Quantitative genetic analyses of conserved C. elegans signaling pathways

描述（由申请人提供）：许多基因的突变相互作用和与环境导致最常见的人类疾病。然而，这些突变很难识别，因为大多数突变引起的表型效应很小，而基因修饰剂可以改变疾病的严重程度。许多有重大影响的基因是已知的，但使某些人易患疾病的影响不大的基因却不太为人所知，而且在人群中各不相同。因此，在一种遗传背景下导致严重疾病的同一突变，在另一种遗传背景下可能不会导致同样严重的疾病。利用群体中个体之间的遗传背景差异，定量遗传研究可以确定改变疾病易感性的基因。秀丽隐杆线虫促进了人类疾病基因的鉴定，因为大多数细胞信号通路是保守的，尤其是tgf - β和胰岛素通路。在本研究中，我将使用秀丽隐杆线虫的定量遗传学结合经典遗传上位性来鉴定对保守的tgf - β和胰岛素通路有主要和中等影响的基因。首先，我将收集来自英国的参考菌株和来自夏威夷的多态菌株创建的重组自交系（RILs），用于途径表型。这些数量性状分析将迅速确定控制任何表型差异的主要影响基因。接下来，我将通过将参考遗传背景中的现存突变与夏威夷遗传背景杂交，并对tgf - β和胰岛素途径表型的抑制或增强进行评分，来确定其他菌株背景中是否存在微妙的遗传修饰因子。最后，我将创建敏化RIL集合，以促进识别改变tgf - β和胰岛素途径活性的适度效应基因。

DESCRIPTION (provided by applicant): Mutations in many genes interacting with each other and with the environment cause most common human diseases. However, these mutations are difficult to identify because the majority cause small phenotypic effects and genetic modifiers can alter the severity of a disease. Numerous genes of large effect are known, but the genes of modest effect that predispose certain individuals to disease are less well known and vary in populations. Therefore, the same mutation that causes a severe disease in one genetic background may not cause the same severity of disease in a different genetic background. Using the genetic background differences among individuals in a population, quantitative genetic studies can identify the genes that modify disease predisposition. Caenorhabditis elegans facilitates the identification of human disease genes because most cell-signaling pathways are conserved, especially the TGF-beta and insulin pathways. In this study, I will use C. elegans quantitative genetics coupled with classical genetic epistasis to identify the genes of both major and modest effects on conserved TGF-beta and insulin pathways. First, I will score a collection of recombinant inbred lines (RILs) created from the reference strain from England and a polymorphic strain from Hawaii for pathway phenotypes. These quantitative trait analyses will rapidly identify the major effect genes that control any phenotypic differences. Next, I will determine whether subtle genetic modifiers exist in other strain backgrounds by crossing extant mutations from the reference genetic background into the Hawaiian genetic background and scoring for suppression or enhancement of TGF-beta and insulin pathway phenotypes. Last, I will create sensitized RIL collections to facilitate the identification of modest-effect genes that alter TGF-beta and insulin pathway activities. Public Health Relevance: Common disease-causing mutations are time-consuming and costly to identify in humans. Because the TGF-beta and insulin pathways are similar in the simple nematode C. elegans as in humans, genes that modify these pathways can be rapidly and cheaply identified. These modifier genes will broaden our understanding of diseases associated with these pathways, like epithelia-derived cancers and diabetes, and suggest new therapeutics.