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, remai...

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Autores principales:	Nasna Nassir, Asma Bankapur, Bisan Samara, Abdulrahman Ali, Awab Ahmed, Ibrahim M. Inuwa, Mehdi Zarrei, Seyed Ali Safizadeh Shabestari, Ammar AlBanna, Jennifer L. Howe, Bakhrom K. Berdiev, Stephen W. Scherer, Marc Woodbury-Smith, Mohammed Uddin
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Single-cell transcriptomics Autism spectrum disorder De novo LOF variant Glial cell type Brain tissue Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/00dc4650ae5a4c8da8d8c168cea1f017
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spelling	oai:doaj.org-article:00dc4650ae5a4c8da8d8c168cea1f0172021-11-28T12:13:49ZSingle-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells10.1186/s40246-021-00368-71479-7364https://doaj.org/article/00dc4650ae5a4c8da8d8c168cea1f0172021-11-01T00:00:00Zhttps://doi.org/10.1186/s40246-021-00368-7https://doaj.org/toc/1479-7364Abstract 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.Nasna NassirAsma BankapurBisan SamaraAbdulrahman AliAwab AhmedIbrahim M. InuwaMehdi ZarreiSeyed Ali Safizadeh ShabestariAmmar AlBannaJennifer L. HoweBakhrom K. BerdievStephen W. SchererMarc Woodbury-SmithMohammed UddinBMCarticleSingle-cell transcriptomicsAutism spectrum disorderDe novo LOF variantGlial cell typeBrain tissueMedicineRGeneticsQH426-470ENHuman Genomics, Vol 15, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Single-cell transcriptomics Autism spectrum disorder De novo LOF variant Glial cell type Brain tissue Medicine R Genetics QH426-470
spellingShingle	Single-cell transcriptomics Autism spectrum disorder De novo LOF variant Glial cell type Brain tissue Medicine R Genetics QH426-470 Nasna Nassir Asma Bankapur Bisan Samara Abdulrahman Ali Awab Ahmed Ibrahim M. Inuwa Mehdi Zarrei Seyed Ali Safizadeh Shabestari Ammar AlBanna Jennifer L. Howe Bakhrom K. Berdiev Stephen W. Scherer Marc Woodbury-Smith Mohammed Uddin Single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells
description	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.
format	article
author	Nasna Nassir Asma Bankapur Bisan Samara Abdulrahman Ali Awab Ahmed Ibrahim M. Inuwa Mehdi Zarrei Seyed Ali Safizadeh Shabestari Ammar AlBanna Jennifer L. Howe Bakhrom K. Berdiev Stephen W. Scherer Marc Woodbury-Smith Mohammed Uddin
author_facet	Nasna Nassir Asma Bankapur Bisan Samara Abdulrahman Ali Awab Ahmed Ibrahim M. Inuwa Mehdi Zarrei Seyed Ali Safizadeh Shabestari Ammar AlBanna Jennifer L. Howe Bakhrom K. Berdiev Stephen W. Scherer Marc Woodbury-Smith Mohammed Uddin
author_sort	Nasna Nassir
title	Single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells
title_short	Single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells
title_full	Single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells
title_fullStr	Single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells
title_full_unstemmed	Single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells
title_sort	single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells
publisher	BMC
publishDate	2021
url	https://doaj.org/article/00dc4650ae5a4c8da8d8c168cea1f017
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Single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells

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