A Model System for Studying the Transcriptomic and Physiological Changes Associated with Mammalian Host-Adaptation by Leptospira interrogans Serovar Copenhageni

PLoS Pathogens

Volumn 10, Issue 3, 2014, Pages

  Caimano, Melissa J ^a   Sivasankaran, Sathesh K ^b   Allard, Anna ^a   Hurley, Daniel ^c   Hokamp, Karsten ^b   Grassmann, André A ^a,d   Hinton, Jay C D ^b,e   Nally, Jarlath E ^c  

^a UNIVERSITY OF CONNECTICUT HEALTH CENTER   (United States)

^b TRINITY COLLEGE DUBLIN   (Ireland)

^c UNIVERSITY COLLEGE DUBLIN   (Ireland)

^d FEDERAL UNIVERSITY OF PELOTAS   (Brazil)

^e UNIVERSITY OF LIVERPOOL   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

HEME; LIPOPROTEIN; TRANSCRIPTOME;

ADAPTATION; ARTICLE; BACTERIAL VIRULENCE; DIALYSIS MEMBRANE; FEMALE; FEVER; GENE EXPRESSION; LEPTOSPIRA; LEPTOSPIRA INTERROGANS; LEPTOSPIROSIS; LUNG HEMORRHAGE; MOUSE; NONHUMAN; OXIDATIVE STRESS; PARASITE TRANSMISSION; PATHOGENICITY; POLYACRYLAMIDE GEL ELECTROPHORESIS; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; RNA SEQUENCE; TEMPERATURE STRESS; TRANSCRIPTION REGULATION;

ANIMALS; GENES, BACTERIAL; HOST-PATHOGEN INTERACTIONS; IMMUNOBLOTTING; LEPTOSPIRA INTERROGANS; LEPTOSPIROSIS; MODELS, BIOLOGICAL; RATS; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; TRANSCRIPTOME;

EID: 84897373393     PISSN: 15537366     EISSN: 15537374     Source Type: Journal    
DOI: 10.1371/journal.ppat.1004004     Document Type: Article

References (112)

1. Ko AI, Goarant C, Picardeau M, (2009) Leptospira: the dawn of the molecular genetics era for an emerging zoonotic pathogen. Nat Rev Microbiol 7: 736-747.
2. Bharti AR, Nally JE, Ricaldi JN, Matthias MA, Diaz MM, et al. (2003) Leptospirosis: a zoonotic disease of global importance. Lancet Infect Dis 3: 757-771.
3. Athanazio DA, Silva EF, Santos CS, Rocha GM, Vannier-Santos MA, et al. (2008) Rattus norvegicus as a model for persistent renal colonization by pathogenic Leptospira interrogans. Acta Trop 105: 176-180.
4. Marshall RB, (1976) The route of entry of leptospires into the kidney tubule. J Med Microbiol 9: 149-152.
5. Faine S, (1957) Virulence in Leptospira. I. Reactions of guinea-pigs to experimental infection with Leptospira icterohaemorrhagiae. British Journal of Experimental Pathology 38: 1-7.
6. Adler B, Lo M, Seemann T, Murray GL, (2011) Pathogenesis of leptospirosis: the influence of genomics. Vet Microbiol 153: 73-81.
7. Faine S, Adler B., Bolin C. and Perolat P. (1999) Leptospira and Leptospirosis. Melbourne, Australia: MediSci.
8. Monahan AM, Callanan JJ, Nally JE, (2008) Proteomic analysis of Leptospira interrogans shed in urine of chronically infected hosts. Infect Immun 76: 4952-4958.
9. Ido Y, Hoki R, Ito H, Wani H, (1917) The rat as a carrier of Spirocheta icterohaemorrhagiae, the causative agent of Weil's disease (spirochaetosis icterohaemorrhagica. Journal of Experimental Medicine 26: 341-353.
10. Bonilla-Santiago R, Nally JE, (2011) Rat model of chronic leptospirosis. Curr Protoc Microbiol Chapter 12: Unit12E 13.
11. Nascimento AL, Ko AI, Martins EA, Monteiro-Vitorello CB, Ho PL, et al. (2004) Comparative genomics of two Leptospira interrogans serovars reveals novel insights into physiology and pathogenesis. J Bacteriol 186: 2164-2172.
12. Nascimento AL, Verjovski-Almeida S, Van Sluys MA, Monteiro-Vitorello CB, Camargo LE, et al. (2004) Genome features of Leptospira interrogans serovar Copenhageni. Braz J Med Biol Res 37: 459-477.
13. Bulach DM, Zuerner RL, Wilson P, Seemann T, McGrath A, et al. (2006) Genome reduction in Leptospira borgpetersenii reflects limited transmission potential. Proc Natl Acad Sci U S A 103: 14560-14565.
14. Picardeau M, Bulach DM, Bouchier C, Zuerner RL, Zidane N, et al. (2008) Genome sequence of the saprophyte Leptospira biflexa provides insights into the evolution of Leptospira and the pathogenesis of leptospirosis. PLoS One 3: e1607.
15. Chou LF, Chen YT, Lu CW, Ko YC, Tang CY, et al. (2012) Sequence of Leptospira santarosai serovar Shermani genome and prediction of virulence-associated genes. Gene 511: 364-370.
16. Ricaldi JN, Fouts DE, Selengut JD, Harkins DM, Patra KP, et al. (2012) Whole genome analysis of Leptospira licerasiae provides insight into leptospiral evolution and pathogenicity. PLoS Negl Trop Dis 6: e1853.
17. Xue F, Yan J, Picardeau M, (2009) Evolution and pathogenesis of Leptospira spp.: lessons learned from the genomes. Microbes Infect 11: 328-333.
18. Lo M, Bulach DM, Powell DR, Haake DA, Matsunaga J, et al. (2006) Effects of temperature on gene expression patterns in Leptospira interrogans serovar Lai as assessed by whole-genome microarrays. Infect Immun 74: 5848-5859.
19. Qin JH, Sheng YY, Zhang ZM, Shi YZ, He P, et al. (2006) Genome-wide transcriptional analysis of temperature shift in L. interrogans serovar Lai strain 56601. BMC Microbiol 6: 51.
20. Matsunaga J, Lo M, Bulach DM, Zuerner RL, Adler B, et al. (2007) Response of Leptospira interrogans to physiologic osmolarity: relevance in signaling the environment-to-host transition. Infect Immun 75: 2864-2874.
21. Patarakul K, Lo M, Adler B, (2010) Global transcriptomic response of Leptospira interrogans serovar Copenhageni upon exposure to serum. BMC Microbiol 10: 31.
22. Lo M, Murray GL, Khoo CA, Haake DA, Zuerner RL, et al. (2010) Transcriptional response of Leptospira interrogans to iron limitation and characterization of a PerR homolog. Infect Immun 78: 4850-4859.
23. Akins DR, Bourell KW, Caimano MJ, Norgard MV, Radolf JD, (1998) A new animal model for studying Lyme disease spirochetes in a mammalian host-adapted state. Journal of Clinical Investigation 101: 2240-2250.
24. Caimano MJ, (2005) Cultivation of Borrelia burgdorferi in dialysis membrane chambers in rat peritonea. Curr Protoc Microbiol Chapter 12: Unit 12C 13.
25. Thiermann AB, (1981) The Norway rat as a selective chronic carrier of Leptospira icterohaemorrhagiae. J Wildl Dis 17: 39-43.
26. Levett PN, (2001) Leptospirosis. Clin Microbiol Rev 14: 296-326.
27. Caimano MJ, Iyer R, Eggers CH, Gonzalez C, Morton EA, et al. (2007) Analysis of the RpoS regulon in Borrelia burgdorferi in response to mammalian host signals provides insight into RpoS function during the enzootic cycle. Molecular Microbiology 65: 1193-1217.
28. Revel AT, Talaat AM, Norgard MV, (2002) DNA microarray analysis of differential gene expression in Borrelia burgdorferi, the Lyme disease spirochete. Proceedings of the National Academy of Sciences 99: 1562-1567.
29. Brooks CS, Hefty PS, Jolliff SE, Akins DR, (2003) Global analysis of Borrelia burgdorferi genes regulated by mammalian host-specific signals. Infect Immun 71: 3371-3383.
30. Croucher NJ, Thomson NR, (2010) Studying bacterial transcriptomes using RNA-seq. Current Opinion in Microbiology 13: 619-624.
31. Filiatrault MJ, (2011) Progress in prokaryotic transcriptomics. Current Opinion in Microbiology 14: 579-586.
32. Caimano MJ, Eggers CH, Gonzalez CA, Radolf JD, (2005) Alternate sigma factor RpoS is required for the in vivo-specific repression of Borrelia burgdorferi plasmid lp54-borne ospA and lp6.6 genes. Journal of Bacteriology 187: 7845-7852.
33. Narayanavari SA, Sritharan M, Haake DA, Matsunaga J, (2012) Multiple leptospiral sphingomyelinases (or are there?). Microbiology 158: 1137-1146.
34. Matsunaga J, Medeiros MA, Sanchez Y, Werneid KF, Ko AI, (2007) Osmotic regulation of expression of two extracellular matrix-binding proteins and a haemolysin of Leptospira interrogans: differential effects on LigA and Sph2 extracellular release. Microbiology 153: 3390-3398.
35. Artiushin S, Timoney JF, Nally J, Verma A, (2004) Host-inducible immunogenic sphingomyelinase-like protein, Lk73.5, of Leptospira interrogans. Infect Immun 72: 742-749.
36. Zhang YX, Geng Y, Bi B, He JY, Wu CF, et al. (2005) Identification and classification of all potential hemolysin encoding genes and their products from Leptospira interrogans serogroup Icterohae-morrhagiae serovar Lai. Acta Pharmacol Sin 26: 453-461.
37. Carvalho E, Barbosa AS, Gomez RM, Oliveira ML, Romero EC, et al. (2010) Evaluation of the expression and protective potential of Leptospiral sphingomyelinases. Curr Microbiol 60: 134-142.
38. Haake DA, Chao G, Zuerner RL, Barnett JK, Barnett D, et al. (2000) The leptospiral major outer membrane protein LipL32 is a lipoprotein expressed during mammalian infection. Infect Immun 68: 2276-2285.
39. Shang ES, Summers TA, Haake DA, (1996) Molecular cloning and sequence analysis of the gene encoding LipL41, a surface-exposed lipoprotein of pathogenic Leptospira species. Infect Immun 64: 2322-2330.
40. Nally JE, Monahan AM, Miller IS, Bonilla-Santiago R, Souda P, et al. (2011) Comparative proteomic analysis of differentially expressed proteins in the urine of reservoir hosts of leptospirosis. PLoS One 6: e26046.
41. Baseman JB, Cox CD, (1969) Intermediate energy metabolism of Leptospira. J Bacteriol 97: 992-1000.
42. Zhang Q, Zhang Y, Zhong Y, Ma J, Peng N, et al. (2011) Leptospira interrogans encodes an ROK family glucokinase involved in a cryptic glucose utilization pathway. Acta Biochim Biophys Sin (Shanghai) 43: 618-629.
43. Anders S, Huber W, (2010) Differential expression analysis for sequence count data. Genome Biol 11: R106.
44. Marchler-Bauer A, Zheng C, Chitsaz F, Derbyshire MK, Geer LY, et al. (2013) CDD: conserved domains and protein three-dimensional structure. Nucleic Acids Res 41: D348-352.
45. Marchler-Bauer A, Bryant SH, (2004) CD-Search: protein domain annotations on the fly. Nucleic Acids Research 32: W327-W331.
46. Marcsisin RA, Bartpho T, Bulach DM, Srikram A, Sermswan RW, et al. (2013) Use of a high-throughput screen to identify Leptospira mutants unable to colonise the carrier host or cause disease in the acute model of infection. J Med Microbiol 62 (Pt 10):: 1601-8.
47. Setubal JC, Reis M, Matsunaga J, Haake DA, (2006) Lipoprotein computational prediction in spirochaetal genomes. Microbiology 152: 113-121.
48. Haake DA, (2000) Spirochaetal lipoproteins and pathogenesis. Microbiology 146 (Pt 7):: 1491-1504.
49. Janwitthayanan W, Keelawat S, Payungporn S, Lowanitchapat A, Suwancharoen D, et al. (2013) In vivo gene expression and immunoreactivity of Leptospira collagenase. Microbiol Res 168: 268-272.
50. Choy HA, Kelley MM, Croda J, Matsunaga J, Babbitt JT, et al. (2011) The multifunctional LigB adhesin binds homeostatic proteins with potential roles in cutaneous infection by pathogenic Leptospira interrogans. PLoS One 6: e16879.
51. Lin Y-P, McDonough SP, Sharma Y, Chang Y-F, (2011) Leptospira immunoglobulin-like protein B (LigB) binding to the C-terminal fibrinogen αC domain inhibits fibrin clot formation, platelet adhesion and aggregation. Molecular Microbiology 79: 1063-1076.
52. Lin Y-P, McDonough SP, Sharma Y, Chang Y-F, (2010) The terminal immunoglobulin-like repeats of LigA and LigB of Leptospira enhance their binding to gelatin binding domain of fibronectin and host cells. PLoS One 5: e11301.
53. Coutinho ML, Choy HA, Kelley MM, Matsunaga J, Babbitt JT, et al. (2011) A LigA three-domain region protects hamsters from lethal infection by Leptospira interrogans. PLoS Negl Trop Dis 5: e1422.
54. Vaughn JL, Feher V, Naylor S, Strauch MA, Cavanagh J, (2000) Novel DNA binding domain and genetic regulation model of Bacillus subtilis transition state regulator AbrB. Nature Structural Biology 7: 1139-1146.
55. Bobay BG, Mueller GA, Thompson RJ, Murzin AG, Venters RA, et al. (2006) NMR structure of AbhN and comparison with AbrBN: FIRST insights into the DNA binding promiscuity and specificity of AbrB-like transition state regulator proteins. J Biol Chem 281: 21399-21409.
56. Sullivan DM, Bobay BG, Kojetin DJ, Thompson RJ, Rance M, et al. (2008) Insights into the nature of DNA binding of AbrB-like transcription factors. Structure 16: 1702-1713.
57. Posey JE, Gherardini FC, (2000) Lack of a role for iron in the Lyme disease pathogen. Science 288: 1651-1653.
58. Louvel H, Bommezzadri S, Zidane N, Boursaux-Eude C, Creno S, et al. (2006) Comparative and functional genomic analyses of iron transport and regulation in Leptospira spp. J Bacteriol 188: 7893-7904.
59. Noinaj N, Guillier M, Barnard TJ, Buchanan SK, (2010) TonB-dependent transporters: regulation, structure, and function. Annu Rev Microbiol 64: 43-60.
60. Murray GL, Ellis KM, Lo M, Adler B, (2008) Leptospira interrogans requires a functional heme oxygenase to scavenge iron from hemoglobin. Microbes Infect 10: 791-797.
61. Escolar L, Perez-Martin J, de Lorenzo V, (1999) Opening the iron box: transcriptional metalloregulation by the Fur protein. J Bacteriol 181: 6223-6229.
62. Davey NE, Haslam NJ, Shields DC, Edwards RJ, (2011) SLiMSearch 2.0: biological context for short linear motifs in proteins. Nucleic Acids Research 39: W56-W60.
63. Hantke K, (2001) Iron and metal regulation in bacteria. Curr Opin Microbiol 4: 172-177.
64. Imlay JA, (2008) Cellular defenses against superoxide and hydrogen peroxide. Annu Rev Biochem 77: 755-776.
65. Eshghi A, Lourdault K, Murray GL, Bartpho T, Sermswan RW, et al. (2012) Leptospira interrogans catalase is required for resistance to H2O2 and for virulence. Infect Immun 80: 3892-3899.
66. Seaver LC, Imlay JA, (2001) Alkyl hydroperoxide reductase is the primary scavenger of endogenous hydrogen peroxide in Escherichia coli. J Bacteriol 183: 7173-7181.
67. Parsonage D, Desrosiers DC, Hazlett KR, Sun Y, Nelson KJ, et al. (2010) Broad specificity AhpC-like peroxiredoxin and its thioredoxin reductant in the sparse antioxidant defense system of Treponema pallidum. Proc Natl Acad Sci U S A 107: 6240-6245.
68. Lo M, Cordwell SJ, Bulach DM, Adler B, (2009) Comparative transcriptional and translational analysis of leptospiral outer membrane protein expression in response to temperature. PLoS Negl Trop Dis 3: e560.
69. Nally JE, Timoney JF, Stevenson B, (2001) Temperature-regulated protein synthesis by Leptospira interrogans. Infect Immun 69: 400-404.
70. Galperin MY, Nikolskaya AN, Koonin EV, (2001) Novel domains of the prokaryotic two-component signal transduction systems. FEMS Microbiol Lett 203: 11-21.
71. Ramos JL, Martínez-Bueno M, Molina-Henares AJ, Terán W, Watanabe K, et al. (2005) The TetR family of transcriptional repressors. Microbiology and Molecular Biology Reviews 69: 326-356.
72. Hammer-Jespersen K, Munch-Ptersen A, (1975) Multiple regulation of nucleoside catabolizing enzymes: regulation of the deo operon by the cytR and deoR gene products. Mol Gen Genet 137: 327-335.
73. Xu C, Shi W, Rosen BP, (1996) The chromosomal arsR gene of Escherichia coli encodes a trans-acting metalloregulatory protein. Journal of Biological Chemistry 271: 2427-2432.
74. Guegan R, Camadro JM, Saint Girons I, Picardeau M, (2003) Leptospira spp. possess a complete haem biosynthetic pathway and are able to use exogenous haem sources. Mol Microbiol 49: 745-754.
75. Louvel H, Betton JM, Picardeau M, (2008) Heme rescues a two-component system Leptospira biflexa mutant. BMC Microbiol 8: 25.
76. Kazantsev AV, Pace NR, (2006) Bacterial RNase P: a new view of an ancient enzyme. Nat Rev Microbiol 4: 729-740.
77. Keiler KC, (2007) Physiology of tmRNA: what gets tagged and why? Curr Opin Microbiol 10: 169-175.
78. Franklund CV, Kadner RJ, (1997) Multiple transcribed elements control expression of the Escherichia coli btuB gene. J Bacteriol 179: 4039-4042.
79. Bonner ER, D'Elia JN, Billips BK, Switzer RL, (2001) Molecular recognition of pyr mRNA by the Bacillus subtilis attenuation regulatory protein PyrR. Nucleic Acids Res 29: 4851-4865.
80. Ren SX, Fu G, Jiang XG, Zeng R, Miao YG, et al. (2003) Unique physiological and pathogenic features of Leptospira interrogans revealed by whole-genome sequencing. Nature 422: 888-893.
81. Matsui M, Rouleau V, Bruyere-Ostells L, Goarant C, (2011) Gene expression profiles of immune mediators and histopathological findings in animal models of leptospirosis: comparison between susceptible hamsters and resistant mice. Infect Immun 79: 4480-4492.
82. Monahan AM, Callanan JJ, Nally JE, (2009) Review paper: Host-pathogen interactions in the kidney during chronic leptospirosis. Vet Pathol 46: 792-799.
83. Xue F, Dong H, Wu J, Wu Z, Hu W, et al. (2010) Transcriptional responses of Leptospira interrogans to host innate immunity: significant changes in metabolism, oxygen tolerance, and outer membrane. PLoS Negl Trop Dis 4: e857.
84. Taal MW, Chertow GM, Marsden PA, Skorecki K, UYu ASL, et al. (2012) Brenner and Rector's The Kidney: Elsevier Mosby Saunders.
85. Grimm D, Eggers CH, Caimano MJ, Tilly K, Stewart PE, et al. (2004) Experimental assessment of the roles of linear plasmids lp25 and lp28-1 of Borrelia burgdorferi throughout the infectious cycle. Infection and Immunity 72: 5938-5946.
86. Smythe L, Adler B, Hartskeerl RA, Galloway RL, Turenne CY, et al. (2013) Classification of Leptospira genomospecies 1, 3, 4 and 5 as Leptospira alstonii sp. nov., Leptospira vanthielii sp. nov., Leptospira terpstrae sp. nov. and Leptospira yanagawae sp. nov., respectively. Int J Syst Evol Microbiol 63: 1859-1862.
87. Fraser CM, Casjens S, Huang WM, Sutton GG, Clayton R, et al. (1997) Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi. Nature 390: 580-586.
88. Fraser CM, Norris SJ, Weinstock GM, White O, Sutton GG, et al. (1998) Complete genome sequence of Treponema pallidum, the syphilis spirochete. Science 281: 375-388.
89. Murray GL, Srikram A, Henry R, Puapairoj A, Sermswan RW, et al. (2009) Leptospira interrogans requires heme oxygenase for disease pathogenesis. Microbes Infect 11: 311-314.
90. Kumar S, Bandyopadhyay U, (2005) Free heme toxicity and its detoxification systems in human. Toxicol Lett 157: 175-188.
91. Tong Y, Guo M, (2009) Bacterial heme-transport proteins and their heme-coordination modes. Arch Biochem Biophys 481: 1-15.
92. Lote CJ, (2012) Principles of Renal Physiology: Springer.
93. Stone MJ, Waterman MR, Harimoto D, Murray G, Willson N, et al. (1977) Serum myoglobin level as diagnostic test in patients with acute myocardial infarction. Br Heart J 39: 375-380.
94. Repoila F, Darfeuille F, (2009) Small regulatory non-coding RNAs in bacteria: physiology and mechanistic aspects. Biol Cell 101: 117-131.
95. Altuvia S, (2007) Identification of bacterial small non-coding RNAs: experimental approaches. Curr Opin Microbiol 10: 257-261.
96. Storz G, Vogel J, Wassarman KM, (2011) Regulation by small RNAs in bacteria: expanding frontiers. Mol Cell 43: 880-891.
97. Waters LS, Storz G, (2009) Regulatory RNAs in bacteria. Cell 136: 615-628.
98. Schauer K, Rodionov DA, de Reuse H, (2008) New substrates for TonB-dependent transport: do we only see the 'tip of the iceberg'? Trends Biochem Sci 33: 330-338.
99. Chao Y, Papenfort K, Reinhardt R, Sharma CM, Vogel J, (2012) An atlas of Hfq-bound transcripts reveals 3′ UTRs as a genomic reservoir of regulatory small RNAs. EMBO J 31: 4005-4019.
100. Österberg S, Peso-Santos Td, Shingler V, (2011) Regulation of alternative sigma factor use. Annual Review of Microbiology 65: 37-55.
101. Capra EJ, Laub MT, (2012) Evolution of two-component signal transduction systems. Annual Review of Microbiology 66: 325-347.
102. Hengge R, (2009) Principles of c-di-GMP signalling in bacteria. Nat Rev Micro 7: 263-273.
103. Croda J, Figueira CP, Wunder EA Jr, Santos CS, Reis MG, et al. (2008) Targeted mutagenesis in pathogenic Leptospira species: disruption of the LigB gene does not affect virulence in animal models of leptospirosis. Infect Immun 76: 5826-5833.
104. Murray GL, Morel V, Cerqueira GM, Croda J, Srikram A, et al. (2009) Genome-wide transposon mutagenesis in pathogenic Leptospira species. Infect Immun 77: 810-816.
105. Bourhy P, Louvel H, Saint Girons I, Picardeau M, (2005) Random insertional mutagenesis of Leptospira interrogans, the agent of leptospirosis, using a mariner transposon. J Bacteriol 187: 3255-3258.
106. Ristow P, Bourhy P, da Cruz McBride FW, Figueira CP, Huerre M, et al. (2007) The OmpA-like protein Loa22 is essential for leptospiral virulence. PLoS Pathog 3: e97.
107. Johnson RC, Walby J, Henry RA, Auran NE, (1973) Cultivation of parasitic leptospires: effect of pyruvate. Appl Microbiol 26: 118-119.
108. Mulay VB, Caimano MJ, Iyer R, Dunham-Ems S, Liveris D, et al. (2009) Borrelia burgdorferi bba74 is expressed exclusively during tick feeding and is regulated by both arthropod- and mammalian host-specific signals. Journal of Bacteriology 191: 2783-2794.
109. Hoffmann S, Otto C, Kurtz S, Sharma CM, Khaitovich P, et al. (2009) Fast Mapping of short sequences with mismatches, insertions and deletions using index structures. PLoS Comput Biol 5: e1000502.
110. Kroger C, Dillon SC, Cameron AD, Papenfort K, Sivasankaran SK, et al. (2012) The transcriptional landscape and small RNAs of Salmonella enterica serovar Typhimurium. Proc Natl Acad Sci U S A 109: E1277-1286.
111. Nicol JW, Helt GA, Blanchard SG Jr, Raja A, Loraine AE, (2009) The Integrated Genome Browser: free software for distribution and exploration of genome-scale datasets. Bioinformatics 25: 2730-2731.
112. Pearson WR, (2000) Flexible sequence similarity searching with the FASTA3 program package. Methods Mol Biol 132: 185-219.