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Nucleic acid sequencing is a fundamental technique that was recognized with the 1980 Nobel Prize in Chemistry. The method allows delineation of DNA sequences with extraordinary accuracy and, since its introduction in the 1970s, has undergone many important modifications and improvements. Among these are the achievement of long reads (up to ∼1000 bp per analysis), better accuracy (related to the discovery of highly versatile and thermostable sequencing enzymes), improved sensitivity with thermocycling protocols (linear amplifications), full automation, higher speed (related to the introduction of thin gels), and substitution of radioactivity with fluorescent and other probes. All of these improvements have allowed scientists to attempt something that was unthinkable 15–20 years ago, i.e., delineation of the complete sequence of the human genome (∼3 × 109 bp) and genomes of other organisms. We have already witnessed, over the last few years, the release of the complete sequence of simple organisms as well as of more complex ones, the latest being the Drosophila genome (1). We are now very close to the completion of the entire Human Genome Project (2). These achievements represent a triumph of the DNA sequencing methodology.Now that we (almost) know the complete DNA sequences of these organisms and humans, the question arises. How are we to use this information? The next step will be the complete annotation of the human genome, which will include classification of the raw DNA sequence into well-defined gene structures. We will then need to predict and experimentally verify the encoded proteins and their possible biological functions (physiology). Once this is done, we can begin to ask questions about how genomic variation in certain genes (polymorphisms, mutations) can cause or predispose to specific human diseases (pathophysiology). We already have many examples of subtle genetic changes that can cause very serious human diseases, including …

Sequencing with Microarray Technology—A Powerful New Tool For Molecular Diagnostics