Cells and organisms, from simple to complex, carry the same genetic DNA sequence organized into genes.
Multicellular eukaryotes transcribe and process genes into RNA isoforms through a process called alternative
splicing. Alternative splicing is developmentally and cell-type specifically regulated. It is foundational to how
higher organisms’ genomes are decoded. Yet, critical and fundamental questions regarding its regulation and
the function of its output remain unanswered. For example, circRNA being a ubiquitous product of alternative
splicing was only discovered in 2012, and its regulation and function remains enigmatic. circRNAs’ discovery
revealed a larger critical knowledge gap in the field for “what, how and why” genes are alternatively spliced.
What RNA splice variants are expressed, how splicing is regulated and which spliced RNAs have essential
functions? Answering these questions is critical for predicting which of myriad genetic variants cause disease
and why they do so. Answers will also enable a new generation of digital nucleic acid biomarkers and
diagnostics for disease, drug targets for correcting dysregulated splicing and identification of pathogenic
protein- or non-coding products (respectively) as well as fundamental basic scientific insight into evolution and
function of eukaryotic genomes. The proposed research will couple novel statistical analyses of -omics data by
taking an unbiased approach and including biological features that are understudied or un-annotated.
Predictions will be coupled with incisive experimental validation to reveal new principles of how RNAs,
including circRNAs, are spliced and how they function. This research potentiates significant new discoveries in
why alternative splicing exists and how this understanding can be used for precision medicine.