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“基因组”--基因组--进行分类，但同时 转录体、蛋白质组、代谢体等，下至单个细胞的水平。系统生物学是一种 生物学的一个方兴未艾的分支，目的是了解分子之间的相互作用。 有机体的组成部分，以及这些相互作用如何起作用来建立、运行和维护有机体 在其环境的背景下。这种互动的数量是巨大的，但经验表明， 将是潜在的一致规则。一种潜在的前进方式是仔细检查大型系统的功能-- 例如，转录组--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入的遗传变异与现有的遗传进行比较 种群的变异。这是因为长期的遗传变异已经被自然 选择。由自发突变引起的遗传变异与 物种中存在的长期遗传变异是自然选择的明确标志。反过来, 确定一个生物体的某些特征是显而易见的自然选择的初步证据 该特征具有显著的生物功能，即使该功能不是立即明显的。 系统生物学家的原始材料是一套衡量个体丰富度的(大量)指标。 转录本、蛋白质、代谢物等。似乎在大多数情况下，个体的突变目标 成绩单等，将是很小的。如果突变目标很小，必须对许多基因组进行筛选，以提供 对产生遗传变异的突变过程的可靠表征 利息。拟议工作的目标是构建模型的大量复制种群 线虫线虫是在最低限度的自然选择下进化的线虫，因此除了 最有害的突变累积起来，就像自然选择看不见一样。归根结底， 一组突变累积线预计包含大约10万个自发突变。C。 在这种情况下，与其他动物模型相比，优雅提供了主要的优势，最重要的是 线虫可以容易和可靠地超低温保存。因此，这种资源将是持久的，并进行试验 可以在几十年后在(几乎)完全相同的基因库上完成。这些品系的基因组将是 测序，从而使研究人员能够将基因类型与其感兴趣的特定特征联系起来。这两个 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，以及基因和基因之间的相互作用 环境。秀丽隐杆线虫等模式生物在这方面特别有价值，因为 而且环境都可以被仔细控制，而这两种情况在人类受试者身上都是不可能的。

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.