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Novel semantic similarity measure improves an integrative approach to predicting gene functional associations

Fatemeh Vafaee, Daniela Rosu, Fiona Broackes-Carter, Igor Jurisica
2013 BMC Systems Biology  
Elucidation of the direct/indirect protein interactions and gene associations is required to fully understand the workings of the cell. This can be achieved through the use of both low-and high-throughput biological experiments and in silico methods. We present GAP (Gene functional Association Predictor), an integrative method for predicting and characterizing gene functional associations. GAP integrates different biological features using a novel taxonomy-based semantic similarity measure in
more » ... edicting and prioritizing high-quality putative gene associations. The proposed similarity measure increases information gain from the available gene annotations. The annotation information is incorporated from several public pathway databases, Gene Ontology annotations as well as drug and disease associations from the scientific literature. Results: We evaluated GAP by comparing its prediction performance with several other well-known functional interaction prediction tools over a comprehensive dataset of known direct and indirect interactions, and observed significantly better prediction performance. We also selected a small set of GAP's highly-scored novel predicted pairs (i.e., currently not found in any known database or dataset), and by manually searching the literature for experimental evidence accessible in the public domain, we confirmed different categories of predicted functional associations with available evidence of interaction. We also provided extra supporting evidence for subset of the predicted functionally-associated pairs using an expert curated database of genes associated to autism spectrum disorders. Conclusions: GAP's predicted "functional interactome" contains ≈1M highly-scored predicted functional associations out of which about 90% are novel (i.e., not experimentally validated). GAP's novel predictions connect disconnected components and singletons to the main connected component of the known interactome. It can, therefore, be a valuable resource for biologists by providing corroborating evidence for and facilitating the prioritization of potential direct or indirect interactions for experimental validation. GAP is freely accessible through a web portal: http://ophid.utoronto.ca/gap.
doi:10.1186/1752-0509-7-22 pmid:23497449 pmcid:PMC3663825 fatcat:dheiggdiojax5b44p6rv6zqa2q

Atypical 5′ Splice Sites Cause CFTR Exon 9 To Be Vulnerable to Skipping

Timothy W. Hefferon, Fiona C. Broackes-Carter, Ann Harris, Garry R. Cutting
2002 American Journal of Human Genetics  
The molecular basis of the skipping of constitutive exons in many messenger RNAs is not fully understood. A wellstudied example is exon 9 of the human cystic fibrosis transmembrane conductance regulator gene (CFTR), in which an abbreviated polypyrimidine tract between the branch point A and the 3 splice site is associated with increased exon skipping and disease. However, many exons, both in CFTR and in other genes and have short polypyrimidine tracts in their 3 splice sites, yet they are not
more » ... ipped. Inspection of the 5 splice sites immediately up-and downstream of exon 9 revealed deviations from consensus sequence, so we hypothesized that this exon may be inherently vulnerable to skipping. To test this idea, we constructed a CFTR minigene and replicated exon 9 skipping associated with the length of the polypyrimidine tract upstream of exon 9. We then mutated the flanking 5 splice sites and determined the effect on exon skipping. Conversion of the upstream 5 splice site to consensus by replacing a pyrimidine at position +3 with a purine resulted in increased exon skipping. In contrast, conversion of the downstream 5 splice site to consensus by insertion of an adenine at position +4 resulted in a substantial reduction in exon 9 skipping, regardless of whether the upstream 5 splice site was consensus or not. These results suggested that the native downstream 5 splice site plays an important role in CFTR exon 9 skipping, a hypothesis that was supported by data from sheep and mouse genomes. Although CFTR exon 9 in sheep is preceded by a long polypyrimidine tract (Y 14 ), it skips exon 9 in vivo and has a nonconsensus downstream 5 splice site identical to that in humans. On the other hand, CFTR exon 9 in mice is preceded by a short polypyrimidine tract (Y 5 ) but is not skipped in vivo. Its downstream 5 splice site differs from that in humans by a 2-nt insertion, which, when introduced into the human CFTR minigene, abolished exon 9 skipping. Taken together, these observations place renewed emphasis on deviations at 5 splice sites in nucleotides other than the invariant GT, particularly when such changes are found in conjunction with other altered splicing sequences, such as a shortened polypyrimidine tract. Thus, careful inspection of entire 5 splice sites may identify constitutive exons that are vulnerable to skipping.
doi:10.1086/341664 pmid:12068373 pmcid:PMC379162 fatcat:ayz5jh62a5b23d6rmqqjemdmvu

Quantitative methods for the analysis of CFTR transcripts/splicing variants

Margarida D. Amaral, Luka A. Clarke, Anabela S. Ramalho, Sebastian Beck, Fiona Broackes-Carter, Rebecca Rowntree, Nathalie Mouchel, Sarah H. Williams, Ann Harris, Maria Tzetis, Bernhard Steiner, Javier Sanz (+7 others)
2004 Journal of Cystic Fibrosis  
In cystic fibrosis (CF), transcript analysis and quantification are important for diagnosis, prognosis and also as surrogate markers for some therapies including gene therapy. Classical RNA-based methods require significant expression levels in target samples for appropriate analysis, thus PCR-based methods are evolving towards reliable quantification. Various protocols for the quantitative analysis of CFTR transcripts (including those resulting from splicing variants) are described and discussed here.
doi:10.1016/j.jcf.2004.05.047 pmid:15463919 fatcat:rcfdtlcfebh3rhnvfvpn6xj55e

The MIntAct project—IntAct as a common curation platform for 11 molecular interaction databases

Sandra Orchard, Mais Ammari, Bruno Aranda, Lionel Breuza, Leonardo Briganti, Fiona Broackes-Carter, Nancy H. Campbell, Gayatri Chavali, Carol Chen, Noemi del-Toro, Margaret Duesbury, Marine Dumousseau (+23 others)
2013 Nucleic Acids Research  
IntAct (freely available at http://www.ebi.ac.uk/ intact) is an open-source, open data molecular interaction database populated by data either curated from the literature or from direct data depositions. IntAct has developed a sophisticated web-based curation tool, capable of supporting both IMExand MIMIx-level curation. This tool is now utilized by multiple additional curation teams, all of whom annotate data directly into the IntAct database. Members of the IntAct team supply appropriate
more » ... s of training, perform quality control on entries and take responsibility for long-term data maintenance. Recently, the MINT and IntAct databases decided to merge their separate efforts to make optimal use of limited developer resources and maximize the curation output. All data manually curated by the MINT curators have been moved into the IntAct database at EMBL-EBI and are merged with the existing IntAct dataset. Both IntAct and MINT are active contributors to the IMEx consortium
doi:10.1093/nar/gkt1115 pmid:24234451 pmcid:PMC3965093 fatcat:5qemzevwgzdjln3y4pxvgfz7aa

Abstracts of papers presented at the fourteenth Genetics Society's Mammalian Genetics and Development Workshop held at the Institute of Child Health, University College London on 3 and 4 December 2003

ANDREW J. COPP, ELIZABETH M. C. FISHER
2004 Genetics Research  
Expression of arylamine N-acetyl transferase in the developing heart LARISSA WAKEFIELD 1 , VALERIE CORNISH 1 , HILARY LONG 1 , FIONA BROACKES-CARTER, MIMI MO, SHOUMO BHATTACHARYA 2 and EDITH SIM 1 1 Department  ... 
doi:10.1017/s0016672304007104 fatcat:qnauyej6ejbtrmw4wqhbekeszu