Single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells

Abstract

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 < 5.23 × 10–11) 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 < 6.40 × 10–11, oligodendrocyte, p < 1.31 × 10–09). 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.

Construction of copy number variation landscape and characterization of associated genes in a Bangladeshi cohort of neurodevelopmental disorders

“…The remaining eight patients carried different lengths of deletion and duplication CNVs that disrupt the vital regions of the chromosome containing bona fide genes ( SCN1A , KANK1 , DOCK8, etc. ) associated with different types of neurodevelopmental disorders ( Nassir et al, 2021 ) ( Table 1 ).…”

“…We scanned the KEGG pathway database, which comprises an assembly of the up-to-date interactions, reactions, and relations of molecular networks ( https://www.genome.jp/kegg/pathway.html ), and the GO database ( http://geneontology.org/ ) to identify all the pathways in which five or more genes were expressed. Only the pathways having more than 50 genes and less than 1,000 genes were considered for this analysis ( Cline et al, 2007 ; Bader et al, 2014 ; Nassir et al, 2021 ). The pathways were identified by their unique KEGG ID and name.…”

Decoding microRNAs in autism spectrum disorder

“…Single-cell RNA sequencing of cortical regions of autopsy samples showed largely differentially expressed genes in the neurons of the upper 2–3 layers of the cerebral cortex and microglia compared with the control group, 109 as well as neuroepithelial cells, 138 oligodendrocytes, and astrocytes. 139 So, how to regenerate the new cells to fulfill the function becomes an intriguing question to both researchers and clinicians. Direct generation of neurons from other cell types has been demonstrated by taking advantage of neuron specific transcription factors 140 or small chemical molecules.…”

Defining specific cell states of MPTP-induced Parkinson’s disease by single-nucleus RNA sequencing

“…2f, j and SM 3). For example, Slc1a2, Prdm16, Kank1 and Ddah1 were target genes of Dbx2, the high expression of Slc1a2 was found to reduce the risk for PD in a Chinese cohort 19 , and the other genes are associated with cognitive function 20 , autism spectrum disorder 21 and depressionlike behavior 22 , respectively. Meanwhile, Sox13 target genes Ptch1, Pdgfrb, Vcan, Lhfpl2 and A2m have been reported to be related to PD.…”