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This volume details methods of identifying synthetic lethal, genetic interactions by various approaches in different model systems including human cancer cells. Chapters guide readers through genetic interactions in model organisms, RNA interference, CRISPR/Cas9 based genome editing technologies, drug-gene interactions, mapping chemical genetic interactions, synergistic drug-gene relations, single cell sequencing, gene expression profiling, and novel genetic interactions. Written in the format of the highly successful Methods in Molecular Biology series, each chapter includes an introduction to the topic, lists necessary materials and reagents, includes tips on troubleshooting and known pitfalls, and step-by-step, readily reproducible protocols. Authoritative and cutting-edge, Genetic Interaction Mapping aims to be a useful practical guide to researches to help further their study in this field.
Book Synopsis Mapping Genetic Interactions by : Franco Joseph Vizeacoumar
Download or read book Mapping Genetic Interactions written by Franco Joseph Vizeacoumar and published by . This book was released on 2021 with total page 361 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume details methods of identifying synthetic lethal, genetic interactions by various approaches in different model systems including human cancer cells. Chapters guide readers through genetic interactions in model organisms, RNA interference, CRISPR/Cas9 based genome editing technologies, drug-gene interactions, mapping chemical genetic interactions, synergistic drug-gene relations, single cell sequencing, gene expression profiling, and novel genetic interactions. Written in the format of the highly successful Methods in Molecular Biology series, each chapter includes an introduction to the topic, lists necessary materials and reagents, includes tips on troubleshooting and known pitfalls, and step-by-step, readily reproducible protocols. Authoritative and cutting-edge, Genetic Interaction Mapping aims to be a useful practical guide to researches to help further their study in this field.
This volume details methods of identifying synthetic lethal, genetic interactions by various approaches in different model systems including human cancer cells. Chapters guide readers through genetic interactions in model organisms, RNA interference, CRISPR/Cas9 based genome editing technologies, drug-gene interactions, mapping chemical genetic interactions, synergistic drug-gene relations, single cell sequencing, gene expression profiling, and novel genetic interactions. Written in the format of the highly successful Methods in Molecular Biology series, each chapter includes an introduction to the topic, lists necessary materials and reagents, includes tips on troubleshooting and known pitfalls, and step-by-step, readily reproducible protocols. Authoritative and cutting-edge, Genetic Interaction Mapping aims to be a useful practical guide to researches to help further their study in this field.
Book Synopsis Mapping Genetic Interactions by : Franco Joseph Vizeacoumar
Download or read book Mapping Genetic Interactions written by Franco Joseph Vizeacoumar and published by Humana. This book was released on 2022-10-01 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume details methods of identifying synthetic lethal, genetic interactions by various approaches in different model systems including human cancer cells. Chapters guide readers through genetic interactions in model organisms, RNA interference, CRISPR/Cas9 based genome editing technologies, drug-gene interactions, mapping chemical genetic interactions, synergistic drug-gene relations, single cell sequencing, gene expression profiling, and novel genetic interactions. Written in the format of the highly successful Methods in Molecular Biology series, each chapter includes an introduction to the topic, lists necessary materials and reagents, includes tips on troubleshooting and known pitfalls, and step-by-step, readily reproducible protocols. Authoritative and cutting-edge, Genetic Interaction Mapping aims to be a useful practical guide to researches to help further their study in this field.
Book Synopsis Mapping Genetic Interaction Networks in Yeast by : Anastasija Baryshnikova
Download or read book Mapping Genetic Interaction Networks in Yeast written by Anastasija Baryshnikova and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
There is growing enthusiasm in the scientific community about the prospect of mapping and sequencing the human genome, a monumental project that will have far-reaching consequences for medicine, biology, technology, and other fields. But how will such an effort be organized and funded? How will we develop the new technologies that are needed? What new legal, social, and ethical questions will be raised? Mapping and Sequencing the Human Genome is a blueprint for this proposed project. The authors offer a highly readable explanation of the technical aspects of genetic mapping and sequencing, and they recommend specific interim and long-range research goals, organizational strategies, and funding levels. They also outline some of the legal and social questions that might arise and urge their early consideration by policymakers.
Book Synopsis Mapping and Sequencing the Human Genome by : National Research Council
Download or read book Mapping and Sequencing the Human Genome written by National Research Council and published by National Academies Press. This book was released on 1988-01-01 with total page 128 pages. Available in PDF, EPUB and Kindle. Book excerpt: There is growing enthusiasm in the scientific community about the prospect of mapping and sequencing the human genome, a monumental project that will have far-reaching consequences for medicine, biology, technology, and other fields. But how will such an effort be organized and funded? How will we develop the new technologies that are needed? What new legal, social, and ethical questions will be raised? Mapping and Sequencing the Human Genome is a blueprint for this proposed project. The authors offer a highly readable explanation of the technical aspects of genetic mapping and sequencing, and they recommend specific interim and long-range research goals, organizational strategies, and funding levels. They also outline some of the legal and social questions that might arise and urge their early consideration by policymakers.
Over 7,000 rare diseases have been identified in the human population that, in aggregate, affect over 400 million people worldwide. The majority of rare diseases that have been identified are genetic in origin. However, a key challenge in developing therapies is that the functions of many rare disease-associated genes are poorly understood and consequently, their role in disease pathogenesis. There is strong appreciation that genes do not act in isolation and many disease phenotypes may arise from complex genetic interactions (GIs). Systematic mapping of GIs offers a wealth of information about gene function and advancements in gene-editing technology, such as clustered regularly interspaced short palindromic repeats (CRISPR), allows for GI mapping in human cells. In this thesis, I describe how lentiviral-based genome-wide pooled CRISPR/Cas9 screens offer insight into the function of rare disease-associated genes including NGLY1 and the genes encoding the complement regulatory proteins (CRPs): CD46, CD55, and CD59. Autosomal recessive mutations in NGLY1 give rise to NGLY1-deficiency, a congenital disorder of deglycosylation. How the loss of NGLY1 function contributes to disease pathogenesis is poorly understood. The CRPs are key inhibitors of the complement cascade and their impaired function contributes to a wide range of common and rare diseases. Similar to NGLY1, the functions of the CRPs independent of complement-regulation and roles in disease have not been explored using functional genomics approaches. To further our functional understanding of NGLY1 and the genes encoding the CRPs, I performed pooled genome-wide CRISPR/Cas9 screens to identify GIs, and uncovered a novel genetic relationship between the CRPs and the NGLY1 pathway involving genes in the secretory pathway that may coordinate different aspects of intracellular cholesterol trafficking. My work demonstrates the utility in mapping GIs in order to reveal functional relationships with rare disease genes, offering critical insight into the genetic underpinnings of NGLY1-deficiency and complement-independent functions of the CRPs. As the functions of many rare disease-associated genes are poorly characterized, mapping genetic interactions in co-isogenic human cell lines using genome-wide CRISPR screening approaches offers a powerful framework that may be exploited to gain insight into gene function and direct future therapeutic efforts.
Book Synopsis Mapping Genetic Interactions for Rare Disease-Associated Genes by : Kristin Kantautas
Download or read book Mapping Genetic Interactions for Rare Disease-Associated Genes written by Kristin Kantautas and published by . This book was released on 2020 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Over 7,000 rare diseases have been identified in the human population that, in aggregate, affect over 400 million people worldwide. The majority of rare diseases that have been identified are genetic in origin. However, a key challenge in developing therapies is that the functions of many rare disease-associated genes are poorly understood and consequently, their role in disease pathogenesis. There is strong appreciation that genes do not act in isolation and many disease phenotypes may arise from complex genetic interactions (GIs). Systematic mapping of GIs offers a wealth of information about gene function and advancements in gene-editing technology, such as clustered regularly interspaced short palindromic repeats (CRISPR), allows for GI mapping in human cells. In this thesis, I describe how lentiviral-based genome-wide pooled CRISPR/Cas9 screens offer insight into the function of rare disease-associated genes including NGLY1 and the genes encoding the complement regulatory proteins (CRPs): CD46, CD55, and CD59. Autosomal recessive mutations in NGLY1 give rise to NGLY1-deficiency, a congenital disorder of deglycosylation. How the loss of NGLY1 function contributes to disease pathogenesis is poorly understood. The CRPs are key inhibitors of the complement cascade and their impaired function contributes to a wide range of common and rare diseases. Similar to NGLY1, the functions of the CRPs independent of complement-regulation and roles in disease have not been explored using functional genomics approaches. To further our functional understanding of NGLY1 and the genes encoding the CRPs, I performed pooled genome-wide CRISPR/Cas9 screens to identify GIs, and uncovered a novel genetic relationship between the CRPs and the NGLY1 pathway involving genes in the secretory pathway that may coordinate different aspects of intracellular cholesterol trafficking. My work demonstrates the utility in mapping GIs in order to reveal functional relationships with rare disease genes, offering critical insight into the genetic underpinnings of NGLY1-deficiency and complement-independent functions of the CRPs. As the functions of many rare disease-associated genes are poorly characterized, mapping genetic interactions in co-isogenic human cell lines using genome-wide CRISPR screening approaches offers a powerful framework that may be exploited to gain insight into gene function and direct future therapeutic efforts.
Whereas genetic studies have traditionally focused on explaining heritance of single traits and their phenotypes, recent technological advances have made it possible to comprehensively dissect the genetic architecture of complex traits and quantify how genes interact to shape phenotypes. This exciting new area has been termed systems genetics and is born out of a synthesis of multiple fields, integrating a range of approaches and exploiting our increased ability to obtain quantitative and detailed measurements on a broad spectrum of phenotypes. Gathering the contributions of leading scientists, both computational and experimental, this book shows how experimental perturbations can help us to understand the link between genotype and phenotype. A snapshot of current research activity and state-of-the-art approaches to systems genetics are provided, including work from model organisms such as Saccharomyces cerevisiae and Drosophila melanogaster, as well as from human studies.
Book Synopsis Systems Genetics by : Florian Markowetz
Download or read book Systems Genetics written by Florian Markowetz and published by Cambridge University Press. This book was released on 2015-07-02 with total page 287 pages. Available in PDF, EPUB and Kindle. Book excerpt: Whereas genetic studies have traditionally focused on explaining heritance of single traits and their phenotypes, recent technological advances have made it possible to comprehensively dissect the genetic architecture of complex traits and quantify how genes interact to shape phenotypes. This exciting new area has been termed systems genetics and is born out of a synthesis of multiple fields, integrating a range of approaches and exploiting our increased ability to obtain quantitative and detailed measurements on a broad spectrum of phenotypes. Gathering the contributions of leading scientists, both computational and experimental, this book shows how experimental perturbations can help us to understand the link between genotype and phenotype. A snapshot of current research activity and state-of-the-art approaches to systems genetics are provided, including work from model organisms such as Saccharomyces cerevisiae and Drosophila melanogaster, as well as from human studies.
In chapter four, I describe the application of SGA analysis to the large-scale mapping of genetic interactions. A genetic interaction network containing & sim;1000 genes and & sim;4000 interactions was mapped by crossing mutations in 132 different query genes into a set of & sim;4700 viable gene deletion mutants and scoring the double mutant progeny for fitness defects. Network connectivity is predictive of function because interactions often occur among functionally related genes. Genetic interactions are largely orthogonal (non-overlapping) with protein-protein interactions, but genes coding for proteins that occur in the same pathway or complex display similar patterns of genetic interactions. The genetic network shows dense local neighbourhoods, implying the position of a gene on a partially mapped network is predictive of interactions. Because genetic networks are likely conserved, synthetic genetic interactions may underlie the complex genetics associated with inherited phenotypes in other organisms. In chapter three, I describe the development of a new method for automated identification of genetic interactions, termed synthetic genetic array (SGA) analysis. SGA analysis allows systematic construction of double mutants and examination of their fitness on a genome-wide scale. Functional genomics approaches have provided the opportunity for systematic examination of all genes in a genome, generating functional information such as gene expression profiles, protein expression and localization profiles, protein-protein interaction networks, and systematic characterization of mutants. Budding yeast has been the organism of choice for many of these pioneering studies because of its facile genetics. Large-scale studies have made significant contributions to our understanding of complex biological systems, and this trend is continuously fueled by new development of high-throughput technologies. In this thesis, I describe a general strategy to study protein-protein interaction modules (chapter two). A protein-protein interaction network was generated by focusing on yeast SH3 domains and combining data derived from phage-display ligand consensus sequences and large-scale two-hybrid physical interactions. This study produced a network that is depleted of most false positive interactions and enriched for biologically relevant interactions.
Book Synopsis Large-scale Mapping of Genetic Interactions in Saccharomyces Cerevisiae [microform] by : Amy Hin Yan Tong
Download or read book Large-scale Mapping of Genetic Interactions in Saccharomyces Cerevisiae [microform] written by Amy Hin Yan Tong and published by Library and Archives Canada = Bibliothèque et Archives Canada. This book was released on 2005 with total page 474 pages. Available in PDF, EPUB and Kindle. Book excerpt: In chapter four, I describe the application of SGA analysis to the large-scale mapping of genetic interactions. A genetic interaction network containing & sim;1000 genes and & sim;4000 interactions was mapped by crossing mutations in 132 different query genes into a set of & sim;4700 viable gene deletion mutants and scoring the double mutant progeny for fitness defects. Network connectivity is predictive of function because interactions often occur among functionally related genes. Genetic interactions are largely orthogonal (non-overlapping) with protein-protein interactions, but genes coding for proteins that occur in the same pathway or complex display similar patterns of genetic interactions. The genetic network shows dense local neighbourhoods, implying the position of a gene on a partially mapped network is predictive of interactions. Because genetic networks are likely conserved, synthetic genetic interactions may underlie the complex genetics associated with inherited phenotypes in other organisms. In chapter three, I describe the development of a new method for automated identification of genetic interactions, termed synthetic genetic array (SGA) analysis. SGA analysis allows systematic construction of double mutants and examination of their fitness on a genome-wide scale. Functional genomics approaches have provided the opportunity for systematic examination of all genes in a genome, generating functional information such as gene expression profiles, protein expression and localization profiles, protein-protein interaction networks, and systematic characterization of mutants. Budding yeast has been the organism of choice for many of these pioneering studies because of its facile genetics. Large-scale studies have made significant contributions to our understanding of complex biological systems, and this trend is continuously fueled by new development of high-throughput technologies. In this thesis, I describe a general strategy to study protein-protein interaction modules (chapter two). A protein-protein interaction network was generated by focusing on yeast SH3 domains and combining data derived from phage-display ligand consensus sequences and large-scale two-hybrid physical interactions. This study produced a network that is depleted of most false positive interactions and enriched for biologically relevant interactions.
This timely text presents a comprehensive guide to genetic association, a new and rapidly expanding field that aims to elucidate how our genetic code (genotypes) influences the traits we possess (phenotypes). The book provides a detailed review of methods of gene mapping used in association with experimental crosses, as well as genome-wide association studies. Emphasis is placed on model selection procedures for analyzing data from large-scale genome scans based on specifically designed modifications of the Bayesian information criterion. Features: presents a thorough introduction to the theoretical background to studies of genetic association (both genetic and statistical); reviews the latest advances in the field; illustrates the properties of methods for mapping quantitative trait loci using computer simulations and the analysis of real data; discusses open challenges; includes an extensive statistical appendix as a reference for those who are not totally familiar with the fundamentals of statistics.
Book Synopsis Phenotypes and Genotypes by : Florian Frommlet
Download or read book Phenotypes and Genotypes written by Florian Frommlet and published by Springer. This book was released on 2016-02-12 with total page 232 pages. Available in PDF, EPUB and Kindle. Book excerpt: This timely text presents a comprehensive guide to genetic association, a new and rapidly expanding field that aims to elucidate how our genetic code (genotypes) influences the traits we possess (phenotypes). The book provides a detailed review of methods of gene mapping used in association with experimental crosses, as well as genome-wide association studies. Emphasis is placed on model selection procedures for analyzing data from large-scale genome scans based on specifically designed modifications of the Bayesian information criterion. Features: presents a thorough introduction to the theoretical background to studies of genetic association (both genetic and statistical); reviews the latest advances in the field; illustrates the properties of methods for mapping quantitative trait loci using computer simulations and the analysis of real data; discusses open challenges; includes an extensive statistical appendix as a reference for those who are not totally familiar with the fundamentals of statistics.
Biological phenotypes are mediated by a network of functional interactions between genes, proteins, and other biomolecules present in the cell. While high-throughput screening efforts have largely mapped the role of individual genes in controlling phenotypes such as cellular proliferation, interactions between genes/proteins remain largely unmapped and untargeted. In this dissertation, we develop and apply novel screening methodologies to map and exploit interactions between genes/proteins. We use pairwise CRISPR-Cas9 mediated gene knockouts to map the full set of genetic interactions among cyclin-dependent kinases (CDKs) and interacting proteins, identifying several synthetic-lethal and synergistic relationships. We perform single-cell RNA sequencing on the CDK knockout populations, quantifying the cell-cycle effects and cell states mediated by individual CDK proteins. While CDKs are readily druggable via small molecules, many cancer drivers have structures which are not amenable to traditional pharmacological inhibition approaches. To address this challenge, we developed a peptide tiling (PepTile) approach to engineer protein inhibitors of cancer drivers and protein-protein interactions in general. By overexpressing pooled libraries of peptides within cancer cells, we map bioactive protein domains and identify peptides derived from key protein-protein interaction (PPI) interfaces which have strong anti-proliferative effects. We show that these peptides can be modified for extracellular delivery, functioning as anticancer drugs with micromolar IC50s. Finally, we demonstrated the versatility of the PepTile approach to alternative contexts, mining physical interactions to improve delivery of therapeutic payloads in vivo. We show our screening datasets can be used to train predictive models, with applications for future engineering efforts towards targeting and delivery of therapeutic biomolecules.
Book Synopsis Mapping and Targeting Genetic and Physical Interactions at Scale by : Kyle Ford
Download or read book Mapping and Targeting Genetic and Physical Interactions at Scale written by Kyle Ford and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Biological phenotypes are mediated by a network of functional interactions between genes, proteins, and other biomolecules present in the cell. While high-throughput screening efforts have largely mapped the role of individual genes in controlling phenotypes such as cellular proliferation, interactions between genes/proteins remain largely unmapped and untargeted. In this dissertation, we develop and apply novel screening methodologies to map and exploit interactions between genes/proteins. We use pairwise CRISPR-Cas9 mediated gene knockouts to map the full set of genetic interactions among cyclin-dependent kinases (CDKs) and interacting proteins, identifying several synthetic-lethal and synergistic relationships. We perform single-cell RNA sequencing on the CDK knockout populations, quantifying the cell-cycle effects and cell states mediated by individual CDK proteins. While CDKs are readily druggable via small molecules, many cancer drivers have structures which are not amenable to traditional pharmacological inhibition approaches. To address this challenge, we developed a peptide tiling (PepTile) approach to engineer protein inhibitors of cancer drivers and protein-protein interactions in general. By overexpressing pooled libraries of peptides within cancer cells, we map bioactive protein domains and identify peptides derived from key protein-protein interaction (PPI) interfaces which have strong anti-proliferative effects. We show that these peptides can be modified for extracellular delivery, functioning as anticancer drugs with micromolar IC50s. Finally, we demonstrated the versatility of the PepTile approach to alternative contexts, mining physical interactions to improve delivery of therapeutic payloads in vivo. We show our screening datasets can be used to train predictive models, with applications for future engineering efforts towards targeting and delivery of therapeutic biomolecules.
Book Synopsis Large-scale Mapping of Chemical-genetic Interaction Phenotypes in Human Cells by : Christian Scheeder
Download or read book Large-scale Mapping of Chemical-genetic Interaction Phenotypes in Human Cells written by Christian Scheeder and published by . This book was released on 2022* with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
