During the 1960s and 1970s, observations regarding 5mC raised many more questions than could be answered with the tools that were widely available at that time. During this same period, however, the genetic code and the rules whereby cells read information encoded in DNA were established (Figure 1.1), and biologists were more inclined to think of hereditary transactions in terms of the flow of information from DNA to RNA to protein. The availability of recombinant DNA technologies for cloning, sequencing, and expression of genes, and the invention of Southern blots for identifying DNA polymorphisms and Northern blots for determining levels of gene expression, afforded investigators the tools they needed to relate allelic variants of genes directly to biochemical and pharmacological variants of enzymes, receptors, and other proteins.
But we should recall that the central dogma of molecular biology as formulated in the 1950s asserted the cardinal function of gene action to be the synthesis of proteins according to the program of instructions encoded in the DNA that was subsequently transcribed into RNA and translated into the primary protein sequence. The gene was judged to be deterministic of wm'd/recf/onai gene expression and for more than 50 years, the bulk of genomics research was guided by this model. However, recent discoveries have revealed certain inadequacies in this model of the gene-protein relationship. To begin with, the discovery of reverse transcriptase by Howard Temin and David Baltimore negated the idea that gene expression was unidirectional. The posttranslational modification of protein added another twist. More recently, it became apparent that some genes encoded just one protein, while other genes encoded more than one protein, and still others did not encode any protein, confounding the predictive value of the genotype. The identification of previously unknown pathway components illustrated the complexity of cellular events, and recognition of the fact that gene expression could be altered at the translational, transcriptional, and posttransla-tional levels by a host of factors necessitated an expanded view of the basic principles of gene expression and phenotypic expression as originally formulated (Figure 6.2).
Additional advances in molecular biology in the 1980s are brought into sharper focus by the cloning and sequencing of a vast number of genes predictive of disease, the expression of the proteins they encode, and fixing their chromosomal location in the human genome. The polymerase chain reaction (PCR) combined
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