[PDF] Global Gene Expression Profiling Of Healthy Human Brain And Its Application In Studying Neurological Disorders eBook

Author : Simarjeet K. Negi
Publisher :
Page : 120 pages
File Size : 15,47 MB
Release : 2016
Category :
ISBN :

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The human brain is the most complex structure known to mankind and one of the greatest challenges in modern biology is to understand how it is built and organized. The power of the brain arises from its variety of cells and structures, and ultimately where and when different genes are switched on and off throughout the brain tissue. In other words, brain function depends on the precise regulation of gene expression in its sub-anatomical structures. But, our understanding of the complexity and dynamics of the transcriptome of the human brain is still incomplete. To fill in the need, we designed a gene expression model that accurately defines the consistent blueprint of the brain transcriptome; thereby, identifying the core brain specific transcriptional processes conserved across individuals. Functionally characterizing this model would provide profound insights into the transcriptional landscape, biological pathways and the expression distribution of neurotransmitter systems. Here, in this dissertation we developed an expression model by capturing the similarly expressed gene patterns across congruently annotated brain structures in six individual brains by using data from the Allen Brain Atlas (ABA). We found that 84% of genes are expressed in at least one of the 190 brain structures. By employing hierarchical clustering we were able to show that distinct structures of a bigger brain region can cluster together while still retaining their expression identity. Further, weighted correlation network analysis identified 19 robust modules of coexpressing genes in the brain that demonstrated a wide range of functional associations. Since signatures of local phenomena can be masked by larger signatures, we performed local analysis on each distinct brain structure. Pathway and gene ontology enrichment analysis on these structures showed, striking enrichment for brain region specific processes. Besides, we also mapped the structural distribution of the gene expression profiles of genes associated with major neurotransmission systems in the human. We also postulated the utility of healthy brain tissue gene expression to predict potential genes involved in a neurological disorder, in the absence of data from diseased tissues. To this end, we developed a supervised classification model, which achieved an accuracy of 84% and an AUC (Area Under the Curve) of 0.81 from ROC plots, for predicting autism-implicated genes using the healthy expression model as the baseline. This study represents the first use of healthy brain gene expression to predict the scope of genes in autism implication and this generic methodology can be applied to predict genes involved in other neurological disorders.

Author : Yannis Karamanos
Publisher : Springer Science+Business Media
Page : 284 pages
File Size : 46,61 MB
Release : 2012
Category : Medical
ISBN : 9781617794483

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Transcriptomics and proteomics are increasingly deployed in a variety of investigations, including research into brain disorders. Cutting-edge and highly practical, this book sets out easily reproducible methods of both gene- and protein expression profiling.

Author : Christopher Hartl
Publisher :
Page : 172 pages
File Size : 38,54 MB
Release : 2019
Category :
ISBN :

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Neuropsychiatric disorders are behavioral conditions marked by intellectual, social, or emotional deficits that can be linked to diseases of the nervous system. Autism spectrum disorder (ASD), schizophrenia (SCZ), bipolar disorder (BP), major depressive disorder (MDD), and attention deficit and hyperactivity disorder (ADHD) are common, heritable diseases each with a prevalence exceeding 1% of the population, none of which can be characterized by discernable anatomical or neurological pathologies. Genetic association studies have identified mutations in hundreds of genes that contribute to risk for at least one of these disorders, and have shown that a substantial fraction of the genetic liability is shared between many of these neuropsychiatric diseases. It has long been hoped that with enough genetic evidence we will identify the biological pathways, developmental time points, and brain regions that, when disrupted, give rise to neuropsychiatric disorders. However, the cellular and functional complexity of the human brain, as well as the genetic complexity of neuropsychiatric disease, make it difficult to search for such convergence. In this thesis, I investigate global and local transcriptional regulation within and across 12 regions of the human brain in order to investigate the regional specificity of neuropsychiatric disorders. I develop novel bioinformatics methods - ranging from data processing to network construction - to identify whether the transcriptional regulation of a set of genes is shared or specific. I hypothesize that local, region-specific transcriptional regulation corresponds directly to cell types and processes that are specific to, or far more prevalent in, a given region; that cross-regional transcriptional regulation corresponds to cell types that show little heterogeneity across brain regions; and that genetic disruption of region-specific transcriptional programs results in regional susceptibility. I use a systems-biology approach to summarize transcriptional regulation into reproducibly co-expressed gene sets ("co-expression modules"), which can be analyzed statistically to identify common functions, pathways, and cell types. I then integrate data from genetic association studies to ascertain gene sets conferring outsized risk for neuropsychiatric disorders, thereby implicating the corresponding pathways for further investigation in disease etiology. Finally, I use the network structure itself to investigate the genetic architecture of ASD and SCZ in terms of omnigenics and network polygenics. Chapter 1 presents the biological background for the studies and summarizes some of the major studies of neuropsychiatric disorders along with their principal methods and conclusions. In chapter 2, utilizing my multi-regional co-expression approach, I identify 12 brain-wide, 114 region-specific, and 50 cross-regional co-expression modules. Nearly 40% of expressed genes fall into brain-wide modules and correspond to major cell classes and conserved biological processes, while region-specific modules comprise 25% of expressed genes and correspond to region-specific cell types. The detailed study in chapter 3 demonstrates that neuropsychiatric risk concentrates in both brain wide and multi-regional modules, implicating major core cell types in disease etiology but not region-specific susceptibility. Chapter 4 presents a new and more general framework for defining genetic networks. Using this framework, I show that the network pattern of ASD-associated rare loss-of-function mutations, as well as the large number of significant targets for trans master regulators in BP and SCZ, support a classical polygenic architecture with thousands of directly causal genes. These results suggest that a nontrivial component of risk for neuropsychiatric disease comes from the global polygenic disruption of neuronal function and neuronal maturation.

Author :
Publisher : Elsevier
Page : 373 pages
File Size : 11,61 MB
Release : 2011-04-21
Category : Science
ISBN : 0444538852

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How does the genome, interacting with the multi-faceted environment, translate into the development by which the human brain achieves its astonishing, adaptive array of cognitive and behavioral capacities? Why and how does this process sometimes lead to neurodevelopmental disorders with a major, lifelong personal and social impact? This volume of Progress in Brain Research links findings on the structural development of the human brain, the expression of genes in behavioral and cognitive phenotypes, environmental effects on brain development, and developmental processes in perception, action, attention, cognitive control, social cognition, and language, in an attempt to answer these questions. Leading authors review the state-of-the-art in their field of investigation and provide their views and perspectives for future research Chapters are extensively referenced to provide readers with a comprehensive list of resources on the topics covered All chapters include comprehensive background information and are written in a clear form that is also accessible to the non-specialist

Author :
Publisher : Elsevier
Page : 218 pages
File Size : 22,60 MB
Release : 2004-12-10
Category : Medical
ISBN : 0080495516

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DNA array technology is a technique for studying gene expression by comparing samples of different genes. The result is an enormous amount of data that must be carefully analyzed in order for it to be useful and meaningful. This book examines both data analysis and techniques for ensuring optimal experimental conditions. The array approach has applications in a number of model systems, including development, learning and drug abuse. In addition, the technique has applications in a number of neurological disorders such as Alzheimer's disease, schizophrenia, multiple sclerosis, and neurological cancers.

Author : Yang Tang
Publisher :
Page : pages
File Size : 39,48 MB
Release : 2002
Category :
ISBN :

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Gene expression profiling has the power to sensitively reflect a myriad of biological states and perturbations. This is highlighted by the recent progress in molecular classification of various cancers using DNA microarray technology. However, the application of this technology in studying most other human diseases is likely to be slow because of the paucity of biopsy and postmortem samples. The studies presented here sought to determine whether global expression profiling of blood cells could provide peripheral markers for diseases or phenotypes that do not involve the hematological system. This hypothesis was addressed by the following experiments. Firstly, rat models of brain ischemia, intracerebral hemorrhage, seizure, hypoglycemia and hypoxia were used to investigate whether each disease model produced characteristic blood genomic expression fingerprints. At the same time, brain gene expression changes were also surveyed to study the mechanisms of brain injuries associated with each condition. Secondly, rat models were used to determine whether there is a common blood genomic expression pattern that correlates with the occurrence of various neuronal injuries. Finally, neurofibromatosis type 1 was used as a test case to examine whether blood expression profiling is capable of diagnosing clinical diseases. The effects of common confounding factors - age and gender - on blood genomics were also characterized. These results were consistent with the suggestion that diseases and phenotypes may produce unique expression signatures in blood cells and blood expression profiling can be used in diagnostic, mechanistic, and therapeutic assessment of these disease states.

Author :
Publisher : Elsevier
Page : 448 pages
File Size : 47,61 MB
Release : 2018-02-27
Category : Medical
ISBN : 0444636420

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Brain Banking, Volume 150, serves as the only book on the market offering comprehensive coverage of the functional realities of brain banking. It focuses on brain donor recruitment strategies, brain bank networks, ethical issues, brain dissection/tissue processing/tissue dissemination, neuropathological diagnosis, brain donor data, and techniques in brain tissue analysis. In accordance with massive initiatives, such as BRAIN and the EU Human Brain Project, abnormalities and potential therapeutic targets of neurological and psychiatric disorders need to be validated in human brain tissue, thus requiring substantial numbers of well characterized human brains of high tissue quality with neurological and psychiatric diseases. Offers comprehensive coverage of the functional realities of brain banking, with a focus on brain donor recruitment strategies, brain bank networks, ethical issues, and more Serves as a valuable resource for staff in existing brain banks by highlighting best practices Enhances the sharing of expertise between existing banks and highlights a range of techniques applicable to banked tissue for neuroscience researchers Authored by leaders from brain banks around the globe – the broadest, most expert coverage available

Author : Yulia Kovas
Publisher : Springer Nature
Page : 241 pages
File Size : 34,87 MB
Release : 2021-10-30
Category : Psychology
ISBN : 1349960489

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This book explores the answers to fundamental questions about the human mind and human behaviour with the help of two ancient texts. The first is Oedipus Rex (Oedipus Tyrannus) by Sophocles, written in the 5th century BCE. The second is human DNA, with its origins around 4 billion years ago, and continuously revised by chance and evolution. With Sophocles as a guide, the authors take a journey into the Genomic era, an age marked by ever-expanding insights into the human genome. Over the course of this journey, the book explores themes of free will, fate, and chance; prediction, misinterpretation, and the burden that comes with knowledge of the future; self-fulfilling and self-defeating prophecies; the forces that contribute to similarities and differences among people; roots and lineage; and the judgement of oneself and others. Using Oedipus Rex as its lens, this novel work provides an engaging overview of behavioural genetics that demonstrates its relevance across the humanities and the social and life sciences. It will appeal in particular to students and scholars of genetics, education, psychology, sociology, and law.

Author : Institute of Medicine
Publisher : National Academies Press
Page : 90 pages
File Size : 47,92 MB
Release : 2008-12-07
Category : Science
ISBN : 0309120926

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Neuroscience has made phenomenal advances over the past 50 years and the pace of discovery continues to accelerate. On June 25, 2008, the Institute of Medicine (IOM) Forum on Neuroscience and Nervous System Disorders hosted more than 70 of the leading neuroscientists in the world, for a workshop titled "From Molecules to Minds: Challenges for the 21st Century." The objective of the workshop was to explore a set of common goals or "Grand Challenges" posed by participants that could inspire and rally both the scientific community and the public to consider the possibilities for neuroscience in the 21st century. The progress of the past in combination with new tools and techniques, such as neuroimaging and molecular biology, has positioned neuroscience on the cusp of even greater transformational progress in our understanding of the brain and how its inner workings result in mental activity. This workshop summary highlights the important issues and challenges facing the field of neuroscience as presented to those in attendance at the workshop, as well as the subsequent discussion that resulted. As a result, three overarching Grand Challenges emerged: How does the brain work and produce mental activity? How does physical activity in the brain give rise to thought, emotion, and behavior? How does the interplay of biology and experience shape our brains and make us who we are today? How do we keep our brains healthy? How do we protect, restore, or enhance the functioning of our brains as we age?