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Fungal Biol."],"abstract":"<jats:p>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 <jats:italic>Aspergillus<\/jats:italic> only a few are known to be clinically relevant, with the major pathogen <jats:italic>Aspergillus fumigatus<\/jats:italic> being responsible for ~50% of all invasive mold infections. Genomic comparisons between <jats:italic>A. fumigatus<\/jats:italic> and other <jats:italic>Aspergillus<\/jats:italic> species have historically focused on protein-coding regions. However, most <jats:italic>A. fumigatus<\/jats:italic> 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 \u2013 mediated through the non-coding regions upstream of genes\u2019 first codon \u2013 contributes to <jats:italic>A. fumigatus<\/jats:italic> pathogenicity. To begin testing this, we compared non-coding regions upstream of the first codon of single-copy orthologous genes from the two <jats:italic>A. fumigatus<\/jats:italic> reference strains Af293 and A1163 and eight closely related <jats:italic>Aspergillus<\/jats:italic> section <jats:italic>Fumigati<\/jats:italic> 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 <jats:italic>A. fumigatus<\/jats:italic> virulence, whose non-coding regions exhibit a different rate of evolution in <jats:italic>A. fumigatus<\/jats:italic>. 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 <jats:italic>A. fumigatus<\/jats:italic> compared to its close relatives. These results show that closely related <jats:italic>Aspergillus<\/jats:italic> species that vary greatly in their pathogenicity exhibit extensive non-coding sequence variation and identify numerous changes in non-coding regions of <jats:italic>A. fumigatus<\/jats:italic> genes known to contribute to virulence.<\/jats:p>","DOI":"10.3389\/ffunb.2022.802494","type":"journal-article","created":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T08:49:50Z","timestamp":1657183790000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Extensive Non-Coding Sequence Divergence Between the Major Human Pathogen Aspergillus fumigatus and its Relatives"],"prefix":"10.3389","volume":"3","author":[{"given":"Alec","family":"Brown","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew E.","family":"Mead","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob L.","family":"Steenwyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo H.","family":"Goldman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonis","family":"Rokas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003573","article-title":"Regulation of Sulphur Assimilation Is Essential for Virulence and Affects Iron Homeostasis of the Human-Pathogenic Mould Aspergillus Fumigatus","volume":"9","author":"Amich","year":"2013","journal-title":"PloS Pathog."},{"key":"B2","doi-asserted-by":"publisher","first-page":"878","DOI":"10.1016\/j.molcel.2008.11.020","article-title":"A Library of Yeast Transcription Factor Motifs Reveals a Widespread Function for Rsc3 in Targeting Nucleosome Exclusion at Promoters","volume":"32","author":"Badis","year":"2008","journal-title":"Mol. 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