Metabolic Gene Clusters in Eukaryotes

Nützmann, Hans Wilhelm; Scazzocchio, Claudio; Osbourn, Anne

doi:10.1146/annurev-genet-120417-031237

Cited by 155 publications

(151 citation statements)

References 190 publications

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“…into A. nidulans removed nitrogen-related regulation of the cluster that was evident in the donor species. Estimates from natural isolates suggest that 0.1 to 5% of genes in fungi, and perhaps more in Pezizomycotina (a group containing Aspergillus) (48), are thought to be the result of HGT (49,50). Indeed, HGT of secondary-metabolism BGCs may occur or be retained more often than other types of gene clusters (19).…”

Section: Discussionmentioning

confidence: 99%

Diversity of Secondary Metabolism in Aspergillus nidulans Clinical Isolates

Drott

Bastos

Rokas

et al. 2020

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The filamentous fungus Aspergillus nidulans has been a primary workhorse used to understand fungal genetics. Much of this work has focused on elucidating the genetics of biosynthetic gene clusters (BGCs) and the secondary metabolites (SMs) they produce. SMs are both niche defining in fungi and of great economic importance to humans. Despite the focus on A. nidulans, very little is known about the natural diversity in secondary metabolism within this species. We determined the BGC content and looked for evolutionary patterns in BGCs from whole-genome sequences of two clinical isolates and the A4 reference genome of A. nidulans. Differences in BGC content were used to explain SM profiles determined using liquid chromatography–high-resolution mass spectrometry. We found that in addition to genetic variation of BGCs contained by all isolates, nine BGCs varied by presence/absence. We discovered the viridicatumtoxin BGC in A. nidulans and suggest that this BGC has undergone a horizontal gene transfer from the Aspergillus section Nigri lineage into Penicillium sometime after the sections Nigri and Nidulantes diverged. We identified the production of viridicatumtoxin and several other compounds previously not known to be produced by A. nidulans. One isolate showed a lack of sterigmatocystin production even though it contained an apparently intact sterigmatocystin BGC, raising questions about other genes and processes known to regulate this BGC. Altogether, our work uncovers a large degree of intraspecies diversity in BGC and SM production in this genetic model species and offers new avenues to understand the evolution and regulation of secondary metabolism. IMPORTANCE Much of what we know about the genetics underlying secondary metabolite (SM) production and the function of SMs in the model fungus Aspergillus nidulans comes from a single reference genome. A growing body of research indicates the importance of biosynthetic gene cluster (BGC) and SM diversity within a species. However, there is no information about the natural diversity of secondary metabolism in A. nidulans. We discovered six novel clusters that contribute to the considerable variation in both BGC content and SM production within A. nidulans. We characterize a diverse set of mutations and emphasize how findings of single nucleotide polymorphisms (SNPs), deletions, and differences in evolutionary history encompass much of the variation observed in nonmodel systems. Our results emphasize that A. nidulans may also be a strong model to use within-species diversity to elucidate regulatory cross talk, fungal ecology, and drug discovery systems.

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Section: Discussionmentioning

confidence: 99%

Diversity of Secondary Metabolism in Aspergillus nidulans Clinical Isolates

Drott

Bastos

Rokas

et al. 2020

mSphere

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“…It is known that functionally related genes reside in the same genomic neighborhood more often than expected at chance 3,4,5,6,7,15,16,17 . We employed a simple framework to systematically quantify the extent of such co-occurrence in neighborhoods across many genomes, separately for individual gene functions.…”

Section: Resultsmentioning

confidence: 99%

“…However, this concept extends more broadly --neighboring genes that are not part of the same operon are also often co-regulated and share function. Moreover, in eukaryotic organisms, which generally lack operons, gene regulation is organized regionally and this pattern can be conserved across evolutionary time 10,11,12,13,14 Consistently, gene function is non-randomly distributed also across eukaryotic chromosomes 15,16 , even though the neighborhood signal is overall more subtle than in prokaryotes, important exceptions notwithstanding (reviewed in 17 ).…”

Section: Introductionmentioning

confidence: 99%

Patterns of diverse gene functions in genomic neighborhoods predict gene function and phenotype

Mihelčić

Šmuc

Supek

2019

Preprint

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Genes with similar roles in the cell are known to cluster on chromosomes, thus benefiting from coordinated regulation. This allows gene function to be inferred by transferring annotations from genomic neighbors, following the guilt-by-association principle. We performed a systematic search for co-occurrence of >1000 gene functions in genomic neighborhoods across 1669 prokaryotic, 49 fungal and 80 metazoan genomes, revealing prevalent patterns that cannot be explained by clustering of functionally similar genes. It is a very common occurrence that pairs of dissimilar gene functionscorresponding to semantically distant Gene Ontology termsare significantly co-located on chromosomes. These neighborhood associations are often as conserved across genomes as the known associations between similar functions, suggesting selective benefits from clustering of certain diverse functions, which may conceivably play complementary roles in the cell. We propose a simple encoding of chromosomal gene order, the neighborhood function profiles (NFP), which draws on diverse gene clustering patterns to predict gene function and phenotype. NFPs yield a 26-46% increase in predictive power over state-of-the-art approaches that propagate function across neighborhoods, thus providing hundreds of novel, high-confidence gene function inferences per genome. Furthermore, we demonstrate that the effect of structural variation on gene function distribution across chromosomes may be used to predict phenotype of individuals from their genome sequence.

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“…First, specialized metabolites produced by plants are typically the products of 292 pathways involving multiple enzymes. Although the underlying genes can be clustered in the 293 genome as has been shown for a number of plant specialized metabolite pathways (Nutzmann 294 et al, 2016;Nützmann et al, 2018), this is not always the case. Here, we show that the gene 295 coding for zingiberene oxidase is on chromosome 1 in a different locus than the two genes 296 required for the production of 7epiZ, which are clustered on chromosome 8.…”

Section: -Epi-zingiberene and Its Derivatives Have Moderate Antimicrmentioning

confidence: 98%

Two novel 7-epi-zingiberene derivatives with biological activity fromSolanum habrochaitesare produced by a single cytochrome P450 monooxygenase

Zabel

Brandt

Porzel

et al. 2020

Preprint

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13Secretions from glandular trichomes potentially protect the plant against a variety of 14 aggressors. In the tomato genus, wild species constitute a rich source of chemical diversity 15 produced at the leaf surface by glandular trichomes. Previously, 7-epi-zingiberene produced 16 in several accessions of Solanum habrochaites was found to confer resistance to whiteflies 17 (Bemisia tabaci) and other insect pests. Here, we identify two derivatives of 7-epi-zingiberene 18 from S. habrochaites that had not been reported as yet. We identified them as 9-hydroxy-19 zingiberene and 9-hydroxy-10,11-epoxyzingiberene. Using a combination of genetics and 20 transcriptomics we identified a single cytochrome P450 oxygenase, ShCYP71D184 that 21 carries out two successive oxidations to generate the two sesquiterpenoids. Bioactivity assays 22 showed that only 9-hydroxy-10,11-epoxyzingiberene exhibits substantial toxicity against B. 23tabaci. In addition, both 9-hydroxy-zingiberene and 9-hydroxy-10,11-epoxyzingiberene display 24 substantial growth inhibitory activities against a range of microorganisms, including Bacillus 25 subtilis, Phytophtora infestans and Botrytis cinerea. Our work shows that trichome secretions 26 from wild tomato species can provide protection against a wide variety of organisms. In 27 addition, the availability of the genes encoding the enzymes for the pathway of 7-epi-28 zingiberene derivatives makes it possible to introduce this trait in cultivated tomato by precision 29 breeding. 30 sesquiterpene synthases able to convert Z,Z-FPP have been identified in S. habrochaites. The 59 santalene and bergamotene synthase (ShSBS) is a multiproduct cyclase which makes (+)-α-60

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Metabolic Gene Clusters in Eukaryotes

Cited by 155 publications

References 190 publications

Diversity of Secondary Metabolism in Aspergillus nidulans Clinical Isolates

Diversity of Secondary Metabolism in Aspergillus nidulans Clinical Isolates

Patterns of diverse gene functions in genomic neighborhoods predict gene function and phenotype

Two novel 7-epi-zingiberene derivatives with biological activity fromSolanum habrochaitesare produced by a single cytochrome P450 monooxygenase

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