scholarly journals Developmental and genetic regulation of the human cortex transcriptome in schizophrenia

2017 ◽  
Author(s):  
Andrew E Jaffe ◽  
Richard E Straub ◽  
Joo Heon Shin ◽  
Ran Tao ◽  
Yuan Gao ◽  
...  
Keyword(s):  
Genetic Regulation ◽  
Cellular Systems ◽  
Developmental Genetic ◽  
Developmentally Regulated ◽  
Human Cortex ◽  
Quality Adjustment ◽  
Control Dataset ◽  
Risk Variants ◽  
Brain Transcriptome ◽  
Independent Case

SummaryGWAS have identified 108 loci that confer risk for schizophrenia, but risk mechanisms for individual loci are largely unknown. Using developmental, genetic, and illness-based RNA sequencing expression analysis, we characterized the human brain transcriptome around these loci and found enrichment for developmentally regulated genes with novel examples of shifting isoform usage across pre- and post-natal life. We found widespread expression quantitative trait loci (eQTLs), including many with transcript specificity and previously unannotated sequence that were independently replicated. We leveraged this eQTL database to show that 48.1% of risk variants for schizophrenia associated with nearby expression. Within patients and controls, we implemented a novel algorithm for RNA quality adjustment, and identified 237 genes significantly associated with diagnosis that replicated in an independent case-control dataset. These genes implicated synaptic processes and were strongly regulated in early development (p < 10-20). These data offer new targets for modeling schizophrenia risk in cellular systems.

scholarly journals Different Principles Govern Different Scales of Brain Folding

2020 ◽  
Vol 30 (9) ◽  
pp. 4938-4948
Author(s):  
Arka N Mallela ◽  
Hansen Deng ◽  
Alan Bush ◽  
Ezequiel Goldschmidt
Keyword(s):  
Large Scale ◽  
Volumetric Analysis ◽  
Adult Brain ◽  
Random Pattern ◽  
Cortical Folding ◽  
Developmentally Regulated ◽  
Human Cortex ◽  
External Volume ◽  
In Silico Models

Abstract The signature folds of the human brain are formed through a complex and developmentally regulated process. In vitro and in silico models of this process demonstrate a random pattern of sulci and gyri, unlike the highly ordered and conserved structure seen in the human cortex. Here, we account for the large-scale pattern of cortical folding by combining advanced fetal magnetic resonance imaging with nonlinear diffeomorphic registration and volumetric analysis. Our analysis demonstrates that in utero brain growth follows a logistic curve, in the absence of an external volume constraint. The Sylvian fissure forms from interlobar folding, where separate lobes overgrow and close an existing subarachnoid space. In contrast, other large sulci, which are the ones represented in existing models, fold through an invagination of a flat surface, a mechanistically different process. Cortical folding is driven by multiple spatially and temporally different mechanisms; therefore regionally distinct biological process may be responsible for the global geometry of the adult brain.

scholarly journals Different principles govern different scales of brain folding

2019 ◽  
Author(s):  
Arka N. Mallela ◽  
Hansen Deng ◽  
Alan Bush ◽  
Ezequiel Goldschmidt
Keyword(s):  
Large Scale ◽  
Fetal Mri ◽  
Volumetric Analysis ◽  
Adult Brain ◽  
Random Pattern ◽  
Cortical Folding ◽  
Developmentally Regulated ◽  
Human Cortex ◽  
External Volume

ABSTRACTThe signature folds of the human brain are formed through a complex and developmentally regulated process. In vitro and in silico models of this process demonstrate a random pattern of sulci and gyri, unlike the highly ordered and conserved structure seen in the human cortex. Here, we account for the large-scale pattern of cortical folding by combining advanced fetal MRI with nonlinear diffeomorphic registration and volumetric analysis. Our analysis demonstrates that in utero brain growth follows a logistic curve, in the absence of an external volume constraint. The Sylvian fissure forms from interlobar folding, where separate lobes overgrow and close an existing subarachnoid space. In contrast, other large sulci, which are the ones represented in existing models, fold through an invagination of a flat surface, a mechanistically different process. Cortical folding is driven by multiple spatially and temporally different mechanisms, therefore regionally distinct biological process may be responsible for the global geometry of the adult brain.

scholarly journals Central neurogenetic signatures of the visuomotor integration system

2020 ◽  
Vol 117 (12) ◽  
pp. 6836-6843 ◽  
Author(s):  
Elisenda Bueichekú ◽  
Maite Aznárez-Sanado ◽  
Ibai Diez ◽  
Federico d’Oleire Uquillas ◽  
Laura Ortiz-Terán ◽  
...  
Keyword(s):  
Human Brain ◽  
Neural Development ◽  
Fragile X ◽  
Autism Spectrum ◽  
Brain Atlas ◽  
Functional Impairments ◽  
Visuomotor Integration ◽  
Human Cortex ◽  
Genetic Expression ◽  
Brain Transcriptome

Visuomotor impairments characterize numerous neurological disorders and neurogenetic syndromes, such as autism spectrum disorder (ASD) and Dravet, Fragile X, Prader–Willi, Turner, and Williams syndromes. Despite recent advances in systems neuroscience, the biological basis underlying visuomotor functional impairments associated with these clinical conditions is poorly understood. In this study, we used neuroimaging connectomic approaches to map the visuomotor integration (VMI) system in the human brain and investigated the topology approximation of the VMI network to the Allen Human Brain Atlas, a whole-brain transcriptome-wide atlas of cortical genetic expression. We found the genetic expression of four genes—TBR1, SCN1A, MAGEL2, and CACNB4—to be prominently associated with visuomotor integrators in the human cortex. TBR1 gene transcripts, an ASD gene whose expression is related to neural development of the cortex and the hippocampus, showed a central spatial allocation within the VMI system. Our findings delineate gene expression traits underlying the VMI system in the human cortex, where specific genes, such as TBR1, are likely to play a central role in its neuronal organization, as well as on specific phenotypes of neurogenetic syndromes.

scholarly journals Developmental and genetic regulation of the human cortex transcriptome illuminate schizophrenia pathogenesis

2018 ◽  
Vol 21 (8) ◽  
pp. 1117-1125 ◽  
Author(s):  
Andrew E. Jaffe ◽  
◽  
Richard E. Straub ◽  
Joo Heon Shin ◽  
Ran Tao ◽  
...  
Keyword(s):  
Genetic Regulation ◽  
Human Cortex

scholarly journals Molecular genetic insights into deuterostome evolution from the direct-developing hemichordate Saccoglossus kowalevskii

2008 ◽  
Vol 363 (1496) ◽  
pp. 1569-1578 ◽  
Author(s):  
Christopher J Lowe
Keyword(s):  
Developmental Biology ◽  
Expression Patterns ◽  
Molecular Genetic ◽  
Genetic Regulation ◽  
The Body ◽  
Developmental Genetic ◽  
The Past ◽  
Deuterostome Evolution ◽  
Saccoglossus Kowalevskii ◽  
Insight Into

Progress in developmental biology, phylogenomics and palaeontology over the past five years are all making major contributions to a long-enduring problem in comparative biology: the early origins of the deuterostome phyla. Recent advances in the developmental biology of hemichordates have given a unique insight into developmental similarities between this phylum and chordates. Transcriptional and signalling gene expression patterns between the two groups during the early development of the anteroposterior and dorsoventral axes reveal close similarities, despite large morphological disparity between the body plans. These genetic networks have been proposed to play conserved roles in patterning centralized nervous systems in metazoans, yet seem to play a conserved role in patterning the diffusely organized basiepithelial nerve net of the hemichordates. Developmental genetic data are providing a unique insight into early deuterostome evolution, revealing a complexity of genetic regulation previously attributed only to vertebrates. While these data allow for key insights into the development of early deuterostomes, their utility for reconstructing ancestral morphologies is less certain, and morphological, palaeontological and molecular datasets should all be considered carefully when speculating about ancestral deuterostome features.

scholarly journals Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk

Science ◽  
2018 ◽  
Vol 362 (6420) ◽  
pp. eaat4311 ◽  
Author(s):  
Prashanth Rajarajan ◽  
Tyler Borrman ◽  
Will Liao ◽  
Nadine Schrode ◽  
Erin Flaherty ◽  
...  
Keyword(s):  
Neural Progenitor Cells ◽  
Disease Risk ◽  
Three Dimensional ◽  
Cell Type ◽  
Contact Map ◽  
Developmentally Regulated ◽  
Risk Variants ◽  
Cell Type Specific ◽  
Spatial Genome Organization ◽  
Developmental Remodeling

To explore the developmental reorganization of the three-dimensional genome of the brain in the context of neuropsychiatric disease, we monitored chromosomal conformations in differentiating neural progenitor cells. Neuronal and glial differentiation was associated with widespread developmental remodeling of the chromosomal contact map and included interactions anchored in common variant sequences that confer heritable risk for schizophrenia. We describe cell type–specific chromosomal connectomes composed of schizophrenia risk variants and their distal targets, which altogether show enrichment for genes that regulate neuronal connectivity and chromatin remodeling, and evidence for coordinated transcriptional regulation and proteomic interaction of the participating genes. Developmentally regulated chromosomal conformation changes at schizophrenia-relevant sequences disproportionally occurred in neurons, highlighting the existence of cell type–specific disease risk vulnerabilities in spatial genome organization.

scholarly journals Genetic risk factors for endometriosis near estrogen receptor 1 and co-expression of genes in this region in endometrium

2021 ◽  
Author(s):  
S Marla ◽  
S Mortlock ◽  
S Houshdaran ◽  
J Fung ◽  
B McKinnon ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Menstrual Cycle ◽  
Disease Risk ◽  
Association Studies ◽  
Genetic Regulation ◽  
Receptor Expression ◽  
Genome Wide Association Studies ◽  
Risk Variants ◽  
Expression Of Genes ◽  
Estrogen Receptor 1

Abstract The aetiology and pathogenesis of endometriosis are complex with both genetic and environmental factors contributing to disease risk. Genome-wide association studies (GWAS) have identified multiple signals in the estrogen receptor 1 (ESR1) region associated with endometriosis and other reproductive traits and diseases. In addition, candidate gene association studies identified signals in the ESR1 region associated with endometriosis risk suggesting genetic regulation of genes in this region may be important for reproductive health. This study aimed to investigate hormonal and genetic regulation of genes in the ESR1 region in human endometrium. Changes in serum oestradiol and progesterone concentrations and expression of hormone receptors ESR1 and progesterone receptor (PGR) were assessed in endometrial samples from 135 women collected at various stages of the menstrual cycle. Correlation between hormone concentrations, receptor expression and expression of genes in the ESR1 locus was investigated. The effect of endometriosis risk variants on expression of genes in the region was analysed to identify gene targets. Hormone concentrations and receptor expression varied significantly across the menstrual cycle. Expression of genes in the ESR1 region correlated with progesterone concentration, however, they were more strongly correlated with expression of ESR1 and PGR suggesting co-regulation of genes. There was no evidence that endometriosis risk variants directly regulated expression of genes in the region. Limited sample size and cellular heterogeneity in endometrial tissue may impact the ability to detect significant genetic effects on gene expression. Effects of these variants should be validated in a larger dataset and in relevant individual cell types.

scholarly journals Enrichment of disease-associated genes in cortical areas defined by transcriptome-based parcellation

2020 ◽  
Author(s):  
Gryglewski Gregor ◽  
Murgaš Matej ◽  
Michenthaler Paul ◽  
Klöbl Manfred ◽  
Reed Murray Bruce ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Human Cortex ◽  
Brain Functions ◽  
Cortical Areas ◽  
Risk Variants ◽  
Gene Sets ◽  
Genome Wide ◽  
Disease Associated Genes ◽  
Similar Enrichment

AbstractThe parcellation of the cerebral cortex serves the investigation of the emergence of uniquely human brain functions and disorders. We employed hierarchical clustering based on comprehensive transcriptomic data of the human cortex in order to delineate areas with distinct gene expression profiles. These profiles were analyzed for the enrichment of gene sets associated with brain disorders by genome-wide studies (GWAS) and expert curation. This suggested new roles of specific cortical areas in psychiatric, neurodegenerative, congenital and other neurological disorders while reproducing some well-established links for movement disorders and dementias. GWAS-derived gene sets for psychiatric disorders exhibited similar enrichment patterns in the posterior fusiform gyrus and inferior parietal lobule driven by pleiotropic genes. This implies that the effects of risk variants shared between neuropsychiatric disorders might converge in these areas. For several diseases, specific genes were highlighted, which may aid the discovery of novel disease mechanisms and urgently needed treatments.

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