期刊
CELL
卷 163, 期 3, 页码 698-711出版社
CELL PRESS
DOI: 10.1016/j.cell.2015.09.054
关键词
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资金
- National Science Foundation (NSF) [0954566]
- Burroughs Wellcome Career Award at the Scientific Interface
- Direct For Computer & Info Scie & Enginr
- Division of Computing and Communication Foundations [1317694] Funding Source: National Science Foundation
- Div Of Chem, Bioeng, Env, & Transp Sys
- Directorate For Engineering [0954566] Funding Source: National Science Foundation
Most human transcripts are alternatively spliced, and many disease-causing mutations affect RNA splicing. Toward better modeling the sequence determinants of alternative splicing, we measured the splicing patterns of over two million (M) synthetic mini-genes, which include degenerate subsequences totaling over 100 M bases of variation. The massive size of these training data allowed us to improve upon current models of splicing, as well as to gain new mechanistic insights. Our results show that the vast majority of hexamer sequence motifs measurably influence splice site selection when positioned within alternative exons, with multiple motifs acting additively rather than cooperatively. Intriguingly, motifs that enhance (suppress) exon inclusion in alternative 50 splicing also enhance (suppress) exon inclusion in alternative 30 or cassette exon splicing, suggesting a universal mechanism for alternative exon recognition. Finally, our empirically trained models are highly predictive of the effects of naturally occurring variants on alternative splicing in vivo.
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