Cellular And Animal Models In Human Genomics Research

Cellular and Animal Models in Human Genomics Research provides an indispensable resource for applying comparative genomics in the annotation of disease-gene associated variants that are identified by human genomic sequencing. The book presents a thorough overview of effective protocols for the use of cellular and animal modeling methods to turn lists of plausible genes into causative biomarkers. With chapters written by international experts, the book first addresses the fundamental aspects of using cellular and animal models in genetic and genomic studies, including in-depth examples of specific models and their utility, i.e., yeast, worms, flies, fish, mice and large animals. Protocols for properly conducting model studies, genomic technology, modeling candidate genes vs. genetic variants, integrative modeling, utilizing induced pluripotent stem cells, and employing CRISPR-Cas9 are also discussed in-depth. Provides a thorough, accessible resource that helps researchers and students employ cellular and animal models in their own genetic and genomic studies Offers guidance on how to effectively interpret the results and significance of genetic and genomic model studies for human health Features chapters from international experts in the use of specific cellular and animal models, including yeast, worms, flies, fish, mice, and large animals, among other organisms

Genome-wide association (GWA) studies and tumor-specific epigenome, transcriptome and genome sequencing projects are generating an ever-growing list of susceptibility alleles, as well as putative gain- and loss-of-function gene mutations associated with cancer. These genetic changes ultimately need to be validated to determine their contribution to the initiation, progression and likelihood of treatment response for various cancers. The bottle-neck is no longer obtaining sequence data or completion of the GWA studies, but rather the ability efficiently to validate candidate genes identified by these projects. In vivo studies in animal models are the “gold standard” for validation of these candidate drivers and modifiers of cancer. Furthermore, once a gene product or molecular pathway has been validated as playing an important role in the development or progression of cancer, animal models provide the necessary preclinical data for evaluation of the efficacy and toxicity of new therapeutics targeting that gene or pathway. As such, animal models play an essential role in cancer research by facilitating the translation of genomic discoveries into preclinical studies that precede new targeted therapies for cancer. In this chapter, we will discuss vertebrate and invertebrate animal models as they apply to cancer genomics, as well as key technologies employed. In particular, we will focus on the use of murine and zebrafish human tumor xenografts and transgenic models.

Precision medicine is focused on the individual and will require the rapid and accurate identification and prioritization of causative factors of disease. To move forward and accelerate the delivery of the anticipated benefits of precision medicine, developing predictable, reproducible, and reliable animal models will be essential. In order to explore the topic of animal-based research and its relevance to precision medicine, the National Academies of Sciences, Engineering, and Medicine convened a 2-day workshop on October 5 and 6, 2017. The workshop was designed to focus on the development, implementation, and interpretation of model organisms to advance and accelerate the field of precision medicine. Participants examined the extent to which next-generation animal models, designed using patient data and phenotyping platforms targeted to reveal and inform disease mechanisms, will be essential to the successful implementation of precision medicine. This publication summarizes the presentations and discussions from the workshop.

Scientific Frontiers in Developmental Toxicology and Risk Assessment reviews advances made during the last 10-15 years in fields such as developmental biology, molecular biology, and genetics. It describes a novel approach for how these advances might be used in combination with existing methodologies to further the understanding of mechanisms of developmental toxicity, to improve the assessment of chemicals for their ability to cause developmental toxicity, and to improve risk assessment for developmental defects. For example, based on the recent advances, even the smallest, simplest laboratory animals such as the fruit fly, roundworm, and zebrafish might be able to serve as developmental toxicological models for human biological systems. Use of such organisms might allow for rapid and inexpensive testing of large numbers of chemicals for their potential to cause developmental toxicity; presently, there are little or no developmental toxicity data available for the majority of natural and manufactured chemicals in use. This new approach to developmental toxicology and risk assessment will require simultaneous research on several fronts by experts from multiple scientific disciplines, including developmental toxicologists, developmental biologists, geneticists, epidemiologists, and biostatisticians.

To create and establish mutant mice as models for human diseases and traits, various forward and reverse genetics tools are currently available. Newly developed tools of high-throughput identification of novel mutations and site-directed mutagenesis, or gene targeting, in the mouse genome have caused forward and reverse genetics, respectively, to rapidly expand during the last two decades. Worldwide efforts including a variety of international consortiums have been producing many useful mutant mouse strains for functional genomics to elucidate the mechanisms behind diseases and traits. Resource centers and public databases have also been built to enhance their utilities. The modeling has started from Mendelian monogenic traits and has expanded to more complex quantitative traits as well. Multidisciplinary integration among, for example, molecular, cellular, and developmental biology; genetics; genomics; medicine; statistics; and informatics must be orchestrated to fully utilize the resources and knowledge of model mice.

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.

The collection of systems represented in Sourcebook of genomic programs, although this work is certainly well Models for Biomedical Research is an effort to re?ect the represented and indexed. diversity and utility of models that are used in biomedicine. Some models have been omitted due to page limitations That utility is based on the consideration that observations and we have encouraged the authors to use tables and made in particular organisms will provide insight into the ? gures to make comparisons of models so that observations workings of other, more complex, systems. Even the cell not available in primary publications can become useful to cycle in the simple yeast cell has similarities to that in the reader. humans and regulation with similar proteins occurs. We thank Richard Lansing and the staff at Humana for Some models have the advantage that the reproductive, guidance through the publication process. mitotic, development or aging cycles are rapid compared As this book was entering production, we learned of the with those in humans; others are utilized because individual loss of Tom Lanigan, Sr. Tom was a leader and innovator proteins may be studied in an advantageous way and that in scienti?c publishing and a good friend and colleague to have human homologs. Other organisms are facile to grow all in the exploratory enterprise. We dedicate this book to in laboratory settings or lend themselves to convenient analy- his memory. We will miss him greatly.

Genetically modified animals were created about 30 years ago, and are considered good models of human diseases. In this chapter, the types of genetically engineered mice, such as transgenic, knockout conditional knockout, and knockin animals, and the general techniques on how to obtain them are described. In addition, the available genetically modified models for genetic diseases, multifactorial and polygenic (complex) disorders, neurodegenerative, inflammatory diseases, besides cancer models, are presented. The aim of the chapter is to help investigators to find out the best models for their studies.