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A major challenge in molecular systems biology is to understand how proteins work to transmit external signals to changes in gene expression. Computationally reconstructing these signaling pathways from protein interaction networks can help understand what is missing from existing pathway databases. We formulate a new pathway reconstruction problem, one that iteratively grows directed acyclic graphs (DAGs) from a set of starting proteins in a protein interaction network. We present an algorithm that provably returns the optimal DAGs for two different cost functions and evaluate the pathway reconstructions when applied to six diverse signaling pathways from the NetPath database. The optimal DAGs outperform an existing k-shortest paths method for pathway reconstruction, and the new reconstructions are enriched for different biological processes. Growing DAGs is a promising step toward reconstructing pathways that provably optimize a specific cost function.
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Reconstructing signaling pathways using regular language constrained paths
Abstract MotivationHigh-quality curation of the proteins and interactions in signaling pathways is slow and painstaking. As a result, many experimentally detected interactions are not annotated to any pathways. A natural question that arises is whether or not it is possible to automatically leverage existing pathway annotations to identify new interactions for inclusion in a given pathway. ResultsWe present RegLinker, an algorithm that achieves this purpose by computing multiple short paths from pathway receptors to transcription factors within a background interaction network. The key idea underlying RegLinker is the use of regular language constraints to control the number of non-pathway interactions that are present in the computed paths. We systematically evaluate RegLinker and five alternative approaches against a comprehensive set of 15 signaling pathways and demonstrate that RegLinker recovers withheld pathway proteins and interactions with the best precision and recall. We used RegLinker to propose new extensions to the pathways. We discuss the literature that supports the inclusion of these proteins in the pathways. These results show the broad potential of automated analysis to attenuate difficulties of traditional manual inquiry. Availability and implementationhttps://github.com/Murali-group/RegLinker. Supplementary informationSupplementary data are available at Bioinformatics online.
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- Award ID(s):
- 1759858
- PAR ID:
- 10425983
- Publisher / Repository:
- Oxford University Press
- Date Published:
- Journal Name:
- Bioinformatics
- Volume:
- 35
- Issue:
- 14
- ISSN:
- 1367-4803
- Page Range / eLocation ID:
- p. i624-i633
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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