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的原因最常见的人类疾病。然而，这些突变很难识别，因为大多数引起小的表型效应，遗传修饰剂可以改变疾病的严重程度。已知有许多影响大的基因，但使某些个体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，在一种遗传背景中导致严重疾病的相同突变可能不会在不同的遗传背景中导致相同的疾病严重程度。利用群体中个体之间的遗传背景差异，定量遗传学研究可以确定改变疾病易感性的基因。秀丽隐杆线虫有利于人类疾病基因的鉴定，因为大多数细胞信号传导途径是保守的，特别是TGF-β和胰岛素途径。在本研究中，我们将使用C。elegans定量遗传学结合经典遗传上位性来鉴定对保守的TGF-β和胰岛素途径具有主要和适度影响的基因。首先，我将从来自英格兰的参考菌株和来自夏威夷的多态性菌株中创建重组近交系（RILs），并对这些重组近交系的途径表型进行评分。这些数量性状分析将迅速确定控制任何表型差异的主要效应基因。接下来，我将通过将参考遗传背景中的现存突变交叉到夏威夷遗传背景中，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剂。最后，我将创建敏化RIL集合，以便于识别改变TGF-β和胰岛素通路活性的适度效应基因。 公共卫生相关性：在人类中识别常见的致病突变既耗时又昂贵。因为在简单线虫C中TGF-β和胰岛素途径是相似的。与人类一样，修饰这些途径的基因可以被快速而廉价地鉴定出来。这些修饰基因将拓宽我们对与这些途径相关的疾病的理解，如上皮来源的癌症和糖尿病，并提出新的治疗方法。

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.