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Quantitative analysis of genetic and neuronal multi-perturbation experiments.

ABSTRACT: Perturbation studies, in which functional performance is measured after deletion, mutation, or lesion of elements of a biological system, have been traditionally employed in many fields in biology. The vast majority of these studies have been qualitative and have employed single perturbations, often resulting in little phenotypic effect. Recently, newly emerging experimental techniques have allowed researchers to carry out concomitant multi-perturbations and to uncover the causal functional contributions of system elements. This study presents a rigorous and quantitative multi-perturbation analysis of gene knockout and neuronal ablation experiments. In both cases, a quantification of the elements' contributions, and new insights and predictions, are provided. Multi-perturbation analysis has a potentially wide range of applications and is gradually becoming an essential tool in biology.

SUBMITTER: Kaufman A

PROVIDER: S-EPMC1289391 | biostudies-literature | 2005 Nov

REPOSITORIES: biostudies-literature

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Quantitative analysis of genetic and neuronal multi-perturbation experiments.

Kaufman Alon A Keinan Alon A Meilijson Isaac I Kupiec Martin M Ruppin Eytan E

PLoS computational biology 20051125 6

Perturbation studies, in which functional performance is measured after deletion, mutation, or lesion of elements of a biological system, have been traditionally employed in many fields in biology. The vast majority of these studies have been qualitative and have employed single perturbations, often resulting in little phenotypic effect. Recently, newly emerging experimental techniques have allowed researchers to carry out concomitant multi-perturbations and to uncover the causal functional cont ...[more]

PMID: 16322764

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Project description:Most studies of gene regulatory network (GRN) inference have focused extensively on identifying the interaction map of the GRNs. However, in order to predict the cellular behavior, modeling the GRN in terms of logic circuits, i.e., Boolean networks, is necessary. The perturbation techniques, e.g., knock-down and over-expression, should be utilized for identifying the underlying logic behind the interactions. However, we will show that by using only transcriptomic data obtained by single-perturbation experiments, we cannot observe all regulatory interactions, and this invisibility causes ambiguity in our model. Consequently, we need to employ the data of multiple omics layers (genome, transcriptome, and proteome) as well as multiple perturbation experiments to reduce or eliminate ambiguity in our modeling. In this paper, we introduce a multi-step perturbation experiment to deal with ambiguity. Moreover, we perform a thorough analysis to investigate which types of perturbations and omics layers play the most important role in the unambiguous modeling of the GRNs and how much ambiguity will be eliminated by considering more perturbations and more omics layers. Our analysis shows that performing both knock-down and over-expression is necessary in order to achieve the least ambiguous model. Moreover, the more steps of the perturbation are taken, the more ambiguity is eliminated. In addition, we can even achieve an unambiguous model of the GRN by using multi-step perturbation and integrating transcriptomic, protein-protein interaction, and cis-element data. Finally, we demonstrate the effect of utilizing different types of perturbation experiment and integrating multi-omics data on identifying the logic behind the regulatory interactions in a synthetic GRN. In conclusion, relying on the results of only knock-down experiments and not including as many omics layers as possible in the GRN inference, makes the results ambiguous, unreliable, and less accurate.

Dataset Information

Quantitative analysis of genetic and neuronal multi-perturbation experiments.

Publications

Quantitative analysis of genetic and neuronal multi-perturbation experiments.

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