Discovering buffered developmental networks underlying C. elegans embryogenesis

描述(申请人提供)：这项研究将描述线虫秀丽线虫早期胚胎发生的隐蔽遗传变异。隐蔽的遗传变异包括对表型产生功能影响的等位基因，但只有在遗传或环境扰动后才能检测到。人类疾病遗传不足的基因很少被发现，而且由于复杂的疾病受到上位性和环境相互作用的严重影响，大多数因果基因的行为都是隐晦的，这是有道理的。激发生物系统来识别隐秘的遗传变异可以揭示其他方法，如连锁或关联图谱所遗漏的决定因素。线虫是探索隐蔽遗传变异的一个很好的模型，因为资源和易操纵性使确定参与后生动物发育的完整基因网络成为线虫系统中一个可实现的目标。对隐蔽遗传变异的描述依赖于从起源于野生种群的等位基因变异中检测表型差异。为了刺激系统发现产生表型差异的隐蔽功能等位基因，RNA干扰(RNAi)将诱导遗传扰动；为了将等位基因映射到基因组的精确区域，将在重组自交系(RILs)上进行实验。本工作的具体目标包括：目的1.产生线虫ril。目的2.研究早期胚胎发育过程中隐性遗传变异的结构特征。目的3.发现影响胚胎发育的新基因和新核苷酸。通过利用简单的遗传操作和实施最近开发的高通量胚胎表型分析，这项工作有可能为复杂性状的基因组结构提供新的见解，并为重要的发育过程识别新的遗传决定因素。公共卫生研究的一个主要目标是确定哪些基因是不完全可遗传的疾病。然而，大多数疾病的复杂性使传统方法无法识别出这些原因基因中的一小部分以上。这项研究以线虫胚胎发生为模型系统，实现了一种揭示复杂特征基因的替代方法。

DESCRIPTION (provided by applicant): This research will characterize cryptic genetic variation for early embryogenesis in the nematode Caenorhabditis elegans. Cryptic genetic variation includes alleles that confer functional effects on phenotype, but which are detectable only after genetic or environmental perturbation. Few of the genes that underly heritable human diseases have been identified, and because complex diseases are heavily influenced by epistatic and environmental interactions, it makes sense that a majority of the causal loci behave cryptically. Provoking a biological system to identify cryptic genetic variation can uncover the very determinants that other approaches, such as linkage or association mapping, miss. C. elegans is an excellent model for exploring cryptic genetic variation, because resources and tractability make determination of the complete network of genes involved in metazoan development a realizable goal in the nematode system. Characterization of cryptic genetic variation relies on detecting phenotypic differences from allelic variation that originated in wild populations. To provoke the system to uncover cryptic functional alleles that produce phenotypic differences, RNA interference (RNAi) will induce genetic perturbation; to map the alleles to precise regions of the genome, the experiments will be performed on recombinant inbred lines (RILs). The specific aims of this work include: Aim 1. Generate C. elegans RILs. Aim 2. Characterize the architecture of cryptic genetic variation in early embryogenesis. Aim 3. Identify new genes and nucleotides that affect embryogenesis. By taking advantage of easy genetic manipulation and implementing recently developed high throughput assays for embryonic phenotypes, this work has the potential to contribute new insight into the genomic architecure of complex traits, as well as identify novel genetic determinants for an important developmental process. Identifying the genes that underly heritable disease is a major aim in public health research. However, the complexity of most diseases prevents traditional approaches from identifying more than a fraction of those causal genes. This research implements an alternate approach to uncovering complex trait genes, using C. elegans embryogenesis as a model system.