An interpretable model of pre-mRNA splicing for animal and plant genes

McCue, Kayla; Burge, Christopher B.

doi:10.1126/sciadv.adn1547

An interpretable model of pre-mRNA splicing for animal and plant genes

Journal Article · Wed May 08 00:00:00 EDT 2024 · Science Advances

DOI:https://doi.org/10.1126/sciadv.adn1547· OSTI ID:2471914

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Massachusetts Institute of Technology (MIT), Cambridge, MA (United States); , Massachusetts Institute of Technology, Cambridge, MA (United States)
Massachusetts Institute of Technology (MIT), Cambridge, MA (United States)

Pre-mRNA splicing is a fundamental step in gene expression, conserved across eukaryotes, in which the spliceosome recognizes motifs at the 3' and 5' splice sites (SSs), excises introns, and ligates exons. SS recognition and pairing is often influenced by protein splicing factors (SFs) that bind to splicing regulatory elements (SREs). Here, we describe SMsplice, a fully interpretable model of pre-mRNA splicing that combines models of core SS motifs, SREs, and exonic and intronic length preferences. We learn models that predict SS locations with 83 to 86% accuracy in fish, insects, and plants and about 70% in mammals. Learned SRE motifs include both known SF binding motifs and unfamiliar motifs, and both motif classes are supported by genetic analyses. Our comparisons across species highlight similarities between non-mammals, increased reliance on intronic SREs in plant splicing, and a greater reliance on SREs in mammalian splicing.

View Accepted Manuscript (DOE)

Research Organization:: Krell Institute, Ames, IA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: FG02-97ER25308

OSTI ID:: 2471914

Journal Information:: Science Advances, Journal Name: Science Advances Journal Issue: 19 Vol. 10; ISSN 2375-2548

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

References (42)

Evolution of SR protein and hnRNP splicing regulatory factors Busch, Anke; Hertel, Klemens J. WIREs RNA, Vol. 3, Issue 1 https://doi.org/10.1002/wrna.100	journal	September 2011
Exon and intron definition in pre-mRNA splicing: Exon and intron definition in pre-mRNA splicing De Conti, Laura; Baralle, Marco; Buratti, Emanuele Wiley Interdisciplinary Reviews: RNA, Vol. 4, Issue 1 https://doi.org/10.1002/wrna.1140	journal	October 2012
A minimal intron length but no specific internal sequence is required for splicing the large rabbit β-globin intron Wieringa, B.; Hofer, E.; Weissmann, C. Cell, Vol. 37, Issue 3 https://doi.org/10.1016/0092-8674(84)90426-4	journal	July 1984
Pre-mRNA splicing in higher plants Lorković, Zdravko J.; Wieczorek Kirk, Dominika A.; Lambermon, Mark H. L. Trends in Plant Science, Vol. 5, Issue 4 https://doi.org/10.1016/S1360-1385(00)01595-8	journal	April 2000
Systematic Identification and Analysis of Exonic Splicing Silencers Wang, Zefeng; Rolish, Michael E.; Yeo, Gene Cell, Vol. 119, Issue 6 https://doi.org/10.1016/j.cell.2004.11.010	journal	December 2004
The Spliceosome: Design Principles of a Dynamic RNP Machine Wahl, Markus C.; Will, Cindy L.; Lührmann, Reinhard Cell, Vol. 136, Issue 4 https://doi.org/10.1016/j.cell.2009.02.009	journal	February 2009
Learning the Sequence Determinants of Alternative Splicing from Millions of Random Sequences Rosenberg, Alexander B.; Patwardhan, Rupali P.; Shendure, Jay Cell, Vol. 163, Issue 3 https://doi.org/10.1016/j.cell.2015.09.054	journal	October 2015
Combinatorial Genetics Reveals a Scaling Law for the Effects of Mutations on Splicing Baeza-Centurion, Pablo; Miñana, Belén; Schmiedel, Jörn M. Cell, Vol. 176, Issue 3 https://doi.org/10.1016/j.cell.2018.12.010	journal	January 2019
Predicting Splicing from Primary Sequence with Deep Learning Jaganathan, Kishore; Kyriazopoulou Panagiotopoulou, Sofia; McRae, Jeremy F. Cell, Vol. 176, Issue 3 https://doi.org/10.1016/j.cell.2018.12.015	journal	January 2019
Comparative Analysis Identifies Exonic Splicing Regulatory Sequences—The Complex Definition of Enhancers and Silencers Goren, Amir; Ram, Oren; Amit, Maayan Molecular Cell, Vol. 22, Issue 6 https://doi.org/10.1016/j.molcel.2006.05.008	journal	June 2006
Sequence, Structure, and Context Preferences of Human RNA Binding Proteins Dominguez, Daniel; Freese, Peter; Alexis, Maria S. Molecular Cell, Vol. 70, Issue 5 https://doi.org/10.1016/j.molcel.2018.05.001	journal	June 2018
Quantitative Activity Profile and Context Dependence of All Human 5′ Splice Sites Wong, Mandy S.; Kinney, Justin B.; Krainer, Adrian R. Molecular Cell, Vol. 71, Issue 6 https://doi.org/10.1016/j.molcel.2018.07.033	journal	September 2018
Deciphering the splicing code Barash, Yoseph; Calarco, John A.; Gao, Weijun Nature, Vol. 465, Issue 7294 https://doi.org/10.1038/nature09000	journal	May 2010
A compendium of RNA-binding motifs for decoding gene regulation Ray, Debashish; Kazan, Hilal; Cook, Kate B. Nature, Vol. 499, Issue 7457 https://doi.org/10.1038/nature12311	journal	July 2013
Lessons from non-canonical splicing Sibley, Christopher R.; Blazquez, Lorea; Ule, Jernej Nature Reviews Genetics, Vol. 17, Issue 7 https://doi.org/10.1038/nrg.2016.46	journal	May 2016
Alternative splicing and evolution: diversification, exon definition and function Keren, Hadas; Lev-Maor, Galit; Ast, Gil Nature Reviews Genetics, Vol. 11, Issue 5 https://doi.org/10.1038/nrg2776	journal	April 2010
Context-dependent control of alternative splicing by RNA-binding proteins Fu, Xiang-Dong; Ares, Manuel Nature Reviews Genetics, Vol. 15, Issue 10 https://doi.org/10.1038/nrg3778	journal	August 2014
Intronic splicing enhancers, cognate splicing factors and context-dependent regulation rules Wang, Yang; Ma, Meng; Xiao, Xinshu Nature Structural & Molecular Biology, Vol. 19, Issue 10 https://doi.org/10.1038/nsmb.2377	journal	September 2012
A complex network of factors with overlapping affinities represses splicing through intronic elements Wang, Yang; Xiao, Xinshu; Zhang, Jianming Nature Structural & Molecular Biology, Vol. 20, Issue 1 https://doi.org/10.1038/nsmb.2459	journal	December 2012
A large-scale binding and functional map of human RNA-binding proteins Van Nostrand, Eric L.; Freese, Peter; Pratt, Gabriel A. Nature, Vol. 583, Issue 7818 https://doi.org/10.1038/s41586-020-2077-3	journal	July 2020
Prediction of protein–ligand binding affinity from sequencing data with interpretable machine learning Rube, H. Tomas; Rastogi, Chaitanya; Feng, Siqian Nature Biotechnology, Vol. 40, Issue 10 https://doi.org/10.1038/s41587-022-01307-0	journal	May 2022
Variation in sequence and organization of splicing regulatory elements in vertebrate genes Yeo, G.; Hoon, S.; Venkatesh, B. Proceedings of the National Academy of Sciences, Vol. 101, Issue 44 https://doi.org/10.1073/pnas.0404901101	journal	October 2004
A computational analysis of sequence features involved in recognition of short introns Lim, L. P.; Burge, C. B. Proceedings of the National Academy of Sciences, Vol. 98, Issue 20 https://doi.org/10.1073/pnas.201407298	journal	September 2001
Maximum Entropy Modeling of Short Sequence Motifs with Applications to RNA Splicing Signals Yeo, Gene; Burge, Christopher B. Journal of Computational Biology, Vol. 11, Issue 2-3 https://doi.org/10.1089/1066527041410418	journal	March 2004
Bayesian prediction of tissue-regulated splicing using RNA sequence and cellular context Xiong, Hui Yuan; Barash, Yoseph; Frey, Brendan J. Bioinformatics, Vol. 27, Issue 18 https://doi.org/10.1093/bioinformatics/btr444	journal	July 2011
TimeTree 5: An Expanded Resource for Species Divergence Times Kumar, Sudhir; Suleski, Michael; Craig, Jack M. Molecular Biology and Evolution, Vol. 39, Issue 8 https://doi.org/10.1093/molbev/msac174	journal	August 2022
RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression Shapiro, Marvin B.; Senapathy, Periannan Nucleic Acids Research, Vol. 15, Issue 17 https://doi.org/10.1093/nar/15.17.7155	journal	January 1987
APPRIS: annotation of principal and alternative splice isoforms Rodriguez, Jose Manuel; Maietta, Paolo; Ezkurdia, Iakes Nucleic Acids Research, Vol. 41, Issue D1 https://doi.org/10.1093/nar/gks1058	journal	November 2012
In silico prediction of splice-altering single nucleotide variants in the human genome Jian, Xueqiu; Boerwinkle, Eric; Liu, Xiaoming Nucleic Acids Research, Vol. 42, Issue 22 https://doi.org/10.1093/nar/gku1206	journal	November 2014
Splice-switching antisense oligonucleotides as therapeutic drugs Havens, Mallory A.; Hastings, Michelle L. Nucleic Acids Research, Vol. 44, Issue 14 https://doi.org/10.1093/nar/gkw533	journal	June 2016
Saturation mutagenesis reveals manifold determinants of exon definition Ke, Shengdong; Anquetil, Vincent; Zamalloa, Jorge Rojas Genome Research, Vol. 28, Issue 1 https://doi.org/10.1101/gr.219683.116	journal	December 2017
An efficient forward-backward algorithm for an explicit-duration hidden Markov model No authors listed IEEE Signal Processing Letters, Vol. 10, Issue 1 https://doi.org/10.1109/LSP.2002.806705	journal	January 2003
Predictive Identification of Exonic Splicing Enhancers in Human Genes Fairbrother, W. G. Science, Vol. 297, Issue 5583 https://doi.org/10.1126/science.1073774	journal	July 2002
The human splicing code reveals new insights into the genetic determinants of disease Xiong, H. Y.; Alipanahi, B.; Lee, L. J. Science, Vol. 347, Issue 6218 https://doi.org/10.1126/science.1254806	journal	December 2014
Introns and Splicing Elements of Five Diverse Fungi Kupfer, Doris M.; Drabenstot, Scott D.; Buchanan, Kent L. Eukaryotic Cell, Vol. 3, Issue 5 https://doi.org/10.1128/EC.3.5.1088-1100.2004	journal	October 2004
The evolution, impact and properties of exonic splice enhancers Cáceres, Eva Fernández; Hurst, Laurence D. Genome Biology, Vol. 14, Issue 12 https://doi.org/10.1186/gb-2013-14-12-r143	journal	December 2013
MutPred Splice: machine learning-based prediction of exonic variants that disrupt splicing Mort, Matthew; Sterne-Weiler, Timothy; Li, Biao Genome Biology, Vol. 15, Issue 1 https://doi.org/10.1186/gb-2014-15-1-r19	journal	January 2014
MMSplice: modular modeling improves the predictions of genetic variant effects on splicing Cheng, Jun; Nguyen, Thi Yen Duong; Cygan, Kamil J. Genome Biology, Vol. 20, Issue 1 https://doi.org/10.1186/s13059-019-1653-z	journal	March 2019
Improved modeling of RNA-binding protein motifs in an interpretable neural model of RNA splicing Gupta, Kavi; Yang, Chenxi; McCue, Kayla Genome Biology, Vol. 25, Issue 1 https://doi.org/10.1186/s13059-023-03162-x	journal	January 2024
CI-SpliceAI—Improving machine learning predictions of disease causing splicing variants using curated alternative splice sites Strauch, Yaron; Lord, Jenny; Niranjan, Mahesan PLOS ONE, Vol. 17, Issue 6 https://doi.org/10.1371/journal.pone.0269159	journal	June 2022
The kinetics of pre-mRNA splicing in the Drosophila genome and the influence of gene architecture Pai, Athma A.; Henriques, Telmo; McCue, Kayla eLife, Vol. 6 https://doi.org/10.7554/eLife.32537	journal	December 2017
Mutations primarily alter the inclusion of alternatively spliced exons Baeza-Centurion, Pablo; Miñana, Belén; Valcárcel, Juan eLife, Vol. 9 https://doi.org/10.7554/eLife.59959	journal	October 2020

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