Final Report Summary - ATD (The Alternate Transcript Diversity Project)
Production of mature transcripts in vertebrates is regulated at three stages: transcription initiation, splicing and polyadenylation. The combinatorial arrangement of variations at each stage generates, from a single gene, a variety of messenger RNA (mRNA) isoforms with different start sites, exons or 3' untranslated regions (UTRs). Expression of these alternative transcripts (ATs) has been observed to be specific to tissue type or developmental stage. Disruptions in expression patterns have serious consequences for an organism and are associated with numerous diseases, including cancer, multiple sclerosis, heart failure and neurodegenerative disorders. Identifying disease-specific ATs can lead to development of novel drug targets or markers.
The eight partners of the ATD project spent three years working together, organising six scientific meetings and many inter-group visits, and exchanged hundreds of e-mails. The results were gratifying in many respects. First, they produced one of the best resources on alternative transcription worldwide. This resource is known as the ASTD, the Alternative Splicing and Transcript Diversity database, and is hosted at the European Bioinformatics Institute (EBI) website (http://www.ebi.ac.uk/astd/). The database was the result of a computational pipeline developed by ATD partners. Alternative transcript information is provided for human, mouse and rat.
The ASTD query interface was another major deliverable of the ATD project and the key to a widespread dissemination of the work. This interface enables researchers to query the immense complexity of the alternative transcriptome along many different lines. Users can locate alternative transcripts in the complete genome and track them down to the gene level visualising synthetically all known isoforms for a gene, to the transcript level visualising detailed exon information, or to the "event" level visualising how alternative splicing events occur. Furthermore, for each transcript isoform, users have access to expression information presented using a normalised vocabulary.
The ASTD web server also provides various analysis tools that enable researchers to identify alternative transcripts of special medical or biological interest. Users may analyse specific genes or genome positions, or select a larger group of genes on the basis of their function or their expression in specific tissues or diseases. In one powerful analysis tool, users can select two complex pools of tissues or diseases, and the ASTD server will display all alternative transcripts that are specifically expressed in one of the pools and not in the other.
The ATD project had a significant emphasis on the experimental validation of predicted transcripts. In the third year, partners completed the experimental validation of over 500 different transcripts in human and mouse. Mouse transcripts were selected for their particularly long 3' end structure and inter-species conservation. About 40 previously unknown transcripts with long 3' extension were discovered and published. Human transcripts were selected for their putative expression in cancer cells. Starting with a selection of over 400 genes from ASTD queries, successive screening procedures produced a short list of 73 alternative transcripts with proven cancer-specific expression. This was probably one of the most exciting results of the ATD project, and was also very rewarding because it involved collaborative inputs from many ATD partners who supported this effort all the way from the initial computational predictions to the final, high-impact biomedical findings. These experimental validations of tumour-specific isoforms were published.
En route to these final achievements, partners developed several tools and methods that will serve the general alternative transcription community. This included a new benchmark to evaluate alternative splicing annotation methods, new software for the identification of tissue biases in expression data and a new annotation model for the representation of alternative. The team also published several computational analyses that exploited ATD data to focus on diverse biological aspects of alternative splicing and polyadenylation.
The eight partners of the ATD project spent three years working together, organising six scientific meetings and many inter-group visits, and exchanged hundreds of e-mails. The results were gratifying in many respects. First, they produced one of the best resources on alternative transcription worldwide. This resource is known as the ASTD, the Alternative Splicing and Transcript Diversity database, and is hosted at the European Bioinformatics Institute (EBI) website (http://www.ebi.ac.uk/astd/). The database was the result of a computational pipeline developed by ATD partners. Alternative transcript information is provided for human, mouse and rat.
The ASTD query interface was another major deliverable of the ATD project and the key to a widespread dissemination of the work. This interface enables researchers to query the immense complexity of the alternative transcriptome along many different lines. Users can locate alternative transcripts in the complete genome and track them down to the gene level visualising synthetically all known isoforms for a gene, to the transcript level visualising detailed exon information, or to the "event" level visualising how alternative splicing events occur. Furthermore, for each transcript isoform, users have access to expression information presented using a normalised vocabulary.
The ASTD web server also provides various analysis tools that enable researchers to identify alternative transcripts of special medical or biological interest. Users may analyse specific genes or genome positions, or select a larger group of genes on the basis of their function or their expression in specific tissues or diseases. In one powerful analysis tool, users can select two complex pools of tissues or diseases, and the ASTD server will display all alternative transcripts that are specifically expressed in one of the pools and not in the other.
The ATD project had a significant emphasis on the experimental validation of predicted transcripts. In the third year, partners completed the experimental validation of over 500 different transcripts in human and mouse. Mouse transcripts were selected for their particularly long 3' end structure and inter-species conservation. About 40 previously unknown transcripts with long 3' extension were discovered and published. Human transcripts were selected for their putative expression in cancer cells. Starting with a selection of over 400 genes from ASTD queries, successive screening procedures produced a short list of 73 alternative transcripts with proven cancer-specific expression. This was probably one of the most exciting results of the ATD project, and was also very rewarding because it involved collaborative inputs from many ATD partners who supported this effort all the way from the initial computational predictions to the final, high-impact biomedical findings. These experimental validations of tumour-specific isoforms were published.
En route to these final achievements, partners developed several tools and methods that will serve the general alternative transcription community. This included a new benchmark to evaluate alternative splicing annotation methods, new software for the identification of tissue biases in expression data and a new annotation model for the representation of alternative. The team also published several computational analyses that exploited ATD data to focus on diverse biological aspects of alternative splicing and polyadenylation.
