scholarly journals Incomplete annotation of disease-associated genes is limiting our understanding of Mendelian and complex neurogenetic disorders

2018 ◽  
Author(s):  
David Zhang ◽  
Sebastian Guelfi ◽  
Sonia Garcia Ruiz ◽  
Beatrice Costa ◽  
Regina H. Reynolds ◽  
...  
Keyword(s):  
Gene Annotation ◽  
Brain Regions ◽  
Sequencing Data ◽  
Protein Coding ◽  
Brain Transcriptome ◽  
Genomics Research ◽  
Neurological Phenotype ◽  
Neurogenetic Disorders ◽  
Disease Associated Genes ◽  
The Brain

AbstractThere is growing evidence to suggest that human gene annotation remains incomplete, with a disproportionate impact on the brain transcriptome. We used RNA-sequencing data from GTEx to detect novel transcription in an annotation-agnostic manner across 13 human brain regions and 28 human tissues. We found that genes highly expressed in brain are significantly more likely to be re-annotated, as are genes associated with Mendelian and complex neurodegenerative disorders. We improved the annotation of 63% of known OMIM-morbid genes and 65% of those with a neurological phenotype. We determined that novel transcribed regions, particularly those identified in brain, tend to be poorly conserved across mammals but are significantly depleted for genetic variation within humans. As exemplified by SNCA, we explored the implications of re-annotation for Mendelian and complex Parkinson’s disease. We validated in silico and experimentally a novel, brain-specific, potentially protein-coding exon of SNCA. We release our findings as tissue-specific transcriptomes in BED format and via vizER: http://rytenlab.com/browser/app/vizER. Together these resources will facilitate basic genomics research with the greatest impact on neurogenetics.

scholarly journals Incomplete annotation has a disproportionate impact on our understanding of Mendelian and complex neurogenetic disorders

2020 ◽  
Vol 6 (24) ◽  
pp. eaay8299 ◽  
Author(s):  
David Zhang ◽  
Sebastian Guelfi ◽  
Sonia Garcia-Ruiz ◽  
Beatrice Costa ◽  
Regina H. Reynolds ◽  
...  
Keyword(s):  
Human Gene ◽  
Gene Annotation ◽  
Tissue Expression ◽  
Mendelian Inheritance ◽  
Disease Genes ◽  
Human Tissues ◽  
Sequencing Data ◽  
Protein Coding ◽  
Neurogenetic Disorders ◽  
Different Tissues

Growing evidence suggests that human gene annotation remains incomplete; however, it is unclear how this affects different tissues and our understanding of different disorders. Here, we detect previously unannotated transcription from Genotype-Tissue Expression RNA sequencing data across 41 human tissues. We connect this unannotated transcription to known genes, confirming that human gene annotation remains incomplete, even among well-studied genes including 63% of the Online Mendelian Inheritance in Man–morbid catalog and 317 neurodegeneration-associated genes. We find the greatest abundance of unannotated transcription in brain and genes highly expressed in brain are more likely to be reannotated. We explore examples of reannotated disease genes, such as SNCA, for which we experimentally validate a previously unidentified, brain-specific, potentially protein-coding exon. We release all tissue-specific transcriptomes through vizER: http://rytenlab.com/browser/app/vizER. We anticipate that this resource will facilitate more accurate genetic analysis, with the greatest impact on our understanding of Mendelian and complex neurogenetic disorders.

scholarly journals LNCRNA expression landscape and specificity between brain regions

2021 ◽  
Author(s):  
Adewale Joseph Ogunleye ◽  
Umair Ali ◽  
Michael Juwon Olufemi
Keyword(s):  
Tissue Expression ◽  
Brain Regions ◽  
Cell Type ◽  
Sequencing Data ◽  
Protein Coding ◽  
Rna Molecules ◽  
The Subject ◽  
Mrna Markers ◽  
The Brain

Long noncoding RNAs (lncRNAs) are transcribed into low potential protein coding RNA molecules, which account for over 70% of mammalian transcriptional products. The role of lncRNAs and their expression is still largely unknown, and the subject of recent investigations. Here, we used bulk RNA sequencing data from the Genotype-Tissue Expression (GTEx) project to reveal the occurrence and identify the specificity of lncRNAs in 13 brain regions (1000 samples). We observed that these highly specific lncRNA were co-expressed with previously known mRNA markers for the 13 study regions of the brain. Further investigation revealed that splicing could influence the divergent biogenesis and enrichment of specific lncRNA alleles in different brain regions. Overall, we demonstrate the use of lncRNA as an independent tool for deconvolving brain regions and further highlights its use for cell-type identification from bulk transcriptome data.

scholarly journals Sex-Dependent Effects of Perinatal Inflammation on the Brain: Implication for Neuro-Psychiatric Disorders

2019 ◽  
Vol 20 (9) ◽  
pp. 2270 ◽  
Author(s):  
Maryam Ardalan ◽  
Tetyana Chumak ◽  
Zinaida Vexler ◽  
Carina Mallard
Keyword(s):  
Developmental Trajectories ◽  
Neuropsychiatric Disorders ◽  
Brain Regions ◽  
Inflammatory Reactions ◽  
Glia Cells ◽  
Complex Interactions ◽  
Early Life Programming ◽  
Brain Transcriptome ◽  
Attention Deficit Hyperactivity Disorders ◽  
The Brain

Individuals born preterm have higher rates of neurodevelopmental disorders such as schizophrenia, autistic spectrum, and attention deficit/hyperactivity disorders. These conditions are often sexually dimorphic and with different developmental trajectories. The etiology is likely multifactorial, however, infections both during pregnancy and in childhood have emerged as important risk factors. The association between sex- and age-dependent vulnerability to neuropsychiatric disorders has been suggested to relate to immune activation in the brain, including complex interactions between sex hormones, brain transcriptome, activation of glia cells, and cytokine production. Here, we will review sex-dependent effects on brain development, including glia cells, both under normal physiological conditions and following perinatal inflammation. Emphasis will be given to sex-dependent effects on brain regions which play a role in neuropsychiatric disorders and inflammatory reactions that may underlie early-life programming of neurobehavioral disturbances later in life.

An atlas of the protein-coding genes in the human, pig, and mouse brain

Science ◽  
2020 ◽  
Vol 367 (6482) ◽  
pp. eaay5947 ◽  
Author(s):  
Evelina Sjöstedt ◽  
Wen Zhong ◽  
Linn Fagerberg ◽  
Max Karlsson ◽  
Nicholas Mitsios ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Expression Profiles ◽  
Brain Regions ◽  
Brain Atlas ◽  
Mammalian Brain ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Human Protein Atlas ◽  
The Brain ◽  
Complex Organ

The brain, with its diverse physiology and intricate cellular organization, is the most complex organ of the mammalian body. To expand our basic understanding of the neurobiology of the brain and its diseases, we performed a comprehensive molecular dissection of 10 major brain regions and multiple subregions using a variety of transcriptomics methods and antibody-based mapping. This analysis was carried out in the human, pig, and mouse brain to allow the identification of regional expression profiles, as well as to study similarities and differences in expression levels between the three species. The resulting data have been made available in an open-access Brain Atlas resource, part of the Human Protein Atlas, to allow exploration and comparison of the expression of individual protein-coding genes in various parts of the mammalian brain.

scholarly journals Proteomic and Transcriptomic Analyses of the Hippocampus and Cortex in SUDEP and High-Risk SUDEP Cases

2020 ◽  
Author(s):  
Dominique F. Leitner ◽  
James D. Mills ◽  
Geoffrey Pires ◽  
Arline Faustin ◽  
Eleanor Drummond ◽  
...  
Keyword(s):  
High Risk ◽  
Differentially Expressed Genes ◽  
Molecular Mechanisms ◽  
Brain Activity ◽  
Brain Regions ◽  
Sudden Unexpected Death ◽  
Differentially Expressed ◽  
Unexpected Death ◽  
Protein Coding ◽  
The Brain

AbstractSudden unexpected death in epilepsy (SUDEP) is the leading type of epilepsy-related death. Severely depressed brain activity in these cases may impair respiration, arousal, and protective reflexes, occurring as a prolonged postictal generalized EEG suppression (PGES) and resulting in a high-risk for SUDEP. In autopsy hippocampus and cortex, we observed no proteomic differences between SUDEP and epilepsy cases, contrasting our previously reported robust differences between epilepsy and controls. Transcriptomics in hippocampus and cortex from surgical epilepsy cases segregated by PGES identified 55 differentially expressed genes (37 protein-coding, 15 lncRNAs, three pending) in hippocampus. Overall, the SUDEP proteome and high-risk SUDEP transcriptome largely reflected other epilepsy cases in the brain regions analyzed, consistent with diverse epilepsy syndromes and comorbidities associated with SUDEP. Thus, studies with larger cohorts and different epilepsy syndromes, as well as additional anatomic regions may identify molecular mechanisms of SUDEP.

scholarly journals Dynamic RNA Regulation in the Brain Underlies Physiological Plasticity in a Hibernating Mammal

2021 ◽  
Vol 11 ◽  
Author(s):  
Rui Fu ◽  
Austin E. Gillen ◽  
Katharine R. Grabek ◽  
Kent A. Riemondy ◽  
L. Elaine Epperson ◽  
...  
Keyword(s):  
Group Dynamics ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Software Tool ◽  
Brain Regions ◽  
Physiological Status ◽  
Temperature Dependent ◽  
Cluster Group ◽  
Brain Transcriptome ◽  
The Brain

Hibernation is a physiological and behavioral phenotype that minimizes energy expenditure. Hibernators cycle between profound depression and rapid hyperactivation of multiple physiological processes, challenging our concept of mammalian homeostasis. How the hibernator orchestrates and survives these extremes while maintaining cell to organismal viability is unknown. Here, we enhance the genome integrity and annotation of a model hibernator, the 13-lined ground squirrel. Our new assembly brings this genome to near chromosome-level contiguity and adds thousands of previously unannotated genes. These new genomic resources were used to identify 6,505 hibernation-related, differentially-expressed and processed transcripts using RNA-seq data from three brain regions in animals whose physiological status was precisely defined using body temperature telemetry. A software tool, squirrelBox, was developed to foster further data analyses and visualization. SquirrelBox includes a comprehensive toolset for rapid visualization of gene level and cluster group dynamics, sequence scanning of k-mer and domains, and interactive exploration of gene lists. Using these new tools and data, we deconvolute seasonal from temperature-dependent effects on the brain transcriptome during hibernation for the first time, highlighting the importance of carefully timed samples for studies of differential gene expression in hibernation. The identified genes include a regulatory network of RNA binding proteins that are dynamic in hibernation along with the composition of the RNA pool. In addition to passive effects of temperature, we provide evidence for regulated transcription and RNA turnover during hibernation. Significant alternative splicing, largely temperature dependent, also occurs during hibernation. These findings form a crucial first step and provide a roadmap for future work toward defining novel mechanisms of tissue protection and metabolic depression that may 1 day be applied toward improving human health.

scholarly journals Chromosome genome assembly and annotation of Artocarpus Nanchuanensis with Nanopore and Hi-C sequencing data

2020 ◽  
Author(s):  
Jiaoyu He ◽  
Shanfei bao ◽  
Junhang Deng ◽  
Qiufu Li ◽  
zhilin song ◽  
...  
Keyword(s):  
Genome Assembly ◽  
Tree Species ◽  
Gene Annotation ◽  
Sequence Information ◽  
Sequencing Data ◽  
Endangered Tree ◽  
Protein Coding ◽  
Sequencing Platform ◽  
Endangered Tree Species ◽  
Conserved Genes

The A.nanchuanensis (Artocarpus Nanchuanensis, Moraceae) is an evergreen Artocarpus genus representative tree species in the northernmost natural distribution and one of the extremely endangered tree species in China. In this study, we obtained a high-quality chromosome-scale genome assembly and annotation for A.nanchuanensis using inter-grated approaches, including Illumina, Nanopore sequencing platform as well as Hi-C. A total of 128.71 gigabases (Gb) raw Nanopore Sequel reads were generated from 20 kb libraries. After filtering, 123.38 Gb clean reads were obtained, giving 160.34x coverage depth. The final assembled A.nanchuanensis genome was 769.44 Mb with a contig N50 of 2.09 Mb, and 99.62% (766.50 Mb) of the assembly data was assigned to 28 pseudochromosomes. Gene modelling predicted 41,636 protein-coding genes, of which 95.10% were annotated. The gene annotation completeness was evaluated by BUSCO, and 94.44% conserved genes could be found in the assembly data. The disclosure of A.nanchuanensis genome sequence information provides an important resource to expand our understanding of the molecular mechanism in its unique biological processes and nutritional, medicinal benefits.

Management of Glioblastoma Multiforme by Phytochemicals: Applications of Nanoparticle Based Targeted Drug Delivery System

2020 ◽  
Vol 21 ◽  
Author(s):  
Sayed Md Mumtaz ◽  
Gautam Bhardwaj ◽  
Shikha Goswami ◽  
Rajiv Kumar Tonk ◽  
Ramesh K. Goyal ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Glioblastoma Multiforme ◽  
Drug Delivery System ◽  
Delivery System ◽  
Genetic Disorder ◽  
Drug Regimen ◽  
Brain Regions ◽  
Radio Therapy ◽  
Novel Drug ◽  
The Brain

: The Glioblastoma Multiforme (GBM; grade IV astrocytoma) exhort tumor of star-shaped glial cell in the brain. It is a fast-growing tumor that spreads to nearby brain regions specifically to cerebral hemispheres in frontal and temporal lobes. The etiology of GBM is unknown, but major risk factors are genetic disorder like neurofibromatosis and schwanomatosis which develop the tumor in the nervous system. The management of GBM with chemo-radio therapy leads to resistance and current drug regimen like Temozolomide (TMZ) is less efficacious. The reasons behind failure of drugs are due to DNA alkylation in cell cycle by enzyme DNA guanidase and mitochondrial dysfunction. Naturally occurring bio-active compounds from plants known as phytochemicals, serve as vital sources for anti-cancer drugs. Some typical examples include taxol analogs, vinca alkaloids such as vincristine, vinblastine, podophyllotoxin analogs, camptothecin, curcumin, aloe emodin, quercetin, berberine e.t.c. These phytochemicals often act via regulating molecular pathways which are implicated in growth and progression of cancers. However the challenges posed by the presence of BBB/BBTB to restrict passage of these phytochemicals, culminates in their low bioavailability and relative toxicity. In this review we integrated nanotech as novel drug delivery system to deliver phytochemicals from traditional medicine to the specific site within the brain for the management of GBM.

Neuro-Clinical Signatures of Language Impairments: A Theoretical Framework for Function-to-structure Mapping in Clinics

2020 ◽  
Vol 20 (9) ◽  
pp. 800-811 ◽  
Author(s):  
Ferath Kherif ◽  
Sandrine Muller
Keyword(s):  
Brain Mapping ◽  
Theoretical Framework ◽  
Brain Regions ◽  
Language Impairments ◽  
Structure Mapping ◽  
Language Functions ◽  
The Past ◽  
Language Recovery ◽  
The Brain ◽  
Bow Tie

In the past decades, neuroscientists and clinicians have collected a considerable amount of data and drastically increased our knowledge about the mapping of language in the brain. The emerging picture from the accumulated knowledge is that there are complex and combinatorial relationships between language functions and anatomical brain regions. Understanding the underlying principles of this complex mapping is of paramount importance for the identification of the brain signature of language and Neuro-Clinical signatures that explain language impairments and predict language recovery after stroke. We review recent attempts to addresses this question of language-brain mapping. We introduce the different concepts of mapping (from diffeomorphic one-to-one mapping to many-to-many mapping). We build those different forms of mapping to derive a theoretical framework where the current principles of brain architectures including redundancy, degeneracy, pluri-potentiality and bow-tie network are described.

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