Recognition, variability and regulation of 5 ́ splicing sites

MAXIMILIANO BECKEL; MARCELO YANOVSKY; ARIEL CHERNOMORETZ; ANDRES RABINOVICH

Conferencia; Stochastic Physics in Biology; 2019

Gordon Research Conference

Genes of eukaryotic organisms are usually composed of coding sequences called exons (used explicitly to assemble a protein) interrupted by non-coding sequences called introns. After transcription, the latter must be removed from the mRNA molecule so that a functional protein can be synthesized from the information contained in the now mature transcript. This process is called splicing and involves the coordinated action of hundreds of proteins that are known as 'the cellular spliceosome'. One key step in this 'splicing' procedure involves the identification of exon-intron interfaces (a.k.a 5' splicing sites). This molecular recognition process, however, should deal with the natural variability present throughout the genome sequences of eukaryotic organisms.In this work, we analyzed more than 300,000 exon-intron interfaces of the Arabidospis Thaliana genomewe and developed an information-based model to account for 5'ss sequence statistics up to two-site correlations. We verified that the introduced information-based energetic scale correlates well with expected biochemical binding energies, and served to measure distances from the completely ordered sequence up to random ones. Analyzing the transcriptome of two natural variants of Arabidopsis we  verified that our model served to  quantify the strength of a given site. In addition, we used our model to analyzed the effect of the mutation of PRMT5, a protein that methylates splicing-related proteins, on both natural arabidiospsis variants. We found that PRMT5 plays a key role in the splicing of weak sites. Furthermore, despite being an indirect regulator, the observed effects showed a major cis-component .