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Open Access Methodology article

Genetic interaction motif finding by expectation maximization – a novel statistical model for inferring gene modules from synthetic lethality

Yan Qi12, Ping Ye12 and Joel S Bader12*

Author Affiliations

1 Biomedical Engineering Department, Johns Hopkins University, North Charles Street, Baltimore, MD, 21218, USA

2 High-Throughput Biology Center, Johns Hopkins School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA

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BMC Bioinformatics 2005, 6:288  doi:10.1186/1471-2105-6-288

Published: 6 December 2005

Abstract

Background

Synthetic lethality experiments identify pairs of genes with complementary function. More direct functional associations (for example greater probability of membership in a single protein complex) may be inferred between genes that share synthetic lethal interaction partners than genes that are directly synthetic lethal. Probabilistic algorithms that identify gene modules based on motif discovery are highly appropriate for the analysis of synthetic lethal genetic interaction data and have great potential in integrative analysis of heterogeneous datasets.

Results

We have developed Genetic Interaction Motif Finding (GIMF), an algorithm for unsupervised motif discovery from synthetic lethal interaction data. Interaction motifs are characterized by position weight matrices and optimized through expectation maximization. Given a seed gene, GIMF performs a nonlinear transform on the input genetic interaction data and automatically assigns genes to the motif or non-motif category. We demonstrate the capacity to extract known and novel pathways for Saccharomyces cerevisiae (budding yeast). Annotations suggested for several uncharacterized genes are supported by recent experimental evidence. GIMF is efficient in computation, requires no training and automatically down-weights promiscuous genes with high degrees.

Conclusion

GIMF effectively identifies pathways from synthetic lethality data with several unique features. It is mostly suitable for building gene modules around seed genes. Optimal choice of one single model parameter allows construction of gene networks with different levels of confidence. The impact of hub genes the generic probabilistic framework of GIMF may be used to group other types of biological entities such as proteins based on stochastic motifs. Analysis of the strongest motifs discovered by the algorithm indicates that synthetic lethal interactions are depleted between genes within a motif, suggesting that synthetic lethality occurs between-pathway rather than within-pathway.