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的格特隐球菌种群最近在北美出现。现在，检查格特隐球菌亚型的“群体基因组”以确定基因组与其表型差异的关联是可行且必要的。该提案中描述的计划是通过在北美格特隐球菌主要类群和亚类之间进行大规模全基因组序列和表达比较，阐明临床疾病、结果和其他差异的基因组原因。 尽管最近的一些研究已经发现了明显的基因表达变异，这可能有助于解释一些表型差异，但结果不一致，这可能是由于目标亚型中分析的分离株数量有限。所述方法的第一部分是对 200 个 C. gattii 基因组（约 18Mb 基因组）进行测序，包括北美新菌株 (VGIIc) 的所有已知分离株，以及北美和世界各地其他 VGII 种群的高度多样化样本，从而提供比以前更多的数据用于比较分析。此外，我们将对各个基因型在不同生长条件下进行转录组分析。这种基于生物信息学的分析方法将包括群体内部和群体之间的基因组成分比较、目标基因序列变异、重组分析、系统发育和表达分析。这将允许识别这些群体中的泛基因组，包括稳定（核心）基因组以及可能更可变且易于重组的可塑（辅助）基因组。具有测序分离株的全面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的关联进行统计分析。这种基因组-转录组学-流行病学方法可以根据基因组内容提供改进的临床结果预测。除了设计之外，该提案的一大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，访问具有相关临床和流行病学元数据的综合菌株存储库将有助于针对这一新出现的健康问题采取进一步有针对性的探索性方法。这些是将基因组信息转化为诊断和治疗行动所必需的基础研究。 公共卫生相关性：最近在北美西北部出现了新的格特隐球菌种群，导致了与以前不同的疾病类型和结果的爆发。 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 流行病学上重要的基因组变化可能有助于预测患者的结果以及对受影响当地人群的健康影响。