Genome-wide patterns of non-coding sequence variation in the major fungal pathogenAspergillus fumigatus

Abstract

AbstractA. fumigatusis a deadly fungal pathogen, responsible for >400,000 infections/year and high mortality rates.A. fumigatusstrains exhibit variation in infection-relevant traits, including in their virulence. However, mostA. fumigatusprotein-coding genes, including those that modulate its virulence, are shared betweenA. fumigatusstrains and closely related non-pathogenic relatives. We hypothesized thatA. fumigatusgenes 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 263A. fumigatusstrains.A. fumigatusnon-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 modulateA. fumigatusvirulence. Non-coding region variation betweenA. fumigatusstrains included single nucleotide polymorphisms and insertions or deletions of at least a few nucleotides. These results show that non-coding regions ofA. fumigatusgenes harbor greater sequence variation than protein-coding regions, raising the hypothesis that this variation may contribute toA. fumigatusphenotypic heterogeneity.