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Stephen Ramsey

Publications and source records attributed to Stephen Ramsey.

6 recordsLinked to original sources

A data integration methodology for systems biology.

Different experimental technologies measure different aspects of a system and to differing depth and breadth. High-throughput assays have inherently high false-positive and false-negative rates. Moreover, each technology includes systematic biases of a different nature. These differences make network reconstruction from multiple data sets difficult and error-prone. Additionally, because of the rapid rate of progress in biotechnology, there is usually no curated exemplar data set from which one might estimate data integration parameters. To address these concerns, we have developed data integration methods that can handle multiple data sets differing in statistical power, type, size, and network coverage without requiring a curated training data set. Our methodology is general in purpose and may be applied to integrate data from any existing and future technologies. Here we outline our methods and then demonstrate their performance by applying them to simulated data sets. The results show that these methods select true-positive data elements much more accurately than classical approaches. In an accompanying companion paper, we demonstrate the applicability of our approach to biological data. We have integrated our methodology into a free open source software package named POINTILLIST.

Informatics↗

A data integration methodology for systems biology: experimental verification.

The integration of data from multiple global assays is essential to understanding dynamic spatiotemporal interactions within cells. In a companion paper, we reported a data integration methodology, designated Pointillist, that can handle multiple data types from technologies with different noise characteristics. Here we demonstrate its application to the integration of 18 data sets relating to galactose utilization in yeast. These data include global changes in mRNA and protein abundance, genome-wide protein-DNA interaction data, database information, and computational predictions of protein-DNA and protein-protein interactions. We divided the integration task to determine three network components: key system elements (genes and proteins), protein-protein interactions, and protein-DNA interactions. Results indicate that the reconstructed network efficiently focuses on and recapitulates the known biology of galactose utilization. It also provided new insights, some of which were verified experimentally. The methodology described here, addresses a critical need across all domains of molecular and cell biology, to effectively integrate large and disparate data sets.

Chromatin Immunoprecipitation↗

Is the regulation of galactose 1-phosphate tuned against gene expression noise?

The average number of mRNA molecules per active gene in yeast can be remarkably low. Consequently, the relative number of copies of each transcript per cell can vary greatly from moment to moment. When these transcripts are encoding metabolic enzymes, how do the resulting variations in enzyme concentrations affect the regulation of metabolic intermediates? Using a kinetic model of galactose utilization in yeast, we analysed the transmission of noise from transcription and translation on metabolic intermediate regulation. In particular, the effect of the kinetic properties of the galactose-1-phosphate uridylyltransferase reaction on the transmission of noise was analysed.

Galactose↗

Dizzy: stochastic simulation of large-scale genetic regulatory networks.

We describe Dizzy, a software tool for stochastically and deterministically modeling the spatially homogeneous kinetics of integrated large-scale genetic, metabolic, and signaling networks. Notable features include a modular simulation framework, reusable modeling elements, complex kinetic rate laws, multi-step reaction processes, steady-state noise estimation, and spatial compartmentalization.

Algorithms↗

A method for estimating stochastic noise in large genetic regulatory networks.

MOTIVATION: Genetic regulatory networks are often affected by stochastic noise, due to the low number of molecules taking part in certain reactions. The networks can be simulated using stochastic techniques that model each reaction as a stochastic event. As models become increasingly large and sophisticated, however, the solution time can become excessive; particularly if one wishes to determine the effect on noise of changes to a series of parameters, or the model structure. Methods are therefore required to rapidly estimate stochastic noise. RESULTS: This paper presents an algorithm, based on error growth techniques from non-linear dynamics, to rapidly estimate the noise characteristics of genetic networks of arbitrary size. The method can also be used to determine analytical solutions for simple sub-systems. It is demonstrated on a number of cases, including a prototype model of the galactose regulatory pathway in yeast. AVAILABILITY: A software tool which incorporates the algorithm is available for use as part of the stochastic simulation package Dizzy. It is available for download at http://labs.systemsbiology.net/bolouri/software/Dizzy/ CONTACT: dorrell@systemsbiology.org SUPPLEMENTARY INFORMATION: A conceptual model of the regulatory part of the galactose utilization pathway in yeast, used as an example in the paper, is available at http://labs.systemsbiology.net/bolouri/models/galconcept.dizzy

Algorithms↗