The nematode C. elegans is one of the most thoroughly studied organisms in biology. It is used by thousands of scientists to gain insight into basic biological processes, many of which are shared with humans. Its genome is fully sequenced and is now the subject of several systematic studies to identify the functional elements of the genome and to integrate this knowledge into an understanding of the larger question of how a genome specifies an organism. Although disruption of DNA sequence is one of the most powerful ways to probe its function, mutations have been described for fewer than 8,000 of its >20,000 protein coding genes and almost none of the other functional elements, including regulatory sequences. RNAi, discovered in C. elegans, provides an alternative means of altering gene function, but it has several important limitations, including variable effectiveness, a requirement for an RNA intermediate, variable tissue sensitivity and a lack of heritability. The available mutants are not readily studied in large systematic projects;they exist in a variety of different backgrounds, and their sheer number complicates handling. The present project aims to create a set of 2,000 sequenced strains derived from mutagenesis, each with 500-750 mutations, in a standard background that will be readily used both by investigators who are pursuing the function of particular DNA elements and by investigators looking broadly across the genome for elements affecting particular phenotypes. In addition, through the creation of a large set of mutations that can be associated with phenotype the collection will provide a platform for understanding the broader question of how different amino acid changes in varying contexts may affect function. This latter question is of key importance, as large numbers of human variants will be discovered in whole genome and exome resequencing projects in the coming years, which will require a strong framework to facilitate interpretation. Such projects include the 1,000 genomes project already underway and the NHLBI project currently soliciting proposals (RFA-OD-09-004).
For genomics to realize its full potential in improving public health and health care delivery, it will be essential for scientists and physicians to be able to predict the effect of the many rare mutations that each of us harbor. By generating a data set of more than 1,000,000 mutations across the C. elegans genome, we will provide a platform that will facilitate the discovery of both direct precedents and general principles that will enable improved predictions.
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