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）： 最近在北美出现了临床和流行病学上新颖的格特隐球菌种群。现在，研究C. gattii亚型，以确定其表型差异的基因组关联。该计划描述的计划是通过进行大规模的全基因组序列和表达比较的主要群体和亚群的C.在北美的gattii。 虽然最近的一些研究已经确定了明显的基因表达变异，可能有助于解释一些表型差异，但结果不一致，可能是由于在目标亚型内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（~ 18 Mb基因组），包括新的北美菌株（VGIIc）的所有已知分离株，以及北美和世界各地其他VGII种群的高度多样性样本，提供了比以前更多的数据进行比较分析。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种群间的基因组成分比较、靶基因序列变异、重组分析、遗传学和表达分析。这将允许在这些群体中鉴定泛基因组，包括稳定的（核心）基因组以及可塑的（辅助）基因组，其可能更易突变且易于重组。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的关联进行统计分析。这种基因组学-转录组学-流行病学方法可以提供基于基因组内容的改进的临床结果预测。除了设计之外，该提案的一个主要优势是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，获得具有相关临床和流行病学元数据的全面菌株储存库将允许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真菌隐球菌种群，导致了与以前所见不同的疾病类型和结果的爆发。 本文所述的方法是全面探索这些新菌株类型的整个群体的基因组，以在临床上识别 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局和对受影响当地人群的健康影响。