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Discovering the basis for the unique properties of the human brain is a major goal of modern science. Yet, many fundamental gaps remain in our knowledge of the human brain development and evolution.
In this study we analyzed the transcriptome from sixteen human brain regions, comprising the cerebellar cortex, mediodorsal nucleus of the thalamus, striatum, amygdala, hippocampus, and eleven areas of the neocortex, throughout the entire prenatal development and postnatal life. Approximately 86% of genes were found to be expressed, and over 90% of these were differentially expressed across regions and/or time. Genes were organized into functionally distinct co-expression networks. Furthermore, sex differences were present in both gene expression and exon usage. We also demonstrate that these results can be used to profile trajectories of genes associated with several neurobiological themes, such as developmental processes, cell types, neurotransmitter systems, autism, and schizophrenia.
In the second part of this study, we analyzed the temporal dynamics and laterality of gene expression across the eleven neocortical areas. We found that inter-areal transcriptional differences exhibit a temporal hourglass pattern, characterized by more expression differences prenatally and from adolescence onward, and almost no differences in infancy and childhood. Further analyses revealed distinct gradients and areal-restricted expression. We also found that global gene expression trajectories of each area become increasingly synchronized, especially after birth. Furthermore, analyses of gene expression between corresponding left and right areas revealed global symmetry throughout the fetal development and postnatal lifespan.
Finally, we analyzed the gene expression from human, chimpanzee, and rhesus macaque adult brains, using the aforementioned sixteen regions. We found 6,389 genes were differentially expressed among species, with 3,154 specifically up- or downregulated in humans. Furthermore, a multi-regional approach allowed us to examine intra-species differentially expressed genes among all regions. In addition, we found region-specific gene co-expression modules that are conserved across all three species, as well as species-specific transcription modules. We also found several genes involved in the dopamine synthesis pathway were upregulated in humans, especially in the striatum. Lastly, we analyzed the co-expression patterns of neurotransmitter receptors systems and found that the glutamatergic and GABAergic systems receptors were the most conserved among species, while serotoninergic and cholinergic systems were the least conserved.
This study provides a comprehensive dataset on the spatiotemporal human brain transcriptome and new insights into the transcriptional foundations of human neurodevelopment, as well as new insights into species-specific gene expression patterns.