Phenotypic variability due to genetic buffering: The role of environmental factors

遗传缓冲引起的表型变异：环境因素的作用

• 批准号: 506104882
• 负责人: Privatdozent Dr. Thomas Haarmann-Stemmann
• 金额: --
• 依托单位: Leibniz-Institut für umweltmedizinische Forschung (IUF)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/506104882?language=en
• 关键词: Phenotypic; variability; due; genetic; buffering

Genetic factors can induce and contribute to the development of diseases and aging phenotypes. The dominant and recessive genetic patterns of inheritance described by Mendel represent the extremes of a spectrum of states. It has been demonstrated that the effects of deleterious genetic variations, which would be expected to cause severe phenotypes, can be buffered by cells, thereby mitigating the resulting phenotype. This process known as genetic buffering is based on different mechanisms, such as genetic compensation, transcriptional adaptation and phenotypic plasticity. The factors which are known to contribute to genetic buffering are, in part, thought to be non-genetic in nature, but knowledge in this regard is scarce.In the present application, we postulate that genetic buffering is affected by changing environmental conditions. Genetic buffering is often achieved through the expression of modifier genes. One example is the upregulation of Utrophin in patients with Duchenne muscular dystrophy (DMD), a rare genetic disorder caused by mutations of the dystrophin gene. We want to elucidate whether and how genetic buffering and the regulation of modifier genes are influenced by environmental factors. To this end, we already generated and characterized human induced pluripotent stem cells (iPSCs) and respective mutants which recapitulate, at a molecular level, DMD and Actin-B (ACTB)-associated syndromes, i.e. human monogenic diseases with a wide phenotypic variance. The corresponding modifier genes were identified and validated by RNA sequencing and qPCR analyses, respectively. In the applied research project, we will expose the generated iPSCs to sub-toxic and low toxic concentrations of exposure-relevant environmental factors (air pollutants, food contaminants) and assess their impact on the expression of modifier genes. Given that all of the applied environmental factors may stimulate the generation of reactive oxygen species, and oxidative stress is capable of modulating the expression of genes, incl. including modifier genes, in rodent disease models, we expect to find profound alterations in the expression pattern of the modifier genes. We will next assess the underlying mode of action by focusing on direct effects either on modifier gene regulation or on the genetic compensation machinery. Particularly, we will investigate the effect of the exposure to environmental pollutants at nucleic acid resolution, i.e. by analyzing epigenetic DNA- and epitranscriptomic RNA modifications as well as the global transcriptome. Given that the modulation of genetic buffering and modifier genes is clinically relevant, libraries of small molecules which may modulate the environmentally-susceptible modifiers, will be screened. These studies will provide fundamental insights into the relevance of environmental factors for genetic buffering.

遗传因素可以诱导和促进疾病和衰老表型的发展。孟德尔描述的显性和隐性遗传模式代表了一系列状态的极端。已经证明，预期会导致严重表型的有害遗传变异的影响可以被细胞缓冲，从而减轻所产生的表型。这个过程被称为遗传缓冲，是基于不同的机制，如遗传补偿，转录适应和表型可塑性。已知有助于遗传缓冲的因素部分地被认为是非遗传的，但是在这方面的知识是稀缺的。在本申请中，我们假设遗传缓冲受变化的环境条件的影响。遗传缓冲通常通过修饰基因的表达来实现。一个例子是在杜氏肌营养不良症（DMD）患者中Utrophin的上调，杜氏肌营养不良症是一种由肌营养不良蛋白基因突变引起的罕见遗传疾病。我们希望阐明遗传缓冲和修饰基因的调节是否以及如何受到环境因素的影响。为此，我们已经产生并表征了人诱导多能干细胞（iPSC）和相应的突变体，其在分子水平上概括了DMD和肌动蛋白-B（ACTB）相关综合征，即具有广泛表型变异的人单基因疾病。分别通过RNA测序和qPCR分析鉴定和验证相应的修饰基因。在应用研究项目中，我们将使产生的iPSCs暴露于亚毒性和低毒性浓度的安全相关环境因素（空气污染物，食品污染物），并评估其对修饰基因表达的影响。鉴于所有的应用环境因素都可以刺激活性氧的产生，氧化应激能够调节基因的表达，包括。包括修饰基因，在啮齿动物疾病模型中，我们期望发现修饰基因表达模式的深刻改变。接下来，我们将通过关注修饰基因调控或遗传补偿机制的直接影响来评估潜在的作用模式。特别是，我们将研究暴露于环境污染物在核酸分辨率的影响，即通过分析表观遗传DNA和epitranscriptomic RNA修饰以及全球转录组。考虑到遗传缓冲和修饰基因的调节是临床相关的，将筛选可调节环境敏感性修饰基因的小分子文库。这些研究将为遗传缓冲的环境因素的相关性提供基本的见解。