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Transcriptome analysis of human brain provides fundamental insight into development and disease, but it largely relies on existing annotation. We sequenced transcriptomes of 72 prefrontal cortex samples across six life stages and identified 50,650 differentially expression regions (DERs) associated with developmental and aging, agnostic of annotation. While many DERs annotated to non-exonic sequence (41.1%), most were similarly regulated in cytosolic mRNA extracted from independent samples. The DERs were developmentally conserved across 16 brain regions and in the developing mouse cortex, and were expressed in diverse cell and tissue types. The DERs were further enriched for active chromatin marks and clinical risk for neurodevelopmental disorders such as schizophrenia. Lastly, we demonstrate quantitatively that these DERs associate with a changing neuronal phenotype related to differentiation and maturation. These data show conserved molecular signatures of transcriptional dynamics across brain development, have potential clinical relevance and highlight the incomplete annotation of the human brain transcriptome.

Developmental regulation of human cortex transcription and its clinical relevance at single base resolution