.

[116]  B. Bowers,et al.  Identification of a Novel Giardia lamblia Cyst Wall Protein with Leucine-rich Repeats , 1995, The Journal of Biological Chemistry.

[117]  J. Thompson,et al.  CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. , 1994, Nucleic acids research.

[118]  L. Mendonça-Previato,et al.  O-Glycosidically linked oligosaccharides from peptidorhamnomannans ofSporothrix schenckii , 1992, Glycoconjugate Journal.

[119]  A. Lambowitz,et al.  Involvement of aminoacyl-tRNA synthetases and other proteins in group I and group II intron splicing. , 1990, Trends in biochemical sciences.

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

[121]  Kenneth L. McNally,et al.  The complete DNA sequence of the mitochondrial genome of Podospora anserina , 1990, Current Genetics.

[122]  B. Dujon,et al.  Group I introns as mobile genetic elements: facts and mechanistic speculations--a review. , 1989, Gene.

[123]  L. Travassos,et al.  Sialic acids are surface components of Sporothrix schenckii yeast forms , 1982 .

[124]  L. Travassos,et al.  Sporothrix schenckii and related species of Ceratocystis. , 1980, Microbiological reviews.

[125]  L. Travassos,et al.  Soluble and insoluble glucans from different cell types of the human pathogen , 1979 .

[126]  P. Gorin,et al.  Cell wall composition in different cell types of the dimorphic species Sporothrix schenckii , 1979 .

[127]  M. Felipe,et al.  Pulmonary cavitation and skin lesions mimicking tuberculosis in a HIV negative patient caused by Sporothrix brasiliensis. , 2013, Medical mycology case reports.

[128]  Fangliang Zheng,et al.  Molecular cloning, characterization and differential expression of DRK1 in Sporothrix schenckii. , 2013, International Journal of Molecular Medicine.

[129]  D. Drubin,et al.  Clathrin-mediated endocytosis in budding yeast. , 2012, Trends in cell biology.

[130]  H. Mora-Montes,et al.  Sporothrix schenckii complex and sporotrichosis, an emerging health problem. , 2011, Future microbiology.

[131]  O. Gascuel,et al.  Estimating maximum likelihood phylogenies with PhyML. , 2009, Methods in molecular biology.

[132]  P. Płonka,et al.  Melanin synthesis in microorganisms--biotechnological and medical aspects. , 2006, Acta biochimica Polonica.

[133]  J. Heitman,et al.  Ras1 and Ras2 contribute shared and unique roles in physiology and virulence of Cryptococcus neoformans. , 2002, Microbiology.

[134]  Alex Bateman,et al.  The InterPro database, an integrated documentation resource for protein families, domains and functional sites , 2001, Nucleic Acids Res..

[135]  G. Benson,et al.  Tandem repeats finder: a program to analyze DNA sequences. , 1999, Nucleic acids research.

[136]  Sean R. Eddy,et al.  Profile hidden Markov models , 1998, Bioinform..

[137]  仲村 洋一 Purification and isolation of a biologically active peptido-rhamnogalactan from Sporothrix schenckii , 1976 .