Cellular context defines brain-specific functions of genes associated with neurodevelopmental disorders
- 1Institute of Molecular Biology
Abstract
Differential gene expression rarely explains why certain genes, e.g. associated with tissue-specific manifestations of human disease, exert tissue-specific functions. To understand how gene expression and molecular context act in concert to drive tissue-specific gene function, we focus on Neurodevelopmental disorders (NDDs), for which underlying disease mechanisms are still poorly understood. We developed a computational framework that harmonizes and integrates spatiotemporal transcriptome datasets enabling us to systematically quantify preferential gene expression across tissues and developmental stages. Applying this pipeline to approximately 1,000 NDD-associated genes, we find that only about 10% show brain-preferential expression, with distinct gene clusters instead exhibiting significant upregulation in non-brain tissues. Investigation of these clusters reveals regulatory mechanisms that govern mitochondrial function to meet neurons' high energetic demands, which are mechanistically distinct from those employed by other energy-intensive tissues such as heart and skeletal muscle. Furthermore, by integrating tissue-agnostic protein-protein interaction data with our expression resource, we identify putative brain-specific interaction partners for 22 uniformly expressed NDD-associated genes. We experimentally validate these interactions for QRICH1 and demonstrate that disease-associated mutations disrupt them, providing a molecular hypothesis for how QRICH1 acquires brain-specific function and how its disruption might cause Ververi-Brady syndrome. Together, our findings highlight the importance of molecular context for brain-specific gene function in the context of neurodevelopmental disease. We provide a framework for dissecting molecular mechanisms of tissue-specific Mendelian-like disorders and for exploring how biological processes are adapted to tissue-specific needs.
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BibTeX
@misc{djokic2026cellular,
title = {{Cellular context defines brain-specific functions of genes associated with neurodevelopmental disorders}},
author = {M. Djokic and S. Karunanithi and M. Welzel and F. Kielisch and K. Luck},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.26.761783},
url = {https://www.biorxiv.org/content/10.64898/2026.10.26.761783v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Cellular context defines brain-specific functions of genes associated with neurodevelopmental disorders
AU - M. Djokic
AU - S. Karunanithi
AU - M. Welzel
AU - F. Kielisch
AU - K. Luck
PY - 2026
DA - 2026/10/26
PB - bioRxiv
DO - 10.64898/2026.10.26.761783
UR - https://www.biorxiv.org/content/10.64898/2026.10.26.761783v1
AB - Differential gene expression rarely explains why certain genes, e.g. associated with tissue-specific manifestations of human disease, exert tissue-specific functions. To understand how gene expression and molecular context act in concert to drive tissue-specific gene function, we focus on Neurodevelopmental disorders (NDDs), for which underlying disease mechanisms are still poorly understood. We developed a computational framework that harmonizes and integrates spatiotemporal transcriptome datasets enabling us to systematically quantify preferential gene expression across tissues and developmental stages. Applying this pipeline to approximately 1,000 NDD-associated genes, we find that only about 10% show brain-preferential expression, with distinct gene clusters instead exhibiting significant upregulation in non-brain tissues. Investigation of these clusters reveals regulatory mechanisms that govern mitochondrial function to meet neurons' high energetic demands, which are mechanistically distinct from those employed by other energy-intensive tissues such as heart and skeletal muscle. Furthermore, by integrating tissue-agnostic protein-protein interaction data with our expression resource, we identify putative brain-specific interaction partners for 22 uniformly expressed NDD-associated genes. We experimentally validate these interactions for QRICH1 and demonstrate that disease-associated mutations disrupt them, providing a molecular hypothesis for how QRICH1 acquires brain-specific function and how its disruption might cause Ververi-Brady syndrome. Together, our findings highlight the importance of molecular context for brain-specific gene function in the context of neurodevelopmental disease. We provide a framework for dissecting molecular mechanisms of tissue-specific Mendelian-like disorders and for exploring how biological processes are adapted to tissue-specific needs.
ER -