Linking secondary metabolites to gene clusters through genome sequencing of six diverseAspergillusspecies

Abstract

<p id="d10139028e546">The genus of <i>Aspergillus</i> holds fungi relevant to plant and human pathology, food biotechnology, enzyme production, model organisms, and a selection of extremophiles. Here we present six whole-genome sequences that represent unexplored branches of the <i>Aspergillus</i> genus. The comparison of these genomes with previous genomes, coupled with extensive chemical analysis, has allowed us to identify genes for toxins, antibiotics, and anticancer compounds, as well as show that <i>Aspergillus novofumigatus</i> is potentially as pathogenic as <i>Aspergillus fumigatus</i>, and has an even more diverse set of secreted bioactive compounds. The findings are of interest to industrial biotechnology and basic research, as well as medical and clinical research. </p><p class="first" id="d10139028e561">The fungal genus of <i>Aspergillus</i> is highly interesting, containing everything from industrial cell factories, model organisms, and human pathogens. In particular, this group has a prolific production of bioactive secondary metabolites (SMs). In this work, four diverse <i>Aspergillus</i> species ( <i>A. campestris</i>, <i>A. novofumigatus</i>, <i>A. ochraceoroseus</i>, and <i>A. steynii</i>) have been whole-genome PacBio sequenced to provide genetic references in three <i>Aspergillus</i> sections. <i>A. taichungensis</i> and <i>A. candidus</i> also were sequenced for SM elucidation. Thirteen <i>Aspergillus</i> genomes were analyzed with comparative genomics to determine phylogeny and genetic diversity, showing that each presented genome contains 15–27% genes not found in other sequenced Aspergilli. In particular, <i>A. novofumigatus</i> was compared with the pathogenic species <i>A. fumigatus</i>. This suggests that <i>A. novofumigatus</i> can produce most of the same allergens, virulence, and pathogenicity factors as <i>A. fumigatus</i>, suggesting that <i>A. novofumigatus</i> could be as pathogenic as <i>A. fumigatus</i>. Furthermore, SMs were linked to gene clusters based on biological and chemical knowledge and analysis, genome sequences, and predictive algorithms. We thus identify putative SM clusters for aflatoxin, chlorflavonin, and ochrindol in <i>A. ochraceoroseus</i>, <i>A. campestris</i>, and <i>A. steynii</i>, respectively, and novofumigatonin, <i>ent</i>-cycloechinulin, and <i>epi</i>-aszonalenins in <i>A. novofumigatus</i>. Our study delivers six fungal genomes, showing the large diversity found in the <i>Aspergillus</i> genus; highlights the potential for discovery of beneficial or harmful SMs; and supports reports of <i>A. novofumigatus</i> pathogenicity. It also shows how biological, biochemical, and genomic information can be combined to identify genes involved in the biosynthesis of specific SMs. </p>