Genome-wide association between branch point properties and alternative splicing.
The branch point (BP) is one of the three obligatory signals required for pre-mRNA splicing. In mammals, the degeneracy of the motif combined with the lack of a large set of experimentally verified BPs complicates the task of modeling it in silico, and therefore of predicting the location of natural...
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Public Library of Science (PLoS)
2010-11-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1001016&type=printable |
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| author | André Corvelo Martina Hallegger Christopher W J Smith Eduardo Eyras |
| author_facet | André Corvelo Martina Hallegger Christopher W J Smith Eduardo Eyras |
| author_sort | André Corvelo |
| collection | DOAJ |
| description | The branch point (BP) is one of the three obligatory signals required for pre-mRNA splicing. In mammals, the degeneracy of the motif combined with the lack of a large set of experimentally verified BPs complicates the task of modeling it in silico, and therefore of predicting the location of natural BPs. Consequently, BPs have been disregarded in a considerable fraction of the genome-wide studies on the regulation of splicing in mammals. We present a new computational approach for mammalian BP prediction. Using sequence conservation and positional bias we obtained a set of motifs with good agreement with U2 snRNA binding stability. Using a Support Vector Machine algorithm, we created a model complemented with polypyrimidine tract features, which considerably improves the prediction accuracy over previously published methods. Applying our algorithm to human introns, we show that BP position is highly dependent on the presence of AG dinucleotides in the 3' end of introns, with distance to the 3' splice site and BP strength strongly correlating with alternative splicing. Furthermore, experimental BP mapping for five exons preceded by long AG-dinucleotide exclusion zones revealed that, for a given intron, more than one BP can be chosen throughout the course of splicing. Finally, the comparison between exons of different evolutionary ages and pseudo exons suggests a key role of the BP in the pathway of exon creation in human. Our computational and experimental analyses suggest that BP recognition is more flexible than previously assumed, and it appears highly dependent on the presence of downstream polypyrimidine tracts. The reported association between BP features and the splicing outcome suggests that this, so far disregarded but yet crucial, element buries information that can complement current acceptor site models. |
| format | Article |
| id | doaj-art-c0e60278c15542e58e298e6ea04b5cdd |
| institution | DOAJ |
| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2010-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj-art-c0e60278c15542e58e298e6ea04b5cdd2025-08-20T03:07:20ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582010-11-01611e100101610.1371/journal.pcbi.1001016Genome-wide association between branch point properties and alternative splicing.André CorveloMartina HalleggerChristopher W J SmithEduardo EyrasThe branch point (BP) is one of the three obligatory signals required for pre-mRNA splicing. In mammals, the degeneracy of the motif combined with the lack of a large set of experimentally verified BPs complicates the task of modeling it in silico, and therefore of predicting the location of natural BPs. Consequently, BPs have been disregarded in a considerable fraction of the genome-wide studies on the regulation of splicing in mammals. We present a new computational approach for mammalian BP prediction. Using sequence conservation and positional bias we obtained a set of motifs with good agreement with U2 snRNA binding stability. Using a Support Vector Machine algorithm, we created a model complemented with polypyrimidine tract features, which considerably improves the prediction accuracy over previously published methods. Applying our algorithm to human introns, we show that BP position is highly dependent on the presence of AG dinucleotides in the 3' end of introns, with distance to the 3' splice site and BP strength strongly correlating with alternative splicing. Furthermore, experimental BP mapping for five exons preceded by long AG-dinucleotide exclusion zones revealed that, for a given intron, more than one BP can be chosen throughout the course of splicing. Finally, the comparison between exons of different evolutionary ages and pseudo exons suggests a key role of the BP in the pathway of exon creation in human. Our computational and experimental analyses suggest that BP recognition is more flexible than previously assumed, and it appears highly dependent on the presence of downstream polypyrimidine tracts. The reported association between BP features and the splicing outcome suggests that this, so far disregarded but yet crucial, element buries information that can complement current acceptor site models.https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1001016&type=printable |
| spellingShingle | André Corvelo Martina Hallegger Christopher W J Smith Eduardo Eyras Genome-wide association between branch point properties and alternative splicing. PLoS Computational Biology |
| title | Genome-wide association between branch point properties and alternative splicing. |
| title_full | Genome-wide association between branch point properties and alternative splicing. |
| title_fullStr | Genome-wide association between branch point properties and alternative splicing. |
| title_full_unstemmed | Genome-wide association between branch point properties and alternative splicing. |
| title_short | Genome-wide association between branch point properties and alternative splicing. |
| title_sort | genome wide association between branch point properties and alternative splicing |
| url | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1001016&type=printable |
| work_keys_str_mv | AT andrecorvelo genomewideassociationbetweenbranchpointpropertiesandalternativesplicing AT martinahallegger genomewideassociationbetweenbranchpointpropertiesandalternativesplicing AT christopherwjsmith genomewideassociationbetweenbranchpointpropertiesandalternativesplicing AT eduardoeyras genomewideassociationbetweenbranchpointpropertiesandalternativesplicing |