Abstract
Down syndrome (DS) is due to the presence of an extra full or partial chromosome 21 (Hsa21). The identification of genes contributing to DS pathogenesis could be the key to any rational therapy of the associated intellectual disability. We aim at generating quantitative transcriptome maps in DS integrating all gene expression profile datasets available for any cell type or tissue, to obtain a complete model of the transcriptome in terms of both expression values for each gene and segmental trend of gene expression along each chromosome. We used the TRAM (Transcriptome Mapper) software for this meta-analysis, comparing transcript expression levels and profiles between DS and normal brain, lymphoblastoid cell lines, blood cells, fibroblasts, thymus and induced pluripotent stem cells, respectively. TRAM combined, normalized, and integrated datasets from different sources and across diverse experimental platforms. The main output was a linear expression value that may be used as a reference for each of up to 37,181 mapped transcripts analyzed, related to both known genes and expression sequence tag (EST) clusters. An independent example in vitro validation of fibroblast transcriptome map data was performed through “Real-Time” reverse transcription polymerase chain reaction showing an excellent correlation coefficient (r = 0.93, p < 0.0001) with data obtained in silico. The availability of linear expression values for each gene allowed the testing of the gene dosage hypothesis of the expected 3:2 DS/normal ratio for Hsa21 as well as other human genes in DS, in addition to listing genes differentially expressed with statistical significance. Although a fraction of Hsa21 genes escapes dosage effects, Hsa21 genes are selectively over-expressed in DS samples compared to genes from other chromosomes, reflecting a decisive role in the pathogenesis of the syndrome. Finally, the analysis of chromosomal segments reveals a high prevalence of Hsa21 over-expressed segments over the other genomic regions, suggesting, in particular, a specific region on Hsa21 that appears to be frequently over-expressed (21q22). Our complete datasets are released as a new framework to investigate transcription in DS for individual genes as well as chromosomal segments in different cell types and tissues.
Highlights
Down syndrome (DS) is the first genetic alteration to have been described in humans (Lejeune et al, 1959), is the most frequent human chromosomal disorder and it causes mainly intellectual disability (ID)
The exclusion criteria were data derived from treated cells or tissues or arising from fetuses and embryonic annexes; experiments conducted on exon arrays; experiments on platforms whose probes are divided across multiple slides; lack of gene identifiers corresponding to those found in the records of GEO (GSM standards) or ArrayExpress; platforms that analyze an atypical number of genes (i.e., 60,000)
Sequence in 2000 (Hattori et al, 2000) allowed to identify, to date, 273 validated or reviewed known genes on Hsa21 (Piovesan et al, 2016), which have become the objects of various research aimed to assess their expression in DS and their involvement in pathways and molecular mechanisms that may be related to the pathogenesis of DS (Vilardell et al, 2011; Briggs et al, 2013; Weick et al, 2013; Letourneau et al, 2014; Olmos-Serrano et al, 2016; Sullivan et al, 2016)
Summary
Down syndrome (DS) is the first genetic alteration to have been described in humans (Lejeune et al, 1959), is the most frequent human chromosomal disorder and it causes mainly intellectual disability (ID). DS or trisomy 21 (T21) is characterized by the presence of an extra full or partial chromosome 21 (Hsa21), but the molecular mechanisms at the basis of the pathogenesis are still unclear. According to the first hypothesis, the presence of an extra Hsa globally disturbs the correct balance of gene expression in DS cells during development (Saran et al, 2003) and determines a non-specific disturbance of genomic regulation and expression (Vilardell et al, 2011) resulting in a disruption of homeostasis throughout the genome. The second theory of the “gene dosage effect” states that the overexpression of duplicated genes on Hsa directly contributes to different aspects of DS phenotype (Korenberg, 1990). To determine which hypothesis applies to the etiology of DS, a number of investigators have conducted gene-expression studies in mouse models and human tissues or cell lines. Several methods have been used, including microarrays, serial analysis of gene expression (SAGE), Real-Time RT-PCR, RNA-seq or proteomic approaches (Lockstone et al, 2007; Prandini et al, 2007; Volk et al, 2013; Kong et al, 2014; Zhao et al, 2016; Liu et al, 2017)
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