A genome-wide mutation resource for C. elegans

描述：线虫秀丽隐杆线虫是生物学中研究最彻底的生物之一。成千上万的科学家使用它来深入了解基本的生物过程，其中许多与人类共享。它的基因组被完全测序，现在是几个系统研究的主题，以确定基因组的功能元素，并将这些知识整合到对基因组如何指定生物体的更大问题的理解中。尽管DNA序列的破坏是探测其功能的最有效方法之一，但在其1,000,000个蛋白质编码基因中，只有不到8,000个被描述为突变，而几乎没有其他功能元件，包括调控序列。在秀丽隐杆线虫中发现的RNAi提供了一种改变基因功能的替代方法，但它有几个重要的局限性，包括可变的有效性，对RNA中间物的要求，可变的组织敏感性和缺乏遗传性。可用的突变体不容易在大型系统项目中进行研究；它们存在于各种不同的背景中，它们的数量使处理变得复杂。目前的项目旨在创建一套2000个突变衍生的序列菌株，每个菌株有500-750个突变，在标准背景下，这将很容易被研究特定DNA元素功能的研究人员使用，也可以被研究人员广泛地在基因组中寻找影响特定表型的元素。此外，通过创建大量与表型相关的突变，该集合将为理解不同背景下不同氨基酸变化如何影响功能的更广泛问题提供平台。后一个问题至关重要，因为未来几年将在全基因组和外显子组重测序项目中发现大量人类变异，这将需要一个强大的框架来促进解释。这类项目包括正在进行的1000个基因组项目和正在征求建议的NHLBI项目（RFA-OD-09-004）。

DESCRIPTION: 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). PUBLIC HEALTH RELEVANCE: 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.