Network Analysis of Down Syndrome-Associated Genes

Abstract

Down Syndrome (DS) or Trisomy 21, caused by an extra, normal copy of the long arm of human chromosome 21 (21q), is the most common genetic cause of cognitive impairment and congenital heart defects in the human population. The major current concept for the pathogenesis of DS is the gene dosage effect, in which multiple genes affect developmental processes and functions and not a single gene. MicroRNAs (miRNAs), which are small non-coding RNA approximately 21 to 23 nucleotides in length, reduce the transcription and translation of mRNA, thereby down-regulating gene expression. This study was conducted to determine the corresponding brain-relevant targets of miRNAs in Chromosome 21, and to propose mechanisms on the interaction of these brainrelevant targets that could lead to DS. MiRBase was utilized for the identification of miRNAs involved in DS and specific target genes were determined using miRanda algorithm. These were validated against the list at the Allen Institute for Brain Science, and the resulting gene lists inputted into Ingenuity Pathways Analysis (IPA) for interactome generation. Five miRNAs (miR-99a, let-7c, miR-125b-2, miR-155, and miR-802), having a total of 160 gene targets were identified, 66 of which are included in the networks. It is speculated that the overexpression of the five miRNAS, results in the decreased expression of specific target proteins and contributes, in part, to features of the DS phenotype.