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

被引:29
|
作者
Yang, Ei-Wen [1 ]
Bahn, Jae Hoon [1 ]
Hsiaol, Esther Yun-Hua [1 ,2 ]
Tan, Boon Xin [1 ]
Sun, Yiwei [1 ]
Fu, Ting [1 ,3 ]
Zhou, Bo [4 ]
Van Nostrand, Eric L. [5 ,6 ]
Pratt, Gabriel A. [5 ,6 ]
Freese, Peter [7 ]
Wei, Xintao [8 ]
Quinones-Valdez, Giovanni [2 ]
Urban, Alexander E. [4 ]
Graveley, Brenton R. [8 ]
Burge, Christopher B. [7 ]
Yeo, Gene W. [5 ,6 ,9 ,10 ]
Xiao, Xinshu [1 ,2 ,3 ,11 ]
机构
[1] UCLA, Dept Integrat Biol & Physiol, Los Angeles, CA 90095 USA
[2] UCLA, Dept Bioengn, Los Angeles, CA 90095 USA
[3] UCLA, Mol Cellular & Integrat Physiol Interdept Program, Los Angeles, CA 90095 USA
[4] Stanford Univ, Dept Psychiat & Behav Sci, Dept Genet, Sch Med, Palo Alto, CA 94305 USA
[5] UCSD, Dept Cellular & Mol Med, La Jolla, CA 92093 USA
[6] UCSD, Inst Genom Med, La Jolla, CA 92093 USA
[7] MIT, Dept Biol, Cambridge, MA 02139 USA
[8] UConn Hlth, Dept Genet & Genome Sci, Inst Syst Genom, Farmington, CT 06030 USA
[9] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117593, Singapore
[10] ASTAR, Mol Engn Lab, Singapore, Singapore
[11] UCLA, Mol Biol Inst, Los Angeles, CA 90095 USA
关键词
3' SPLICE-SITE; EXPRESSION; DISCOVERY; GENOTYPE; INVASION; SEQUENCE; INTRONS; ATPASE; GEMIN5;
D O I
10.1038/s41467-019-09292-w
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:15
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