Single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells
| Autor: | Stephen W. Scherer, Mehdi Zarrei, Jennifer L. Howe, Marc Woodbury-Smith, Nasna Nassir, Ammar Albanna, Mohammed Uddin, Seyed Ali Safizadeh Shabestari, Bisan Samara, Asma Bankapur, Bakhrom K Berdiev, Abdulrahman Ali, Awab Ahmed, Ibrahim Mohammed Inuwa |
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| Rok vydání: | 2021 |
| Předmět: |
Cell type
Autism Spectrum Disorder Nerve Tissue Proteins Receptors Cell Surface QH426-470 Biology Transcriptome Mice Drug Discovery Genetics medicine Animals Glial cell type De novo LOF variant Molecular Biology Gene Loss function Human brain Exons Brain tissue Oligodendrocyte Dorsolateral prefrontal cortex medicine.anatomical_structure Gene Expression Regulation Medicine Molecular Medicine Primary Research Neuroglia Single-cell transcriptomics Astrocyte |
| Zdroj: | Human Genomics Human Genomics, Vol 15, Iss 1, Pp 1-16 (2021) |
| ISSN: | 1479-7364 |
| Popis: | Background In recent years, several hundred autism spectrum disorder (ASD) implicated genes have been discovered impacting a wide range of molecular pathways. However, the molecular underpinning of ASD, particularly from the point of view of ‘brain to behaviour’ pathogenic mechanisms, remains largely unknown. Methods We undertook a study to investigate patterns of spatiotemporal and cell type expression of ASD-implicated genes by integrating large-scale brain single-cell transcriptomes (> million cells) and de novo loss-of-function (LOF) ASD variants (impacting 852 genes from 40,122 cases). Results We identified multiple single-cell clusters from three distinct developmental human brain regions (anterior cingulate cortex, middle temporal gyrus and primary visual cortex) that evidenced high evolutionary constraint through enrichment for brain critical exons and high pLI genes. These clusters also showed significant enrichment with ASD loss-of-function variant genes (p –11) that are transcriptionally highly active in prenatal brain regions (visual cortex and dorsolateral prefrontal cortex). Mapping ASD de novo LOF variant genes into large-scale human and mouse brain single-cell transcriptome analysis demonstrate enrichment of such genes into neuronal subtypes and are also enriched for subtype of non-neuronal glial cell types (astrocyte, p –11, oligodendrocyte, p –09). Conclusion Among the ASD genes enriched with pathogenic de novo LOF variants (i.e. KANK1, PLXNB1), a subgroup has restricted transcriptional regulation in non-neuronal cell types that are evolutionarily conserved. This association strongly suggests the involvement of subtype of non-neuronal glial cells in the pathogenesis of ASD and the need to explore other biological pathways for this disorder. |
| Databáze: | OpenAIRE |
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