Hamilton Smith

The Genomics Revolution


Abstract

The invention of DNA sequencing in 1975 and the subsequent introduction of automated sequencing machines in the 1980's have initiated a genomics revolution in biology and medicine. It is now possible to obtain the complete DNA sequence of organisms ranging in complexity from microbes to man. The genomic DNA sequence contains the total information to build an organism, to take it through the various stages of development, and to run all of its biochemical reactions. We have entered a new era of biology and medicine that considers not just single genes, but the entire genetic composition of organisms and their global features of expression. The comparison of whole genome sequences is revealing evolutionary details and relationships between organisms that were not previously accessible.

Two approaches are being used to sequence genomes: (1) A map and sequence approach, and (2) whole genome shotgun sequencing and assembly. The latter is now widely used for microbial genomes. All that is required is a few micrograms of the cell DNA. No prior genetic analysis of the organism is required. Over 20 microbes have been sequenced since 1995 with another 50 in various stages of completion, including import human pathogens and environmentally significant organisms. Publicly funded centers are sequencing the human genome using the map and sequence approach, while at least one commercial company is using the shotgun assembly approach, with completion estimated for as early as the end of 2001. Sequencing of model organisms such as mouse and Drosophila, and plants such as arabidopsis and rice are also underway. By the end of this year, some 500 new PE Biosystems Model 3700 automated DNA sequencers will be installed worldwide. Each machine can produce up to 4000,000bp or raw DNA sequence per day. The outflow of data will put heavy strains on current biomedical computing resources.

Most of what we will learn from genome sequencing is yet to come. Analysis will take decades. However, we are already learning some interesting things. Typically, about 40% of the genes in each genome have no known function. The others can be assigned functions based on studies in model organisms. A core of genes for the essential functions of replication, transcription, translation, membrane transport, and so forth are highly conserved between organisms. Systematic knockout of genes in the smallest known microbial genome, that of Mycoplasma genitalium, with only about 470 genes total, indicates that at least 150 of its genes are nonessential. Thus the basic set of essential genes to sustain the life of a simple microbial cell may number only about 300. Typically, bacteria have a repertoire of 1500 to 5000 genes.


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