Genetic studies have identified dozens of autism spectrum disorder (ASD) susceptibility genes, raising two critical questions: (1) do these genetic loci converge on specific biological processes, and ...(2) where does the phenotypic specificity of ASD arise, given its genetic overlap with intellectual disability (ID)? To address this, we mapped ASD and ID risk genes onto coexpression networks representing developmental trajectories and transcriptional profiles representing fetal and adult cortical laminae. ASD genes tightly coalesce in modules that implicate distinct biological functions during human cortical development, including early transcriptional regulation and synaptic development. Bioinformatic analyses suggest that translational regulation by FMRP and transcriptional coregulation by common transcription factors connect these processes. At a circuit level, ASD genes are enriched in superficial cortical layers and glutamatergic projection neurons. Furthermore, we show that the patterns of ASD and ID risk genes are distinct, providing a biological framework for further investigating the pathophysiology of ASD.
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•Exome sequencing identifies an ASD gene, Ankyrin 2, neuronal (ANK2)•Data from developing human brain are used for coexpression analyses of nine ASD genes•ASD genes converge in midfetal frontal cortex deep projection neurons•Approach clarifies when, where, and in what cell type to study specific ASD mutations
Network analysis of nine genes previously implicated in autism spectrum disorders (ASD) identifies a key point of convergence in midfetal deep frontal cortex glutamatergic projection neurons, providing a temporal and spatial framework for studying ASD pathophysiology.
Rare mutations, including copy-number variants (CNVs), contribute significantly to autism spectrum disorder (ASD) risk. Although their importance has been established in families with only one ...affected child (simplex families), the contribution of both de novo and inherited CNVs to ASD in families with multiple affected individuals (multiplex families) is less well understood. We analyzed 1,532 families from the Autism Genetic Resource Exchange (AGRE) to assess the impact of de novo and rare CNVs on ASD risk in multiplex families. We observed a higher burden of large, rare CNVs, including inherited events, in individuals with ASD than in their unaffected siblings (odds ratio OR = 1.7), but the rate of de novo events was significantly lower than in simplex families. In previously characterized ASD risk loci, we identified 49 CNVs, comprising 24 inherited events, 19 de novo events, and 6 events of unknown inheritance, a significant enrichment in affected versus control individuals (OR = 3.3). In 21 of the 30 families (71%) in whom at least one affected sibling harbored an established ASD major risk CNV, including five families harboring inherited CNVs, the CNV was not shared by all affected siblings, indicating that other risk factors are contributing. We also identified a rare risk locus for ASD and language delay at chromosomal region 2q24 (implicating NR4A2) and another lower-penetrance locus involving inherited deletions and duplications of WWOX. The genetic architecture in multiplex families differs from that in simplex families and is complex, warranting more complete genetic characterization of larger multiplex ASD cohorts.
Neural stem cells have been adopted to model a wide range of neuropsychiatric conditions in vitro. However, how well such models correspond to in vivo brain has not been evaluated in an unbiased, ...comprehensive manner. We used transcriptomic analyses to compare in vitro systems to developing human fetal brain and observed strong conservation of in vivo gene expression and network architecture in differentiating primary human neural progenitor cells (phNPCs). Conserved modules are enriched in genes associated with ASD, supporting the utility of phNPCs for studying neuropsychiatric disease. We also developed and validated a machine learning approach called CoNTExT that identifies the developmental maturity and regional identity of in vitro models. We observed strong differences between in vitro models, including hiPSC-derived neural progenitors from multiple laboratories. This work provides a systems biology framework for evaluating in vitro systems and supports their value in studying the molecular mechanisms of human neurodevelopmental disease.
•Quantitative framework permits comparisons of in vitro models to in vivo brain•phNPCs recapitulate cortical development up to late mid-fetal periods•In vivo cortical gene networks implicated in ASD are preserved in phNPCs•Highlights key differences between widely used stem cell models and in vivo brain
Human neural stem cells have been adopted to model a wide range of neuropsychiatric conditions in vitro. Here, Stein et al. develop a bioinformatic framework to quantitatively evaluate their ability to model in vivo cortical development and their translational potential.
Autism spectrum disorder (ASD) is a common, highly heritable neurodevelopmental condition characterized by marked genetic heterogeneity. Thus, a fundamental question is whether autism represents an ...aetiologically heterogeneous disorder in which the myriad genetic or environmental risk factors perturb common underlying molecular pathways in the brain. Here, we demonstrate consistent differences in transcriptome organization between autistic and normal brain by gene co-expression network analysis. Remarkably, regional patterns of gene expression that typically distinguish frontal and temporal cortex are significantly attenuated in the ASD brain, suggesting abnormalities in cortical patterning. We further identify discrete modules of co-expressed genes associated with autism: a neuronal module enriched for known autism susceptibility genes, including the neuronal specific splicing factor A2BP1 (also known as FOX1), and a module enriched for immune genes and glial markers. Using high-throughput RNA sequencing we demonstrate dysregulated splicing of A2BP1-dependent alternative exons in the ASD brain. Moreover, using a published autism genome-wide association study (GWAS) data set, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism. In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic aetiology for this process. Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We performed RNA sequencing on 40,000 cells to create a high-resolution single-cell gene expression atlas of developing human cortex, providing the first single-cell characterization of previously ...uncharacterized cell types, including human subplate neurons, comparisons with bulk tissue, and systematic analyses of technical factors. These data permit deconvolution of regulatory networks connecting regulatory elements and transcriptional drivers to single-cell gene expression programs, significantly extending our understanding of human neurogenesis, cortical evolution, and the cellular basis of neuropsychiatric disease. We tie cell-cycle progression with early cell fate decisions during neurogenesis, demonstrating that differentiation occurs on a transcriptomic continuum; rather than only expressing a few transcription factors that drive cell fates, differentiating cells express broad, mixed cell-type transcriptomes before telophase. By mapping neuropsychiatric disease genes to cell types, we implicate dysregulation of specific cell types in ASD, ID, and epilepsy. We developed CoDEx, an online portal to facilitate data access and browsing.
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•High-resolution transcriptome map of 40,000 cells from developing human brain•Cell-type-specific transcription factor (TF) expression and TF-gene networks•Defines intermediate cell transition states during early neurogenesis•Implicates specific cell types in neuropsychiatric disorders
An extensive single-cell catalog of cell types in the mid-gestation human neocortex extends our understanding of early cortical development, including subplate neuron transcriptomes, cell-type-specific regulatory networks, brain evolution, and the cellular basis of neuropsychiatric disease.
Prions are proteins that adopt alternative conformations that become self-propagating; the PrPScprion causes the rare human disorder Creutzfeldt–Jakob disease (CJD). We report here that multiple ...system atrophy (MSA) is caused by a different human prion composed of the α-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein. To determine whether human α-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human α-synuclein fused to yellow fluorescent protein (α-syn140*A53T–YFP) and TgM83+/−mice expressing α-synuclein (A53T). The TgM83+/−mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83+/+mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83+/−mice after incubation periods of ∼120 d, which was accompanied by deposition of α-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of α-syn*A53T–YFP in cultured cells, whereas none of six Parkinson’s disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of α-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83+/+mice. Remarkably, α-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.
Autism spectrum disorder (ASD) involves substantial genetic contributions. These contributions are profoundly heterogeneous but may converge on common pathways that are not yet well understood. Here, ...through post-mortem genome-wide transcriptome analysis of the largest cohort of samples analysed so far, to our knowledge, we interrogate the noncoding transcriptome, alternative splicing, and upstream molecular regulators to broaden our understanding of molecular convergence in ASD. Our analysis reveals ASD-associated dysregulation of primate-specific long noncoding RNAs (lncRNAs), downregulation of the alternative splicing of activity-dependent neuron-specific exons, and attenuation of normal differences in gene expression between the frontal and temporal lobes. Our data suggest that SOX5, a transcription factor involved in neuron fate specification, contributes to this reduction in regional differences. We further demonstrate that a genetically defined subtype of ASD, chromosome 15q11.2-13.1 duplication syndrome (dup15q), shares the core transcriptomic signature observed in idiopathic ASD. Co-expression network analysis reveals that individuals with ASD show age-related changes in the trajectory of microglial and synaptic function over the first two decades, and suggests that genetic risk for ASD may influence changes in regional cortical gene expression. Our findings illustrate how diverse genetic perturbations can lead to phenotypic convergence at multiple biological levels in a complex neuropsychiatric disorder.
Justice William Rufus Day served on the Court from 1903 to 1922. Justice William Brennan's introduction to his colleagues on the Supreme Court came during the 1956 World Series opening game. Chief ...Justice Earl Warren quickly introduced him to the other justices, who then returned to watching the game on a television set placed in the Court's conference room. After he stepped down from the Court, Supreme Court Justice Arthur Goldberg, a longtime labor lawyer, represented Major League Baseball three-time All-Star player Curt Flood in his 1972 suit seeking free agency and the end of the reserve clause in baseball. Justice Samuel Alito is a Philadelphia Phillies fan, and the justices invited the team's mascot, the Phillie Phanatic, to the welcome dinner they hosted when Justice Alito joined the Court. JENNIFER M LOWE is director of programs and strategic planning at the Supreme Court Historical Society.
OBJECTIVES: African American (AA) children affected by autism spectrum disorder (ASD) experience delays in diagnosis and obstacles to service access, as well as a disproportionate burden of ...intellectual disability (ID) as documented in surveillance data recently published by the US Centers for Disease Control and Prevention. Our objective in this study was to analyze data from the largest-available repository of diagnostic and phenotypic information on AA children with ASD, and to explore the wide variation in outcome within the cohort as a function of sociodemographic risk and specific obstacles to service access for the purpose of informing a national approach to resolution of these disparities. METHODS: Parents of 584 AA children with autism consecutively enrolled in the Autism Genetic Resource Exchange across 4 US data collection sites completed event history calendar interviews of the diagnostic odysseys for their children with ASD. These data were examined in relation to developmental outcomes of the children with autism and their unaffected siblings. RESULTS: The average age of ASD diagnosis was 64.9 months (±49.6), on average 42.3 months (±45.1) after parents' first concerns about their children's development. The relationship between timing of diagnosis and ASD severity was complex, and ID comorbidity was not predicted in a straightforward manner by familial factors associated with cognitive variation in the general population. CONCLUSIONS: These findings document significant opportunity to expedite diagnosis, the need to further understand causes of ID comorbidity, and the necessity to identify effective approaches to the resolution of disparities in severity-of-outcome for AA children with autism.
We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected ...children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.
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•Identification of rare inherited variants associated with ASD and 16 new ASD risk genes•Inherited risk reveals both new biological pathways and shared PPI with known genes•We develop and validate a machine learning algorithm (ARC) to remove WGS artifacts•NR3C2 mutations define a novel syndromic form of ASD, which we model in zebrafish
Whole-genome sequencing from families with multiple ASD-affected children allows identification of rare inherited variants associated with disease and definition of a syndromic form of disease caused by mutations in NR3C2.
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