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The precise regulation of gene expression is fundamental to neurodevelopment, plasticity and cognitive function. Although several studies have profiled transcription in the developing human brain, there is a gap in understanding of accompanying translational regulation. In this study, we performed ribosome profiling on 73 human prenatal and adult cortex samples. We characterized the translational regulation of annotated open reading frames (ORFs) and identified thousands of previously unknown translation events, including small ORFs that give rise to human-specific and/or brain-specific microproteins, many of which we independently verified using proteomics. Ribosome profiling in stem-cell-derived human neuronal cultures corroborated these findings and revealed that several neuronal activity-induced non-coding RNAs encode previously undescribed microproteins. Physicochemical analysis of brain microproteins identified a class of proteins that contain arginine-glycine-glycine (RGG) repeats and, thus, may be regulators of RNA metabolism. This resource expands the known translational landscape of the human brain and illuminates previously unknown brain-specific protein products.

The precise regulation of gene expression is fundamental to neurodevelopment, plasticity, and cognitive function. While several studies have deeply profiled mRNA dynamics in the developing human brain, there is a fundamental gap in our understanding of accompanying translational regulation. We perform ribosome profiling from more than 70 human prenatal and adult cortex samples across ontogeny and into adulthood, mapping translation events at nucleotide resolution. In addition to characterizing the translational regulation of annotated open reading frames (ORFs), we identify thousands of previously unknown translation events, including small open reading frames (sORFs) that give rise to human- and/or brain-specific microproteins, many of which we independently verify using size-selected proteomics. Ribosome profiling in stem cell-derived human neuronal cultures further corroborates these findings and shows that several neuronal activity-induced long non-coding RNAs (lncRNAs), including LINC00473, a primate-specific lncRNA implicated in depression, encode previously undescribed microproteins. Physicochemical analysis of these brain microproteinss identifies a large class harboring arginine-glycine-glycine (RGG) repeats as strong candidates for regulating RNA metabolism. Moreover, we find that, collectively, these previously unknown human brain sORFs are enriched for variants associated with schizophrenia. In addition to significantly expanding the translational landscape of the developing brain, this atlas will serve as a rich resource for the annotation and functional interrogation of thousands of previously unknown brain-specific protein products.