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Genome-wide patterns of non-coding sequence variation in the major fungal pathogen Aspergillus fumigatus
Alec Brown1,2, Jacob L Steenwyk1,2,3, Antonis Rokas1,2
1Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA.
Abstract:
A.fumigatus is a deadly fungal pathogen, responsible for >400,000 infections/year and high mortality rates. A. fumigatus strains exhibit variation in infection-relevant traits, including in their virulence. However, most A. fumigatus protein-coding genes, including those that modulate its virulence, are shared between A. fumigatus strains and closely related non-pathogenic relatives. We hypothesized that A. fumigatus genes exhibit substantial genetic variation in the non-coding regions immediately upstream to the start codons of genes, which could reflect differences in gene regulation between strains. To begin testing this hypothesis, we identified 5,812 single-copy orthologs across the genomes of 263 A. fumigatus strains. A. fumigatus non-coding regions showed higher levels of sequence variation compared to their corresponding protein-coding regions. Specifically, we found that 1,274 non-coding regions exhibited <75% nucleotide sequence similarity (compared to 928 protein-coding regions) and 3,721 non-coding regions exhibited between 75% and 99% similarity (compared to 2,482 protein-coding regions) across strains. Only 817 non-coding regions exhibited ≥99% sequence similarity compared to 2,402 protein-coding regions. By examining 2,482 genes whose protein-coding sequence identity scores ranged between 75% and 99%, we identified 478 total genes with signatures of positive selection only in their non-coding regions and 65 total genes with signatures only in their protein-coding regions. 28 of the 478 non-coding regions and 5 of the 65 protein-coding regions under selection are associated with genes known to modulate A. fumigatus virulence. Non-coding region variation between A. fumigatus strains included single nucleotide polymorphisms and insertions or deletions of at least a few nucleotides. These results show that non-coding regions of A. fumigatus genes harbor greater sequence variation than protein-coding regions, raising the hypothesis that this variation may contribute to A. fumigatus phenotypic heterogeneity.
Insights
Genetic variation in non-coding regions of Aspergillus fumigatus (A. fumigatus) contributes to strain differences. These non-coding regions show higher sequence variation than protein-coding genes, potentially explaining phenotypic heterogeneity in this fungal pathogen.
Area of Science:
- Genomics
- Mycology
- Evolutionary Biology
Background:
- Aspergillus fumigatus is a significant fungal pathogen causing over 400,000 infections annually with high mortality.
- Pathogenic traits, including virulence, vary among A. fumigatus strains, yet most protein-coding genes are conserved.
- Genetic variation in non-coding regions may drive differences in gene regulation and phenotypic diversity.
Approach:
- Analyzed genomes from 263 A. fumigatus strains to identify 5,812 single-copy orthologs.
- Compared sequence variation levels between non-coding and protein-coding regions across strains.
- Investigated signatures of positive selection in both coding and non-coding regions.
Key Points:
- Non-coding regions of A. fumigatus genes exhibit substantially higher sequence variation than protein-coding regions.
- A significant number of non-coding regions showed low nucleotide sequence similarity (<75%) across strains.
- Positive selection was detected in non-coding regions of genes associated with A. fumigatus virulence.
Conclusions:
- Non-coding regions are a major source of genetic variation in A. fumigatus.
- This variation in regulatory elements may underlie phenotypic heterogeneity and differences in virulence among strains.
- Further research into non-coding region variation is crucial for understanding A. fumigatus pathogenesis.
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