NEW YORK – A team led by researchers at Yale School of Medicine and the University of California, San Francisco has developed a resource of paired whole-genome and bulk tissue RNA sequencing from the dorsolateral prefrontal cortex, in order to investigate gene expression levels across different developmental stages, cell types, and regions in the brain.
As they reported in a new study published on Tuesday in Cell Reports, the researchers conducted WGS and RNA-seq on 176 samples from the human dorsolateral prefrontal cortex (DLPFC) across development, from six post-conception weeks to 20 years. They identified common variants that altered gene expression either constantly across development or predominantly during the prenatal or postnatal stages, and noted that both the constant and temporal-predominant expression quantitative trait loci (eQTLs) were enriched for loci associated with neuropsychiatric traits and disorders and co-localized with specific variants.
"Expression levels of more than 12,000 genes rise or fall in a concerted late-fetal transition, with the transitional genes enriched for cell-type-specific genes and neuropsychiatric risk loci, underscoring the importance of cataloging developmental trajectories in understanding cortical physiology and pathology," the authors wrote.
The resource the researchers generated, which they called BrainVar, focused on the DLPFC because of its importance in higher-order cognition and because previous studies have found that many risk genes for autism spectrum disorder and schizophrenia are co-expressed in the DLPFC during mid-fetal development. The researchers identified 252,629 cis-eQTLs affecting 8,421 genes, and classified their effects as prenatal-predominant, postnatal-predominant, or constant across brain development, and also identified eQTLs that linked specific genes to neuropsychiatric phenotypes.
Using the increased resolution from the 176 brains in BrainVar, the researchers showed that the late-fetal transition begins around 19 post-conception weeks and that the most dramatic changes are complete by six postnatal months. They found that more than half of the genes expressed in the cortex exhibited a persistent, progressive, and statistically significant expression variance across this late-fetal transition, and identified three distinct trajectories, with 6,934 genes showing higher postnatal expression (rising genes) and 5,143 genes showing higher prenatal expression (falling genes).
Further analyses showed that developmental delay, ASD, and educational attainment genes were enriched for falling genes, consistent with a prenatal origin for aspects of their neurobiology. The researchers also observed a non-significant trend toward enrichment for rising genes for Parkinson's disease and Alzheimer's disease.
"The eQTLs identified here also provide insights into CNS traits and disorders, with co-localization in 13 of 108 GWAS loci for schizophrenia and 52 of 1,271 GWAS loci for educational attainment, including the lncRNA LOC101926933 and the protein-coding gene RHEBL1," the authors wrote. "LOC101926933 remains largely uncharacterized, whereas RHEBL1 (Ras homolog enriched in brain-like 1) is a highly conserved G-protein that activates mTOR, a pathway that has been implicated previously in neurodevelopmental and neurodegenerative disorders."
They concluded that the combination of genomic and transcriptomic data across the developmental stages of the brain allows for an interrogation of human cortical development from a molecular perspective, at a higher resolution than was possible before.
"Understanding patterns of temporal and cell type specificity, along with eQTL co-localization to resolve GWAS loci, has already provided insights into the pathology underlying neuropsychiatric disorders," the researchers added. "Further delineation of these patterns is likely to be critical for a detailed understanding of etiology as a foundation for therapeutic development."