Genome-wide discovery of human splicing branchpoints

Mercer, Tim R., Clark, Michael B., Anderson, Stacey B., Brunck, Marion E., Haerty, Wilifried, Crawford, Joanna, Taft, Ryan J., Nielsen, Lars K., Dinger, Marcel E. and Mattick, John S. (2015) Genome-wide discovery of human splicing branchpoints. Genome Research, 25 2: 290-303. doi:10.1101/gr.182899.114

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Author Mercer, Tim R.
Clark, Michael B.
Anderson, Stacey B.
Brunck, Marion E.
Haerty, Wilifried
Crawford, Joanna
Taft, Ryan J.
Nielsen, Lars K.
Dinger, Marcel E.
Mattick, John S.
Title Genome-wide discovery of human splicing branchpoints
Journal name Genome Research   Check publisher's open access policy
ISSN 1549-5469
Publication date 2015-02
Year available 2015
Sub-type Article (original research)
DOI 10.1101/gr.182899.114
Open Access Status File (Publisher version)
Volume 25
Issue 2
Start page 290
End page 303
Total pages 14
Place of publication Cold Spring Harbor, NY, United States
Publisher Cold Spring Harbor Laboratory Press
Collection year 2016
Language eng
Abstract During the splicing reaction, the 5′ intron end is joined to the branchpoint nucleotide, selecting the next exon to incorporate into the mature RNA and forming an intron lariat, which is excised. Despite a critical role in gene splicing, the locations and features of human splicing branchpoints are largely unknown. We use exoribonuclease digestion and targeted RNA-sequencing to enrich for sequences that traverse the lariat junction and, by split and inverted alignment, reveal the branchpoint. We identify 59,359 high-confidence human branchpoints in >10,000 genes, providing a first map of splicing branchpoints in the human genome. Branchpoints are predominantly adenosine, highly conserved, and closely distributed to the 3′ splice site. Analysis of human branchpoints reveals numerous novel features, including distinct features of branchpoints for alternatively spliced exons and a family of conserved sequence motifs overlapping branchpoints we term B-boxes, which exhibit maximal nucleotide diversity while maintaining interactions with the keto-rich U2 snRNA. Different B-box motifs exhibit divergent usage in vertebrate lineages and associate with other splicing elements and distinct intron–exon architectures, suggesting integration within a broader regulatory splicing code. Lastly, although branchpoints are refractory to common mutational processes and genetic variation, mutations occurring at branchpoint nucleotides are enriched for disease associations.
Keyword Gene splicing
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published in Advance January 5, 2015

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Created: Mon, 09 Feb 2015, 09:39:06 EST by Cathy Fouhy on behalf of Aust Institute for Bioengineering & Nanotechnology