Reverse transcriptase

Figure 1.5 Expanding the central dogma of molecular biology. With permission from The Scientist.

Phosphorylation Glycosylation Acetylation

Other

Phosphorylation Glycosylation Acetylation

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Other proceeded according to a well-defined program of instructions encoded in the DNA that was transcribed into RNA and subsequently translated into the primary protein sequence. Hence, the gene was deterministic of unidirectional gene expression. For more than 50 years, genomic research has been guided by this model of genetic inheritance. The insights into human development, physiology, medicine, and evolution gained through the maturation of this work constitute a signal achievement in modern biology, but recent discoveries have revealed that such a simplistic model of the gene-protein relationship was no longer tenable. The idea of a unidirectional nature gene expression was negated by reverse transcriptase; posttranslational protein modifications added another twist, and more recently, the predictive value of the genotype was confounded when 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. The complexity of cellular events was illustrated by the identification of previously unknown pathway components, and the recognition that gene expression could be altered at the translational, transcriptional, and posttranslational levels by a host of factors has necessitated wider views of phenotypic expression and expansion of the basic principles of gene expression as originally formulated (Figure 1.5).12 Advances in molecular biology were brought into sharper focus during the 1980s and 1990s by cloning and sequencing genes predictive of disease, expression of the proteins they encode, and fixing their chromosomal location in the human genome. Allelic variants that could be inferred only from familial inheritance patterns prior to the advent of molecular genetics could now be demonstrated by direct evidence. The polymerase chain reaction (PCR) combined with gene expression systems increased the availability of well-defined recombinant proteins in quantities sufficient for biochemical and pharmacological characterization. Strategies to target and modify genes in a predictable manner could be created in animal and cell models possessing knockout, overexpressed, and ''humanized'' alleles in specific tissues and at specific developmental stages. In short, molecular biological approaches in many forms permeated and dominated biological research, setting the stage for the convergence of basic research and clinical medicine. The changing scene surrounding these events solidified the foundations of genetics by providing novel insights into the multiplicity of factors affecting gene expression, and invigorating and redefining pharma-cogenetics.

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