scholarly journals Varying intolerance of gene pathways to mutational classes explain genetic convergence across neuropsychiatric disorders

2016 ◽  
Author(s):  
Shahar Shohat ◽  
Eyal Ben-David ◽  
Sagiv Shifman
Keyword(s):  
Gene Expression ◽  
Genome Wide Association Study ◽  
De Novo ◽  
Expression Patterns ◽  
Neuropsychiatric Disorders ◽  
Autism Spectrum ◽  
Specific Gene ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Brain Gene Expression

AbstractGenetic susceptibility to Intellectual disability (ID), autism spectrum disorder (ASD) and schizophrenia (SCZ) often arises from mutations in the same genes, suggesting that they share common mechanisms. We studied genes with de novo mutations in the three disorders and genes implicated by SCZ genome-wide association study (GWAS). Using biological annotations and brain gene expression, we show that mutation class explains enrichment patterns more than specific disorder. Genes with loss of function mutations and genes with missense mutations were enriched with different pathways, shared with genes intolerant to mutations. Specific gene expression patterns were found for each disorder. ID genes were preferentially expressed in fetal cortex, ASD genes also in fetal cerebellum and striatum, and genes associated with SCZ were most significantly enriched in adolescent cortex. Our study suggests that convergence across neuropsychiatric disorders stems from vulnerable pathways to genetic variations, but spatiotemporal activity of genes contributes to specific phenotypes.

scholarly journals Agonal Factors Distort Gene-Expression Patterns in Human Postmortem Brains

2021 ◽  
Vol 15 ◽  
Author(s):  
Jiacheng Dai ◽  
Yu Chen ◽  
Rujia Dai ◽  
Yi Jiang ◽  
Jianghua Tian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Patterns ◽  
Brain Cell ◽  
Terminal State ◽  
Specific Gene ◽  
Brain Gene Expression ◽  
Postmortem Brains ◽  
Cell Type Specific ◽  
Study Designs

Agonal factors, the conditions that occur just prior to death, can impact the molecular quality of postmortem brains, influencing gene expression results. Our study used gene expression data of 262 samples from ROSMAP with the detailed terminal state recorded for each donor, such as fever, infection, and unconsciousness. Fever and infection were the primary contributors to brain gene expression changes, brain cell-type-specific gene expression, and cell proportion changes. Furthermore, we also found that previous studies of gene expression in postmortem brains were confounded by agonal factors. Therefore, correction for agonal factors is important in the step of data preprocessing. Our analyses revealed fever and infection contributing to gene expression changes in postmortem brains and emphasized the necessity of study designs that document and account for agonal factors.

scholarly journals Transcriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Bret Sanders ◽  
Daniel D’Andrea ◽  
Mark O. Collins ◽  
Elliott Rees ◽  
Tom G. J. Steward ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Neuronal Differentiation ◽  
Human Embryonic Stem Cells ◽  
De Novo ◽  
Embryonic Stem ◽  
Neuropsychiatric Disorders ◽  
Loss Of Function ◽  
Excitatory Neurons

AbstractCoordinated programs of gene expression drive brain development. It is unclear which transcriptional programs, in which cell-types, are affected in neuropsychiatric disorders such as schizophrenia. Here we integrate human genetics with transcriptomic data from differentiation of human embryonic stem cells into cortical excitatory neurons. We identify transcriptional programs expressed during early neurogenesis in vitro and in human foetal cortex that are down-regulated in DLG2−/− lines. Down-regulation impacted neuronal differentiation and maturation, impairing migration, morphology and action potential generation. Genetic variation in these programs is associated with neuropsychiatric disorders and cognitive function, with associated variants predominantly concentrated in loss-of-function intolerant genes. Neurogenic programs also overlap schizophrenia GWAS enrichment previously identified in mature excitatory neurons, suggesting that pathways active during prenatal cortical development may also be associated with mature neuronal dysfunction. Our data from human embryonic stem cells, when combined with analysis of available foetal cortical gene expression data, de novo rare variants and GWAS statistics for neuropsychiatric disorders and cognition, reveal a convergence on transcriptional programs regulating excitatory cortical neurogenesis.

Maternal oxytocin administration modulates gene expression in the brains of perinatal mice

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Frances F. Hsieh ◽  
Ilya Korsunsky ◽  
Andrew J. Shih ◽  
Matthew A. Moss ◽  
Prodyot K. Chatterjee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Neurite Outgrowth ◽  
Quantitative Pcr ◽  
Expression Patterns ◽  
Specific Gene ◽  
Neonatal Brain ◽  
Real Time Quantitative Pcr ◽  
Brain Gene Expression ◽  
Gene Expression Analyses ◽  
Differential Gene

Abstract Objectives Oxytocin (OXT) is widely used to facilitate labor. However, little is known about the effects of perinatal OXT exposure on the developing brain. We investigated the effects of maternal OXT administration on gene expression in perinatal mouse brains. Methods Pregnant C57BL/6 mice were treated with saline or OXT at term (n=6–7/group). Dams and pups were euthanized on gestational day (GD) 18.5 after delivery by C-section. Another set of dams was treated with saline or OXT (n=6–7/group) and allowed to deliver naturally; pups were euthanized on postnatal day 9 (PND9). Perinatal/neonatal brain gene expression was determined using Illumina BeadChip Arrays and real time quantitative PCR. Differential gene expression analyses were performed. In addition, the effect of OXT on neurite outgrowth was assessed using PC12 cells. Results Distinct and sex-specific gene expression patterns were identified in offspring brains following maternal OXT administration at term. The microarray data showed that female GD18.5 brains exhibited more differential changes in gene expression compared to male GD18.5 brains. Specifically, Cnot4 and Frmd4a were significantly reduced by OXT exposure in male and female GD18.5 brains, whereas Mtap1b, Srsf11, and Syn2 were significantly reduced only in female GD18.5 brains. No significant microarray differences were observed in PND9 brains. By quantitative PCR, OXT exposure reduced Oxtr expression in female and male brains on GD18.5 and PND9, respectively. PC12 cell differentiation assays revealed that OXT induced neurite outgrowth. Conclusions Prenatal OXT exposure induces sex-specific differential regulation of several nervous system-related genes and pathways with important neural functions in perinatal brains.

scholarly journals CHD8 Regulates Cellular Homeostasis and Neuronal Function Genes Across Multiple Models of CHD8 Haploinsufficiency

2018 ◽  
Author(s):  
A. Ayanna Wade ◽  
Kenneth Lim ◽  
Rinaldo Catta-Preta ◽  
Alex S. Nord
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Chromatin Remodeling ◽  
De Novo ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Cell Functions ◽  
High Affinity

ABSTRACTThe packaging of DNA into chromatin determines the transcriptional potential of cells and is central to eukaryotic gene regulation. Recent sequencing of patient mutations has linked de novo loss-of-function mutations to chromatin remodeling factors with specific, causal roles in neurodevelopmental disorders. Characterizing cellular and molecular phenotypes arising from haploinsufficiency of chromatin remodeling factors could reveal convergent mechanisms of pathology. Chromodomain helicase DNA binding protein 8 (CHD8) encodes a chromatin remodeling factor gene and has among the highest de novo loss-of-function mutations rates in patients with autism spectrum disorder (ASD). Mutations to CHD8 are expected to drive neurodevelopmental pathology through global disruptions to gene expression and chromatin state, however, mechanisms associated with CHD8 function have yet to be fully elucidated. We analyzed published transcriptomic and epigenomic data across CHD8 in vitro and in vivo knockdown and knockout models to identify convergent mechanisms of gene regulation by CHD8. We found reproducible high-affinity interactions of CHD8 near promoters of genes necessary for basic cell functions and gene regulation, especially chromatin organization and RNA processing genes. Overlap between CHD8 interaction and differential expression suggests that reduced dosage of CHD8 directly relates to decreased expression of these genes. In addition, genes important for neuronal development and function showed consistent dysregulation, though there was a reduced rate and decreased affinity for CHD8 interactions near these genes. This meta-analysis verifies CHD8 as a critical regulator of gene expression and reveals a consistent set of high affinity CHD8 interaction targets observed across human and mouse in vivo and in vitro studies. Our findings highlight novel core functions of CHD8 and indicate direct and downstream gene regulatory impacts that are likely to be associated with neuropathology underlying CHD8-associated neurodevelopmental disorder.

scholarly journals In vivo Perturb-Seq reveals neuronal and glial abnormalities associated with Autism risk genes

2019 ◽  
Author(s):  
Xin Jin ◽  
Sean K. Simmons ◽  
Amy X. Guo ◽  
Ashwin S. Shetty ◽  
Michelle Ko ◽  
...  
Keyword(s):  
De Novo ◽  
Disease Risk ◽  
Autism Spectrum ◽  
Specific Gene ◽  
Functional Evaluation ◽  
Loss Of Function ◽  
Risk Genes ◽  
Biologically Relevant ◽  
Relevant Context

AbstractThe thousands of disease risk genes and loci identified through human genetic studies far outstrip our current capacity to systematically study their functions. New experimental approaches are needed for functional investigations of large panels of genes in a biologically relevant context. Here, we developed a scalable genetic screen approach, in vivo Perturb-Seq, and applied this method to the functional evaluation of 35 autism spectrum disorder (ASD) de novo loss-of-function risk genes. Using CRISPR-Cas9, we introduced frameshift mutations in these risk genes in pools, within the developing brain in utero, and then performed single-cell RNA-Seq in the postnatal brain. We identified cell type-specific gene signatures from both neuronal and glial cell classes that are affected by genetic perturbations, and pointed at elements of both convergent and divergent cellular effects across this cohort of ASD risk genes. In vivo Perturb-Seq pioneers a systems genetics approach to investigate at scale how diverse mutations affect cell types and states in the biologically relevant context of the developing organism.

scholarly journals DNMT3A Mutations in Acute Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-31-SCI-31
Author(s):  
Timothy J. Ley ◽  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Gene Expression Signature ◽  
Adverse Outcomes ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Hematopoietic Stem

Abstract Abstract SCI-31 DNMT3A is one of the two human de novo methyltransferases; both are essential for methylating specific cytosine residues, a process that is critical for regulating gene expression during early development. In 2010, recurring mutations in DNMT3A were discovered in patients with AML (1, 2); mutations were not found in the other de novo methyltransferase (DNMT3B) or in the binding partner for both (DNMT3L). After discovering the first mutation by whole genome sequencing, we sequenced all of the exons of DNMT3A in 281 additional AML patients and found a total of 62 mutations (22% of all cases) in the gene that were predicted to affect translation. Eighteen different missense mutations were found, the most common of which was at amino acid R882 (37 patients). We identified six frameshift, six nonsense, and three splice site mutations, and also a 1.5 MB deletion that included the entire DNMT3A gene. DNMT3A mutations are highly enriched in patients with intermediate risk cytogenetics (56 of 166 patients, 33.7%) and were absent in 79 patients with favorable risk cytogenetics (p < 0.001 for both). In our series, DNMT3A mutations were independently associated with poor outcomes in multivariate analyses. Since the initial reports, DNMT3A mutations have been identified in ∼5%–10% of patients with myelodysplastic syndromes (3, 4), in 10%–20% of patients with myeloproliferative neoplasms and secondary AML (5), and in pediatric AML cases, but at much lower frequencies than adult AML (0%–1%) (6, 7). The adverse clinical outcomes associated with DNMT3A mutations have been confirmed by Yan et al (8) and by Thol et al (9). DNMT3A mutations are therefore among the most common in AML and other myeloid malignancies, and may be important for identifying patients with adverse outcomes. However, the mechanisms by which DNMT3A mutations influence AML pathogenesis are not yet clear. In our original study, we did not identify a clear gene expression signature associated with DNMT3A mutations, nor were we able to identify global or focal alterations in DNA methylation patterns that are clearly caused by the mutations. Yan et al (8) reported that DNMT3A mutations were associated with increased expression and hypomethylation of several HOXB genes, but this could not be validated with our data. Many important questions about DNMT3A mutations remain to be answered, including: 1) What are the relationships between DNMT3A mutations and other mutations that affect outcomes?, 2) Do DNMT3A mutations predict responses to hypomethylating agents or other regimens?, 3) Are the recurring mutations at R882 associated with a gain-of-function activity or do they act as dominant negatives?, and 4) Do the missense mutations alter methylase activity, DNA binding and/or methylation specificity, protein/protein interactions, or other (as yet unknown) functions of DNMT3A? Although the mechanism of action of DNMT3A mutations is currently unknown, Challen et al (10) noted that loss of Dnmt3a in the hematopoietic cells of mice caused a dramatic expansion of stem cells upon serial transplantation. These results strongly suggest that loss-of-function mutations in DNMT3A may affect the self-renewal properties of hematopoietic stem cells, which may be relevant for AML pathogenesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A machine learning approach to predicting autism risk genes: Validation of known genes and discovery of new candidates

2018 ◽  
Author(s):  
Ying Lin ◽  
Anjali M. Rajadhyaksha ◽  
James B. Potash ◽  
Shizhong Han
Keyword(s):  
Gene Expression ◽  
Machine Learning ◽  
Human Brain ◽  
Candidate Genes ◽  
De Novo ◽  
Expression Patterns ◽  
Autism Spectrum ◽  
Gene Expression Patterns ◽  
Risk Genes ◽  
Gene Level

AbstractAutism spectrum disorder (ASD) is a complex neurodevelopmental condition with a strong genetic basis. The role ofde novomutations in ASD has been well established, but the set of genes implicated to date is still far from complete. The current study employs a machine learning-based approach to predict ASD risk genes using features from spatiotemporal gene expression patterns in human brain, gene-level constraint metrics, and other gene variation features. The genes identified through our prediction model were enriched for independent sets of ASD risk genes, and tended to be differentially expressed in ASD brains, especially in the frontal and parietal cortex. The highest-ranked genes not only included those with strong prior evidence for involvement in ASD (for example,TCF20andFBOX11), but also indicated potentially novel candidates, such asDOCK3,MYCBP2andCAND1, which are all involved in neuronal development. Through extensive validations, we also showed that our method outperformed state-of-the-art scoring systems for ranking ASD candidate genes. Gene ontology enrichment analysis of our predicted risk genes revealed biological processes clearly relevant to ASD, including neuronal signaling, neurogenesis, and chromatin remodeling, but also highlighted other potential mechanisms that might underlie ASD, such as regulation of RNA alternative splicing and ubiquitination pathway related to protein degradation. Our study demonstrates that human brain spatiotemporal gene expression patterns and gene-level constraint metrics can help predict ASD risk genes. Our gene ranking system provides a useful resource for prioritizing ASD candidate genes.

scholarly journals Voltage-Gated Ca2+-Channel α1-Subunit de novo Missense Mutations: Gain or Loss of Function – Implications for Potential Therapies

2021 ◽  
Vol 13 ◽  
Author(s):  
Jörg Striessnig
Keyword(s):  
De Novo ◽  
Current Knowledge ◽  
Autism Spectrum ◽  
Special Focus ◽  
Endocrine Disorders ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Functional Changes ◽  
Voltage Sensors ◽  
Voltage Gated

This review summarizes our current knowledge of human disease-relevant genetic variants within the family of voltage gated Ca2+ channels. Ca2+ channelopathies cover a wide spectrum of diseases including epilepsies, autism spectrum disorders, intellectual disabilities, developmental delay, cerebellar ataxias and degeneration, severe cardiac arrhythmias, sudden cardiac death, eye disease and endocrine disorders such as congential hyperinsulinism and hyperaldosteronism. A special focus will be on the rapidly increasing number of de novo missense mutations identified in the pore-forming α1-subunits with next generation sequencing studies of well-defined patient cohorts. In contrast to likely gene disrupting mutations these can not only cause a channel loss-of-function but can also induce typical functional changes permitting enhanced channel activity and Ca2+ signaling. Such gain-of-function mutations could represent therapeutic targets for mutation-specific therapy of Ca2+-channelopathies with existing or novel Ca2+-channel inhibitors. Moreover, many pathogenic mutations affect positive charges in the voltage sensors with the potential to form gating-pore currents through voltage sensors. If confirmed in functional studies, specific blockers of gating-pore currents could also be of therapeutic interest.

AML with Translocation T(8;16) Shows Unique Cytomorphological, Cytogenetic, Molecular, and Prognostic Features and Therefore Qualifies as An Own Entity According to WHO Criteria.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1197-1197
Author(s):  
Alexander Kohlmann ◽  
Martin Dugas ◽  
Hans-Ulrich Klein ◽  
Christian Ruckert ◽  
Wolfgang Kern ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Pattern ◽  
De Novo ◽  
Expression Patterns ◽  
Gene Expression Pattern ◽  
Gene Expression Patterns ◽  
Specific Gene ◽  
Differentiation Potential ◽  
Who Criteria ◽  
Prognostic Features

Abstract Balanced chromosomal rearrangements define distinct biological subsets in acute myeloid leukemia (AML). It is recognized that recurrent balanced aberrations, such as t(15;17), t(8;21), inv(16), and 11q23/MLL translocations, show a close correlation to cytomorphology and also harbor specific gene expression signatures. We here present a cohort of 13 AML cases with t(8;16)(p11;p13). This translocation is rare with only 13 cases (6 males, 7 females) diagnosed from our overall cohort of 6124 cases of AML over recent years, and is more frequently found in therapy-related AML than in de novo AML (7/438 t-AML, and 6/5686 de novo, p=0.00001). Prognosis was poor with median overall survival of 4.7 months. Five patients deceased within the first month after diagnosis. AML with t(8;16) is characterized by striking cytomorphologic features: In all 13 cases the positivity for myeloperoxidase (MPO) on bone marrow smears was &gt;30% (median: 85%) and intriguingly, in parallel also &gt;40% (median: 88%) of blast cells stained strongly positive for non-specific esterase (NSE) in the same cell, suggesting that AML with t(8;16) arise from a very early stem cell with both myeloid and monoblastic differentiation potential. Therefore, AML with t(8;16) cases can not be classified according to standard FAB categories. Morphologically we also detected erythrophagocytosis in 7/13 cases, a specific feature in AML with t(8;16) that was previously described. With respect to cytogenetics, 6/13 patients had t(8;16)(p11;p13) as sole abnormality. 7/13 patients demonstrated additional non-recurrent abnormalities, 4 cases with single additional aberrations, and 3 cases with two or more additional aberrations. Molecular analyses detected the MYST3- CREBBP fusion transcript in all cases tested (12/12). We then compared gene expression patterns in 7 cases of AML with t(8;16) to: (i) AML FAB subtypes M1 and M4/5 with strong MPO or NSE with normal karyotype and to (ii) distinct AML subtypes with balanced chromosomal aberrations according to WHO classification. In a first series using Affymetrix HG-U133A+B microarrays 4 cases of AML with t(8;16) were compared to FAB M1 (n=46), M4 (n=41), M5a (n=9), and M5b (n=16). Hierarchical clustering and principal component analyses revealed that AML with t(8;16) were intercalating rather with FAB subtypes M4 and M5b and did not cluster near to FAB M1, although strong positivity for MPO was seen in all t(8;16) cases. Thus, monocytic characteristics influence the gene expression pattern stronger than myeloid features. When further compared to AML WHO subtypes t(15;17) (n=43), t(8;21) (n=43), inv(16) (n=49), and 11q23/MLL (n=50), AML with t(8;16) samples were repeatedly grouped in the vicinity of the 11q23/MLL cases. This can be explained by a similar expression of genes such as EAF2, HOXA9, HOXA10, PRKCD, or HNMT. Yet, in a subsequent pairwise comparison AML with t(8;16) could also be clearly discriminated from 11q23/MLL with differentially expressed genes including CAPRIN1, RAN, SMARCD2, LRRC41, or H2BFS, higher expressed in AML with t(8;16) and SOCS2, PRAME, RUNX3, or TPT1, lower expressed in AML with t(8;16), respectively. Moreover, the respective FAB-type or WHO-type signatures were validated on a separate cohort of patients (n=3 AML with t(8;16); n=107 other AML subtypes as above), all prospectively analyzed with the successor HG-U133 Plus 2.0 microarray. Again, in direct comparison to FAB-type or WHO-type cases, dominant and unique gene expression patterns were seen for AML with t(8;16), confirming the molecular distinctiveness of this rare AML entity. Using a classification algorithm we were able to correctly predict all AML with t(8;16) cases by their gene expression pattern. This accuracy was observed not only for both FAB-type and WHO-type signatures, but also correctly classified the cases across the different patient cohorts and microarray designs. In conclusion, AML with t(8;16) is a specific subtype of AML with very poor prognosis that often presents as treatment-related AML and with particular characteristics not only in morphology and clinical profile, but also on a molecular level. Due to these unique features, it qualifies as a specific recurrent entity according to WHO criteria.

Sign in / Sign up

Export Citation Format

Share Document