It is the aim of this proposal to develop a large number of new sequence-specific endonucleases to recognize and target almost any possible DNA sequence in any living cell or organism, as well as to optimize homologous recombination, to provide scientists with a powerful tool to do functional genomics. The genome sequence programs have contributed a huge amount of information, and opened even more possibilities. An exhaustive catalogue of genes is now available for many organisms, but the real meaning of this information remains to be deciphered.
For example, most identified genes have no known function. Sometimes, homologies with other identified genes might give insight into the function, although this exercise can prove relatively perilous. In fact, a large amount of experimental work will be necessary to address the complexity of functional genomics, and the classical approaches might prove vain.
Two kinds of large scale approaches have been envisioned so far. On one hand DNA chips have provided temporal information about the expression of all genes in an organism. On the other hand, knock-out and RNAi knock-down experiments provide information on the effect of loss-of-function of a particular gene. Ideally, one will like to have other possibilities like modifying, adding or subtracting genetic material in a controlled manner and target not only protein-coding sequences but any kind of DNA sequence like regulatory regions, introns etc' The way to achieve this is through homologous recombination and the most efficient way to induce homologous recombination is through DNA double strand break. In order to do this, very specific endonucleases should be used that ideally would target only one nucleotide stretch in a whole genome. This proposal aims at making a large number of such endonucleases for in vivo genome targeting available to the research community, and thus provide it with a unique and powerful tool for functional genomics.'
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