title: The Dynamic Genome and Transcriptome of the Human Fungal Pathogen Blastomyces and Close Relative Emmonsia.
abstract: Three closely related thermally dimorphic pathogens are causal agents of major fungal diseases affecting humans in the Americas: blastomycosis, histoplasmosis and paracoccidioidomycosis. Here we report the genome sequence and analysis of four strains of the etiological agent of blastomycosis, Blastomyces, and two species of the related genus Emmonsia, typically pathogens of small mammals. Compared to related species, Blastomyces genomes are highly expanded, with long, often sharply demarcated tracts of low GC-content sequence. These GC-poor isochore-like regions are enriched for gypsy elements, are variable in total size between isolates, and are least expanded in the avirulent B. dermatitidis strain ER-3 as compared with the virulent B. gilchristii strain SLH14081. The lack of similar regions in related species suggests these isochore-like regions originated recently in the ancestor of the Blastomyces lineage. While gene content is highly conserved between Blastomyces and related fungi, we identified changes in copy number of genes potentially involved in host interaction, including proteases and characterized antigens. In addition, we studied gene expression changes of B. dermatitidis during the interaction of the infectious yeast form with macrophages and in a mouse model. Both experiments highlight a strong antioxidant defense response in Blastomyces, and upregulation of dioxygenases in vivo suggests that dioxide produced by antioxidants may be further utilized for amino acid metabolism. We identify a number of functional categories upregulated exclusively in vivo, such as secreted proteins, zinc acquisition proteins, and cysteine and tryptophan metabolism, which may include critical virulence factors missed before in in vitro studies. Across the dimorphic fungi, loss of certain zinc acquisition genes and differences in amino acid metabolism suggest unique adaptations of Blastomyces to its host environment. These results reveal the dynamics of genome evolution and of factors contributing to virulence in Blastomyces.
authors.affiliation: Cellular and Molecular Biology Unit, Corporación para Investigaciones Biológicas, Medellín, Colombia; Institute of Biology, Universidad de Antioquia, Medellín, Colombia.
authors.forename: José F
authors.initials: JF
authors.lastname: Muñoz
authors.affiliation: Department of Medicine, University of Wisconsin, Madison, Madison, Wisconsin, United States of America.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Gauthier
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Desjardins
authors.affiliation: Cellular and Molecular Biology Unit, Corporación para Investigaciones Biológicas, Medellín, Colombia; Doctoral Program in Biomedical Sciences, Universidad del Rosario, Bogotá, Colombia.
authors.forename: Juan E
authors.initials: JE
authors.lastname: Gallo
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Jason
authors.initials: J
authors.lastname: Holder
authors.affiliation: Department of Pediatrics, University of Wisconsin, Madison, Madison, Wisconsin, United States of America.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Sullivan
authors.affiliation: Department of Medicine, University of Wisconsin, Madison, Madison, Wisconsin, United States of America.
authors.forename: Amber J
authors.initials: AJ
authors.lastname: Marty
authors.affiliation: Department of Pediatrics, University of Wisconsin, Madison, Madison, Wisconsin, United States of America.
authors.forename: John C
authors.initials: JC
authors.lastname: Carmen
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Zehua
authors.initials: Z
authors.lastname: Chen
authors.affiliation: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Sharvari
authors.initials: S
authors.lastname: Gujja
authors.affiliation: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Vincent
authors.initials: V
authors.lastname: Magrini
authors.affiliation: Cellular and Molecular Biology Unit, Corporación para Investigaciones Biológicas, Medellín, Colombia; Institute of Biology, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Misas
authors.affiliation: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Makedonka
authors.initials: M
authors.lastname: Mitreva
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Margaret
authors.initials: M
authors.lastname: Priest
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Sakina
authors.initials: S
authors.lastname: Saif
authors.affiliation: Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, California, United States of America.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Whiston
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Young
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Qiandong
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: William E
authors.initials: WE
authors.lastname: Goldman
authors.affiliation: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.affiliation: Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, California, United States of America.
authors.forename: John W
authors.initials: JW
authors.lastname: Taylor
authors.affiliation: Cellular and Molecular Biology Unit, Corporación para Investigaciones Biológicas, Medellín, Colombia; School of Medicine, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Juan G
authors.initials: JG
authors.lastname: McEwen
authors.affiliation: Cellular and Molecular Biology Unit, Corporación para Investigaciones Biológicas, Medellín, Colombia; School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia.
authors.forename: Oliver K
authors.initials: OK
authors.lastname: Clay
authors.affiliation: Department of Medicine, University of Wisconsin, Madison, Madison, Wisconsin, United States of America; Department of Pediatrics, University of Wisconsin, Madison, Madison, Wisconsin, United States of America; Department of Medical Microbiology & Immunology, University of Wisconsin, Madison, Madison, Wisconsin, United States of America.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Klein
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Cuomo
mesh_terms: D000818:Animals; D001758:Blastomyces / Q000235:genetics* / Q000472:pathogenicity; D001759:Blastomycosis / Q000235:genetics / Q000382:microbiology; D002912:Chrysosporium / Q000235:genetics* / Q000472:pathogenicity; D016681:Genome, Fungal; D006660:Histoplasmosis / Q000235:genetics / Q000382:microbiology; D006801:Humans; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D010229:Paracoccidioidomycosis / Q000235:genetics / Q000382:microbiology; D059467:Transcriptome / Q000235:genetics*