Extensive non-coding sequence divergence between the major human pathogen Aspergillus fumigatus and its relatives

• Published in: Frontiers in fungal biology Vol. 3
• Main Authors: Brown, Alec, Mead, Matthew E, Steenwyk, Jacob L, Goldman, Gustavo H, Rokas, Antonis
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 2022
• Subjects: Aspergillus fumigatus; evolution; evolutionary rate; fungal genomics; non-coding region; virulence factor; non-coding region; virulence factor; evolution; fungal genomics; Aspergillus fumigatus; different evolutionary rate
• ISSN: 2673-6128; 2673-6128
• DOI: 10.3389/ffunb.2022.802494

Invasive aspergillosis is a deadly fungal disease; more than 400,000 patients are infected worldwide each year and the mortality rate can be as high as 50-95%. Of the ~450 species in the genus only a few are known to be clinically relevant, with the major pathogen being responsible for ~50% of all invasive mold infections. Genomic comparisons between and other species have historically focused on protein-coding regions. However, most genes, including those that modulate its virulence, are also present in other pathogenic and non-pathogenic closely related species. Our hypothesis is that differential gene regulation - mediated through the non-coding regions upstream of genes' first codon - contributes to pathogenicity. To begin testing this, we compared non-coding regions upstream of the first codon of single-copy orthologous genes from the two reference strains Af293 and A1163 and eight closely related section species. We found that these non-coding regions showed extensive sequence variation and lack of homology across species. By examining the evolutionary rates of both protein-coding and non-coding regions in a subset of orthologous genes with highly conserved non-coding regions across the phylogeny, we identified 418 genes, including 25 genes known to modulate virulence, whose non-coding regions exhibit a different rate of evolution in . Examination of sequence alignments of these non-coding regions revealed numerous instances of insertions, deletions, and other types of mutations of at least a few nucleotides in compared to its close relatives. These results show that closely related species that vary greatly in their pathogenicity exhibit extensive non-coding sequence variation and identify numerous changes in non-coding regions of genes known to contribute to virulence.