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Analysis of the Genome and Transcriptome of Cryptococcus neoformans var. grubii Reveals Complex RNA Expression and Microevolution Leading to Virulence Attenuation

Janbon, Guilhem and Hsueh, Yen-Ping (2014) Analysis of the Genome and Transcriptome of Cryptococcus neoformans var. grubii Reveals Complex RNA Expression and Microevolution Leading to Virulence Attenuation. PLoS Genetics, 10 (4). Art. No. e1004261. ISSN 1553-7390. PMCID PMC3990503. https://resolver.caltech.edu/CaltechAUTHORS:20140620-090449590

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Abstract

Cryptococcus neoformans is a pathogenic basidiomycetous yeast responsible for more than 600,000 deaths each year. It occurs as two serotypes (A and D) representing two varieties (i.e. grubii and neoformans, respectively). Here, we sequenced the genome and performed an RNA-Seq-based analysis of the C. neoformans var. grubii transcriptome structure. We determined the chromosomal locations, analyzed the sequence/structural features of the centromeres, and identified origins of replication. The genome was annotated based on automated and manual curation. More than 40,000 introns populating more than 99% of the expressed genes were identified. Although most of these introns are located in the coding DNA sequences (CDS), over 2,000 introns in the untranslated regions (UTRs) were also identified. Poly(A)-containing reads were employed to locate the polyadenylation sites of more than 80% of the genes. Examination of the sequences around these sites revealed a new poly(A)-site-associated motif (AUGHAH). In addition, 1,197 miscRNAs were identified. These miscRNAs can be spliced and/or polyadenylated, but do not appear to have obvious coding capacities. Finally, this genome sequence enabled a comparative analysis of strain H99 variants obtained after laboratory passage. The spectrum of mutations identified provides insights into the genetics underlying the micro-evolution of a laboratory strain, and identifies mutations involved in stress responses, mating efficiency, and virulence.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1371/journal.pgen.1004261DOIArticle
http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1004261PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990503/PubMed CentralArticle
Additional Information:© 2014 Janbon et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: September 19, 2013; Accepted: February 7, 2014; Published: April 17, 2014. Funding: This work was supported by the National Human Genome Research Institute, grant number U54HG003067 to the Broad Institute. This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No.:HHSN272200900018C. This work was supported by a grant from ANR (2010-BLAN-1620-01 program YeastIntrons) to GJ. This work was also supported by NIH/NIAID R37 award AI39115-16 and R01 award AI50113-10 (JH), NIH/NIAID R21 award AI094364 (AI), and by NIH/NINDS R01 grant NS042263 (FSD). The intramural support of JNCASR to KS for the centromere work is highly acknowledged. The work on replication origins was funded by a Burroughs Wellcome Scholar Award in Molecular Pathogenic Mycology awarded to CSN. The work on microevolution was funded by the NHMRC Project Grant 455980 (JAF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgments: We thank the Broad Institute Sequencing Platform for generating WGS data for this project, Jon Butler for generating the initial assembly, and Matthew Pearson and Lucia Alvarado-Balderrama for assistance with data submission and release. We thank Nancy Guillen (Institut Pasteur) for valuable discussion. We thank Heesun Shin, Readman Chiu, Martin Krzywinski, and the BAC fingerprinting team at the Genome Sciences Centre for their contributions to data generation and analysis. We thank Scarlett Geunes-Boyer and Cecelia Shertz Wall for editing the manuscript. Author Contributions: Conceived and designed the experiments: GJ YSB MM LDM PAM CN CSN JRP JKL AI JESt JWK KS JH JAF CAC FSD. Performed the experiments: KLO DP EJB GC VY CCH RBB FB WC YC EWLC JYC AFA CG KJG JG SGH SG JLH YPH GI SJ CDK WL FM KN CP TR JESc SS CW IAW QZ LK NM. Analyzed the data: GJ CN CSN JKL AI JWK KS JH JAF CAC FSD. Wrote the paper: GJ KLO DP CSN AI JWK KS JH JAF CAC FSD. Competing interests: The authors have declared that no competing interests exist.
Funders:
Funding AgencyGrant Number
National Human Genome Research InstituteU54HG003067
NIH National Institute of Allergy and Infectious DiseasesHHSN272200900018C
ANR2010-BLAN-1620-01
NIH/NIAID R37 AwardAI39115-16
NIH/NIAID R01 AwardAI50113-10
NIH/NIAID R21 AwardAI094364
NIH/NINDS R01 AwardNS042263
Burroughs Wellcome Scholar Award in Molecular Pathogenic MycologyUNSPECIFIED
NHMRC Project455980
Issue or Number:4
PubMed Central ID:PMC3990503
Record Number:CaltechAUTHORS:20140620-090449590
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20140620-090449590
Official Citation:Janbon G, Ormerod KL, Paulet D, Byrnes EJ III, Yadav V, et al. (2014) Analysis of the Genome and Transcriptome of Cryptococcus neoformans var. grubii Reveals Complex RNA Expression and Microevolution Leading to Virulence Attenuation. PLoS Genet 10(4): e1004261. doi:10.1371/journal.pgen.1004261
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:46387
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:20 Jun 2014 18:09
Last Modified:03 Oct 2019 06:43

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