An integrative single-cell atlas for exploring the cellular and temporal specificity of genes related to neurological disorders during human brain development

Seoyeon Kim, Jihae Lee, In Gyeong Koh, Jungeun Ji, Hyun Jung Kim, Eunha Kim, Jihwan Park, Jong-Eun Park, Joon-Yong An

Abstract: Single-cell technologies have enhanced comprehensive knowledge regarding the human brain by facilitating an extensive transcriptomic census across diverse brain regions. Nevertheless, understanding the cellular and temporal specificity of neurological disorders remains ambiguous due to developmental variations. To address this gap, we illustrated the dynamics of disorder risk gene expression under development by integrating multiple single-cell RNA sequencing datasets. We constructed a comprehensive single-cell atlas of the developing human brain, encompassing 393,060 single cells across diverse developmental stages. Temporal analysis revealed the distinct expression patterns of disorder risk genes, including those associated with autism, highlighting their temporal regulation in different neuronal and glial lineages. We identified distinct neuronal lineages that diverged across developmental stages, each exhibiting temporal-specific expression patterns of disorder-related genes. Lineages of nonneuronal cells determined by molecular profiles also showed temporal-specific expression, indicating a link between cellular maturation and the risk of disorder. Furthermore, we explored the regulatory mechanisms involved in early brain development, revealing enriched patterns of fetal cell types associated with neuronal disorders indicative of the prenatal stage’s influence on disease determination. Our findings facilitate unbiased comparisons of cell type‒disorder associations and provide insight into dynamic alterations in risk genes during development, paving the way for a deeper understanding of neurological disorders. The growth of the human brain is a complicated process that begins before birth and continues into young adulthood. Researchers focused on how genes related to brain disorders are expressed in different cells over time. They gathered data from 114 human brain samples, creating a single-cell atlas that traces brain growth from early fetal stages to adulthood. The results showed distinct patterns of gene expression linked to disorders like autism and developmental delay, especially in neurons during early growth. The study also emphasized the role of glial cells in brain conditions, such as Alzheimer’s and Parkinson’s disease, by showing specific gene expression patterns in these cells related to the disorders. Researchers conclude that their single-cell atlas greatly improves our understanding of brain growth and the molecular mechanisms behind brain disorders. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

External IDs:doi:10.1038/s12276-024-01328-6