Author: Andrew Richards
Publisher:
ISBN:
Category :
Languages : en
Pages : 94
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Book Description
DNA copy number variations (CNVs) have previously been reported in human cortical neurons from non-diseased patients, but these alterations do not appear to be consistent from cell to cell and appear to be rare among neurons overall. Interestingly, Alzheimer's disease patients appear to have a higher prevalence of CNVs than non-diseased, although the biological significance of this observation is still largely unknown. Single-cell whole-genome next-generation sequencing holds promise to investigate these variations and the regions in which they occur in an unbiased manner. Unlike recent advances in single-cell RNA-seq, however, library preparation for single-cell DNA-seq suffers from extremely limited throughput. Furthermore, it is difficult to assess the significance of individual variations from whole-genome sequencing alone, particularly when control samples from non-diseased patients also show some variation at lower frequency. A potential solution is a multi-omics approach, in which information is collected about multiple species of biomolecules simultaneously from each sample, which taken together aid the interpretation of individual observations with respect to biological significance. This dissertation describes the design and development of a technology to physically separate DNA and RNA and to prepare sequencing libraries from each in parallel from limited starting samples without splitting, which we called Gel-seq. Thirty-two paired DNA and RNA sequencing libraries were successfully prepared from a variety of human and mouse cells lines and from mouse liver tissue using Gel-seq. Sample types could be clearly distinguished from each other based on either genomic copy number or transcriptomic profiles. This dissertation also describes the design and development of a technology to prepare a thousand single-cell whole-genome sequencing libraries in a single run. A proof-of-concept was performed with 87 cells from human and mouse lines. Copy number profiles agreed with bulk, and 96% and 92% of human and mouse cells, respectively, clustered correctly within their cell line based on copy number profile alone. These technologies will help to enable the unbiased characterization of genomic alterations not only in neurodegenerative disorders, but potentially also in other conditions associated with mosaic genomic backgrounds, such as cancer, microbiome disorders, or infectious diseases.
Author: Chris Park
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
Neurodegenerative diseases represent a large group of neurological disorders with heterogeneous clinical and pathological presentations--often affecting a specific subset of cells in particular anatomical regions. These complex and often overlapping features presents a challenge in identifying the cause behind the vulnerability of these cell populations and anatomical area. However, with recent advancements in omics technology, the complexity of the mammalian brain is being rapidly teased out. Two of these technologies offer a unique perspective and deeper resolution to study the heterogeneity in the brain: long-read sequencing and single-cell microfluidics. In this dissertation, I demonstrate the use of one or both technologies to further characterize the heterogeneity in human brain and its relationship to various neurodegenerative diseases. My initial work identifies a novel genomic structural variant in the gene SNCA, a causal gene in Parkinson's disease (PD) and other synucleinopathies. These intron-less sequences are known as gencDNAs (genomic cDNA) and are found in human cortical neurons of both PD and age-matched controls in a mosaic manner. Furthermore, it is unveiled that a small subset of copies contains point mutations in loci reported to cause monogenic PD, if mutated in its native counterpart, when using long-read amplicon sequencing. Though much is unknown about of SNCA gencDNAs, it is hypothesized to be created due to a reverse transcription event and re-inserted back into the genome. My subsequent work combines both single-cell RNA sequencing and long-read sequencing to examine and compare the transcriptome of various neurodegenerative diseases in the frontal cortex at a single cell resolution. Despite being a synucleinopathy, dementia with Lewy bodies (DLB) has more transcriptomic similarities to Alzheimer's disease (AD) than with PD. While profiling the isoforms of selected genes within these diseases, a vast number of novel isoforms are also identified, with some specific to a particular cell type, such as NRGN. Finally, some major isoform switching is observed in at a cell type resolution, even in genes that were not differentially expressed in our short-read RNA-seq data, such as BIN1 in DLB oligodendrocyte and CLU in AD and DLB excitatory neurons. This dissertation further illuminates the heterogeneity in the human brain at a genomic and transcriptomic layer in the context of various neurodegeneration using long-read sequencing and single cell microfluidics.
Author: Sean B. Carroll
Publisher: John Wiley & Sons
ISBN: 1118685202
Category : Science
Languages : en
Pages : 475
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Book Description
In this landmark work, the author team led by Dr. Sean Carroll presents the general principles of the genetic basis of morphological change through a synthesis of evolutionary biology with genetics and embryology. In this extensively revised second edition, the authors delve into the latest discoveries, incorporating new coverage of comparative genomics, molecular evolution of regulatory proteins and elements, and microevolution of animal development. An accessible text, focusing on the most well-known genes, developmental processes and taxa. Builds logically from developmental genetics and regulatory mechanisms to evolution at different genetic morphological levels. Adds major insights from recent genome studies, new evo-devo biology research findings, and a new chapter on models of variation and divergence among closely related species. Provides in-depth focus on key concepts through well-developed case studies. Features clear, 4-color illustrations and photographs, chapter summaries, references and a glossary. Presents the research of Dr. Carroll, a pioneer in the field and the past president of the Society for Developmental Biology.
Author: Udo Rüb
Publisher: Springer
ISBN: 331919285X
Category : Medical
Languages : en
Pages : 154
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Book Description
This monograph describes the progress in neuropathological HD research made during the last century, the neuropathological hallmarks of HD and their pathogenic relevance. Starting with the initial descriptions of the progressive degeneration of the striatum as one of the key events in HD, the worldwide practiced Vonsattel HD grading system of striatal neurodegeneration will be outlined. Correlating neuropathological data with results on the functional neuroanatomy of the human brain, subsequent chapters will highlight recent HD findings: the neuronal loss in the cerebral neo-and allocortex, the neurodegeneration of select thalamic nuclei, the affection of the cerebellar cortex and nuclei, the involvement of select brainstem nuclei, as well as the pathophysiological relevance of these pathologies for the clinical picture of HD. Finally, the potential pathophysiological role of neuronal huntingtin aggregations and the most important and enduring challenges of neuropathological HD research are discussed.
Author: Charles Watson
Publisher: Academic Press
ISBN: 0123694973
Category : Science
Languages : en
Pages : 815
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Book Description
The Mouse Nervous System provides a comprehensive account of the central nervous system of the mouse. The book is aimed at molecular biologists who need a book that introduces them to the anatomy of the mouse brain and spinal cord, but also takes them into the relevant details of development and organization of the area they have chosen to study. The Mouse Nervous System offers a wealth of new information for experienced anatomists who work on mice. The book serves as a valuable resource for researchers and graduate students in neuroscience. Systematic consideration of the anatomy and connections of all regions of the brain and spinal cord by the authors of the most cited rodent brain atlases A major section (12 chapters) on functional systems related to motor control, sensation, and behavioral and emotional states A detailed analysis of gene expression during development of the forebrain by Luis Puelles, the leading researcher in this area Full coverage of the role of gene expression during development and the new field of genetic neuroanatomy using site-specific recombinases Examples of the use of mouse models in the study of neurological illness
Author: Ivan Y. Iourov
Publisher: Frontiers Media SA
ISBN: 2832505627
Category : Science
Languages : en
Pages : 82
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Book Description
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 198
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Book Description
Author: Fred H. Gage
Publisher:
ISBN: 9781493972807
Category : Biomedicine
Languages : en
Pages : 382
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Book Description
"This volume presents methods for the analysis of genomic variability in vertebrate neurons and broadens our knowledge in the ways we understand the brain and its neurons. The chapters in this book are divided into 5 parts, and cover the following topics: principles and approaches for discovery of somatic mosaicism in the brain, aneuploidy and ploidy variation, DNA copy number variation, LINE-1 retrotransposition, and genetic and genomic mosaicism in aging and disease. In Neuromethods series style, chapters include the kind of detail and key advice from the specialists needed to get successful results in your laboratory. Cutting-edge and authoritative, Genomic Mosaicism in Neurons and Other Cell Types is a valuable resource for learning about the latest techniques for the analysis of genome and genetic mosaicism in vertebrate neurons"--Publisher's description.
Author: Kevin J. Mitchell
Publisher: Princeton University Press
ISBN: 0691204152
Category : Psychology
Languages : en
Pages : 305
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Book Description
"What makes you the way you are--and what makes each of us different from everyone else? In Innate, leading neuroscientist and popular science blogger Kevin Mitchell traces human diversity and individual differences to their deepest level: in the wiring of our brains. Deftly guiding us through important new research, including his own groundbreaking work, he explains how variations in the way our brains develop before birth strongly influence our psychology and behavior throughout our lives, shaping our personality, intelligence, sexuality, and even the way we perceive the world. We all share a genetic program for making a human brain, and the program for making a brain like yours is specifically encoded in your DNA. But, as Mitchell explains, the way that program plays out is affected by random processes of development that manifest uniquely in each person, even identical twins. The key insight of Innate is that the combination of these developmental and genetic variations creates innate differences in how our brains are wired--differences that impact all aspects of our psychology--and this insight promises to transform the way we see the interplay of nature and nurture. Innate also explores the genetic and neural underpinnings of disorders such as autism, schizophrenia, and epilepsy, and how our understanding of these conditions is being revolutionized. In addition, the book examines the social and ethical implications of these ideas and of new technologies that may soon offer the means to predict or manipulate human traits. Compelling and original, Innate will change the way you think about why and how we are who we are."--Provided by the publisher.
Author: Jan Vijg
Publisher: OUP Oxford
ISBN: 0191524581
Category : Science
Languages : en
Pages : 384
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Book Description
Aging has long since been ascribed to the gradual accumulation of DNA mutations in the genome of somatic cells. However, it is only recently that the necessary sophisticated technology has been developed to begin testing this theory and its consequences. Vijg critically reviews the concept of genomic instability as a possible universal cause of aging in the context of a new, holistic understanding of genome functioning in complex organisms resulting from recent advances in functional genomics and systems biology. It provides an up-to-date synthesis of current research, as well as a look ahead to the design of strategies to retard or reverse the deleterious effects of aging. This is particularly important in a time when we are urgently trying to unravel the genetic component of aging-related diseases. Moreover, there is a growing public recognition of the imperative of understanding more about the underlying biology of aging, driven by continuing demographic change.
