scholarly journals Laundering CNV data for candidate process prioritization in brain disorders

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Maria A. Zelenova ◽  
Yuri B. Yurov ◽  
Svetlana G. Vorsanova ◽  
Ivan Y. Iourov
Keyword(s):  
Snp Array ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Genomic Research ◽  
Molecular Karyotyping ◽  
Molecular Pathways ◽  
Data Sets ◽  
Brain Disorders ◽  
Disease Mechanisms ◽  
Neuropsychiatric Diseases

Abstract Background Prioritization of genomic data has become a useful tool for uncovering the phenotypic effect of genetic variations (e.g. copy number variations or CNV) and disease mechanisms. Due to the complexity, brain disorders represent a major focus of genomic research aimed at revealing pathologic significance of genomic changes leading to brain dysfunction. Here, we propose a “CNV data laundering” algorithm based on filtering and prioritizing of genomic pathways retrieved from available databases for uncovering altered molecular pathways in brain disorders. The algorithm comprises seven consecutive steps of processing individual CNV data sets. First, the data are compared to in-house and web databases to discriminate recurrent non-pathogenic variants. Second, the CNV pool is confined to the genes predominantly expressed in the brain. Third, intergenic interactions are used for filtering causative CNV. Fourth, a network of interconnected elements specific for an individual genome variation set is created. Fifth, ontologic data (pathways/functions) are attributed to clusters of network elements. Sixth, the pathways are prioritized according to the significance of elements affected by CNV. Seventh, prioritized pathways are clustered according to the ontologies. Results The algorithm was applied to 191 CNV data sets obtained from children with brain disorders (intellectual disability and autism spectrum disorders) by SNP array molecular karyotyping. “CNV data laundering” has identified 13 pathway clusters (39 processes/475 genes) implicated in the phenotypic manifestations. Conclusions Elucidating altered molecular pathways in brain disorders, the algorithm may be used for uncovering disease mechanisms and genotype-phenotype correlations. These opportunities are strongly required for developing therapeutic strategies in devastating neuropsychiatric diseases.

scholarly journals The Cytoscan HD Array in the Diagnosis of Neurodevelopmental Disorders

2018 ◽  
Vol 7 (3) ◽  
pp. 28 ◽  
Author(s):  
Francesca Scionti ◽  
Maria Di Martino ◽  
Licia Pensabene ◽  
Valentina Bruni ◽  
Daniela Concolino
Keyword(s):  
Copy Number ◽  
De Novo ◽  
Snp Array ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Clinical Diagnostic Laboratory ◽  
Diagnostic Laboratory ◽  
Unknown Significance ◽  
Pathogenic Cnvs ◽  
Line Test

Submicroscopic chromosomal copy number variations (CNVs), such as deletions and duplications, account for about 15–20% of patients affected with developmental delay, intellectual disability, multiple congenital anomalies, and autism spectrum disorder. Most of CNVs are de novo or inherited rearrangements with clinical relevance, but there are also rare inherited imbalances with unknown significance that make difficult the clinical management and genetic counselling. Chromosomal microarrays analysis (CMA) are recognized as the first-line test for CNV detection and are now routinely used in the clinical diagnostic laboratory. The recent use of CMA platforms that combine classic copy number analysis with single-nucleotide polymorphism (SNP) genotyping has increased the diagnostic yields. Here we discuss the application of the Cytoscan high-density (HD) SNP-array for the detection of CNVs. We provide an overview of molecular analyses involved in identifying pathogenic CNVs and highlight important guidelines to establish pathogenicity of CNV.

scholarly journals The Cytogenomic “Theory of Everything”: Chromohelkosis May Underlie Chromosomal Instability and Mosaicism in Disease and Aging

2020 ◽  
Author(s):  
Ivan Y Iourov ◽  
Svetlana G Vorsanova ◽  
Yuri B. Yurov ◽  
Maria A Zelenova ◽  
Oxana S Kurinnaia ◽  
...  
Keyword(s):  
Chromosomal Instability ◽  
Snp Array ◽  
Prenatal Development ◽  
Copy Number Variations ◽  
Brain Diseases ◽  
Molecular Karyotyping ◽  
Chromosomal Mosaicism ◽  
Chromosome Loss ◽  
Chromosomal Imbalances ◽  
Theory Of Everything

Mechanisms for somatic chromosomal mosaicism (SCM) and chromosomal instability (CIN) are incompletely understood. During SNP-array molecular karyotyping and bioinformatic analyses of children with neurodevelopmental disorders and congenital malformations (n=612), we observed colocalizaion of regular chromosomal imbalances or copy number variations (CNV) with mosaic ones (n=47 or 7.7%). Analyzing molecular karyotyping data and pathways affected by CNV burdens, we proposed a mechanism for SCM/CIN, which had been designated as “chromohelkosis” (from the Greek chromosome ulceration/open wound). Briefly, structural chromosomal imbalances are likely to cause local instability (“wreckage”) at the breakpoints, which results either to partial/whole chromosome loss (e.g. aneuploidy) or elongation of duplicated regions. Accordingly, a function for classical/alpha satellite DNA (protection from the wreckage towards the centromere) has been hypothesized. Since SCM and CIN are ubiquitously involved in development, homeostasis and disease (e.g. prenatal development, cancer, brain diseases, aging), we have metaphorically (ironically) designate the system explaining chromohelkosis contribution to SCM/CIN as the cytogenomic “theory of everything” like the homonymous theory in physics inasmuch as it might explain numerous phenomena in chromosome biology. Recognizing possible empirical and theoretical weaknesses of this “theory”, we nevertheless believe that studies of chromohelkosis-like processes are required to understand structural variability and flexibility of the genome.

scholarly journals Rare Copy Number Variations in a Chinese Cohort of Autism Spectrum Disorder

2018 ◽  
Vol 9 ◽  
Author(s):  
Yanjie Fan ◽  
Xiujuan Du ◽  
Xin Liu ◽  
Lili Wang ◽  
Fei Li ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Copy Number ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Spectrum Disorder ◽  
Chinese Cohort

scholarly journals Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome

2022 ◽  
Author(s):  
Brianna K Unda ◽  
Leon Chalil ◽  
Sehyoun Yoon ◽  
Savannah Kilpatrick ◽  
Sansi Xing ◽  
...  
Keyword(s):  
Copy Number Variations ◽  
Cytoskeletal Proteins ◽  
Network Activity ◽  
Neuronal Dysfunction ◽  
Structured Illumination Microscopy ◽  
Microdeletion Syndrome ◽  
Developmental Defects ◽  
Risk Genes ◽  
Ankyrin G ◽  
Disease Mechanisms

Copy number variations (CNV) are associated with psychiatric and neurodevelopmental disorders (NDDs), and most, including the recurrent 15q13.3 microdeletion disorder, have unknown disease mechanisms. We used a heterozygous 15q13.3 microdeletion mouse model and patient iPSC-derived neurons to reveal developmental defects in neuronal maturation and network activity. To identify the underlying molecular dysfunction, we developed a neuron-specific proximity-labeling proteomics (BioID2) pipeline, combined with patient mutations, to target the 15q13.3 CNV genetic driver OTUD7A. OTUD7A is an emerging independent NDD risk gene with no known function in the brain, but has putative deubiquitinase (DUB) function. The OTUD7A protein-protein interaction (PPI) network revealed interactions with synaptic, axonal, and cytoskeletal proteins and was enriched for known ASD and epilepsy risk genes. The interactions between OTUD7A and the NDD risk genes Ankyrin-G (Ank3) and Ankyrin-B (Ank2) were disrupted by an epilepsy-associated OTUD7A L233F variant. Further investigation of Ankyrin-G in mouse and human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed protein instability, increased polyubiquitination, and decreased levels in the axon initial segment (AIS), while structured illumination microscopy identified reduced Ankyrin-G nanodomains in dendritic spines. Functional analysis of human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed shared and distinct impairments to axonal growth and intrinsic excitability. Importantly, restoring OTUD7A or Ankyrin-G expression in 15q13.3 microdeletion neurons led to a reversal of abnormalities. These data reveal a critical OTUD7A-Ankyrin pathway in neuronal development, which is impaired in the 15q13.3 microdeletion syndrome, leading to neuronal dysfunction. Further, our study highlights the utility of targeting CNV genes using cell-type specific proteomics to identify shared and unexplored disease mechanisms across NDDs.

scholarly journals Neural Substrates of the Drift-Diffusion Model in Brain Disorders

2022 ◽  
Vol 15 ◽  
Author(s):  
Ankur Gupta ◽  
Rohini Bansal ◽  
Hany Alashwal ◽  
Anil Safak Kacar ◽  
Fuat Balci ◽  
...  
Keyword(s):  
Diffusion Model ◽  
Response Times ◽  
Autism Spectrum ◽  
Brain Disorders ◽  
Functional Impairments ◽  
Drift Diffusion Model ◽  
Drift Diffusion ◽  
Obsessive Compulsive ◽  
Theoretical Understanding ◽  
Compulsive Disorder

Many studies on the drift-diffusion model (DDM) explain decision-making based on a unified analysis of both accuracy and response times. This review provides an in-depth account of the recent advances in DDM research which ground different DDM parameters on several brain areas, including the cortex and basal ganglia. Furthermore, we discuss the changes in DDM parameters due to structural and functional impairments in several clinical disorders, including Parkinson's disease, Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorders, Obsessive-Compulsive Disorder (OCD), and schizophrenia. This review thus uses DDM to provide a theoretical understanding of different brain disorders.

scholarly journals Modeling Rare Human Disorders in Mice: The Finnish Disease Heritage

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3158
Author(s):  
Tomáš Zárybnický ◽  
Anne Heikkinen ◽  
Salla M. Kangas ◽  
Marika Karikoski ◽  
Guillermo Antonio Martínez-Nieto ◽  
...  
Keyword(s):  
Human Physiology ◽  
Animal Models ◽  
Mouse Models ◽  
Rare Diseases ◽  
Disease Modeling ◽  
Common Disease ◽  
Molecular Pathways ◽  
Finnish Population ◽  
Disease Mechanisms ◽  
Human Disorders

The modification of genes in animal models has evidently and comprehensively improved our knowledge on proteins and signaling pathways in human physiology and pathology. In this review, we discuss almost 40 monogenic rare diseases that are enriched in the Finnish population and defined as the Finnish disease heritage (FDH). We will highlight how gene-modified mouse models have greatly facilitated the understanding of the pathological manifestations of these diseases and how some of the diseases still lack proper models. We urge the establishment of subsequent international consortiums to cooperatively plan and carry out future human disease modeling strategies. Detailed information on disease mechanisms brings along broader understanding of the molecular pathways they act along both parallel and transverse to the proteins affected in rare diseases, therefore also aiding understanding of common disease pathologies.

scholarly journals Genetic Analysis of Heterosis for Yield Influencing Traits in Brassica juncea Using a Doubled Haploid Population and Its Backcross Progenies

2021 ◽  
Vol 12 ◽  
Author(s):  
Aakanksha ◽  
Satish Kumar Yadava ◽  
Bal Govind Yadav ◽  
Vibha Gupta ◽  
Arundhati Mukhopadhyay ◽  
...  
Keyword(s):  
Brassica Juncea ◽  
Doubled Haploid ◽  
Snp Array ◽  
Hybrid Breeding ◽  
Doubled Haploid Population ◽  
Data Sets ◽  
East European ◽  
Common Qtl ◽  
Backcross Hybrids ◽  
Multiple Trials

The exploitation of heterosis through hybrid breeding is one of the major breeding objectives for productivity increase in crop plants. This research analyzes the genetic basis of heterosis in Brassica juncea by using a doubled haploid (DH) mapping population derived from F1 between two heterotic inbred parents, one belonging to the Indian and the other belonging to the east European gene pool, and their two corresponding sets of backcross hybrids. An Illumina Infinium Brassica 90K SNP array-based genetic map was used to identify yield influencing quantitative trait loci (QTL) related to plant architecture, flowering, and silique- and seed-related traits using five different data sets from multiple trials, allowing the estimation of additive and dominance effects, as well as digenic epistatic interactions. In total, 695 additive QTL were detected for the 14 traits in the three trials using five data sets, with overdominance observed to be the predominant type of effect in determining the expression of heterotic QTL. The results indicated that the design in the present study was efficient for identifying common QTL across multiple trials and populations, which constitute a valuable resource for marker-assisted selection and further research. In addition, a total of 637 epistatic loci were identified, and it was concluded that epistasis among loci without detectable main effects plays an important role in controlling heterosis in yield of B. juncea.

scholarly journals The gut-microbiota-brain axis in autism: what Drosophila models can offer?

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Safa Salim ◽  
Ayesha Banu ◽  
Amira Alwa ◽  
Swetha B. M. Gowda ◽  
Farhan Mohammad
Keyword(s):  
Gut Microbiota ◽  
Gut Microbiome ◽  
Neurological Disorders ◽  
Autism Spectrum ◽  
Brain Disorders ◽  
Mediated Communication ◽  
The Impact ◽  
Insight Into ◽  
Drosophila Models

AbstractThe idea that alterations in gut-microbiome-brain axis (GUMBA)-mediated communication play a crucial role in human brain disorders like autism remains a topic of intensive research in various labs. Gastrointestinal issues are a common comorbidity in patients with autism spectrum disorder (ASD). Although gut microbiome and microbial metabolites have been implicated in the etiology of ASD, the underlying molecular mechanism remains largely unknown. In this review, we have summarized recent findings in human and animal models highlighting the role of the gut-brain axis in ASD. We have discussed genetic and neurobehavioral characteristics of Drosophila as an animal model to study the role of GUMBA in ASD. The utility of Drosophila fruit flies as an amenable genetic tool, combined with axenic and gnotobiotic approaches, and availability of transgenic flies may reveal mechanistic insight into gut-microbiota-brain interactions and the impact of its alteration on behaviors relevant to neurological disorders like ASD.

scholarly journals ASTN2 modulates synaptic strength by trafficking and degradation of surface proteins

2018 ◽  
Vol 115 (41) ◽  
pp. E9717-E9726 ◽  
Author(s):  
Hourinaz Behesti ◽  
Taylor R. Fore ◽  
Peter Wu ◽  
Zachi Horn ◽  
Mary Leppert ◽  
...  
Keyword(s):  
Surface Protein ◽  
Surface Expression ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Surface Proteins ◽  
Synaptic Activity ◽  
Synaptic Proteins ◽  
Immunogold Electron Microscopy ◽  
Dynamic Regulation ◽  
Cerebellar Purkinje Cells

Surface protein dynamics dictate synaptic connectivity and function in neuronal circuits. ASTN2, a gene disrupted by copy number variations (CNVs) in neurodevelopmental disorders, including autism spectrum, was previously shown to regulate the surface expression of ASTN1 in glial-guided neuronal migration. Here, we demonstrate that ASTN2 binds to and regulates the surface expression of multiple synaptic proteins in postmigratory neurons by endocytosis, resulting in modulation of synaptic activity. In cerebellar Purkinje cells (PCs), by immunogold electron microscopy, ASTN2 localizes primarily to endocytic and autophagocytic vesicles in the cell soma and in subsets of dendritic spines. Overexpression of ASTN2 in PCs, but not of ASTN2 lacking the FNIII domain, recurrently disrupted by CNVs in patients, including in a family presented here, increases inhibitory and excitatory postsynaptic activity and reduces levels of ASTN2 binding partners. Our data suggest a fundamental role for ASTN2 in dynamic regulation of surface proteins by endocytic trafficking and protein degradation.

scholarly journals Lessons Learned from CNV Analysis of Major Birth Defects

2020 ◽  
Vol 21 (21) ◽  
pp. 8247
Author(s):  
Alina Christine Hilger ◽  
Gabriel Clemens Dworschak ◽  
Heiko Martin Reutter
Keyword(s):  
Birth Defects ◽  
Copy Number ◽  
Congenital Malformations ◽  
De Novo ◽  
Copy Number Variations ◽  
Lessons Learned ◽  
Organ System ◽  
Molecular Karyotyping ◽  
The Past ◽  
Single Organ

The treatment of major birth defects are key concerns for child health. Hitherto, for the majority of birth defects, the underlying cause remains unknown, likely to be heterogeneous. The implicated mortality and/or reduced fecundity in major birth defects suggest a significant fraction of mutational de novo events among the affected individuals. With the advent of systematic array-based molecular karyotyping, larger cohorts of affected individuals have been screened over the past decade. This review discusses the identification of disease-causing copy-number variations (CNVs) among individuals with different congenital malformations. It highlights the differences in findings depending on the respective congenital malformation. It looks at the differences in findings of CNV analysis in non-isolated complex congenital malformations, associated with central nervous system malformations or intellectual disabilities, compared to isolated single organ-system malformations. We propose that the more complex an organ system is, and the more genes involved during embryonic development, the more likely it is that mutational de novo events, comprising CNVs, will confer to the expression of birth defects of this organ system.

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