Identification of phenotypic capacitors of environmental and genotypic variation

描述(由申请人提供)：项目摘要：表型电容器可以缓冲发育表型，使其不受基因或环境变化的影响。在正常情况下，这种缓冲会产生强健的表型；然而，当受到恶劣环境或突变的挑战时，电容器可能会失效，从而揭示出表型的变异。这种活动既提供了一种隐藏的多态可以积累的机制，也提供了一种通过表型电容器的故障来促进进化变化的机制。表型电容器的主要例子是Hsp90，一种分子伴侣，通常抑制表型变异，但当功能受损时释放这种变异，导致多效性表型效应。虽然只有Hsp90被证明是基因和环境变化的表型电容器，但一些实验和计算研究表明，Hsp90可能并不是唯一的这一角色。在这项研究中，我将检验多个基因产物能够作为环境和基因变异的表型电容器的假设。在初步结果中，我对4718株总体表型变异较大的酿酒酵母单基因缺失菌株的现有定量形态数据进行了分析，并鉴定了多个可能的环境变异电容器。目的1.将编码环境电容的基因缺失的实验室酵母菌株与野生菌株杂交产生遗传变异，以验证能够作为环境变化表型电容的基因产物也可作为基因变异的假设。包含缺失型和野生型F1单倍体分离物的表型变异性将使用一系列定量表型分析进行比较。目的2.对遗传差异较大的实验室菌株与野生分离物杂交的现有基因系进行高、低表型变异的连锁分析，以确定可能作为表型电容的数量性状基因座。新型表型电容器的鉴定和表征将加强对表型稳健性、癌细胞进展以及包括微生物病原体在内的生物体进化变化机制的理解。 相关性：我计划找出影响进化变化速度的关键基因。许多人类病原体进化迅速，以避免免疫反应或抗生素。这项研究将有助于理解这种进化背后的机制和基因。此外，癌细胞还经历了从正常细胞到恶性细胞的进化过程。因此，这里确定的基因可能对了解癌症的进展和可能的治疗非常重要。

DESCRIPTION (provided by applicant): Project Summary: A phenotypic capacitor buffers the developmental phenotype against genotypic or environmental variation. Under normal conditions, this buffering results in a robust phenotype; however, when challenged by a harsh environment or mutation, the capacitor may fail, thereby revealing the variation phenotypically. This activity provides for both a mechanism by which hidden polymorphism can accumulate and, by failure of the phenotypic capacitor, a mechanism by which evolutionary change can be promoted. The primary example of a phenotypic capacitor is Hsp90, a molecular chaperone that normally suppresses phenotypic variation but releases this variation when functionally compromised, resulting in pleiotropic phenotypic effects. While only Hsp90 has been shown to act as a phenotypic capacitor of both genotypic and environmental variation, several experimental and computational studies suggest Hsp90 may not be unique in this role. In this study, I will test the hypothesis that multiple gene products are capable of acting as phenotypic capacitors of environmental and genotypic variation. In the preliminary results, I have analyzed existing quantitative morphological data from 4718 Saccharomyces cerevisiae single-gene deletion strains for high overall phenotypic variance and identified multiple putative capacitors of environmental variation. Aim 1. To test the hypothesis that gene products capable of acting as phenotypic capacitors of environmental variation also act as capacitors of genotypic variation, lab yeast strains with deletions in genes that code for putative environmental capacitors will be crossed with a wild isolate strain to generate genetic variation. The phenotypic variability of deletion-containing and wild-type F1 haploid segregants will be compared using an array of quantitative phenotypic assays. Aim 2. To identify quantitative trait loci that may act as phenotypic capacitors, linkage analysis for high and low phenotypic variance will be performed on existing genotyped lines of a cross between a genetically divergent lab strain and wild isolate. The identification and characterization of novel phenotypic capacitors will enhance the understanding of phenotypic robustness, cancer cell progression, and the mechanisms for evolutionary change of organisms including microbial pathogens. Relevance: I plan to identify key genes that affect the rate of evolutionary change. Many human pathogens evolve rapidly to avoid the immune response or antibiotics. This study will help understand the mechanisms and genes behind this evolution. Additionally, cancer cells go through a form of evolution from being normal cells to becoming malignant. Thus, genes identified here are likely to be important to understanding how cancer progresses and may be treated.