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INTRODUCTION

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Through the ages, physicians and scientists have studied diseases of humans, describing the abnormal lesions (pathology) and their adverse effects on the patient (pathophysiology), seeking to identify risk factors (susceptibility) and causes (etiological agents), and pursuing a greater understanding of how diseases come to be (pathogenesis). With progress in these directions, some human diseases are now well understood from the perspective of risk and causal factors, and effective preventative and/or treatment strategies have been developed. For many other human diseases, investigation into the fundamental elements of the molecular and cellular pathogenesis represents an ongoing endeavor. Nevertheless, in the last several decades, the field of pathology has evolved to recognize that disease manifests in many cases as a direct reflection of changes in patterns of gene expression and often involves changes in the genome. There is also the recognition that gene expression patterns in a given lesion type (e.g., a certain form of cancer) will influence the clinical behavior of that lesion and its response to therapy. Hence, a great effort has been expended to characterize the genetic basis of various human diseases (molecular pathology), leading to a greater understanding of the contributions of genomic alterations to the development and progression of disease. Molecular pathology represents the application of the principles of basic molecular biology to the investigation of human disease processes. Our ever broadening insights into the molecular basis of disease provide opportunities for the development of new and novel approaches for diagnosis, classification, and prognostic assessment of human disease, and for expansion of treatments that are directed at specific molecular targets or pathways. In this chapter, we provide an overview of the role of the genomic alterations in genetic, developmental, and neoplastic diseases, with special emphasis on the role of mutations and epimutations in the pathogenesis of these disease states.

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THE HUMAN GENOME

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DNA is the Source of Genetic Information

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Among the essential building blocks of living cells that were identified and characterized by chemists and early biochemists were nucleic acids—long-chain polymers composed of nucleotides. Nucleic acids were named based partly on their chemical properties and partly on the observation that they represent a major constituent of the cell nucleus. The critical realization that nucleic acids form the chemical basis for the transmission of genetic traits did not occur until about 65 years ago. Prior to that time, there was considerable disagreement among scientists as to whether genetic information was contained in and transmitted by proteins or nucleic acids. It was recognized that chromosomes contained deoxyribonucleic acid (DNA) as a primary constituent, but it was not known if this DNA carried genetic information or merely served as a scaffold for some undiscovered class of proteins that carried genetic information. However, the demonstration that genetic traits could be transmitted through DNA formed the basis for numerous investigations focused on elucidation of the nature of the genetic code. During the last 65 ...

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