Chromosome rearrangements shape the diversification of secondary metabolism in the cyclosporin producing fungus Tolypocladium inflatum
Chromosome rearrangements shape the diversification of secondary metabolism in the cyclosporin producing fungus Tolypocladium inflatum
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DOI：
10.1186/s12864-018-5399-x
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发表时间：
2019-02-07
期刊：
影响因子：
4.4
通讯作者：
Bushley, Kathryn E.
中科院分区：
文献类型：
--
作者：
Olarte, Rodrigo A.;Menke, Jon;Bushley, Kathryn E.
背景真菌中参与次生代谢产物（SMs）产生的基因异常多样。即使是同一物种的菌株也可能在代谢产物的产生上表现出差异，这一发现对药物发现具有重要意义。与其他真核生物不同，产生SM的基因通常在真菌基因组中聚集和共表达，但这些次级代谢产物生物合成基因簇（SMBGCs）的产生和维持所涉及的遗传机制仍然知之甚少。我们生成了六个地理上不同的昆虫病原真菌Tolypocladium inflatum分离株的染色体规模组装体，Tolypocladium inflatum是价值数十亿美元的救生免疫抑制剂药物环孢菌素的生产者，并利用Hi-C染色体构象捕获方法来解决基因组结构和结构变异在SMBGC中产生种内多样性中的作用。我们的研究结果表明，异源染色体之间的DNA交换在真菌SMBGCs中产生新奇方面起着重要作用。特别是，我们证明了运动的聚酮合酶（PKS）和几个相邻的基因易位到一个新的染色体和基因组的背景下，可能产生一个新的PKS集群。我们还提供了位于亚端粒内的非核糖体肽合成酶之间染色体间重组的证据，并发现了仅存在于两种菌株中的多态性簇，该簇与负责真菌毒素黄曲霉毒素（AF）生物合成的簇密切相关，黄曲霉毒素（AF）是一种高度致癌的化合物，是全球主要的公共卫生问题。相比之下，环孢菌素簇，位于内部的染色体上，是保守的跨菌株，这一重要的毒力因子的感染insects.ConclusionsThis研究的地方SMBGCs的进化的背景下，全基因组进化，并建议染色体之间的重组在产生新的SMBGCs在药用真菌Tolypocladium inflatum的作用。
BackgroundGenes involved in production of secondary metabolites (SMs) in fungi are exceptionally diverse. Even strains of the same species may exhibit differences in metabolite production, a finding that has important implications for drug discovery. Unlike in other eukaryotes, genes producing SMs are often clustered and co-expressed in fungal genomes, but the genetic mechanisms involved in the creation and maintenance of these secondary metabolite biosynthetic gene clusters (SMBGCs) remains poorly understood.ResultsIn order to address the role of genome architecture and chromosome scale structural variation in generating diversity of SMBGCs, we generated chromosome scale assemblies of six geographically diverse isolates of the insect pathogenic fungus Tolypocladium inflatum, producer of the multi-billion dollar lifesaving immunosuppressant drug cyclosporin, and utilized a Hi-C chromosome conformation capture approach to address the role of genome architecture and structural variation in generating intraspecific diversity in SMBGCs. Our results demonstrate that the exchange of DNA between heterologous chromosomes plays an important role in generating novelty in SMBGCs in fungi. In particular, we demonstrate movement of a polyketide synthase (PKS) and several adjacent genes by translocation to a new chromosome and genomic context, potentially generating a novel PKS cluster. We also provide evidence for inter-chromosomal recombination between nonribosomal peptide synthetases located within subtelomeres and uncover a polymorphic cluster present in only two strains that is closely related to the cluster responsible for biosynthesis of the mycotoxin aflatoxin (AF), a highly carcinogenic compound that is a major public health concern worldwide. In contrast, the cyclosporin cluster, located internally on chromosomes, was conserved across strains, suggesting selective maintenance of this important virulence factor for infection of insects.ConclusionsThis research places the evolution of SMBGCs within the context of whole genome evolution and suggests a role for recombination between chromosomes in generating novel SMBGCs in the medicinal fungus Tolypocladium inflatum.