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Chronic oxytocin administration stimulates the oxytocinergic system in children with autism
Intranasal administration of oxytocin is increasingly considered as a new therapeutic option for alleviating stress and social problems in children with autism. Here, important insights are provided into how repeated administration of oxytocin influences the functioning of one’s own oxytocin system.
- Matthijs Moerkerke
- , Nicky Daniels
- & Kaat Alaerts
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| Open Access
Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD
Here, the authors clarify the architecture of genetic risk on chromosome X in three male-biased psychiatric disorders. Leveraging this information they identify an exome-wide significant autism risk gene, MAGEC3, and provide a path forward for future gene discovery on this chromosome.
- Sheng Wang
- , Belinda Wang
- & A. Jeremy Willsey
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| Open Access
Endogenous noise of neocortical neurons correlates with atypical sensory response variability in the Fmr1−/y mouse model of autism
Enhanced variability is a hallmark of atypical sensory processing in autism. Here, focusing on variability of neocortical tactile responses in mice, the authors explore the role of endogenous noise sources in neural processing in a model of autism.
- Arjun A. Bhaskaran
- , Théo Gauvrit
- & Andreas Frick
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| Open Access
Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders
An apparent redundant role with EZH2 has rendered EZH1 as a secondary player in PRC2-mediated homeostasis regulation. Here, the authors report that gain- and loss-of-function variants in EZH1 cause neurodevelopmental disorders, highlighting its functional relevance.
- Carolina Gracia-Diaz
- , Yijing Zhou
- & Naiara Akizu
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Elevated levels of FMRP-target MAP1B impair human and mouse neuronal development and mouse social behaviors via autophagy pathway
MAP1B is bound and regulated by fragile X protein FMRP. Here, the authors show that elevated levels of MAP1B reduce the morphological and physiological maturation of human neurons and impair social behavior in mice.
- Yu Guo
- , Minjie Shen
- & Xinyu Zhao
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Article
| Open Access
Neural correlates of hierarchical predictive processes in autistic adults
It remains unclear whether autism spectrum disorder is characterized by changes in predictive mechanisms. Here, the authors show that, in both neurotypical and autistic adults, priors influence percepts at the behavioral and neural levels and are hierarchically encoded in the brain.
- Laurie-Anne Sapey-Triomphe
- , Lauren Pattyn
- & Johan Wagemans
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| Open Access
Kv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice
Seizures can occur in autism spectrum disorders (ASD). Here, the authors report that mice lacking the ASD related Ank2 gene show abnormal behaviours, and juvenile seizure related death, through impaired Kv7 potassium channel function.
- Hyoseon Oh
- , Suho Lee
- & Eunjoon Kim
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| Open Access
Rescue of neuropsychiatric phenotypes in a mouse model of 16p11.2 duplication syndrome by genetic correction of an epilepsy network hub
The 16p11.2 duplication confers risk for autism and schizophrenia, but the disease mechanisms are unknown. Here, the authors use proteomics to show dysregulation of synaptic and epilepsy-associated protein networks in the cortex of model mice, and demonstrate that correcting Prrt2 gene dosage rescues circuit hypersynchrony and behavioural phenotypes.
- Marc P. Forrest
- , Marc Dos Santos
- & Peter Penzes
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Article
| Open Access
Robust odor identification in novel olfactory environments in mice
Detecting relevant odours from background odours is important for animal behaviour. Here the authors design a task to study this process in mice.
- Yan Li
- , Mitchell Swerdloff
- & Gonzalo H. Otazu
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Genome-wide rare variant score associates with morphological subtypes of autism spectrum disorder
Morphological subtypes of autism spectrum disorder (ASD) may differ in their genetic bases. Chan et al. develop a method for calculating a patient-level, genome-wide rare variant score and find significant differences in rare and common variant associations between dysmorphic and nondysmorphic ASD groups.
- Ada J. S. Chan
- , Worrawat Engchuan
- & Stephen W. Scherer
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Article
| Open Access
Multi-omic brain and behavioral correlates of cell-free fetal DNA methylation in macaque maternal obesity models
In animal models, maternal obesity is associated with development of neurodevelopmental disorder like phenotypes. Here the authors show in a macaque model that in obese dams, cell-free fetal DNA methylation, inflammatory cytokines, and metabolites correlated with infant brain DNA methylation, lipids, and metabolites.
- Benjamin I. Laufer
- , Yu Hasegawa
- & Janine M. LaSalle
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Article
| Open Access
Early postnatal serotonin modulation prevents adult-stage deficits in Arid1b-deficient mice through synaptic transcriptional reprogramming
ARID1B is a chromatin remodeler associated with autism spectrum disorders. Here the authors demonstrate that early postnatal serotonin modulation prevents adult stage deficits in Arid1b-deficient mice through synaptic transcriptional reprogramming.
- Hyosang Kim
- , Doyoun Kim
- & Eunjoon Kim
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Article
| Open Access
SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice
The protein SLITRK2 plays an important role in synaptic communication. This study identifies X-linked SLITRK2 variants that underlie neurodevelopmental disorders by impairing excitatory synapses.
- Salima El Chehadeh
- , Kyung Ah Han
- & Ji Won Um
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Pattern decorrelation in the mouse medial prefrontal cortex enables social preference and requires MeCP2
Impaired sociability is often interpreted as social avoidance. Here, the authors show that the problem is actually failure to distinguish social from nonsocial stimuli, caused by indistinguishable coactivity patterns in the medial prefrontal cortex.
- Pan Xu
- , Yuanlei Yue
- & Hui Lu
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| Open Access
Association of mitochondrial DNA content, heteroplasmies and inter-generational transmission with autism
Most genetic studies of autism spectrum disorder (ASD) have focused on the nuclear genome. Here, the authors show that variations in mitochondrial DNA, detectable at birth, are also associated with risk of ASD.
- Yiqin Wang
- , Xiaoxian Guo
- & Zhenglong Gu
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| Open Access
Excess ribosomal protein production unbalances translation in a model of Fragile X Syndrome
Dysregulated protein synthesis is key contributor to Fragile X syndrome. Here the authors identify a relationship between ribosome expression and the translation of long mRNAs that contributes to synaptic weakening in a model of Fragile X syndrome.
- Sang S. Seo
- , Susana R. Louros
- & Emily K. Osterweil
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| Open Access
Association between resting-state functional brain connectivity and gene expression is altered in autism spectrum disorder
Gene expression patterns have been associated with functional activity patterns in the brain. Here the authors determine how gene expression patterns in the human brain supports brain phenotypes obtained from resting state fMRI imaging, identifying brain regions and genes relevant to autism.
- Stefano Berto
- , Alex H. Treacher
- & Genevieve Konopka
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Phase separation and zinc-induced transition modulate synaptic distribution and association of autism-linked CTTNBP2 and SHANK3
Autism impacts synapses. This study reports that autism-linked mutations of CTTNBP2 regulate phase separation to control synaptic enrichment of that protein. A zinc-induced liquid-to-gel transition improves synaptic retention of CTTNBP2 and SHANK3.
- Pu-Yun Shih
- , Yu-Lun Fang
- & Yi-Ping Hsueh
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Article
| Open Access
Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content
Transcription Factor 4 (TCF4) has been associated with autism and schizophrenia. Here, the authors demonstrate aberrant proliferation and differentiation in neural cells and organoids carrying mutations in TCF4.
- Fabio Papes
- , Antonio P. Camargo
- & Alysson R. Muotri
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| Open Access
Changes to gut amino acid transporters and microbiome associated with increased E/I ratio in Chd8+/− mouse model of ASD-like behavior
The gut microbiota has been shown to modulate the neural function via the microbiota-gut-brain axis. Here, the authors show that Bacteroides uniformis, a gut commensal bacterium, restores the ASD-like phenotypes by reducing intestinal amino acid transport in an ASD mouse model.
- You Yu
- , Bing Zhang
- & Fangqing Zhao
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| Open Access
Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures
ASH1L haploinsufficiency is strongly linked to autism, despite the unknown mechanism. Here, the authors show that ASH1L deficiency in prefrontal cortex causes the downregulation of synaptic genes, leading to seizures, which is rescued by chemogenetic and pharmacological restoration of excitation/inhibition balance.
- Luye Qin
- , Jamal B. Williams
- & Zhen Yan
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mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity
Autism spectrum disorder (ASD) is characterised by synaptic surplus and atypical functional connectivity. Here, the authors show that synaptic pathology in Tsc2 haploinsufficient mice is associated with autism-like behavior and cortico-striatal hyperconnectivity, and that analogous functional hyperconnectivity signatures can be linked to mTOR-pathway dysfunction in subgroups of children with idiopathic ASD.
- Marco Pagani
- , Noemi Barsotti
- & Alessandro Gozzi
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Functional and molecular characterization of a non-human primate model of autism spectrum disorder shows similarity with the human disease
Non-human primate models of autism spectrum disorder (ASD) are few and not well characterised. Here, the authors describe synaptic function and gene expression changes in a marmoset model of ASD from birth to juvenile, highlighting its similarity to features observed in human ASD.
- Satoshi Watanabe
- , Tohru Kurotani
- & Noritaka Ichinohe
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| Open Access
Slow update of internal representations impedes synchronization in autism
Autism is characterized by diverse symptoms, including impaired social skills, motor and perceptual atypicalities. Here, using computational modelling, the authors show that impaired synchronization ability in autism stems from reduced error correction, supporting a slow-updating account of autism.
- Gal Vishne
- , Nori Jacoby
- & Merav Ahissar
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| Open Access
Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations
Overlapping genes have been implicated in schizophrenia and neurodevelopmental disorders. Here, the authors overlap de novo variants in the two types of disorders and find variants in these genes with the same functional effect and in some cases the same specific variants.
- Elliott Rees
- , Hugo D. J. Creeth
- & Michael C. O’Donovan
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| Open Access
Cortical overgrowth in a preclinical forebrain organoid model of CNTNAP2-associated autism spectrum disorder
Mutations in CNTNAP2 have been associated with a syndromic form of Autism Spectrum Disorder. Here the authors show that forebrain organoids generated from induced pluripotent stem cells of patients with a syndromic form of ASD with a homozygous truncating mutation in CNTNAP2 displayed an increase in volume and total cell number, which is driven by abnormal cellular proliferation and neurogenesis.
- Job O. de Jong
- , Ceyda Llapashtica
- & Sander Markx
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| Open Access
Excitatory synapses and gap junctions cooperate to improve Pv neuronal burst firing and cortical social cognition in Shank2-mutant mice
How NMDAR and GABA neuronal dysfunctions result in impaired social behaviour is unclear. Here, the authors show that NMDARs and gap junctions in cortical PV interneurons modulate burst firing, affecting social behaviour.
- Eunee Lee
- , Seungjoon Lee
- & Eunjoon Kim
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Article
| Open Access
Genetic dissection identifies Necdin as a driver gene in a mouse model of paternal 15q duplications
Duplication of chromosome 15q11-q13 is associated with autism spectrum disorder (ASD). Here, the authors show that in mice paternal Dup15q results in ASD-like neuronal and behavioural impairment driven by Necdin.
- Kota Tamada
- , Keita Fukumoto
- & Toru Takumi
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Article
| Open Access
FoxG1 regulates the formation of cortical GABAergic circuit during an early postnatal critical period resulting in autism spectrum disorder-like phenotypes
Cortical excitatory/inhibitory (E/I) imbalance is a feature of autism spectrum disorder (ASD). Here, the authors show that FoxG1 regulates the formation of cortical GABAergic circuits affecting social behaviour during a specific postnatal time window in mouse models of ASD.
- Goichi Miyoshi
- , Yoshifumi Ueta
- & Mariko Miyata
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| Open Access
Aberrant dynamics of cognitive control and motor circuits predict distinct restricted and repetitive behaviors in children with autism
Restricted and repetitive behaviors (RRBs) are a core clinical feature of autism, yet the brain basis of RRBs is unknown. Here, the authors demonstrate that aberrant cognitive control and motor circuit dynamics differentially predict three distinct symptom clusters that define RRBs.
- Kaustubh Supekar
- , Srikanth Ryali
- & Vinod Menon
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| Open Access
Impaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice
Astrocytes contribute to autism spectrum disorder (ASD) pathophysiology. Here, the authors show that IP3R2 conditional KO mice show ASD-like behaviours and identify astrocyte-derived ATP as a modulator of these behaviours in mice.
- Qian Wang
- , Ying Kong
- & Tian-Ming Gao
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Article
| Open Access
Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development
De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 (CUL3) lead to autism spectrum disorder (ASD). Here, the authors show that Cul3 is essential to regulate neuronal migration by tightly regulating Plastin3 (Pls3). Pls3 cell-autonomously regulates cell migration by regulating the actin cytoskeleton organization.
- Jasmin Morandell
- , Lena A. Schwarz
- & Gaia Novarino
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Article
| Open Access
RHOA signaling defects result in impaired axon guidance in iPSC-derived neurons from patients with tuberous sclerosis complex
Patients with Tuberous Sclerosis Complex (TSC) show aberrant wiring of neuronal connections. Here, the authors generate iPSC-derived neurons from patients with TSC. TSC2 +/− neurons show impaired mTOR-independent RhoA signaling-mediated axon guidance.
- Timothy S. Catlett
- , Massimo M. Onesto
- & Timothy M. Gómez
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Differences in subcortico-cortical interactions identified from connectome and microcircuit models in autism
Autism is increasingly recognized to impact multiple scales of neural organization. Here, the authors show alterations in individuals with autism relative to typically developing controls, with findings particularly pointing to atypically organized subcortical-cortical networks.
- Bo-yong Park
- , Seok-Jun Hong
- & Boris C. Bernhardt
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Missense mutation of Fmr1 results in impaired AMPAR-mediated plasticity and socio-cognitive deficits in mice
The R138Q mutation in the Fragile X Mental Retardation 1 (FMR1) gene has been associated with Fragile X syndrome (FXS). Here, the authors present a Fmr1R138Q Knock-In mouse model and show that R138Q mutation results in impaired long-term potentiation and socio-cognitive performance in these mice.
- Marta Prieto
- , Alessandra Folci
- & Stéphane Martin
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Neuronal fragile X mental retardation protein activates glial insulin receptor mediated PDF-Tri neuron developmental clearance
Glia are involved in remodelling of neural circuits during development. Here, the authors show that FMRP is required within neurons to activate glial insulin receptor to facilitate Draper- and Shrub-dependent neuronal clearance during neurodevelopment in Drosophila.
- Dominic J. Vita
- , Cole J. Meier
- & Kendal Broadie
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| Open Access
Pogz deficiency leads to transcription dysregulation and impaired cerebellar activity underlying autism-like behavior in mice
POGZ is an autism spectrum disorder risk gene. How POGZ mutations result in ASD is unclear and animal models are lacking. Here, the authors generate a brain specific Pogz deficient mouse presenting ASD-like behaviour and show the effects of Pogz deficiency in the cerebellum.
- Reut Suliman-Lavie
- , Ben Title
- & Sagiv Shifman
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| Open Access
Mutations associated with neuropsychiatric conditions delineate functional brain connectivity dimensions contributing to autism and schizophrenia
The impact of neurodevelopmental mutations on functional brain connectivity is poorly understood. Here the authors identify thalamo-sensorimotor dysconnectivity dimensions shared across 16p11.2 and 22q11.2 copy number variants, autism and schizophrenia, but not ADHD.
- Clara A. Moreau
- , Sebastian G. W. Urchs
- & Sebastien Jacquemont
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Article
| Open Access
Autism spectrum disorder-like behavior caused by reduced excitatory synaptic transmission in pyramidal neurons of mouse prefrontal cortex
CNTNAP2 or AHI1 are autism-associated genes. Here the authors show using knockdown of the genes that this results in reduced excitatory synaptic transmission in layer 2/3 pyramidal neurons in the prefrontal cortex and is associated with impaired social interaction in mice.
- Hiroaki Sacai
- , Kazuto Sakoori
- & Masanobu Kano
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Article
| Open Access
Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.
- Tianyun Wang
- , Kendra Hoekzema
- & Evan E. Eichler
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Article
| Open Access
Integrative genomics identifies a convergent molecular subtype that links epigenomic with transcriptomic differences in autism
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions with repetitive and restrictive behaviours. Here the authors integrate mRNA expression, miRNA expression, DNA methylation, and histone acetylation datasets from a collection of post mortem brain tissues and identify a convergent molecular subtype of ASD.
- Gokul Ramaswami
- , Hyejung Won
- & Daniel H. Geschwind
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Article
| Open Access
Elevated rates of autism, other neurodevelopmental and psychiatric diagnoses, and autistic traits in transgender and gender-diverse individuals
It is unclear if rates of autism and other neurodevelopmental and psychiatric diagnoses are elevated in transgender and gender-diverse individuals compared to cisgender individuals. Here, the authors use data from five different large-scale datasets to identify elevated rates of autism diagnoses, diagnoses of other neurodevelopmental and psychiatric conditions, and elevated traits related to autism in transgender and gender-diverse individuals, compared to cisgender individuals.
- Varun Warrier
- , David M. Greenberg
- & Simon Baron-Cohen
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Article
| Open Access
Topoisomerase 3β knockout mice show transcriptional and behavioural impairments associated with neurogenesis and synaptic plasticity
Topoisomerase 3β (Top3β) solves topological stress in DNA or RNA metabolism and its mutations are linked to mental disorders. Here, the authors describe transcriptional and behavioural impairments in Top3β-knockout mice and show that these are linked to impaired neurogenesis and synaptic plasticity.
- Yuyoung Joo
- , Yutong Xue
- & Weidong Wang
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Article
| Open Access
Weaker neural suppression in autism
Sensory hypersensitivity is common in autism spectrum disorders. Using functional MRI, psychophysics, and computational modeling, Schallmo et al. show that differences in visual motion perception in ASD are accompanied by weaker neural suppression in visual cortex.
- Michael-Paul Schallmo
- , Tamar Kolodny
- & Scott O. Murray
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Article
| Open Access
Multi-model functionalization of disease-associated PTEN missense mutations identifies multiple molecular mechanisms underlying protein dysfunction
Mutations in PTEN have been associated with various human disease, including autism spectrum disorder (ASD) and cancer. Here, the authors assess the function of 106 PTEN variants in yeast, invertebrate models and cell culture and report that PTEN variants generally decrease protein stability.
- Kathryn L. Post
- , Manuel Belmadani
- & Kurt Haas
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Article
| Open Access
Elevated protein synthesis in microglia causes autism-like synaptic and behavioral aberrations
The main cell types involved in autism spectrum disorders through elevated protein synthesis are not well identified. Here, the authors show that overexpression of translation initiation factor eIF4E in microglia results in autism-like behaviour in male, but not female, mice.
- Zhi-Xiang Xu
- , Gyu Hyun Kim
- & Baoji Xu
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Article
| Open Access
Hyperactivated PTP1B phosphatase in parvalbumin neurons alters anterior cingulate inhibitory circuits and induces autism-like behaviors
LMO4 has been linked genetically to autism spectrum disorder and intellectual disability. Here, the authors investigate a role of LMO4 in parvalbumin neurons and, specifically, the regulation of dorsal ACC inhibitory circuits.
- Li Zhang
- , Zhaohong Qin
- & Hsiao-Huei Chen
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Article
| Open Access
Hominin-specific regulatory elements selectively emerged in oligodendrocytes and are disrupted in autism patients
The understanding of the changes regulating gene expression relevant for the emergence of the human brain and its susceptibility to disease is limited. Here, the authors identified a set of regulatory elements that evolved in hominins affecting oligodendrocyte function, and link these to autism.
- Bas Castelijns
- , Mirna L. Baak
- & Menno P. Creyghton
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| Open Access
Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders
Siblings of those with autism spectrum disorder (ASD) have increased likelihood of ASD or related subclinical traits. Here, studying 253 ASD families, D’Abate et al. test the predictive value of genomic copy number variation involving ASD-associated loci, with confirmation in a second cohort.
- L. D’Abate
- , S. Walker
- & S. W. Scherer
Structural models of genome-wide covariance identify multiple common dimensions in autism