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

翻译后摘要：新毒素的发现和表征 微囊藻和其他蓝藻常见于蓝藻有害藻华（cHABs） 含有许多基因簇，编码多种未知天然产物的生物合成。这 该项目将检验这一假设，即这些基因簇是负责生产各种未知的 毒素和生物活性化合物，威胁人类和环境健康，但仍然看不到目前的 通常用于评估水质的方法。目标是确定新的毒素及其特定的遗传 通过研究纯培养物和未培养菌群的生物合成和调节途径 微生物的基因组将从宏基因组和代表性文化的优势 水华蓝藻物种。基因组和宏基因组的高通量生物信息学挖掘 将识别并优先考虑人工策展和结构预测的目标。与这些基于基因的 研究、培养物和现场样品的分析将通过（i）高通量筛选各种 生物活性在密歇根大学化学基因组学中心，和（ii）代谢组学研究（由威廉 和Boyer组），和（iii）与人类疾病相关的潜在生物靶标的评估。综合起来看， 关于遗传/生物化学新奇和伊利湖水华中基因的丰度和表达的结果将是 用于通过异源生物合成途径鉴定高优先级基因簇，用于进一步的生化研究 在遗传上易处理的宿主生物中表达。将开发下一代图形数据库， 促进遗传、实验和环境数据的综合和综合查询。 该项目直接解决COHH 3 RFA中列出的两个研究重点：（1）发现新的 毒素，（2）气候变化如何影响有毒藻华的审讯。更广泛的结果将是 开发一种通用的高通量方法来鉴定来自不同来源的天然产物， 通过整合高通量突破性技术的次级代谢物基因簇 宏基因组学和生物信息学与实验和分析实验室的方法。本研究项目 将由三个有密切合作记录的实验室进行。它将紧密地集成到 拟议中心的活动，利用中心提供的基础设施和资源， 一系列独特的能力。

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.