Long-term stability of acquired drug resistance and resistance associated mutations in the fungal pathogen ().

The limited number of available antifungal drugs and the increasing number of fungal isolates that show drug or multidrug resistance pose a serious medical threat. Several yeast pathogens, such as (), show a remarkable ability to develop drug resistance during treatment through the acquisition of genetic mutations. However, how stable this resistance and the underlying mutations are in non-selective conditions remains poorly characterized.

Recent gene selection and drug resistance underscore clinical adaptation across Candida species.

Understanding how microbial pathogens adapt to treatments, humans and clinical environments is key to infer mechanisms of virulence, transmission and drug resistance. This may help improve therapies and diagnostics for infections with a poor prognosis, such as those caused by fungal pathogens, including Candida. Here we analysed genomic variants across approximately 2,000 isolates from six Candida species (C.

PerSVade: personalized structural variant detection in any species of interest.

Structural variants (SVs) underlie genomic variation but are often overlooked due to difficult detection from short reads. Most algorithms have been tested on humans, and it remains unclear how applicable they are in other organisms. To solve this, we develop perSVade (personalized structural variation detection), a sample-tailored pipeline that provides optimally called SVs and their inferred accuracy, as well as small and copy number variants.

Using genomics to understand the mechanisms of virulence and drug resistance in fungal pathogens.

Fungal pathogens pose an increasingly worrying threat to human health, food security and ecosystem diversity. To tackle fungal infections and improve current diagnostic and therapeutic tools it is necessary to understand virulence and antifungal drug resistance mechanisms in diverse species. Recent advances in genomics approaches have provided a suitable framework to understand these phenotypes, which ultimately depend on genetically encoded determinants.

Narrow mutational signatures drive acquisition of multidrug resistance in the fungal pathogen Candida glabrata.

Fungal infections are a growing medical concern, in part due to increased resistance to one or multiple antifungal drugs. However, the evolutionary processes underpinning the acquisition of antifungal drug resistance are poorly understood. Here, we used experimental microevolution to study the adaptation of the yeast pathogen Candida glabrata to fluconazole and anidulafungin, two widely used antifungal drugs with different modes of action.

Shared evolutionary footprints suggest mitochondrial oxidative damage underlies multiple complex I losses in fungi.

Oxidative phosphorylation is among the most conserved mitochondrial pathways. However, one of the cornerstones of this pathway, the multi-protein complex NADH : ubiquinone oxidoreductase (complex I) has been lost multiple independent times in diverse eukaryotic lineages. The causes and consequences of these convergent losses remain poorly understood.

Poor codon optimality as a signal to degrade transcripts with frameshifts.

Frameshifting errors are common and mRNA quality control pathways, such as nonsense-mediated decay (NMD), exist to degrade these aberrant transcripts. Recent work has shown the existence of a genetic link between NMD and codon-usage mediated mRNA decay. Here we present computational evidence that these pathways are synergic for removing frameshifts.

Promoter Activity Buffering Reduces the Fitness Cost of Misregulation.

Organisms regulate gene expression through changes in the activity of transcription factors (TFs). In yeast, the response of genes to changes in TF activity is generally assumed to be encoded in the promoter. To directly test this assumption, we chose 42 genes and, for each, replaced the promoter with a synthetic inducible promoter and measured how protein expression changes as a function of TF activity.

Promoter architecture determines cotranslational regulation of mRNA.

Information that regulates gene expression is encoded throughout each gene but if different regulatory regions can be understood in isolation, or if they interact, is unknown. Here we measure mRNA levels for 10,000 open reading frames (ORFs) transcribed from either an inducible or constitutive promoter. We find that the strength of cotranslational regulation on mRNA levels is determined by promoter architecture.