Allele-specific binding of RNA-binding proteins reveals functional genetic variants in the RNA

Allele-specific protein-RNA binding is an essential aspect that may reveal functional genetic variants (GVs) mediating post-transcriptional regulation. Recently, genome-wide detection of in vivo binding of RNA-binding proteins is greatly facilitated by the enhanced crosslinking and immunoprecipitation (eCLIP) method. We developed a new computational approach, called BEAPR, to identify allele-specific binding (ASB) events in eCLIP-Seq data. BEAPR takes into account crosslinking-induced sequence propensity and variations between replicated experiments. Using simulated and actual data, we show that BEAPR largely outperforms often-used count analysis methods. Importantly, BEAPR overcomes the inherent overdispersion problem of these methods. Complemented by experimental validations, we demonstrate that the application of BEAPR to ENCODE eCLIP-Seq data of 154 proteins helps to predict functional GVs that alter splicing or mRNA abundance. Moreover, many GVs with ASB patterns have known disease relevance. Overall, BEAPR is an effective method that helps to address the outstanding challenge of functional interpretation of GVs.
National Human Genome Research Institute (U.S.) (ENCODE Project, grant U01HG009417)
National Human Genome Research Institute (U.S.) (ENCODE Project, grant U54HG007005)
National Institutes of Health (U.S.) (NIH R01HG006264)
National Institutes of Health (U.S.) (NIH R01AG056476)
Damon Runyon Cancer Research Foundation (DRG-2172-13, Merck Fellow)
National Institutes of Health (U.S.) (K99 grant from the NIH (HG009530))
National Science Foundation (U.S.) (GraduateResearch Fellowship)