Population structure in a fungal human pathogen is potentially linked to pathogenicity

Authors: HATMAKER, ELIZABETH - Vanderbilt University; BARBER, AMELIA - Friedrick-Schiller University; Drott, Milton; SAUTERS, THOMAS - Vanderbilt University; GUMILANG, ADIYANTARA - Vanderbilt University; ALASRUEY-IZQUIERDO, ANA - National Center For Microbiology, The Institute Of Health Carlos Iii; HERMOSO-GARCIA, DEA - Institut Pasteur - France; EAGAN, JUSTIN - University Of Wisconsin; KELLER, NANCY - University Of Wisconsin; KONTOYIANNIS, DIMITRIOS - University Of Texas; KURZAI, OLIVER - Hans-Knoll Institute; ROKAS, ANTONIS - Vanderbilt University

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/18/2025
Publication Date: 8/15/2025
Citation: Hatmaker, E.A., Barber, A.E., Drott, M.T., Sauters, T.J., Gumilang, A., Alasruey-Izquierdo, A., Hermoso-Garcia, D., Eagan, J.L., Keller, N.P., Kontoyiannis, D.P., Kurzai, O., Rokas, A. 2025. Population structure in a fungal human pathogen is potentially linked to pathogenicity. Nature Communications. 16. Article 7594. https://doi.org/10.1038/s41467-025-62777-9.
DOI: https://doi.org/10.1038/s41467-025-62777-9

Interpretive Summary: The fungus, Aspergillus flavus, is a major pathogen of agricultural products. While this organism is notorious for crop losses and it's production of the carcinogen, aflatoxin, little work has looked at the role of this organism in causing disease of humans. Indeed, A. flavus is the second leading cause of invasive aspergillosis, an often fatal disease that impacts mostly immune-compramized individuals. This pathogen can also cause human keratitis, particularly among agricultural workers who may be exposed in the field. We used whole-genome sequencing of 250 isolates, including 70 newly sequenced clinical isolates to identify that a single lineage of the fungus is more commonly associated with human pathogenesis. We identify a subset of genes that are present only in this lineage as important for future study to understand the evolution of this fungal pathogen.

Technical Abstract: The saprotrophic fungus Aspergillus flavus is a clinically and agriculturally important species responsible for devastating human infections and contamination of seed crops. To examine population structure and define the pan-genome of A. flavus, we collected genomes from 250 (95 clinical and 155 environmental) isolates from 9 countries, including 70 newly sequenced clinical isolates. Using over 900,000 single nucleotide polymorphisms (SNPs), we identified five A. flavus populations based on genetic distance; these five populations corresponded to distinct clades in the genome-wide A. flavus phylogeny of the 250 isolates. The core genome of A. flavus consisted of over 10,000 protein families present in at least 95% of isolates. Of these, 3,375 were single-copy orthologs present in all strains. Accessory genes, including genes within biosynthetic gene clusters, were distributed unequally across the five populations. Strikingly, although clinical isolates were present in all but one population, we found that over 75% of all clinical isolates were from a single population. These results suggest that in contrast to the cosmopolitan major pathogen Aspergillus fumigatus, A. flavus pathogenicity is strongly associated with population structure, highlighting the value of whole genome sequencing of geographically diverse clinical and environmental isolates of clinically relevant fungi.