The role of DNA methylation in generating quantitative traits and inter-individual variations

DNA甲基化在产生数量性状和个体间变异中的作用

• 批准号: RGPIN-2016-04792
• 负责人: Szyf, Moshe
• 金额: $ 3.93万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=615303
• 关键词: role; DNA; methylation; generating; quantitative

Background: A continuous distribution of inter-individual phenotypic variation amongst members of a population is a pervasive feature of all living organisms. While classical genetics can easily explain binary traits caused by Mendelian inheritance of rare alleles, the continuous distribution of quantitative traits is more difficult to explain. It is also well established that the environment could play a role in altering quantitative traits, however the mechanisms responsible are unclear. Understanding the fundamental mechanisms responsible for generating quantitative traits in biological systems have foundational theoretical implications for biology as well as practical implications. DNA methylation is a covalent modification of DNA that silences gene expression without alteration of the gene sequence and in contrast to germ line mutations that are identical across all cells and tissues, the state of methylation of a gene could vary from cell to cell even in the same tissue increasing the potential for a continuous variation. Thus, DNA methylation is well positioned to create a distribution of quantitative traits. Together with my collaborator Ehab Abouheif we addressed this question using ant societies and provided a proof of principle that DNA methylation can generate quantitative variation in a complex trait by quantitatively regulating transcription of the Epidermal growth receptor (Alvarado et al., Nature Com). Ants offer a unique opportunity to approach this foundational biological question since these are natural animals and not inbred lab rodents, we can study large numbers of individuals, easily manipulate the environment and their genomes are compact allowing high throughput deep sequencing. Specific aims: Our study will examine first, whether there is natural interindividual variation in DNA methylation in Camponotus floridanus ants at many loci across the genome, second, whether this is responsible for continuous inter-individual distribution of a battery of quantitative traits, third whether these variations in DNA methylation are environmentally driven and fourth whether these distribution of traits could be shifted by environmental manipulations using genome-wide bisulfite sequencing behavioral and morphometric phenotyping and environmental and genetic manipulations to test causation. Significance: This study will test one of the most foundational hypothesis in biology, that there is a dialogue between environments and genomes and that the phenotypic outcome of this dialogue is the natural inter-individual phenotypic variation that creates the heterogeneity of living populations. Since epigenetics is reversible, an epigenetic basis for natural phenotypic variation would pave a path for targeted interventions that will have an impact on biotechnology fishery, farm animals and agriculture.

背景：群体成员中个体间表型变异的连续分布是所有生物体的普遍特征。虽然经典遗传学可以很容易地解释稀有等位基因的孟德尔遗传引起的二元性状，但数量性状的连续分布更难以解释。众所周知，环境可能在改变数量性状方面发挥作用，但其机制尚不清楚。了解生物系统中产生数量性状的基本机制对生物学具有基础理论意义和实际意义。 DNA甲基化是DNA的共价修饰，可在不改变基因序列的情况下沉默基因表达，与所有细胞和组织中都相同的种系突变相反，即使在同一组织中，基因的甲基化状态也可能因细胞而异，从而增加了连续变异的可能性。因此，DNA 甲基化能够很好地创建数量性状的分布。我们与我的合作者 Ehab Abouheif 一起利用蚂蚁社会解决了这个问题，并提供了原理证明，即 DNA 甲基化可以通过定量调节表皮生长受体的转录来产生复杂性状的数量变异（Alvarado 等人，Nature Com）。蚂蚁为解决这一基本生物学问题提供了独特的机会，因为它们是自然动物，而不是近交的实验室啮齿动物，我们可以研究大量个体，轻松操纵环境，而且它们的基因组紧凑，允许高通量深度测序。 具体目标：我们的研究将首先检查佛罗里达弓背蚁基因组中许多位点的 DNA 甲基化是否存在自然的个体间变异，其次，这是否导致一系列数量性状的连续个体间分布，第三，这些 DNA 甲基化的变异是否是环境驱动的，第四，这些性状的分布是否可以通过使用全基因组的环境操作来改变 亚硫酸氢盐测序、行为和形态测量表型以及环境和遗传操作来测试因果关系。 意义：这项研究将检验生物学中最基本的假设之一，即环境和基因组之间存在对话，而这种对话的表型结果是自然的个体间表型变异，它造成了生活种群的异质性。由于表观遗传学是可逆的，自然表型变异的表观遗传学基础将为有针对性的干预措施铺平道路，从而对生物技术渔业、农场动物和农业产生影响。