Genomics Primer from Mayo Clinic Proceedings

Mayo staff have authored several articles that will be useful for anyone developing a thorough understanding of medical genomics. These articles have been published as a series in the Mayo Clinic Proceedings journal. This section includes outlines of the articles and links to the full copy.

Part I: History of Genetics and Sequencing of the Human Genome
Cindy Pham Lorentz, MS; Eric D. Wieben, PhD; Ayalew Tefferi, MD; David A. H. Whiteman, MD; and Gordon W. DeWald, PhD

The first part of this overview gives an account of the history of genetics that spans from humankind's first attempts at understanding and influencing heredity, to the early scientific work in the field of genetics, and then to the advancements in modern genetics. The second part summarizes the Human Genome Project (HGP) from inception to the publishing of the "first draft" of the human genome sequence.

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Part II: Background Principles and Methods in Molecular Genetics
Ayalew Tefferi, MD; Eric D. Wieben, PhD; Gordon W. DeWald, PhD; David A. H. Whiteman, MD; Matthew E. Bernard, MD; and Thomas C. Spelsberg, PhD

In this second part of an educational series in medical genomics, selected principles and methods in molecular biology are recapped, with the intent to prepare the reader for forthcoming articles with a more direct focus on aspects of the subject matter.

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Part III: Microarray Experiments and Data Analysis
Ayalew Tefferi, MD; Mark E. Bolander, MD; Stephen M. Ansell, MD, PhD; Eric D. Wieben, PhD; and Thomas C. Spelsberg, PhD

Genomics has been defined as the comprehensive study of whole sets of genes, gen products, and their interactions as opposed to the study of single genes or proteins. Microarray technology is one of many novel tools that are allowing global and high-throughput analysis of genes and gene products. In addition to an introduction on underlying principles, the current review focuses on the use of microarrays in gene expression analysis. The current education communication discusses different methods of data analysis including supervised and unsupervised clustering algorithms. The current review should serve as an introduction to the subject for clinician investigators, physicians and medical scientists in training, practicing clinicians, and other students of medicine.

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Part IV: Expression Proteomics
Animesh Pardanani, MD, PhD; Eric D. Wieben, MD; Thomas C. Spelsberg, PhD; and Ayalew Tefferi, MD

Proteomics, simply defined is the study of proteomes. The three broad areas are expression proteomics, which catalogues the relative abundance of proteins; cell-mapping or cellular proteomics, which delineates functional protein-protein interactions and organelle-specific protein distribution; and structural proteomics, which characterizes the 3-dimensional structure of proteins. This articles reviews the area of expression proteomics.

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Part V: Genomics and Molecular Genetics in Clinical Practice
Stephen M. Ansell, MD, PhD; Michael J. Ackerman, MD, PhD; John L. Black, MD; Lewis R. Roberts, MD, PhD; and Ayalew Tefferi, MD

An important milestone in medical science is the recent completion of a "working draft" of the human genome sequence. The identification of all human genes and their regulatory regions provides the framework to expedite our understanding of the molecular basis of disease. This advance has also formed the foundation for a broad range of genomic tools that can be applied to medical science. These developments in global gene and gene product analysis as well as targeted molecular genetic testing are destined to change the practice of modern medicine. Despite these exciting advances, many practicing clinicians perceive that the role of molecular genetics, especially that of genomics, is confined primarily to the research arena with little current clinical applicability. The aim of the article is to highlight advances in DNA/RNA-based methods of susceptibility screening, disease diagnosis and prognostication, and prediction of treatment outcome in regard to both drug toxicity and response as they apply to various areas of clinical medicine.

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Part VI: The Evolving Concept of the Gene
Eric D. Wieben, PhD

The draft sequence of the human genome was reported 2 years ago, and the task of filling gaps and polishing the sequence is nearing completion. However, despite this remarkable achievement, there is still no definitie assessment of the number of genes contained in the human genome. In part, this uncertainty reflects our growing understanding of the complexity and diversity of gene structure. Examples of complex gene structure are considered in the context of the discussion about the evolution of our understanding of gene structure and function.

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Part VII: Essentials of Medical Genetics for the Practicing Physician
Regina E. Ensenauer, MD; Shanda S. Reinke; Michael J. Ackerman, MD, PhD; David J. Tester; David A. H. Whiteman, MD; and Ayalew Tefferi, MD

After the mapping and sequencing of the human genome, medical professionals from essentially all specialties turned their attention to investigating the role genes play in health and disease. Until recently, medical genetics was considered a specialty of minor practical relevance. This view has changed with the development of new diagnostic and therapeutic possibilities. It is now realized that genetic disease represents an important part of medical practice. Achievements in cancer genetics, in the field of prenatal diagnostics (including carrier testing for common recessive disorders), and in newborn screening for treatable metabolic disorders reinforce the rapidly expanding role of genetics in medicine. Diagnosing a genetic disorder not only allows for disease-specific management options but also has implications for the affected individual's entire family. A working understanding of the underlying concepts of genetic disease with regard to chromosome, single gene, mitochondrial, and multifactorial disorders is necessary for today's practicing physician. Routine clinical practice in virtually all medical specialties will soon require integration of these fundamental concepts for use in accurate diagnosis and ensuring appropriate referrals for patients with genetic disease and their families.

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Part IX: Scientific and Clinical Applications of DNA Microarrays -- Multiple Myeloma as a Disease Model
John Shaughnessy, Jr., PhD

Multiple myeloma (MM) is a poorly understood and uniformly fatal malignancy of antibody-secreting plasma cells. Although several key molecular events in disease initiation or progression have been confirmed (e.g., 14q32 translocations) or implicated (e.g., chromosome 13 deletion), a unifying mechanism of myelomagenesis has eluded investigators. Furthermore, although MM is generally indistinguishable morphologically, it exhibits a tremendous degree of variability clinically with some patients surviving only months and others many years, suggesting that MM is composed of distinct clinical entities. Given that abnormal gene expression lies at the heart of most, if not all, cancers, high-throughput global gene expression profiling has become a powerful tool for investigating the molecular biology and clinical behavior of cancer. DNA microarray technology has facilitated the simultaneous quantification of thousands of cellular messenger RNAs (i.e., gene expression). This review discusses progress made in the development of molecular-based diagnostics and prognostics for MM through the dissection of the transcriptome of plasma cells from healthy individuals and patients with MM and other plasma cell dyscrasias.

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Part X: Gene Therapy
Stephen J. Russell, MD, PhD; and Kah-Whye Peng, PhD

Gene therapy is defined as any therapeutic procedure in which genes are intentionally introduced into human somatic cells. Both preclinical and clinical gene therapy research have been progressing rapidly during the past 15 years; gene therapy is now a highly promising new modality for the treatment of numerous human disorders. Since the first clinical test of gene therapy in 1989, more than 600 gene therapy protocols have been approved, and more than 3000 patients have received gene therapy. However, at the time of writing this article, no gene therapy products have been approved for clinical use. This article explains the potential clinical scope of gene therapy and the underlying pharmacological principles, describes some of the major gene transfer systems (or vectors) that are used to deliver genes to their target sites, and discusses the various strategies for controlling expression of therapeutic transgenes. Safety issues regarding clinical use of gene therapy are explored, and the most important technical challenges facing this field of research are highlighted. This review should serve as an introduction to the subject of gene therapy for clinician investigators, physicians and medical scientists in training, practicing clinicians, and other students of medicine.

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