title: Cryptococcus gattii in North American Pacific Northwest: whole-population genome analysis provides insights into species evolution and dispersal.
abstract: The emergence of distinct populations of Cryptococcus gattii in the temperate North American Pacific Northwest (PNW) was surprising, as this species was previously thought to be confined to tropical and semitropical regions. Beyond a new habitat niche, the dominant emergent population displayed increased virulence and caused primary pulmonary disease, as opposed to the predominantly neurologic disease seen previously elsewhere. Whole-genome sequencing was performed on 118 C. gattii isolates, including the PNW subtypes and the global diversity of molecular type VGII, to better ascertain the natural source and genomic adaptations leading to the emergence of infection in the PNW. Overall, the VGII population was highly diverse, demonstrating large numbers of mutational and recombinational events; however, the three dominant subtypes from the PNW were of low diversity and were completely clonal. Although strains of VGII were found on at least five continents, all genetic subpopulations were represented or were most closely related to strains from South America. The phylogenetic data are consistent with multiple dispersal events from South America to North America and elsewhere. Numerous gene content differences were identified between the emergent clones and other VGII lineages, including genes potentially related to habitat adaptation, virulence, and pathology. Evidence was also found for possible gene introgression from Cryptococcus neoformans var. grubii that is rarely seen in global C. gattii but that was present in all PNW populations. These findings provide greater understanding of C. gattii evolution in North America and support extensive evolution in, and dispersal from, South America. Importance: Cryptococcus gattii emerged in the temperate North American Pacific Northwest (PNW) in the late 1990s. Beyond a new environmental niche, these emergent populations displayed increased virulence and resulted in a different pattern of clinical disease. In particular, severe pulmonary infections predominated in contrast to presentation with neurologic disease as seen previously elsewhere. We employed population-level whole-genome sequencing and analysis to explore the genetic relationships and gene content of the PNW C. gattii populations. We provide evidence that the PNW strains originated from South America and identified numerous genes potentially related to habitat adaptation, virulence expression, and clinical presentation. Characterization of these genetic features may lead to improved diagnostics and therapies for such fungal infections. The data indicate that there were multiple recent introductions of C. gattii into the PNW. Public health vigilance is warranted for emergence in regions where C. gattii is not thought to be endemic.
authors.affiliation: Translational Genomics Research Institute, Flagstaff, Arizona, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Engelthaler
authors.affiliation: Translational Genomics Research Institute, Flagstaff, Arizona, USA.
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Hicks
authors.affiliation: Translational Genomics Research Institute, Flagstaff, Arizona, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Gillece
authors.affiliation: Translational Genomics Research Institute, Flagstaff, Arizona, USA.
authors.forename: Chandler C
authors.initials: CC
authors.lastname: Roe
authors.affiliation: Translational Genomics Research Institute, Flagstaff, Arizona, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Schupp
authors.affiliation: Translational Genomics Research Institute, Flagstaff, Arizona, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Driebe
authors.affiliation: Molecular Mycology Research Laboratory, Center for Infectious Diseases and Microbiology, Sydney Medical School, Westmead Hospital, Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Westmead Millennium Institute, Sydney, Australia.
authors.forename: Felix
authors.initials: F
authors.lastname: Gilgado
authors.forename: Fabian
authors.initials: F
authors.lastname: Carriconde
authors.forename: Luciana
authors.initials: L
authors.lastname: Trilles
authors.forename: Carolina
authors.initials: C
authors.lastname: Firacative
authors.forename: Popchai
authors.initials: P
authors.lastname: Ngamskulrungroj
authors.affiliation: Microbiology Group, Instituto Nacional de Salud, Bogotá, Colombia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Castañeda
authors.affiliation: Laboratório de Micologia, Instituto de Pesquisa Clínica Evandro Chagas, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Marcia dos Santos
authors.initials: Mdos S
authors.lastname: Lazera
authors.affiliation: Public Health Reference Laboratory, Institute Adolfo Lutz, São Paulo, SP, Brazil.
authors.forename: Marcia S C
authors.initials: MS
authors.lastname: Melhem
authors.forename: Asa
authors.initials: A
authors.lastname: Pérez-Bercoff
authors.affiliation: John Curtin School of Medical Research, Australian National University, Canberra, Australia.
authors.forename: Gavin
authors.initials: G
authors.lastname: Huttley
authors.affiliation: Molecular Mycology Research Laboratory, Center for Infectious Diseases and Microbiology, Sydney Medical School, Westmead Hospital, Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Westmead Millennium Institute, Sydney, Australia.
authors.forename: Tania C
authors.initials: TC
authors.lastname: Sorrell
authors.forename: Kerstin
authors.initials: K
authors.lastname: Voelz
authors.forename: Robin C
authors.initials: RC
authors.lastname: May
authors.affiliation: Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Fisher
authors.affiliation: University of California, Davis, Davis, California, USA.
authors.forename: George R
authors.initials: GR
authors.lastname: Thompson
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Shawn R
authors.initials: SR
authors.lastname: Lockhart
authors.affiliation: paul.keim@nau.edu wieland.meyer@sydney.edu.au.
authors.forename: Paul
authors.initials: P
authors.lastname: Keim
authors.affiliation: Molecular Mycology Research Laboratory, Center for Infectious Diseases and Microbiology, Sydney Medical School, Westmead Hospital, Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Westmead Millennium Institute, Sydney, Australia paul.keim@nau.edu wieland.meyer@sydney.edu.au.
authors.forename: Wieland
authors.initials: W
authors.lastname: Meyer
mesh_terms: D005075:Biological Evolution; D056285:Cryptococcus gattii / Q000145:classification* / Q000235:genetics*; D016681:Genome, Fungal / Q000235:genetics*; D015205:Northwestern United States; D013020:South America