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

100K 自发突变：线虫进化系统生物学的基础

基本信息

批准号：
9756424
负责人：
CHARLES F BAER
金额：
$ 32.15万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-06 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9756424
关键词：
Address Animal Model Architecture Biological Biological Models Biological Process Biology Caenorhabditis elegans Cartoons Cell Culture Techniques Cell Lineage Cells Collection Communities Controlled Environment Cryopreservation Environment Escherichia coli Foundations Genes Genetic Genetic Code Genetic Variation Genome Genotype Goals Human Biology Inbreeding Individual Instruction Logic Mainstreaming Maintenance Measures Modeling Molecular Molecular Biology Morphologic artifacts Mus Mutation Natural Selections Nematoda Noise Organism Pathologic Phenotype Population Process Property Proteome Research Personnel Resources Signal Transduction Somatic Cell System Systems Biology Technology Time Transcript Variant Work Zebrafish cell type experience experimental study fitness fly genome wide association study human subject in vivo interest metabolome operation personalized medicine protein metabolite rapid technique trait transcriptome

项目摘要

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.

项目概要技术进步使生物学家能够对整个“omes”（基因组）进行分类，但也转录组、蛋白质组、代谢组等，深入到单个细胞的水平，系统生物学是一门研究。生物学的上升分支，其目标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发挥作用来构建、操作和维护有机体在其环境背景下，这种相互作用的数量是巨大的，但经验表明确实存在。将成为潜在的一致规则。例如，转录组——揭示自然选择的一致特征。自然选择的特征是将突变引入的遗传变异与现有遗传进行比较那是因为现有的遗传变异已经过自然的审查。自发突变和选择引起的遗传变异之间存在一致的差异。物种中存在的长期遗传变异是自然选择的明显特征。识别出明显处于自然选择之下的生物体的某些特征是初步证据该特征具有显着的生物学功能，即使该功能不是立即显而易见的。系统生物学家的原材料是一组（大量）个体丰度的测量值转录物、蛋白质、代谢物等。在大多数情况下，个体的突变目标似乎是转录本等会很小，如果突变目标很小，则必须筛选许多基因组以提供突变目标。负责产生性状遗传变异的突变过程的可靠表征拟议工作的目标是构建大量模型的复制群体。线虫秀丽隐杆线虫在最低限度的自然选择下进化，从而允许除了最有害的突变不断积累，就好像自然选择看不见它们一样。一组突变积累系预计包含大约 100,000 个自发突变 C. 在这方面，线虫比其他动物模型具有主要优势，最重要的是线虫可以轻松可靠地冷冻保存，因此该资源将是持久的，并且实验。几十年后，可以在（几乎）完全相同的遗传库存上完成这些品系的基因组。测序，从而使研究人员能够将基因型与其感兴趣的特定特征相关联。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以及基因与基因之间的相互作用环境中的模型生物（例如秀丽隐杆线虫）在这方面特别有价值，因为基因型。和环境都可以被仔细控制，而这对于人类受试者来说都是不可能的。