When pitch adds to volume: Coregulation of transcript diversity predicts gene function

Abstract

Background: Genes corregulate their overall transcript volumes to perform their physiological functions. However, it is unknown if they additionally coregulate their transcript diversities. We studied the reliability, consistency and functional associations of co-splicing correlations of genes of interest, across two independent studies, multiple tissues and two statistical methods. We thoroughly investigated the reproducibility of co-splicing correlations of APP, the candidate gene of Azheimer's disease (AD). We then studied how co-splicing correlations in different tissues contributed to predict functional interactions of three other genes and finally computed co-splicing frequency for 17 thousand genes across 52 human tissues. Results: We replicated co-splicing correlations between APP and 5 AD-related genes and reproduced expected enrichment of APP co-splicing in synaptic vesicle cycle and proteosome pathways. We observed novel associations for tissue vulnerability to disease with enrichment in APP co-splicing, co-expression and epistasis in AD. APP co-splicing was the strongest predictor and replicated between studies. We confirmed known gene interactions of PRPF8 and GRIA1 in testis and brain cortex, and observed a novel interaction of FGFR2, in breast and prostate, modulated by cancer risk-variants. We produced a co-splicing map across 52 human tissues to help predict the function of over 17 thousand genes. Conclusions: We show that coregulation of transcript diversities provides novel biological insights in gene physiology and helps to interpret GWAS results. Co-splicing correlations are reliable and frequent and should be further pursued to help predict gene function. Our results additionally support current AD interventions aiming at the ubiquitin proteosome pathway but unveil the need to consider transcript diversity in addition to volume to assess treatment response and susceptibility to the disease.