Abstract
BackgroundDown syndrome (DS; trisomy 21) is the most common genetic cause of mental retardation in the human population and key molecular networks dysregulated in DS are still unknown. Many different experimental techniques have been applied to analyse the effects of dosage imbalance at the molecular and phenotypical level, however, currently no integrative approach exists that attempts to extract the common information.ResultsWe have performed a statistical meta-analysis from 45 heterogeneous publicly available DS data sets in order to identify consistent dosage effects from these studies. We identified 324 genes with significant genome-wide dosage effects, including well investigated genes like SOD1, APP, RUNX1 and DYRK1A as well as a large proportion of novel genes (N = 62). Furthermore, we characterized these genes using gene ontology, molecular interactions and promoter sequence analysis. In order to judge relevance of the 324 genes for more general cerebral pathologies we used independent publicly available microarry data from brain studies not related with DS and identified a subset of 79 genes with potential impact for neurocognitive processes. All results have been made available through a web server under http://ds-geneminer.molgen.mpg.de/.ConclusionsOur study represents a comprehensive integrative analysis of heterogeneous data including genome-wide transcript levels in the domain of trisomy 21. The detected dosage effects build a resource for further studies of DS pathology and the development of new therapies.
Highlights
Down syndrome (DS; trisomy 21) is the most common genetic cause of mental retardation in the human population and key molecular networks dysregulated in DS are still unknown
45 case-control experiments were interrogated (Additional file 1, Table S1), the alteration for each gene between the trisomic and normal states was scored in each experiment, gene scores were summarised across all experiments and the significance of the summarised scores was judged with a Bootstrap approach
The consistency of the dosage effect was measured for each gene with an entropy criterion and Figure 1A reveals a strong preference for the selection of highentropy genes
Summary
Down syndrome (DS; trisomy 21) is the most common genetic cause of mental retardation in the human population and key molecular networks dysregulated in DS are still unknown. Many different experimental techniques have been applied to analyse the effects of dosage imbalance at the molecular and phenotypical level, currently no integrative approach exists that attempts to extract the common information. Other features occur with less frequency such as organ malformations, of the heart (50% of DS newborns), several types of gastrointestinal tract obstructions or dysfunctions (4-5% of DS newborns), The most commonly accepted pathogenetic hypothesis is that the dosage imbalance of genes on HSA21 is responsible for the molecular dysfunctions in DS, meaning that genes on the triplicated chromosome are overexpressed due to an extra chromosome 21, as demonstrated for selected genes like SOD1 and DYRK1A [8]. An alternative hypothesis is that the phenotype is due to an unstable environment resulting from the dosage imbalance of the hundreds of genes on HSA21
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