![]() ![]() In the present study, we assessed five specific hypotheses relating to primary and secondary transcriptional changes in DS. Recent studies in human and in mouse provide conflicting evidence, with some studies suggesting only limited effects of trisomy on the expression of disomic genes, whereas other studies indicate pervasive effects (see Discussion). It has been hypothesized that gene expression changes in chromosome 21 are likely to affect the expression of genes on other chromosomes through the modulation of transcription factors, chromatin remodeling proteins, or related molecules. For genes assigned to chromosomes other than 21, the effect of trisomy 21 (TS21) could be relatively subtle or massively disruptive. On chromosome 21, gene expression may be regulated by dosage compensation or other mechanisms such that only a subset of those genes is expressed at the expected 50% increased levels. A major unanswered question is the extent to which secondary changes occur in DS as a consequence of the aneuploid state. The secondary, downstream consequences of aneuploidy are complex. We observed a dramatic, statistically significant increase in the expression of trisomic genes assigned to chromosome 21. We previously measured RNA transcript levels in fetal trisomic and euploid cerebrum samples, and in astrocyte cell lines derived from cerebrum. Most of these studies have confirmed a primary gene dosage effect. ![]() More recently, microarrays and other high-throughput technologies have allowed the measurement of steady-state RNA levels for thousands of transcripts in human DS cells and in tissues obtained from mouse models of DS. By the 1980s, a primary effect of increased gene products, proportional to gene dosage, was established for dozens of enzymes in studies of various aneuploidies. As for all aneuploidies, the phenotype of DS is thought to result from the dosage imbalance of multiple genes. It has been known since 1959 that DS is caused by the triplication of a G group chromosome, now known to be human chromosome 21. It is characterized by mental retardation, hypotonia, short stature, and several dozen other anomalies. Among all the autosomal aneuploidies, Down syndrome (DS), with an incidence of 1 in approximately 800 live births, is most frequently compatible with postnatal survival. Human autosomal abnormality is the leading cause of early pregnancy loss, neonatal death, and multiple congenital malformations. The identification of dysregulated genes and pathways suggests molecular changes that may underlie the Down syndrome phenotypes. In Down syndrome, there is a primary transcriptional effect of disruption of chromosome 21 gene expression, without a pervasive secondary effect on the remaining transcriptome. ![]() Our data also indicated functional groups that might be perturbed in trisomy 21. Gene expression values from chromosome 21, but not from other chromosomes, accurately classified trisomy 21 from euploid samples. We validated our microarray data by over 5,600 quantitative real-time PCRs on 28 genes assigned to chromosome 21 and other chromosomes. Moreover, by having a larger sample size, combining the data from four different tissue and cell types, and using an ANOVA approach, we identified individual genes with significantly altered expression in trisomy 21, some of which showed this dysregulation in a tissue-specific manner. We measured levels of transcripts in human fetal cerebellum and heart tissues using DNA microarrays and demonstrated a dosage-dependent increase in transcription across different tissue/cell types as a result of trisomy 21. Also, the statistical significance of differentially expressed genes in human Down syndrome tissues has not been reported. However, it is unclear whether the entire transcriptome is disrupted, or whether there is a more restricted increase in the expression of those genes assigned to chromosome 21. Recent studies demonstrated that dosage-dependent increases in chromosome 21 gene expression occur in trisomy 21. Down syndrome, caused by trisomic chromosome 21, is the leading genetic cause of mental retardation. ![]()
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