RT Journal Article
SR Electronic
T1 Allele-specific binding of RNA-binding proteins reveals functional genetic variants in the RNA
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 396275
DO 10.1101/396275
A1 Ei-Wen Yang
A1 Jae Hoon Bahn
A1 Esther Yun-Hua Hsiao
A1 Boon Xin Tan
A1 Yiwei Sun
A1 Ting Fu
A1 Bo Zhou
A1 Erc L. Van Nostrand
A1 Gabriel A. Pratt
A1 Peter Freese
A1 Xintao Wei
A1 Giovanni Quinones-Valdez
A1 Alexander E. Urban
A1 Brenton R. Graveley
A1 Christopher B. Burge
A1 Gene W. Yeo
A1 Xinshu Xiao
YR 2018
UL http://biorxiv.org/content/early/2018/08/20/396275.abstract
AB Allele-specific protein-RNA binding is an essential aspect that may reveal functional genetic variants influencing RNA processing and gene expression phenotypes. Recently, genome-wide detection of in vivo binding sites of RNA binding proteins (RBPs) is greatly facilitated by the enhanced UV crosslinking and immunoprecipitation (eCLIP) protocol. Hundreds of eCLIP-Seq data sets were generated from HepG2 and K562 cells during the ENCODE3 phase. These data afford a valuable opportunity to examine allele-specific binding (ASB) of RBPs. To this end, we developed a new computational algorithm, called BEAPR (Binding Estimation of Allele-specific Protein-RNA interaction). In identifying statistically significant ASB sites, BEAPR takes into account UV cross-linking induced sequence propensity and technical variations between replicated experiments. Using simulated data and actual eCLIP-Seq data, we show that BEAPR largely outperforms often-used methods Chi-Squared test and Fisher’s Exact test. Importantly, BEAPR overcomes the inherent over-dispersion problem of the other methods. Complemented by experimental validations, we demonstrate that ASB events are significantly associated with genetic regulation of splicing and mRNA abundance, supporting the usage of this method to pinpoint functional genetic variants in post-transcriptional gene regulation. Many variants with ASB patterns of RBPs were found as genetic variants with cancer or other disease relevance. About 38% of ASB variants were in linkage disequilibrium with single nucleotide polymorphisms from genome-wide association studies. Overall, our results suggest that BEAPR is an effective method to reveal ASB patterns in eCLIP and can inform functional interpretation of disease-related genetic variants.