Cortical organoids model early brain development disrupted by 16p11.2 CNV in autism
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA596197 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10720000_1.fastq.gz | Fastqsanger.gz | |||
| SRR10720000_2.fastq.gz | Fastqsanger.gz | |||
| SRR10720001_1.fastq.gz | Fastqsanger.gz | |||
| SRR10720001_2.fastq.gz | Fastqsanger.gz | |||
| SRR10720002_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 216 |
Similar Datasets
Project description:Reciprocal deletion and duplication of 16p11.2 is the most common copy number variation (CNV) associated with Autism Spectrum Disorder (ASD) and other developmental disorders, and has significant effect on brain size. We used cortical organoids derived from ASD cases to investigate neurodevelopmental pathways dysregulated by dosage changes of 16p11.2 CNV. We show that organoids recapitulate patients’ macrocephaly and microcephaly phenotypes. Deletions and duplications have “mirror” effects on cell proliferation, maturation and synapse number, consistent with “mirror” effects on brain development in humans. Neuronal migration was decreased in both, deletion and duplication organoids. Transcriptomic and proteomic profiling revealed synaptic defects and neuronal migration as key drivers of 16p11.2 functional effect. We implicate upregulation of small GTPase RhoA involved in regulation of cytoskeletal dynamics, neuron migration and neurite outgrowth as one of the pathways impacted by the 16p11.2 CNV in ASD. Treatment with the RhoA inhibitor Rhosin rescued neuron migration, but not synaptic defects. This study identifies pathways dysregulated by the 16p11.2 CNV during early neocortical development using cortical organoid models. Grant ID: Simons Foundation, #345469 Grant Title: Translational dysregulation of the RhoA pathway in autism Affiliation: University of California San Diego Name: Lilia M. Iakoucheva; Alysson R. Muotri
2021-07-31 | GSE142174 | GEO
Project description:The 16p11.2 is the most common copy number variant (CNV) associated with Autism Spectrum Disorder (ASD). We used patient-derived cerebral organoids to investigate neurodevelopmental pathways dysregulated by dosage changes of 16p11.2 CNV. To investigate molecular dysregulation in DEL and DUP organoids, we carried out RNA sequencing and Tandem Mass Tag mass spectrometry (TMT-MS) on 1-month and 3-month organoids from the same samples. In proteomic analyses, we quantified a total of 6126 proteins in 1-month and 5481 proteins in 3-month organoids, with 13 and 11 proteins from within 16p11.2 CNV, respectively. Transcriptomic and proteomic profiling of organoids identifies the key drivers of functional effect by 16p11.2 CNV during neocortical development.
2019-12-19 | MSV000084727 | MassIVE
Project description:The 600kb BP4-BP5 16p11.2 CNV (copy number variant) is associated with neuroanatomical, neurocognitive and metabolic disorders. These recurrent rearrangements are associated with reciprocal phenotypes such as obesity and underweight, macro- and microcephaly, as well as autism spectrum disorder (ASD) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal CNVs in 16p11.2. The genome-wide transcript perturbations correlated with clinical endophenotypes of the CNV and were enriched for genes associated with ASD. We uncovered a significant correlation between copy number changes and expression levels of genes mutated in ciliopathies. Transcriptome profiles of lymphoblastoid cell lines of 50 16p11.2 deletion carriers, 31 16p11.2 duplication carriers and 17 controls.
2015-05-10 | E-GEOD-57802 | biostudies-arrayexpress
Project description:Recurrent Copy Number Variations (CNVs) of human 16p11.2 have been associated with a variety of developmental/neurocognitive syndromes. In particular, deletion of 16p11.2 is found in patients with autism, developmental delay, and obesity. Patients with deletions or duplications have a wide range of clinical features, and siblings carrying the same deletion often have diverse symptoms. To study the consequence of 16p11.2 CNVs in a systematic manner, we used chromosome engineering to generate mice harboring deletion of the chromosomal region corresponding to 16p11.2, as well as mice harboring the reciprocal duplication. These 16p11.2 CNV models have dosage-dependent changes in gene expression, viability, brain architecture, and behavior. For each phenotype, the consequence of the deletion is more severe than that of the duplication. Of particular note is that half of the 16p11.2 deletion mice die postnatally; those that survive to adulthood are healthy and fertile, but have alterations in the hypothalamus and exhibit a ‘behavior trap’ phenotype—a specific behavior characteristic of rodents with lateral hypothalamic and nigrostriatal lesions. Our findings indicate that 16p11.2 CNVs cause both brain and behavioral anomalies, providing new insight into human neurodevelopmental disorders.
2011-10-03 | GSE32012 | GEO
Project description:The 600kb BP4-BP5 16p11.2 CNV (copy number variant) is associated with neuroanatomical, neurocognitive and metabolic disorders. These recurrent rearrangements are associated with reciprocal phenotypes such as obesity and underweight, macro- and microcephaly, as well as autism spectrum disorder (ASD) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal CNVs in 16p11.2. The genome-wide transcript perturbations correlated with clinical endophenotypes of the CNV and were enriched for genes associated with ASD. We uncovered a significant correlation between copy number changes and expression levels of genes mutated in ciliopathies.
2015-05-10 | GSE57802 | GEO
Project description:As opposed to syndromic CNVs caused by single genes, extensive phenotypic heterogeneity in variably-expressive CNVs complicates disease gene discovery and functional evaluation. Here, we propose a complex interaction model for pathogenicity of the autism-associated 16p11.2 deletion, where CNV genes interact with each other in conserved pathways to modulate expression of the phenotype. Using multiple quantitative methods in Drosophila RNAi lines, we identify a range of neurodevelopmental phenotypes for knockdown of individual 16p11.2 homologs in different tissues. We test 565 pairwise knockdowns in the developing eye, and identify 24 interactions between pairs of 16p11.2 homologs and 46 interactions between 16p11.2 homologs and neurodevelopmental genes that suppress or enhance cell proliferation phenotypes compared to one-hit knockdowns. These interactions within cell proliferation pathways are also enriched in a human brain-specific network, providing translational relevance in humans. Our study indicates a role for pervasive genetic interactions within CNVs towards cellular and developmental phenotypes.
2017-06-23 | GSE100387 | GEO
Project description:While the neuronal underpinnings of autism spectrum disorders (ASD) are being unraveled, vascular contributions to ASD remain elusive. Here, we investigated postnatal cerebrovascular development in the 16p11.2df/+ mouse model of 16p11.2 deletion ASD syndrome. We discovered that 16p11.2 hemizygosity leads to male-specific, endothelium-dependent structural and functional neurovascular abnormalities. In 16p11.2df/+ mice, endothelial dysfunction resulted in impaired cerebral angiogenesis at postnatal day (P) 14, and in altered neurovascular coupling and cerebrovascular reactivity at P50. Moreover, we showed defective angiogenesis in primary 16p11.2df/+ mouse brain endothelial cells and in iPSC-derived endothelial cells from human 16p11.2 deletion carriers. Finally, we found that mice with endothelium-specific 16p11.2 deletion (16p11.2DEC) partially recapitulated some behavioral changes seen in 16p11.2 syndrome, specifically hyperactivity and impaired motor learning. By showing that developmental 16p11.2 haploinsufficiency from endothelial cells results in neurovascular and behavioral changes in adults, our results point to a potential role for endothelial impairment in ASD.
2020-04-03 | GSE147790 | GEO
Project description:Microdeletions and microduplications of the 16p11.2 chromosomal locus are implicated in a collection of neurodevelopmental disorders and reciprocal physiological conditions such as macro/microcephaly and high/low body mass index. To facilitate cellular and molecular investigations of these phenotypes, we generated 65 clones of human induced pluripotent stem cells (hiPSCs) from 13 individuals with 16p11.2 copy number variations (CNVs) and made each clone available by request from the Simons Foundation Autism Research Initiative (SFARI). Here we report on pluripotency, vector silencing, CNV breakpoint location, inter-clonal relatedness, and differentiation capacity for a majority of the available hiPSC clones. Comprehensive demographic and diagnostic data were collected and tabulated to facilitate investigation across a spectrum of pathologies. We demonstrate a customizable bioinformatic strategy for enhanced detection of the effects of episomal reprogramming and use this tool to identify a subset of clones free of off-target effects on neural progenitor gene transcription and phenotypic variation . With cortical neural progenitor cells (NPCs) derived from these hiPSCs, we identified a set of genes modulated by 16p11.2 deletion that precede morphological abnormalities reported at more mature developmental stages. This publicly available resource of 65 human hiPSC clones will serve as a powerful medium for probing the etiology of developmental disorders associated with 16p11.2 CNVs.
2020-12-03 | GSE144736 | GEO
Project description:16p11.2 microdeletion/microduplication syndrome is one of the common genetic causes of autism spectrum disorder, although it is not wholly penetrant with a wide range of phenotypic manifestations. We have previously explored the transcriptional consequences of the copy number variant (CNV) in cortical tissue of mouse models of the CNV within the syntenic 7qF3 region (Blumenthal et al 2014). We found that the strongest effects were from genes within the region itself, with no evidence for dosage compensation for any gene. Importantly, we found that global transcriptional effects due to the CNV were associated with multiple hypotheses for ASD pathogenesis, at the level of individual genes, networks and functional enrichments. To delineate tissue-specificity effects of the CNV, we embarked on exploration of the transcriptional landscape across multiple tissues for all mice from our earlier study. Specifically to disentangle brain-specific effects from others, we chose two additional brain tissues, namely Cerebellum and Striatum, as well as three other non-neuronal tissues, namely Liver, White Fat and Brown Fat. We present strand-specific RNAseq data for these five tissues in addition to the data for the Cortical tissue from our previous publication. Preliminary analyses of the data suggest that there are strong tissue-specific consequences of the CNV, with the effect being strongest in the Cortical tissue relative to other tissues, and observe low overlaps in differentially expressed genes across tissue. Furthermore, we see that the genes within the CNV region behave in a strong-tissue specific manner, with differences being more pronounced among the neuronal and non-neuronal tissues, relative to within tissue classes. Interestingly, we see that in non-neuronal tissues dosage compensation occurs for a handful of genes, when expressed. Finally, we see that genes within the CNV region show the strongest effects relative to the overall transcriptome in neuronal tissues and these effects are ameliorated in non-neuronal tissues.
2018-10-02 | GSE76872 | GEO
Project description:Vascular contribution to 16p11.2 deletion autism syndrome modeled in mice
| PRJNA616369 | ENA