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

Ei-Wen Yang, Jae Hoon Bahn, Esther Yun-Hua Hsiao, Boon Xin Tan, Yiwei Sun, Ting Fu, Bo Zhou, Eric L. Van Nostrand, Gabriel A. Pratt, Peter Freese, Xintao Wei, Giovanni Quinones-Valdez, Alexander E. Urban, Brenton R. Graveley, Christopher B. Burge, Gene W. Yeo and Xinshu Xiao ()
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Ei-Wen Yang: UCLA
Jae Hoon Bahn: UCLA
Esther Yun-Hua Hsiao: UCLA
Boon Xin Tan: UCLA
Yiwei Sun: UCLA
Ting Fu: UCLA
Bo Zhou: Stanford University School of Medicine
Eric L. Van Nostrand: UCSD
Gabriel A. Pratt: UCSD
Peter Freese: MIT
Xintao Wei: UConn Health
Giovanni Quinones-Valdez: UCLA
Alexander E. Urban: Stanford University School of Medicine
Brenton R. Graveley: UConn Health
Christopher B. Burge: MIT
Gene W. Yeo: UCSD
Xinshu Xiao: UCLA

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-09292-w

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