Genome Variation in <named-content content-type="genus-species">Cryptococcus gattii</named-content>, an Emerging Pathogen of Immunocompetent Hosts
C. A. D’Souza,
J. W. Kronstad,
G. Taylor,
R. Warren,
M. Yuen,
G. Hu,
W. H. Jung,
A. Sham,
S. E. Kidd,
K. Tangen,
N. Lee,
T. Zeilmaker,
J. Sawkins,
G. McVicker,
S. Shah,
S. Gnerre,
A. Griggs,
Q. Zeng,
K. Bartlett,
W. Li,
X. Wang,
J. Heitman,
J. E. Stajich,
J. A. Fraser,
W. Meyer,
D. Carter,
J. Schein,
M. Krzywinski,
K. J. Kwon-Chung,
A. Varma,
J. Wang,
R. Brunham,
M. Fyfe,
B. F. F. Ouellette,
A. Siddiqui,
M. Marra,
S. Jones,
R. Holt,
B. W. Birren,
J. E. Galagan,
C. A. Cuomo
Affiliations
C. A. D’Souza
The Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
J. W. Kronstad
The Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
G. Taylor
Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
R. Warren
Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
M. Yuen
The Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
G. Hu
The Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
W. H. Jung
Department of Biotechnology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, Republic of Korea
A. Sham
The Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
S. E. Kidd
The Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
K. Tangen
The Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
N. Lee
The Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
T. Zeilmaker
The Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
J. Sawkins
The Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
G. McVicker
The Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
S. Shah
The Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
S. Gnerre
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
A. Griggs
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Q. Zeng
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
K. Bartlett
School of Occupational and Environmental Hygiene, University of British Columbia, Vancouver, British Columbia, Canada
W. Li
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA
X. Wang
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA
J. Heitman
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA
J. E. Stajich
Department of Plant Pathology and Microbiology, University of California, Riverside, California, USA
J. A. Fraser
Centre for Infectious Disease Research, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia
W. Meyer
Molecular Mycology Research Laboratory, Centre for Infectious Diseases and Microbiology, Westmead Millennium Institute, Sydney Emerging Disease and Biosecurity Institute, Sydney Medical School—Westmead Hospital, The University of Sydney, Westmead, New South Wales, Australia
D. Carter
School of Molecular Bioscience, University of Sydney, Sydney, New South Wales, Australia
J. Schein
Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
M. Krzywinski
Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
K. J. Kwon-Chung
Molecular Microbiology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA; Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
A. Varma
Molecular Microbiology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA; Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
J. Wang
The Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
R. Brunham
British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada
M. Fyfe
Office of the Medical Health Officer, Vancouver Island Health Authority, Victoria, British Columbia, Canada
B. F. F. Ouellette
The Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
A. Siddiqui
Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
M. Marra
Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
S. Jones
Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
R. Holt
Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
B. W. Birren
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
J. E. Galagan
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
C. A. Cuomo
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
ABSTRACT Cryptococcus gattii recently emerged as the causative agent of cryptococcosis in healthy individuals in western North America, despite previous characterization of the fungus as a pathogen in tropical or subtropical regions. As a foundation to study the genetics of virulence in this pathogen, we sequenced the genomes of a strain (WM276) representing the predominant global molecular type (VGI) and a clinical strain (R265) of the major genotype (VGIIa) causing disease in North America. We compared these C. gattii genomes with each other and with the genomes of representative strains of the two varieties of Cryptococcus neoformans that generally cause disease in immunocompromised people. Our comparisons included chromosome alignments, analysis of gene content and gene family evolution, and comparative genome hybridization (CGH). These studies revealed that the genomes of the two representative C. gattii strains (genotypes VGI and VGIIa) are colinear for the majority of chromosomes, with some minor rearrangements. However, multiortholog phylogenetic analysis and an evaluation of gene/sequence conservation support the existence of speciation within the C. gattii complex. More extensive chromosome rearrangements were observed upon comparison of the C. gattii and the C. neoformans genomes. Finally, CGH revealed considerable variation in clinical and environmental isolates as well as changes in chromosome copy numbers in C. gattii isolates displaying fluconazole heteroresistance. IMPORTANCE Isolates of Cryptococcus gattii are currently causing an outbreak of cryptococcosis in western North America, and most of the cases occurred in the absence of coinfection with HIV. This pattern is therefore in stark contrast to the current global burden of one million annual cases of cryptococcosis, caused by the related species Cryptococcus neoformans, in the HIV/AIDS population. The genome sequences of two outbreak-associated major genotypes of C. gattii reported here provide insights into genome variation within and between cryptococcal species. These sequences also provide a resource to further evaluate the epidemiology of cryptococcal disease and to evaluate the role of pathogen genes in the differential interactions of C. gattii and C. neoformans with immunocompromised and immunocompetent hosts.
