Dataset Information

Computational de novo discovery of distinguishing genes for biological processes and cell types in complex tissues.

ABSTRACT: Bulk tissue samples examined by gene expression studies are usually heterogeneous. The data gained from these samples display the confounding patterns of mixtures consisting of multiple cell types or similar cell types in various functional states, which hinders the elucidation of the molecular mechanisms underlying complex biological phenomena. A realistic approach to compensate for the limitations of experimentally separating homogenous cell populations from mixed tissues is to computationally identify cell-type specific patterns from bulk, heterogeneous measurements. We designed the CellDistinguisher algorithm to analyze the gene expression data of mixed samples, identifying genes that best distinguish biological processes and cell types. Coupled with a deconvolution algorithm that takes cell type specific gene lists as input, we show that CellDistinguisher performs as well as partial deconvolution algorithms in predicting cell type composition without the need for prior knowledge of cell type signatures. This approach is also better in predicting cell type signatures than the one-step traditional complete deconvolution methods. To illustrate its wide applicability, the algorithm was tested on multiple publicly available data sets. In each case, CellDistinguisher identified genes reflecting biological processes typical for the tissues and development stages of interest and estimated the sample compositions accurately.

SUBMITTER: Newberg LA

PROVIDER: S-EPMC5832224 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Computational de novo discovery of distinguishing genes for biological processes and cell types in complex tissues.

Newberg Lee A LA Chen Xiaowei X Kodira Chinnappa D CD Zavodszky Maria I MI

PloS one 20180301 3

Bulk tissue samples examined by gene expression studies are usually heterogeneous. The data gained from these samples display the confounding patterns of mixtures consisting of multiple cell types or similar cell types in various functional states, which hinders the elucidation of the molecular mechanisms underlying complex biological phenomena. A realistic approach to compensate for the limitations of experimentally separating homogenous cell populations from mixed tissues is to computationally ...[more]

PMID: 29494600

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Project description:BackgroundOptimization theory has been applied to complex biological systems to interrogate network properties and develop and refine metabolic engineering strategies. For example, methods are emerging to engineer cells to optimally produce byproducts of commercial value, such as bioethanol, as well as molecular compounds for disease therapy. Flux balance analysis (FBA) is an optimization framework that aids in this interrogation by generating predictions of optimal flux distributions in cellular networks. Critical features of FBA are the definition of a biologically relevant objective function (e.g., maximizing the rate of synthesis of biomass, a unit of measurement of cellular growth) and the subsequent application of linear programming (LP) to identify fluxes through a reaction network. Despite the success of FBA, a central remaining challenge is the definition of a network objective with biological meaning.ResultsWe present a novel method called Biological Objective Solution Search (BOSS) for the inference of an objective function of a biological system from its underlying network stoichiometry as well as experimentally-measured state variables. Specifically, BOSS identifies a system objective by defining a putative stoichiometric "objective reaction," adding this reaction to the existing set of stoichiometric constraints arising from known interactions within a network, and maximizing the putative objective reaction via LP, all the while minimizing the difference between the resultant in silico flux distribution and available experimental (e.g., isotopomer) flux data. This new approach allows for discovery of objectives with previously unknown stoichiometry, thus extending the biological relevance from earlier methods. We verify our approach on the well-characterized central metabolic network of Saccharomyces cerevisiae.ConclusionWe illustrate how BOSS offers insight into the functional organization of biochemical networks, facilitating the interrogation of cellular design principles and development of cellular engineering applications. Furthermore, we describe how growth is the best-fit objective function for the yeast metabolic network given experimentally-measured fluxes.

Dataset Information

Computational de novo discovery of distinguishing genes for biological processes and cell types in complex tissues.

Publications

Computational de novo discovery of distinguishing genes for biological processes and cell types in complex tissues.

Similar Datasets

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