Discovery and characterization of new toxins in genomes and metagenomes of bloom-forming cyanobacteria

文摘：新毒素的发现和特性 蓝藻藻华(CHAB)中常见的微囊藻和其他蓝藻 拥有大量基因簇，这些基因簇编码各种未知天然产物的生物合成。这 该项目将测试这些基因簇负责产生各种未知基因的假设 威胁人类和环境健康的毒素和生物活性化合物目前仍不可见 常用的水质评价方法。目标是识别新的毒素及其特定的基因 通过对纯培养物和未培养菌联合体的研究来研究生物合成和调节的途径 微生物。基因组将由元基因组和具有代表性的优势种文化组装而成。 形成水华的蓝藻物种。基因组和元基因组的高通量生物信息挖掘 将确定手动管理和结构预测的目标并确定其优先顺序。与这些基于基因的 研究、培养和现场样本的分析将通过(I)高通量筛选各种 U-M化学基因组学中心的生物活性，以及(Ii)代谢组学研究(由Wilhelm进行 和Boyer组)，以及(Iii)与人类疾病有关的潜在生物目标的评估。加在一起， 伊利湖水华的遗传/生化新颖性以及基因丰度和表达的结果将是 用于通过异源生物合成途径识别高优先级基因簇以进行进一步的生化研究 在遗传上易驯化的宿主生物中的表达。将开发下一代图形数据库，以 促进遗传、实验和环境数据的合成和集成查询。 该项目直接涉及COHH3 RFA中列出的两个研究重点：(1)发现新的 毒素，(2)询问气候变化如何影响有毒藻类水华。一个更广泛的结果将是 开发一种通用和高通量的方法来识别来自不同来源的天然产品 通过整合突破性技术实现高通量的次生代谢物基因集群 元基因组学和生物信息学与实验和分析实验室方法。这项研究项目 将由三个有密切合作记录的实验室进行。它将紧密地整合到 拟建中心的活动，利用中心提供的基础设施和资源，并提供 一些独一无二的能力给了中心。

Abstract: Discovery and characterization of new toxins Microcystis and other cyanobacteria commonly found in cyanobacterial harmful algal blooms (cHABs) harbor numerous gene clusters that encode the biosynthesis of diverse and unknown natural products. This project will test the hypothesis that these gene clusters are responsible for production of variety of unknown toxins and bioactive compounds that threaten human and environmental health yet remain invisible to current methods commonly used to assess water quality. The goal is to identify novel toxins and their specific genetic pathways for biosynthesis and regulation through the study of both pure cultures and consortia of uncultured microorganisms. Genomes will be assembled from metagenomes and from representative cultures of dominant bloom-forming cyanobacterial species. High-throughput bioinformatic mining of genomes and metagenomes will identify and prioritize targets for manual curation and structure prediction. In parallel to these gene-based studies, analysis of cultures and field samples will be analyzed via (i) high-throughput screening for a variety of bioactivities at the U-M Center for Chemical Genomics, and (ii) metabolomics studies (conducted by Wilhelm and Boyer groups), and (iii) assessment of potential biological targets relating to human disease. Taken together, results on the genetic/biochemical novelty and abundance and expression of genes in Lake Erie blooms will be used to identify high-priority gene clusters for further biochemical studies via heterologous biosynthetic pathway expression in genetically tractable host organisms. A next-generation graph database will be developed to facilitate the synthesis and integrated queries of genetic, experimental, and environmental data. This project directly addresses two research priorities listed in the COHH3 RFA: (1) discovery of new toxins, (2) interrogation of how climate change impacts toxic algal blooms. A broader outcome will be the development of a versatile and high throughput approach to identify natural products from varied sources of secondary metabolite gene clusters through the integration of breakthrough technologies in high throughput metagenomics and bioinformatics with experimental and analytical laboratory approaches. This research project will be carried out by three labs that have a track record of close collaboration. It will be tightly integrated into the activities of the proposed center, drawing on infrastructure and resources provide by the center and providing a number of unique capabilities to the center.