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)：北美最近出现了临床和流行病学上新的加蒂隐球菌群。现在是可行的，也是必要的，检查华支睾吸虫亚型的“群体基因组”，以确定基因组与其表型差异的相关性。这项提案中描述的计划是通过在北美地区的加蒂伊线虫的主要群体和亚群之间进行大规模的全基因组序列和表达比较，来阐明临床疾病、结果和其他差异的基因组原因。尽管最近的一些研究发现了明显的基因表达差异，这可能有助于解释一些表型差异，但结果并不一致，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Gattii的200个基因组(~18MB基因组)进行测序，包括新的北美毒株(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，提供了比以前可用于比较分析的更多数据。此外，我们还将对不同生长条件下的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。这将允许在这些种群中识别PAN基因组，包括稳定的(核心)基因组以及可能更易突变和容易重组的塑料(辅助)基因组。提供具有已排序分离株的综合元数据集将有助于对基因组变化与临床和流行病学特征之间的联系进行统计分析。这种基因组-转录组-流行病学方法可以根据基因组内容提供更好的临床结果预测。除了设计之外，这项提议的一个主要优势是它汇集了世界级的基因组学、生物信息学、真菌学、临床和流行病学专业知识。此外，获得全面的菌株资料库以及相关的临床和流行病学元数据将使我们能够对这一新出现的健康问题采取进一步的有针对性和探索性的方法。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性研究。 与公共卫生相关：最近在北美西北部出现了新的隐球菌群，导致了与以前看到的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毒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，这些变化可能有助于预测患者结局和对受影响的当地人口的健康影响。