Genomic and Precision Medicine

Foundations, Translation, and Implementation

Geoffrey S. Ginsburg, Huntington F Willard

• Publisher: Academic Press
• Year: 2016
• Print ISBN:
  9780128006818
• eBook ISBN:
  9780128006566
• Edition: 3
• Topic: Medicine
• Subtopic: Pharmacology

Genomic and Precision Medicine: Foundations, Translation, and Implementation highlights the various points along the continuum from health to disease where genomic information is impacting clinical decision-making and leading to more personalization of health care. The book pinpoints the challenges, barriers, and solutions that have been, or are being, brought forward to enable translation of genome based technologies into health care. A variety of infrastructure (data systems and EMRs), policy (regulatory, reimbursement, privacy), and research (comparative effectiveness research, learning health system approaches) strategies are also discussed. Readers will find this volume to be an invaluable resource for the translational genomics and implementation science that is required to fully realize personalized health care. - Provides a comprehensive volume on the translation and implementation of biology into health care provision - Presents succinct commentary and key learning points that will assist readers with their local needs for translation and implementation - Includes an up-to-date overview on major 'translational events' in genomic and personalized medicine, along with lessons learned

Chapter 1

The Human Genome

Foundation for Genomic and Precision Medicine

Huntington F. Willard^1,2, ¹Marine Biological Laboratory, Woods Hole, MA, United States, ²University of Chicago, Chicago, IL, United States

Abstract

Understanding the organization, variation, and expression of the human genome is central to the principles of genomic and precision medicine. Based on the availability of a reference sequence of the human genome, on an emerging appreciation of the extent of genome variation among different individuals and populations, and on a growing understanding of the role of genome variation in disease, it is now possible to begin to exploit the impact of that variation on human health on a broad scale. The comparison of individual genomes underlies the conclusion that virtually every individual has his or her own unique constitution of gene products, produced in response to the combined inputs of the genome sequence and one’s particular set of environmental exposures and experiences. This awareness is reminiscent of what the British physician Archibald Garrod termed “chemical individuality” over a century ago and provides a conceptual foundation for the practice of genomic and precision medicine.

Keywords

Human genome; genome sequencing; genome variation; environmental exposures; chemical individuality

Chapter Outline

Introduction 1

The Human Genome 2

Genes in the Human Genome 2

Variation in the Human Genome 6

Types of Variation 7

Variation in Individual Genomes 9

Variation in Populations 10

Expression of the Human Genome 11

The Genome in Three-Dimensional Space 11

Genes, Genomes, and Disease 13

Clinical Sequencing in Search of Causal Variants 13

Microbiomes and Microbiota 15

From Genomes to Precision Medicine 16

Abbreviations 17

References 17

Introduction

That genetic variation can influence health and disease has been a central, if not broadly practiced, principle of medicine for over a hundred years. What has limited full application of this principle until recently has been the special nature and presumed rarity of clinical circumstances or conditions to which genetic variation was relevant. Now, however, with the availability of a reference sequence of the human genome and a growing number of personal genome sequences from both asymptomatic and symptomatic individuals, with emerging appreciation of the extent of genome variation among different individuals and different populations worldwide, and with a growing understanding of the role of common as well as rare variation in disease, we are increasingly able to begin to exploit the impact of that variation on human health on a broad scale, in the context of genomic and precision medicine [1].

Variation in the human genome has long been the cornerstone of the field of human genetics (Box 1.1), and its study led to the establishment of the medical specialty of medical genetics. The general nature and frequency of gene variants in the human genome became apparent with the classic work over 50 years ago on the incidence of polymorphic protein variants in populations of healthy individuals, work that is the conceptual forerunner to the much larger and detailed efforts that mark modern human genetics and genomics. Such data underlie the conclusion that virtually every individual has his or her own unique constitution of gene products, the implications of which provide a foundation for what today we call personalized or precision medicine as a modern application of what the British physician Archibald Garrod called “chemical individuality” in the very early years of the last century [2].

Box 1.1

Genetics and Genomics in Precision Medicine

Throughout this and the many other chapters in these volumes, the terms “genetics” and “genomics” are used repeatedly, both as nouns and in their adjectival forms. While these terms seem similar, they in fact describe quite distinct (though frequently overlapping) approaches in biology and in medicine. Having said that, there are inconsistencies in the way the terms are used, even by those who work in the field. To some, genetics is a subfield of genomics; to others, genomics is a subfield of genetics!

Here, we provide operational definitions to distinguish the various terms and the subfields of medicine to which they contribute.

The field of genetics is the scientific study of heredity and of the genes that provide the physical, biological, and conceptual bases for heredity and inheritance. To say that something—a trait, a disease, a code, or an information—is “genetic” refers to its basis in genes and in DNA.

Heredity refers to the familial phenomenon whereby traits (including clinical traits) are transmitted from generation to generation, due to the transmission of genes from parent to child. A disease that is said to be inherited or hereditary is certainly genetic; however, not all genetic diseases are hereditary (witness cancer, which is always a genetic disease, but is only occasionally an inherited disease).

Genomics is the scientific study of a genome or genomes. A genome is the complete DNA sequence, referring to the entire genetic information of a gamete, an individual, a population, or a species. As such, it is a subfield of genetics when describing an approach taken to study genes. The word “genome” originated as an analogy with the earlier term “chromosome,” referring to the physical entities (visible under the microscope) that carry genes from one cell to its daughter cells or from one generation to the next. “Genomics” gave birth to a series of other “-omics” that refer to the comprehensive study of the full complement of genome products—for example, proteins (hence, proteomics), transcripts (transcriptomics), or metabolites (metabolomics). The essential feature of the “-omes” is that they refer to the complete collection of genes or their derivative proteins, transcripts, or metabolites, not just to the study of individual entities. The distinguishing characteristics of genomics and the other “omics” are their comprehensiveness and scale, their integration with and dependence on technology development, an emphasis on rapid data release and availability, and an awareness of the policy and ethical implications of such work in research, in the practice of medicine, and increasingly in the social arena [3].

By analogy with genetics and genomics, epigenetics and epigenomics refer to the study of factors that affect gene (or, more globally, genome) function, but without an accompanying change in genes or the genome. The epigenome is the comprehensive set of epigenetic changes in a given individual, tissue, tumor, or population. It is the paired combination of the genome and the epigenome that appear to best characterize and determine one’s phenotype.

Medical Genetics is the application of genetics to medicine with a particular emphasis on inherited disease. Medical genetics is a broad and varied field, encompassing many different subfields, including clinical genetics, biochemical genetics, cytogenetics, molecular genetics, the genetics of common diseases, and genetic counseling. Medical Genetics and Genomics is one of 24 medical specialties recognized by the American Board of Medical Specialties, the medical organization overseeing physician certification in the United States.

Genetic Medicine is a term used to refer to the application of genetic principles to the practice of medicine and thus overlaps medical genetics. However, genetic medicine is somewhat broader, as it is not limited to the specialty of Medical Genetics and Genomics, but is relevant to health professionals in many, if not all, specialties and subspecialties. Both medical genetics and genetic medicine approach clinical care largely through consideration of individual genes and their effects on patients and their families.

By contrast, Genomic Medicine refers to the use of large-scale genomic information and to consideration of the full extent of an individual’s genome and other “omes” in the practice of medicine and medical decision making. The principles and approaches of genomic medicine are relevant well beyond the traditional purview of medical genetics and include, as examples, gene expression profiling to characterize tumors or to define prognosis in cancer, genotyping ...

Table of contents

• Cover
• Front-matter
• Table of Contents
• Copyright
• List of Contributors
• List of Illustrations
• List of Tables
• Chapter 1 : The Human Genome: Foundation for Genomic and Precision Medicine
• Chapter 2 : The Functional Genome: Epigenetics and Epigenomics
• Chapter 3 : The State of Whole-Genome Sequencing
• Chapter 4 : The Human Microbiome
• Chapter 5 : Quantitative Proteomics for Clinical Translation
• Chapter 6 : From Data to Knowledge: An Introduction to Biomedical Informatics
• Chapter 7 : Local and Global Challenges in the Clinical Implementation of Precision Medicine
• Chapter 8 : From Biobanking to Precision Medicine: The Estonian Experience
• Chapter 9 : Electronic Health Records and Genomic Medicine
• Chapter 10 : Data Sharing and Privacy
• Chapter 11 : Designing Genetic- and Genomic-Based Clinical Trials
• Chapter 12 : Developing the Evidence to Support Clinical Use of Genomics
• Chapter 13 : Family Health History and Health Risk Assessment in Health Care
• Chapter 14 : Genetics Aware Clinical Decision Support
• Chapter 15 : Implementation Science and Integration into Healthcare Systems
• Chapter 16 : Pharmacogenetics and Pharmacogenomics
• Chapter 17 : Clinical Genomic Testing
• Chapter 18 : Molecular Genetic Testing and the Future of Clinical Genomics1
• Chapter 19 : Bringing Genomics to Medicine: Ethical, Policy, and Social Considerations
• Chapter 20 : Educational Issues and Strategies for Genomic Medicine: For the Public and for Providers
• Chapter 21 : Regulation of Genomic Technologies
• Chapter 22 : Developing the Value Proposition for Personalized Medicine
• Chapter 23 : Technology Assessment and the Road to Reimbursement of Genomic Based Diagnostics
• Chapter 24 : Legal Issues in Genomic and Precision Medicine: Intellectual Property and Beyond
• Index
• A