ABSTRACT
Most clinical diagnostic and genomic research setups focus almost exclusively on coding regions and essential splice sites, thereby overlooking other non-coding variants. As a result, intronic variants that can promote mis-splicing events across a range of diseases, including cancer, are yet to be systematically investigated. Such investigations would require both genomic and transcriptomic data, but there currently exist very few datasets that satisfy these requirements. We address this by developing a single-nucleus full-length RNA-sequencing approach that allows for the detection of potentially pathogenic intronic variants. We exemplify the potency of our approach by applying pancreatic cancer tumor and tumor-derived specimens and linking intronic variants to splicing dysregulation. We specifically find that prominent intron retention and pseudo-exon activation events are shared by the tumors and affect genes encoding key transcriptional regulators. Our work paves the way for the assessment and exploitation of intronic mutations as powerful prognostic markers and potential therapeutic targets in cancer.
ABSTRACT
A novel virus emerged from Wuhan, China, at the end of 2019 and quickly evolved into a pandemic, significantly impacting various industries, especially healthcare. One critical lesson from COVID-19 is the importance of understanding and predicting underlying comorbidities to better prioritize care and pharmacological therapies. Factors like age, race, and comorbidity history are crucial in determining disease mortality. While clinical data from hospitals and cohorts have led to the identification of these comorbidities, traditional approaches often lack a mechanistic understanding of the connections between them. In response, we utilized a deep learning approach to integrate COVID-19 data with data from other diseases, aiming to detect comorbidities with mechanistic insights. Our modified algorithm in the mpDisNet package, based on word-embedding deep learning techniques, incorporates miRNA expression profiles from SARS-CoV-2 infected cell lines and their target transcription factors. This approach is aligned with the emerging field of network medicine, which seeks to define diseases based on distinct pathomechanisms rather than just phenotypes. The main aim is discovery of possible unknown comorbidities by connecting the diseases by their miRNA mediated regulatory interactions. The algorithm can predict the majority of COVID-19's known comorbidities, as well as several diseases that have yet to be discovered to be comorbid with COVID-19. These potentially comorbid diseases should be investigated further to raise awareness and prevention, as well as informing the comorbidity research for the next possible outbreak.
