100K spontaneous mutations: the foundation for an evolutionary systems biology of C. elegans

项目摘要 技术进步使生物学家能够对整个“组”进行分类--基因组， 转录组、蛋白质组、代谢组等，到单个细胞的水平。系统生物学是一个 生物学的一个上升的分支，其目标是了解分子间的相互作用， 有机体的组成部分，以及这些相互作用如何构建，操作和维持有机体 in the context上下文of its environment环境.这种互动的数量是巨大的，但经验表明， 将是潜在的一致性规则。一个潜在的前进方向是仔细检查一个大型系统的特征- 例如，转录组-用于自然选择的一致签名。一种强有力的方式来揭示 自然选择的标志是将突变引起的遗传变异与现有的遗传变异进行比较。 人口的变化。这是因为长期的遗传变异已经被自然界的生物学家仔细研究过了。 选择.自发突变引起的遗传变异和 一个物种中存在的长期遗传变异是自然选择的一个明确无误的标志。反过来， 鉴定出一个有机体的某些特征，并证明其处于自然选择之下，是初步证据。 该特征具有重要的生物学功能，即使该功能不是立即明显的。 系统生物学家的原材料是一套（大型）个体丰度的测量方法。 转录物、蛋白质、代谢物等。似乎在大多数情况下，个体的突变靶点 成绩单等，会很小。如果突变目标很小，则必须筛选许多基因组以提供一个 可靠的表征突变过程负责产生遗传变异的性状， 兴趣所提出的工作的目标是构建一个大的复制人口的模型 线虫秀丽隐杆线虫在最低限度的自然选择下进化，从而允许所有， 最有害的突变积累起来，就好像它们对自然选择是不可见的一样。最终 一组突变积累系预期含有约100，000个自发突变。C. 在这种情况下，秀丽线虫提供了优于其他动物模型的主要优势，最重要的是， 线虫可以容易且可靠地冷冻保存。因此，资源将是持久的，实验 可以在几十年内对（几乎）完全相同的遗传种群进行。这些品系的基因组 测序，从而使研究人员能够将基因型与他们感兴趣的特定性状相关联。两者 品系本身和基因组序列将立即作为社区资源提供。 系统生物学本质上关注基因之间的相互作用，以及基因与系统之间的相互作用。 环境模式生物如C.在这方面，秀丽线虫特别有价值， 和环境都可以被小心地控制，而这两种情况在人类身上都是不可能的。

Project Summary Technological advances have enabled biologists to categorize entire "omes"– genomes, but also transcriptomes, proteomes, metabolomes, etc., down to the level of individual cells. Systems Biology is an ascendant branch of biology, with the goal of understanding the interactions between the molecular components of an organism, and how those interactions function to build, operate, and maintain the organism in the context of its environment. The number of such interactions is vast, but experience suggests that there will be underlying consistent rules. A potential way forward is to scrutinize features of a large system – a transcriptome, for example – for consistent signatures of natural selection. A powerful way to reveal the signature of natural selection is to compare the genetic variation introduced by mutation to the standing genetic variation in the population. That is because the standing genetic variation has been scrutinized by natural selection. A consistent discrepancy between the genetic variation introduced by spontaneous mutation and the standing genetic variation present in a species is an unmistakable signature of natural selection. In turn, identifying some feature of an organism that is demonstrably under natural selection is prima facie evidence that the feature has a significant biological function, even if the function is not immediately obvious. The raw material for systems biologists is a (large) set of measures of the abundance of individual transcripts, proteins, metabolites, etc. It seems likely that in most cases the mutational target of an individual transcript, etc., will be small. If the mutational target is small, many genomes must be screened to provide a reliable characterization of the mutational process responsible for producing genetic variation in the trait of interest. The goal of the proposed work is to construct a large set of replicate populations of the model nematode Caenorhabditis elegans that have evolved under minimal natural selection, thereby allowing all but the most highly deleterious mutations to accumulate as if they are invisible to natural selection. Ultimately, the set of mutation accumulation lines are expected to harbor approximately 100,000 spontaneous mutations. C. elegans provides major advantages over other animal models in this context, the most important being that nematodes can be easily and reliably cryopreserved. The resource will therefore be durable, and experiments can be done on the (nearly) exact same genetic stock for decades hence. The genomes of the lines will be sequenced, thereby allowing researchers to associate genotypes with their specific traits of interest. Both the lines themselves and the genome sequences will be made immediately available as a community resource. Systems Biology is inherently concerned with interactions between genes, and between genes and the environment. Model organisms such as C. elegans are especially valuable in that regard because genotypes and environments can be both carefully controlled, neither of which is possible with human subjects.