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The human cerebral cortex makes up approximately 82% of the total brain mass, has 52 distinct Brodmann areas, and contains approximately 16 billion neurons. In recent years, neuroscientists, geneticists, bioengineers, and bioinformaticians, by working in collaboration have only begun to scratch the surface towards understanding the enormous cellular complexity and heterogeneity that exists in our brains. My thesis work in has focused on the investigation of the immense diversity that comprises both the genomic and the transcriptomic landscapes of the human brain through the use of traditional, and newly engineered, single-cell technologies. Neuronal genomic mosaicism--the phenomenon wherein neurons possess unique somatically altered genomes--was first identified as mosaic aneuploidies, a gain or loss of an entire chromosome. In recent years, multiple labs have now demonstrated that the somatic genomic changes also include LINE-1 retrotransposons, both large (>10 megabases (Mb)) and small (
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.
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
Single-cell omics is a progressing frontier that stems from the sequencing of the human genome and the development of omics technologies, particularly genomics, transcriptomics, epigenomics and proteomics, but the sensitivity is now improved to single-cell level. The new generation of methodologies, especially the next generation sequencing (NGS) technology, plays a leading role in genomics related fields; however, the conventional techniques of omics require number of cells to be large, usually on the order of millions of cells, which is hardly accessible in some cases. More importantly, harnessing the power of omics technologies and applying those at the single-cell level are crucial since every cell is specific and unique, and almost every cell population in every systems, derived in either vivo or in vitro, is heterogeneous. Deciphering the heterogeneity of the cell population hence becomes critical for recognizing the mechanism and significance of the system. However, without an extensive examination of individual cells, a massive analysis of cell population would only give an average output of the cells, but neglect the differences among cells. Single-cell omics seeks to study a number of individual cells in parallel for their different dimensions of molecular profile on genome-wide scale, providing unprecedented resolution for the interpretation of both the structure and function of an organ, tissue or other system, as well as the interaction (and communication) and dynamics of single cells or subpopulations of cells and their lineages. Importantly single-cell omics enables the identification of a minor subpopulation of cells that may play a critical role in biological process over a dominant subpolulation such as a cancer and a developing organ. It provides an ultra-sensitive tool for us to clarify specific molecular mechanisms and pathways and reveal the nature of cell heterogeneity. Besides, it also empowers the clinical investigation of patients when facing a very low quantity of cell available for analysis, such as noninvasive cancer screening with circulating tumor cells (CTC), noninvasive prenatal diagnostics (NIPD) and preimplantation genetic test (PGT) for in vitro fertilization. Single-cell omics greatly promotes the understanding of life at a more fundamental level, bring vast applications in medicine. Accordingly, single-cell omics is also called as single-cell analysis or single-cell biology. Within only a couple of years, single-cell omics, especially transcriptomic sequencing (scRNA-seq), whole genome and exome sequencing (scWGS, scWES), has become robust and broadly accessible. Besides the existing technologies, recently, multiplexing barcode design and combinatorial indexing technology, in combination with microfluidic platform exampled by Drop-seq, or even being independent of microfluidic platform but using a regular PCR-plate, enable us a greater capacity of single cell analysis, switching from one single cell to thousands of single cells in a single test. The unique molecular identifiers (UMIs) allow the amplification bias among the original molecules to be corrected faithfully, resulting in a reliable quantitative measurement of omics in single cells. Of late, a variety of single-cell epigenomics analyses are becoming sophisticated, particularly single cell chromatin accessibility (scATAC-seq) and CpG methylation profiling (scBS-seq, scRRBS-seq). High resolution single molecular Fluorescence in situ hybridization (smFISH) and its revolutionary versions (ex. seqFISH, MERFISH, and so on), in addition to the spatial transcriptome sequencing, make the native relationship of the individual cells of a tissue to be in 3D or 4D format visually and quantitatively clarified. On the other hand, CRISPR/cas9 editing-based In vivo lineage tracing methods enable dynamic profile of a whole developmental process to be accurately displayed. Multi-omics analysis facilitates the study of multi-dimensional regulation and relationship of different elements of the central dogma in a single cell, as well as permitting a clear dissection of the complicated omics heterogeneity of a system. Last but not the least, the technology, biological noise, sequence dropout, and batch effect bring a huge challenge to the bioinformatics of single cell omics. While significant progress in the data analysis has been made since then, revolutionary theory and algorithm logics for single cell omics are expected. Indeed, single-cell analysis exert considerable impacts on the fields of biological studies, particularly cancers, neuron and neural system, stem cells, embryo development and immune system; other than that, it also tremendously motivates pharmaceutic RD, clinical diagnosis and monitoring, as well as precision medicine. This book hereby summarizes the recent developments and general considerations of single-cell analysis, with a detailed presentation on selected technologies and applications. Starting with the experimental design on single-cell omics, the book then emphasizes the consideration on heterogeneity of cancer and other systems. It also gives an introduction of the basic methods and key facts for bioinformatics analysis. Secondary, this book provides a summary of two types of popular technologies, the fundamental tools on single-cell isolation, and the developments of single cell multi-omics, followed by descriptions of FISH technologies, though other popular technologies are not covered here due to the fact that they are intensively described here and there recently. Finally, the book illustrates an elastomer-based integrated fluidic circuit that allows a connection between single cell functional studies combining stimulation, response, imaging and measurement, and corresponding single cell sequencing. This is a model system for single cell functional genomics. In addition, it reports a pipeline for single-cell proteomics with an analysis of the early development of Xenopus embryo, a single-cell qRT-PCR application that defined the subpopulations related to cell cycling, and a new method for synergistic assembly of single cell genome with sequencing of amplification product by phi29 DNA polymerase. Due to the tremendous progresses of single-cell omics in recent years, the topics covered here are incomplete, but each individual topic is excellently addressed, significantly interesting and beneficial to scientists working in or affiliated with this field.
"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.
The volume focuses on the genomics, proteomics, metabolomics, and bioinformatics of a single cell, especially lymphocytes and on understanding the molecular mechanisms of systems immunology. Based on the author’s personal experience, it provides revealing insights into the potential applications, significance, workflow, comparison, future perspectives and challenges of single-cell sequencing for identifying and developing disease-specific biomarkers in order to understand the biological function, activation and dysfunction of single cells and lymphocytes and to explore their functional roles and responses to therapies. It also provides detailed information on individual subgroups of lymphocytes, including cell characters, function, surface markers, receptor function, intracellular signals and pathways, production of inflammatory mediators, nuclear receptors and factors, omics, sequencing, disease-specific biomarkers, bioinformatics, networks and dynamic networks, their role in disease and future prospects. Dr. Xiangdong Wang is a Professor of Medicine, Director of Shanghai Institute of Clinical Bioinformatics, Director of Fudan University Center for Clinical Bioinformatics, Director of the Biomedical Research Center of Zhongshan Hospital, Deputy Director of Shanghai Respiratory Research Institute, Shanghai, China.
This book presents the latest advances in precision medicine in some of the most common cancer types, including hematological, lung and breast malignancies. It also discusses emerging technologies that are making a significant impact on precision medicine in cancer therapy. In addition to describing specific approaches that have already entered clinical practice, the book explores new concepts and tools that are being developed. Precision medicine aims to deliver personalized healthcare tailored to a patient’s genetics, lifestyle and environment, and cancer therapy is one of the areas in which it has flourished in recent years. Documenting the latest advances, this book is of interest to physicians and clinical fellows in the front line of the war on cancer, as well as to basic scientists working in the fields of cancer biology, drug development, biomarker discovery, and biomedical engineering. The contributing authors include translational physicians with first-hand experience in precision patient care.
This fourth edition of the best-selling textbook, Human Genetics and Genomics, clearly explains the key principles needed by medical and health sciences students, from the basis of molecular genetics, to clinical applications used in the treatment of both rare and common conditions. A newly expanded Part 1, Basic Principles of Human Genetics, focuses on introducing the reader to key concepts such as Mendelian principles, DNA replication and gene expression. Part 2, Genetics and Genomics in Medical Practice, uses case scenarios to help you engage with current genetic practice. Now featuring full-color diagrams, Human Genetics and Genomics has been rigorously updated to reflect today’s genetics teaching, and includes updated discussion of genetic risk assessment, “single gene” disorders and therapeutics. Key learning features include: Clinical snapshots to help relate science to practice 'Hot topics' boxes that focus on the latest developments in testing, assessment and treatment 'Ethical issues' boxes to prompt further thought and discussion on the implications of genetic developments 'Sources of information' boxes to assist with the practicalities of clinical research and information provision Self-assessment review questions in each chapter Accompanied by the Wiley E-Text digital edition (included in the price of the book), Human Genetics and Genomics is also fully supported by a suite of online resources at www.korfgenetics.com, including: Factsheets on 100 genetic disorders, ideal for study and exam preparation Interactive Multiple Choice Questions (MCQs) with feedback on all answers Links to online resources for further study Figures from the book available as PowerPoint slides, ideal for teaching purposes The perfect companion to the genetics component of both problem-based learning and integrated medical courses, Human Genetics and Genomics presents the ideal balance between the bio-molecular basis of genetics and clinical cases, and provides an invaluable overview for anyone wishing to engage with this fast-moving discipline.
Recent years have seen spectacular advances in the field of circadian biology. These have attracted the interest of researchers in many fields, including endocrinology, neurosciences, cancer, and behavior. By integrating a circadian view within the fields of endocrinology and metabolism, researchers will be able to reveal many, yet-unsuspected aspects of how organisms cope with changes in the environment and subsequent control of homeostasis. This field is opening new avenues in our understanding of metabolism and endocrinology. A panel of the most distinguished investigators in the field gathered together to discuss the present state and the future of the field. The editors trust that this volume will be of use to those colleagues who will be picking up the challenge to unravel how the circadian clock can be targeted for the future development of specific pharmacological strategies toward a number of pathologies.
This volume provides a balanced and realistic review of the current state of glioblastoma, ranging from traditional histological review, molecular pathology of glioma, modern radiomics, neurosurgical focus, and integration of treatment plans by neuro-oncologists. The book reviews basic principles such as epidemiology and etiology, and modern 2016 WHO classification of CNS tumors. Chapters cover a general overview of common molecular techniques used in molecular pathology, molecular pathology in a developing country, key drivers of patient outcomes and predictors of response to radiation and/or chemotherapy treatment, and immunohistochemical surrogates for key molecular pathology. It concludes with reviews on radiomics, animal and stem cell models of glioblastoma, and a chapter on the emerging field of Glioblastoma Neuroscience. Precision Molecular Pathology of Glioblastoma is intended for pathology residents and fellows interested in glioblastoma, general surgical pathologists who need reviews on how to implement modern glioblastoma classification, as well as neuro-radiologists, oncologists, and radiation oncologists needing a holistic perspective to glioblastoma diagnosis and management.