Functional genomic analyses of emerging Cryptococcus subtypes in North America

北美新兴隐球菌亚型的功能基因组分析

• 批准号: 8386240
• 负责人: Paul Stephen Keim
• 金额: $ 29.12万
• 依托单位: TRANSLATIONAL GENOMICS RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-05 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8386240
• 关键词: Address; Affect; Algorithms; American; Bioinformatics; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Data; Collaborations; Collection; Computational Science; Cryptococcus; Data; Databases; Development; Diagnostic; Disease; Disease Outbreaks; Disease Outcome; Ecology; Epidemiology; Evolution; Exhibits; Gene Expression; Gene Expression Profile; Gene Targeting; Genetic Recombination; Genome; Genomics; Genotype; Growth; Health; Laboratories; Link; Metadata; North America; Organism; Outcome; Outcome Study; Patients; Phylogenetic Analysis; Plastics; Population; Public Health; RNA Sequences; Research; Sampling; Subgroup; Target Populations; Technology; Therapeutic; Translating; United States; Variant; Virulence; base; comparative; design; experience; functional genomics; fungus; genome sequencing; improved; novel; pathogen; patient population; repository; tool; transcriptomics

DESCRIPTION (provided by applicant): Clinically and epidemiologically novel populations of Cryptococcus gattii have recently emerged in North America. It is now feasible, and necessary, to examine the "population genome" of C. gattii subtypes to identify genomic associations with its phenotypic differences. The plan described in this proposal is to elucidate genomic causes of clinical disease, outcome and other differences by conducting large-scale whole genome sequence and expression comparisons among the major groups and subgroups of C. gattii in North America. Although some recent studies have identified apparent gene expression variation that may help explain some phenotypic differences, there have been inconsistent results, perhaps due to the limited number of isolates analyzed within the targeted subtypes. The first part of the described approach is to sequence 200 genomes of C. gattii (~18Mb genome), including all known isolates of the new North American strain (VGIIc), and highly diverse samples of the other VGII populations in North America and from around the world, providing more data than previously available for comparative analysis. In addition, we will conduct transcriptome analysis of each genotype under various growth conditions. This bioinformatic-based analytical approach will include genomic component comparisons within and between populations, targeted gene sequence variations, recombination analysis, phylogenetics, and expression analysis. This will permit the identification of the pan genome within these populations, including the stable (core) genome as well as the plastic (accessory) genome which maybe more mutable and prone to recombination. The availability of comprehensive metadata sets with the sequenced isolates will allow for statistical analyses of the association between genomic changes and clinical and epidemiological features. This genomic-transcriptomic-epidemiologic approach can provide improved clinical outcome prediction based on genome content. Beyond the design, a major strength of this proposal is that it brings together world-class genomics, bioinformatics, mycological, clinical and epidemiological expertise. In addition, access to comprehensive strain repositories with associated clinical and epidemiological metadata will allow for further targeted and exploratory approaches to this emerging health problem. These are foundational studies essential for translating genomic information into diagnostics and therapeutic actions. PUBLIC HEALTH RELEVANCE: The recent emergence of new populations of the fungus Cryptococcus gattii in northwestern North America has caused outbreaks of differing disease types and outcomes than previously seen. The approach described here is to comprehensively explore the genomes of entire populations of these new strain types in order to identify clinically and epidemiologically important genomic changes that may help predict patient outcome and health impacts on the affected local population.

描述（由申请人提供）：临床和流行病学上新型的加密汽车的种群最近出现在北美。现在，检查C. gattii亚型的“种群基因组”以识别与其表型差异的基因组关联是可行的，而且必不可少的。该提案中描述的计划是阐明北美C. gattii的主要组和亚组之间的大规模全基因组序列和表达比较，从而阐明临床疾病，结果和其他差异的基因组原因。 尽管一些最近的研究发现了明显的基因表达变异，可能有助于解释某些表型差异，但结果不一致，这可能是由于靶向亚型中分析的分离株数量有限。所描述的方法的第一部分是对C. gattii（〜18MB基因组）的200个基因组进行序列，包括新北美菌株的所有已知分离株（VGIIC），以及北美其他VGII人群的高度多样性样本以及来自在世界范围内，提供的数据比以前可用于比较分析的数据更多。此外，我们将在各种生长条件下对每个基因型进行转录组分析。这种基于生物信息学的分析方法将包括种群内和人群之间的基因组成分比较，靶向基因序列变化，重组分析，系统发育学和表达分析。这将允许在这些人群中鉴定PAN基因组，包括稳定（核心）基因组以及塑料（附件）基因组，这些基因组可能更可变，更容易重组。与测序分离株的综合元数据集的可用性将允许对基因组变化与临床和流行病学特征之间关联的统计分析。这种基因组 - 转录 - ePIDEMIologic方法可以基于基因组含量提供改进的临床结果预测。除了设计之外，该提案的主要优势在于，它汇集了世界一流的基因组学，生物信息学，真菌学，临床和流行病学专业知识。 此外，与相关的临床和流行病学元数据相关的综合应变存储库将允许进一​​步的针对性和探索性方法解决这一新兴健康问题。这些是将基因组信息转化为诊断和治疗作用必不可少的基本研究。 公共卫生相关性：北美西北部的真菌加密加蒂（Gattii）的新人群最近出现了与以前所看到的不同疾病类型和结局的爆发。 这里描述的方法是全面探索这些新菌株类型的整个种群的基因组，以便在临床上识别 以及流行病学上重要的基因组变化，可能有助于预测患者结果和健康对当地人群的影响。