Meta-analysis of gene expression patterns in Down syndrome highlights significant alterations in mitochondrial and bioenergetic pathways.

Individuals with Down syndrome (DS) have an extra copy of chromosome 21. Clinical observations and preclinical studies both suggest that DS is associated with altered bioenergetic pathways. Several studies have reported that differentially expressed genes in DS are located not only on chromosome 21 but also on all other chromosomes. Numerous sets of microarray and RNA-seq data are publicly accessible through the Gene Expression Omnibus. We have conducted a meta-analysis on differentially expressed genes between DS and control subjects. Data deposited before July 1, 2020, were identified by using the search terms "Down syndrome" or "trisomy 21" and "human". Gene expression data were analyzed and normalized for each study. The mixed effect model was used to identify the differentially expressed genes. We conclude that in DS more than 60% of the genes located on chromosome 21 are significantly upregulated and none of them are downregulated. In addition, a significant dysregulation of genes occurs on all other chromosomes as well. Several of the upregulated genes in DS encode for important components of various bioenergetic pathways, for instance PFKL and ACLY. Genes involved in oxidative phosphorylation are mostly downregulated in DS. The gene expression alterations are consistent with the development of significant metabolic disturbances ("pseudohypoxia") in DS cells, which may explain some of the well-known functional defects (ranging from neuronal dysfunction to reduced exercise tolerance) associated with DS.