Longitudinal Gene Expression Analysis in Human Brain identifies biological processes underlying neuropathology in Down Syndrome

Trisomy 21 (Ts21) or Down syndrome (DS) is the most common genetic cause of intellectual disability. To investigate the consequences of Ts21 on human brain development, we have systematically analyzed the transcriptome of dorsolateral prefrontal cortex (DFC) and cerebellar cortex (CBC) using exon array mapping in DS and matched euploid control brains spanning from prenatal development to adulthood. We identify hundreds of differentially expressed (DEX) genes in the DS brains, many of which exhibit temporal changes in expression over the lifespan. To gain insight into how these DEX genes may cause specific DS phenotypes, we identified functional modules of co-expressed genes using several different bioinformatics approaches, including WGCNA and gene ontology analysis. A module comprised of genes associated with myelination, including those dynamically expressed over the course of oligodendrocyte development, was amongst those with the great levels of differential gene expression. Using Ts65Dn mouse line, the most common rodent model of DS, w e observed significant and novel defects in oligodendrocyte maturation and myelin ultrastructure; establishing a correlative proof-of-principle implicating myelin dysgenesis in DS. Thus, examination of the spatio-temporal transcriptome predicts specific cellular and functional events in the DS brain and is an outstanding resource for determining putative mechanisms involved in the neuropathology of DS. Here, we performed a global unbiased gene expression screen at both gene and exon levels of brain samples representing the continuum of human life from 16 gestational weeks to 42 years-old. This longitudinal approach uncovered a highly dynamic disruption of the transcriptome, with alterations in gene expression in each brain region changing over time. Bioinformatics analyses of the transcriptome profiles indicate that a wide variety of biological processes are affected in the DS dorsolateral prefrontal cortex (PFC) and cerebellar cortex (CBC), presumably underlying the morphological and cytological abnormalities which arise in these structures during brain development and extending into adulthood. These spatial and temporal patterns of gene dysregulation identify key genes and groups of genes potentially responsible for the cognitive disability in DS, including substantial abnormalities in gene associated with the oligodendrocyte lineage and myelination. We also provide proof-of-concept experiments by identifying white matter alterations predicted by our transcriptome data in a widely used trisomic mouse model of DS, Ts65Dn. We have identified. Thus, this longitudinal human brain transcriptome data resource provides a powerful and extensive framework to identify, prioritize and test gene targets and developmental mechanisms underlying the neuropathophysiology of DS