The human developing cerebral cortex is characterized by an increased de novo expression of lncRNAs in excitatory neurons

Abstract

AbstractBackgroundOutstanding human cognitive abilities are computed in the cerebral cortex, a mammalian-specific brain region and the place of massive biological innovation. Long noncoding RNAs (lncRNAs) have emerged as gene regulatory elements with higher evolutionary turnover than mRNAs. The many lncRNAs identified in neural tissues make them candidates for molecular sources of cerebral cortex evolution and disease. Here, we characterized the genomic and cellular shifts that occurred during the evolution of the lncRNA repertoire expressed in the developing cerebral cortex of humans and explored their role in the evolution of this brain region.ResultsUsing systems biology approaches and comparative transcriptomics, we comprehensively annotated the cortical transcriptomes of humans, macaques, mice, and chickens and classified human cortical lncRNAs into evolutionary groups as a function of their predicted minimal ages. LncRNA evolutionary groups showed differences in expression levels, splicing efficiencies, transposable element contents, genomic distributions, and transcription factor binding to their promoters. Furthermore, older lncRNAs showed preferential expression in germinative zones, outer radial glial cells, and cortical inhibitory neurons. In comparison, younger lncRNAs showed preferential expression in cortical excitatory neurons, belonged to human-specific gene coexpression modules, and were dysregulated in autism spectrum disorder.ConclusionsThese results suggest a shift in the roles of cortical lncRNAs over evolution, highlighting the antique lncRNAs as a source of molecular evolution of conserved developmental programs; conversely, thede novoexpression of primate and human-specific lncRNAs are sources of molecular evolution and dysfunction of cortical excitatory neurons.