Global multi-omics profiling reveals evolutionary drivers of phylogeographic diversity of fungal specialized metabolism

Abstract Chemical innovation is essential for fungi to adapt to specific geographical environments and ecological niches. However, it remains unclear how genomic changes drive fungal specialized metabolic differentiation across the biosphere. Here, we studied the global genomic and metabolic diversity of the aflatoxin-producing Aspergillus flavus as a case. We generated paired genome and metabolome data for > 550 strains from across China, and supplemented this with 187 publicly available genomes from other countries. We found that the global genetic diversity of A. flavus shows strong phylogeographic patterns, with specific clades associating with different environments. These clades exhibit distinct specialized metabolic profiles, with low-aflatoxin-producing clades often producing other mycotoxins instead. Furthermore, clade-specific gene clusters do exist that could be linked to clade-specific metabolites, implying that different niches select for the production of different toxins. Our results reveal that these different mycotoxin profiles are generally not explained by loss or gain of biosynthetic gene clusters, but are likely driven by regulatory and primary metabolic variation. Altogether, our findings provide a framework to understand fungal environmental adaptation and pave the path towards enhanced mycotoxin early risk prediction and ‘personalized’ geographical control strategies.