An evolutionary genomic approach reveals both conserved and species-specific genetic elements related to human disease in closely related Aspergillus fungi

Aspergillosis is an
important opportunistic human disease caused by filamentous fungi in the genus Aspergillus.
Roughly 70% of infections are caused by Aspergillus fumigatus, with the rest
stemming from approximately a dozen other Aspergillus species. Several
of these pathogens are closely related
to A. fumigatus and belong in the same taxonomic section,
section Fumigati. Pathogenic species are frequently most closely related
to non-pathogenic ones, suggesting Aspergillus pathogenicity evolved
multiple times independently. To understand the repeated evolution of Aspergillus pathogenicity, we performed comparative genomic analyses on 18 strains from 13 species,
including 8 species in section Fumigati, which
aimed to identify genes, both ones previously connected to virulence as well as
ones never before implicated, whose evolution differs between pathogens and non-pathogens.
We found that most genes were present in all species, including approximately
half of those previously connected to virulence, but a few genes were section-
or species-specific. Evolutionary rate analyses identified over 1,700 genes whose
evolutionary rate differed between pathogens and non-pathogens and dozens of
genes whose rates differed between specific pathogens and the rest of the taxa.
For example, we found 34 genes whose evolutionary rate was uniquely different
in A. fumigatus and 85 genes whose rate was uniquely different in the
pathogen A. lentulus. Functional testing of deletion mutants of 17
transcription factor-encoding genes whose evolution differed between pathogens
and non-pathogens identified eight genes that affect either fungal survival in
a model of phagocytic killing, host survival in an animal model of fungal
disease, or both. These results suggest that the evolution of pathogenicity in Aspergillus
involved both conserved and species-specific genetic elements, illustrating
how an evolutionary genomic approach informs the study of fungal disease.
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