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Massive-scale genomics generates disease models

Pinpointing genes that predispose to disease is the tip of the disease pathophysiology iceberg. Integrative, cross-disciplinary studies that examine gene networks from mega data sets are needed to give new insight into disease mechanisms.
Massive-scale genomics generates disease models
The EURATRANS (European large-scale functional genomics in the rat for translational research) project brought together expert researchers to use next-generation sequencing technologies to generate genomic, transcriptomic and epigenomic data sets. In addition, EURATRANS conducted molecular-level analysis by using quantitative metabonomic and proteomic data sets.

The researchers used the rat as a model organism to identify the major gene pathways involved in human inflammatory, cardiovascular and metabolic, and behavioural disorders. Integrating the datasets in dynamic models, this new approach can be used to elucidate human gene function and open the way to the use of functional genomic networks for comparative medicine.

Also included in the study were epigenetic changes in gene activity. The researchers also devised algorithms to integrate genome-wide chromatin state maps and facilitate a simultaneous analysis of a large number of epigenetic markers.

At the proteome level, a list of more than 12 500 rat proteins has been compiled. The biological effect of metabolites is a crucial factor in many diseases such as type II diabetes. Enzyme downregulation in fat cells or adipocytes has been investigated together with development of a tissue metabolite phenotyping pipeline.

The scientists generated transgenic rats using transposon technology, a non-viral means of inserting genes into a genome. The new lines that may become rat models have been developed to validate the function of genes and proteins under study.

Comparative analysis has led to a large number of expression quantitative trait loci being mapped and the identification of many meaningful gene networks. One of these was identified as a top hit in relation to blood pressure and hypertension.

The EURATRANS publication record is impressive. High-profile journals include Genome Biology and Nature Genetics. The full genomic analysis of 37 rat strains representing the major diseases under analysis appeared in Cell journal. The new version 7.0 of the rat genome assembly was released in Ensembl.

EURATRANS data and deliverables have been incorporated into new databases and in parallel repositories with models, reagents, tools and speciments. The shift away from the function of the single gene has opened the way to fundamental mechanisms in disease aetiology – pathways to targets for both diagnosis and therapy.

Related information

Keywords

Disease models, gene networks, dynamic model, epigenetic, proteome
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