Cortical organoids model early brain development disrupted by 16p11.2 copy number variants in autism

AbstractReciprocal deletion and duplication of the 16p11.2 region is the most common copy number variation (CNV) associated with autism spectrum disorders. We generated cortical organoids from skin fibroblasts of patients with 16p11.2 CNV to investigate impacted neurodevelopmental processes. We show that organoid size recapitulates macrocephaly and microcephaly phenotypes observed in the patients with 16p11.2 deletions and duplications. The CNV dosage affects neuronal maturation, proliferation, and synapse number, in addition to its effect on organoid size. We demonstrate that 16p11.2 CNV alters the ratio of neurons to neural progenitors in organoids during early neurogenesis, with a significant excess of neurons and depletion of neural progenitors observed in deletions. Transcriptomic and proteomic profiling revealed multiple pathways dysregulated by the 16p11.2 CNV, including neuron migration, actin cytoskeleton, ion channel activity, synaptic-related functions, and Wnt signaling. The level of the active form of small GTPase RhoA was increased in both, deletions and duplications. Inhibition of RhoA activity rescued migration deficits, but not neurite outgrowth. This study provides insights into potential neurobiological mechanisms behind the 16p11.2 CNV during neocortical development.

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Cortical Organoids Model Early Brain Development Disrupted by 16p11.2 Copy Number Variants in Autism

10.1101/2020.06.25.172262 ◽

2020 ◽

Cited By ~ 1

Author(s):

Jorge Urresti ◽

Pan Zhang ◽

Patricia Moran-Losada ◽

Nam-Kyung Yu ◽

Priscilla D. Negraes ◽

...

Keyword(s):

Copy Number ◽

Copy Number Variants ◽

Autism Spectrum ◽

Small Gtpase ◽

Neural Progenitors ◽

Proteomic Profiling ◽

Neocortical Development ◽

Number Variation ◽

Early Neurogenesis ◽

Spectrum Disorders

AbstractReciprocal deletion and duplication of 16p11.2 region is the most common copy number variation (CNV) associated with Autism Spectrum Disorders. We generated cortical organoids from skin fibroblasts of patients with 16p11.2 CNV to investigate impacted neurodevelopmental processes. We show that organoid size recapitulates macrocephaly and microcephaly phenotypes observed in the patients with 16p11.2 deletions and duplications. The CNV has mirror-opposite effect on neuronal maturation, proliferation, and synapse number, in concordance with its effect on brain growth in humans. We demonstrate that 16p11.2 CNV alters the ratio of neurons to neural progenitors in organoids during early neurogenesis, with excess of neurons and depletion of neural progenitors observed in deletions, and mirror phenotypes in duplications. Transcriptomic and proteomic profiling revealed multiple dysregulated pathways, including defects in neuron migration. Inhibition of activity of the small GTPase RhoA rescued migration deficits. This study provides insights into potential neurobiological mechanisms behind the 16p11.2 CNV during neocortical development.

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The Role of Copy Number Variation in Psychiatric Disorders

Psychiatric Genetics ◽

10.1093/med/9780190221973.003.0006 ◽

2018 ◽

pp. 84-95

Author(s):

Elliott Rees ◽

George Kirov

Keyword(s):

Autism Spectrum Disorders ◽

Copy Number ◽

Selection Pressure ◽

Copy Number Variants ◽

Autism Spectrum ◽

High Odds ◽

Strong Selection ◽

Increase Risk ◽

Number Variation

Copy number variants (CNVs) are deletions, duplications, inversions, or translocations of large DNA segments. They can play a significant role in human disease. Thirteen CNVs have received strong statistical support for involvement in schizophrenia. They are all rare in cases (<1%), much rarer among controls, and have high odds ratios (ORs) for causing disease. The same CNVs also increase risk for autism spectrum disorders, developmental delay, and medical/physical comorbidities. The penetrance of these CNVs for any disorder is relatively high, ranging from 10% for 15q11.2 deletions to nearly 100% for deletions at 22q11.2. Strong selection pressure operates against carriers of these CNVs. Most of these are formed by non-allelic homologous recombination (NAHR), which leads to high mutation rates, thus maintaining the rates of these CNVs in the general population, despite the strong selection forces.

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HandyCNV: Standardized Summary, Annotation, Comparison, and Visualization of Copy Number Variant, Copy Number Variation Region, and Runs of Homozygosity

Frontiers in Genetics ◽

10.3389/fgene.2021.731355 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jinghang Zhou ◽

Liyuan Liu ◽

Thomas J. Lopdell ◽

Dorian J. Garrick ◽

Yuangang Shi

Keyword(s):

Copy Number ◽

Copy Number Variants ◽

Copy Number Variant ◽

R Package ◽

Copy Number Variation Region ◽

Runs Of Homozygosity ◽

Number Variation ◽

Genomic Studies ◽

Computing Platforms ◽

Analysis System

Detection of CNVs (copy number variants) and ROH (runs of homozygosity) from SNP (single nucleotide polymorphism) genotyping data is often required in genomic studies. The post-analysis of CNV and ROH generally involves many steps, potentially across multiple computing platforms, which requires the researchers to be familiar with many different tools. In order to get around this problem and improve research efficiency, we present an R package that integrates the summarization, annotation, map conversion, comparison and visualization functions involved in studies of CNV and ROH. This one-stop post-analysis system is standardized, comprehensive, reproducible, timesaving, and user-friendly for researchers in humans and most diploid livestock species.

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Rare Pathogenic Copy Number Variation in the 16p11.2 (BP4–BP5) Region Associated with Neurodevelopmental and Neuropsychiatric Disorders: A Review of the Literature

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17249253 ◽

2020 ◽

Vol 17 (24) ◽

pp. 9253

Author(s):

Natália Oliva-Teles ◽

Maria Chiara de Stefano ◽

Louise Gallagher ◽

Severin Rakic ◽

Paula Jorge ◽

...

Keyword(s):

Neurodevelopmental Disorders ◽

Copy Number ◽

Chromosomal Region ◽

Current Knowledge ◽

Copy Number Variants ◽

Inclusion Criteria ◽

Rare Disorders ◽

Number Variation ◽

Malformation Syndromes ◽

Neuropsychiatric Conditions

Copy number variants (CNVs) play an important role in the genetic underpinnings of neuropsychiatric/neurodevelopmental disorders. The chromosomal region 16p11.2 (BP4–BP5) harbours both deletions and duplications that are associated in carriers with neurodevelopmental and neuropsychiatric conditions as well as several rare disorders including congenital malformation syndromes. The aim of this article is to provide a review of the current knowledge of the diverse neurodevelopmental disorders (NDD) associated with 16p11.2 deletions and duplications reported in published cohorts. A literature review was conducted using the PubMed/MEDLINE electronic database limited to papers published in English between 1 January 2010 and 31 July 2020, describing 16p11.2 deletions and duplications carriers’ cohorts. Twelve articles meeting inclusion criteria were reviewed from the 75 articles identified by the search. Of these twelve papers, eight described both deletions and duplications, three described deletions only and one described duplications only. This study highlights the heterogeneity of NDD descriptions of the selected cohorts and inconsistencies concerning accuracy of data reporting.

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Genetics of Schizophrenia and Bipolar Disorder

10.1093/med/9780190681425.003.0013 ◽

2017 ◽

Author(s):

Alexander Charney ◽

Pamela Sklar

Keyword(s):

Bipolar Disorder ◽

Copy Number ◽

Psychotic Disorders ◽

Copy Number Variants ◽

Nucleotide Polymorphisms ◽

Common Variants ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Number Variation

Schizophrenia and bipolar disorder are the classic psychotic disorders. Both diseases are strongly familial, but have proven recalcitrant to genetic methodologies for identifying the etiology until recently. There is now convincing genetic evidence that indicates a contribution of many DNA changes to the risk of becoming ill. For schizophrenia, there are large contributions of rare copy number variants and common single nucleotide variants, with an overall highly polygenic genetic architecture. For bipolar disorder, the role of copy number variation appears to be much less pronounced. Specific common single nucleotide polymorphisms are associated, and there is evidence for polygenicity. Several surprises have emerged from the genetic data that indicate there is significantly more molecular overlap in copy number variants between autism and schizophrenia, and in common variants between schizophrenia and bipolar disorder.

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