Functional relationship between genetic variations and alternative splicing in Yeast

Abstract

newline Candida auris is a newly emerged fungal pathogen which is frequently found to be resistant towards all frontline antifungals. As a result, a greater emphasis is now being laid to uncover the mechanisms governing antifungal resistance. While alterations at the genomic level are frequently addressed, post-transcriptional events are rarely studied. Notably, due to negligible intronic regions within the genes of the Candida genus, information regarding alternative splicing (AS) and its consequences in antifungal resistance remain obscure. To bridge this evident lacuna, in the current study we investigated AS events from transcriptomic datasets of drug-adapted C. auris isolates published recently by our group. We have discovered genome-wide alternative splicing events from two different clades of C. auris. Our analysis shows that alternative splicing events are greatly influenced by non-canonical splice sites and can potentially disrupt gene expression. Since, mutations that interfere with essential splicing events can result in a wide variety of diseases, we mapped the differentially spliced junctions with the mutations specifically missense mutations that lies within such junctions. Our main aim was to find the effect of alternative splicing on genetic variants or vice-versa in term of Phenotype changes (on the dynamics of Protein structures). To further evaluate these functional consequences, we exploited molecular dynamics simulation with the ortholog of C. albicans Nup60 to reveal that alternative splicing and missense mutations can together have implications in changing the structural dynamics of proteins.