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Yeast Phenomics: An Experimental Approach for Modeling Gene Interaction Networks that Buffer Disease.

ABSTRACT: The genome project increased appreciation of genetic complexity underlying disease phenotypes: many genes contribute each phenotype and each gene contributes multiple phenotypes. The aspiration of predicting common disease in individuals has evolved from seeking primary loci to marginal risk assignments based on many genes. Genetic interaction, defined as contributions to a phenotype that are dependent upon particular digenic allele combinations, could improve prediction of phenotype from complex genotype, but it is difficult to study in human populations. High throughput, systematic analysis of S. cerevisiae gene knockouts or knockdowns in the context of disease-relevant phenotypic perturbations provides a tractable experimental approach to derive gene interaction networks, in order to deduce by cross-species gene homology how phenotype is buffered against disease-risk genotypes. Yeast gene interaction network analysis to date has revealed biology more complex than previously imagined. This has motivated the development of more powerful yeast cell array phenotyping methods to globally model the role of gene interaction networks in modulating phenotypes (which we call yeast phenomic analysis). The article illustrates yeast phenomic technology, which is applied here to quantify gene X media interaction at higher resolution and supports use of a human-like media for future applications of yeast phenomics for modeling human disease.

SUBMITTER: Hartman JL

PROVIDER: S-EPMC4377832 | biostudies-other | 2015 Feb

REPOSITORIES: biostudies-other

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Yeast Phenomics: An Experimental Approach for Modeling Gene Interaction Networks that Buffer Disease.

Hartman John L JL Stisher Chandler C Outlaw Darryl A DA Guo Jingyu J Shah Najaf A NA Tian Dehua D Santos Sean M SM Rodgers John W JW White Richard A RA

Genes 20150206 1

The genome project increased appreciation of genetic complexity underlying disease phenotypes: many genes contribute each phenotype and each gene contributes multiple phenotypes. The aspiration of predicting common disease in individuals has evolved from seeking primary loci to marginal risk assignments based on many genes. Genetic interaction, defined as contributions to a phenotype that are dependent upon particular digenic allele combinations, could improve prediction of phenotype from comple ...[more]

PMID: 25668739

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Project description:BACKGROUND: Various computational models have been of interest due to their use in the modelling of gene regulatory networks (GRNs). As a logical model, probabilistic Boolean networks (PBNs) consider molecular and genetic noise, so the study of PBNs provides significant insights into the understanding of the dynamics of GRNs. This will ultimately lead to advances in developing therapeutic methods that intervene in the process of disease development and progression. The applications of PBNs, however, are hindered by the complexities involved in the computation of the state transition matrix and the steady-state distribution of a PBN. For a PBN with n genes and N Boolean networks, the complexity to compute the state transition matrix is O(nN22n) or O(nN2n) for a sparse matrix. RESULTS: This paper presents a novel implementation of PBNs based on the notions of stochastic logic and stochastic computation. This stochastic implementation of a PBN is referred to as a stochastic Boolean network (SBN). An SBN provides an accurate and efficient simulation of a PBN without and with random gene perturbation. The state transition matrix is computed in an SBN with a complexity of O(nL2n), where L is a factor related to the stochastic sequence length. Since the minimum sequence length required for obtaining an evaluation accuracy approximately increases in a polynomial order with the number of genes, n, and the number of Boolean networks, N, usually increases exponentially with n, L is typically smaller than N, especially in a network with a large number of genes. Hence, the computational efficiency of an SBN is primarily limited by the number of genes, but not directly by the total possible number of Boolean networks. Furthermore, a time-frame expanded SBN enables an efficient analysis of the steady-state distribution of a PBN. These findings are supported by the simulation results of a simplified p53 network, several randomly generated networks and a network inferred from a T cell immune response dataset. An SBN can also implement the function of an asynchronous PBN and is potentially useful in a hybrid approach in combination with a continuous or single-molecule level stochastic model. CONCLUSIONS: Stochastic Boolean networks (SBNs) are proposed as an efficient approach to modelling gene regulatory networks (GRNs). The SBN approach is able to recover biologically-proven regulatory behaviours, such as the oscillatory dynamics of the p53-Mdm2 network and the dynamic attractors in a T cell immune response network. The proposed approach can further predict the network dynamics when the genes are under perturbation, thus providing biologically meaningful insights for a better understanding of the dynamics of GRNs. The algorithms and methods described in this paper have been implemented in Matlab packages, which are attached as Additional files.

Dataset Information

Yeast Phenomics: An Experimental Approach for Modeling Gene Interaction Networks that Buffer Disease.

Publications

Yeast Phenomics: An Experimental Approach for Modeling Gene Interaction Networks that Buffer Disease.

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