Discovering buffered developmental networks underlying C. elegans embryogenesis

描述（由申请人提供）：本研究将描述秀丽隐杆线虫早期胚胎发生的隐性遗传变异。隐性遗传变异包括赋予表型功能效应的等位基因，但只有在遗传或环境干扰后才能检测到。人类遗传性疾病的潜在基因很少被发现，而且由于复杂疾病受到上位性和环境相互作用的严重影响，因此大多数致病基因座的行为是神秘的。激发一个生物系统来识别隐藏的遗传变异，可以发现其他方法（如连锁或关联作图）所错过的决定因素。C.线虫是探索隐蔽遗传变异的极好模型，因为资源和易处理性使得确定涉及后生动物发育的完整基因网络成为线虫系统中可实现的目标。 隐性遗传变异的表征依赖于检测来自野生群体的等位基因变异的表型差异。为了激发系统揭示产生表型差异的隐藏功能等位基因，RNA干扰（RNAi）将诱导遗传扰动;为了将等位基因定位到基因组的精确区域，将在重组近交系（RILs）上进行实验。这项工作的具体目标包括：目标1。生成C。elegans RILs.目标2.描述早期胚胎发生中隐性遗传变异的结构。目标3.识别影响胚胎发生的新基因和核苷酸。通过利用简单的遗传操作和实施最近开发的胚胎表型的高通量测定，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确定新的遗传决定因素。 确定遗传性疾病背后的基因是公共卫生研究的主要目标。然而，大多数疾病的复杂性使传统方法无法识别这些致病基因的一小部分。这项研究实现了另一种方法来揭示复杂的性状基因，使用C。elegans胚胎发生作为模型系统。

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.