Current tools for determining gene function simply cannot keep pace with the rapid accumulation of new sequence information produced by the various genome projects. In the case of the human genome, sequence information is now available for most of the estimated 140,000 genes residing in our 3 billion nucleotide genome, yet definitive function has been assigned to less than a thousand of these. How are we to assign function efficiently to the rest, and which of these genes will be the target for the next wonder drug? Newer techniques such as bioinformatics, proteomics, and array-based gene expression profiling are providing excellent clues as to what these genes do and where they are expressed, but they cannot predict the precise role of a gene in a whole organism. What is needed is a technique that can be used to jump directly from sequence to function in a whole animal. In this issue, Driver et al. report a technique with the potential to accomplish just that. Their technique involves the transient administration of a modified antisense oligonucleotide to inhibit gene function during mouse development.
The classical approach to assigning gene function in complex organisms is to inactivate the gene and see what happens. This process is more straightforward in simpler animals, such as Caenorhabditis elegans and Drosophila , where mutagenesis or newer RNA interference techniques can be used2. In mammalian systems, such approaches are not feasible, and gene knockout strategies have been used. Gene knockouts are usually performed at the single-cell stage and the effects are monitored during subsequent development into the adult. Knockouts in mammals have been accomplished on a routine basis only in mice. Mouse knockout studies are relatively slow, requiring a year or more to complete when starting from a partial sequence of a gene such as an expressed sequence tag (EST). Even if knockouts could be made more efficiently, genes often play several different roles during development. If the first role is critical, causing an embryonic lethal phenotype in the knockout, then nothing is learned about the role of the gene in subsequent stages of development.
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