Stochastic principles governing alternative splicing of RNA

The dominance of the major transcript isoform relative to other isoforms from the same gene generated by alternative splicing (AS) is essential to the maintenance of normal cellular physiology. However, the underlying principles that determine such dominance remain unknown. Here, we analyzed the physical AS process and found that it can be modeled by a stochastic minimization process, which causes the scaled expression levels of all transcript isoforms to follow the same Weibull extreme value distribution. Surprisingly, we also found a simple equation to describe the median frequency of transcript isoforms of different dominance. This two-parameter Weibull model provides the statistical distribution of all isoforms of all transcribed genes, and reveals that previously unexplained observations concerning relative isoform expression derive from these principles.Author summary: Alternative RNA splicing within eukaryotic cells enables each gene to generate multiple different mature transcripts which further encode proteins with distinct or even opposing functions. The relative frequencies of the transcript isoforms generated by a particular gene are essential to the maintenance of normal cellular physiology; however, the underlying mechanisms and principles that govern these frequencies are unknown. We analyzed the frequency distribution of all transcript isoforms in highly purified human T cell subsets and built a simple mathematical model, based on the physical process of alternative splicing, which provides statistical principles that govern this process. This model matches very well with the observed distributions of expression levels and relative frequencies of all transcript isoforms from different tissues and cell lines. Notably, we used this model to elucidate many previously unexplained observations concerning transcript isoform expression. More importantly, this model reveals the existence of simple statistical principles that can be applied to understanding an essential and complex biological process such as alternative splicing.