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European Rat Tools for Functional Genomics

Final Report Summary - EURATOOLS (European rat tools for functional genomics)

The EURATOOLS project aimed to:
1. develop reagents and tools for high throughput analysis of the rat genome that would accelerate progress in rat genetics;
2. create a research environment conducive to rapid identification of genes and pathways underlying complex rat disease phenotypes;
3. integrate new and existing data; and
4. develop new tools that would increase the utility and accessibility of rat genome databases.

By the time of its completion, the project had completed the successful positional cloning of more than five rat complex disease genes. The funding led to a substantial growth in genome resources, including new complementary Deoxyribonucleic acid (cDNA) sequences, millions of new sequence variants and platforms for high throughput genotyping, the genome sequence of the spontaneously hypertensive rat and several other rat strains and an outstanding set of genome resources that was coordinated by the European Bioinformatics Institute. The training that was provided in informatics meant that rat genetics was carried out hand in hand with informatics and expert use of genome resources. This was a major change since rat genome resources were previously scarce and the use of informatics was the exception rather than the rule.

A further major achievement was the discovery of a gene network for inflammation in multiple rat tissues that was conserved in humans and that was found to contribute to the pathogenesis of the human autoimmune disease, type one diabetes. This was achieved by the combined work of three partner institutes through integrated use of gene expression, biological resources, genome tools, informatics, and Bayesian statistics.

The diversity and annotation of the rat genome was improved during the project. Moreover, the identification of complex trait disease genes in the rat was facilitated and practical and efficient germline modification procedures were optimised. Nuclear donor cells were also prepared and optimised, while potential nucleus donor cells were screened. A repository of live and frozen rat strains was also provided. More than 500 embryos were cryopreserved from multiple inbred, congenic, transgenic or mutant lines. A panel of heterogeneous stock rats was established to achieve the high resolution genetic mapping of the determinants of behavioural, haematological, cardiovascular, diabetes and immunological phenotypes.

Furthermore, new and existing genome data were integrated and data mining resources were developed. The scope of the compendium was enhanced with the launch of the array express atlas of gene expression at the European Bioinformatics Institute, which offered comprehensive gene expression annotation across multiple experiments and different biological conditions. In order to advance rat genome informatics and integrate worldwide efforts, rat genome coordination meetings were organised. Use case interactive courses for bench scientists took place on eight occasions and involved both basic and advanced workshops.

In addition, candidate Quantitative trait loci (QTL) genes within narrow or 'minimal' congenic intervals were prioritised. Finally, an in depth functional and interaction analysis and transfer of discoveries from rat to human via the identification and positional cloning of new genes and their associated pathways involved in cardiovascular and inflammatory diseases was performed.

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