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

背景资料：个体间表型变异在种群成员中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由罕见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解释。环境也可以在改变数量性状方面发挥作用，但负责的机制尚不清楚。理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践意义。DNA甲基化是DNA的共价修饰，其沉默基因表达而不改变基因序列，并且与在所有细胞和组织中相同的生殖系突变相反，基因的甲基化状态可以在细胞与细胞之间变化，即使在相同的组织中也是如此，从而增加了连续变异的可能性。因此，DNA甲基化很好地定位于创建数量性状的分布。与我的合作者Ehab Abouheif一起，我们使用蚂蚁社会解决了这个问题，并提供了一个原理证明，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定量变异（阿尔瓦拉多等人，Nature Com）。蚂蚁提供了一个独特的机会来解决这个基本的生物学问题，因为它们是自然动物，而不是近亲繁殖的实验室啮齿动物，我们可以研究大量的个体，容易操纵环境，它们的基因组是紧凑的，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在基因组的许多位点上是否存在DNA甲基化的自然个体间变异，其次，这是否是一组数量性状连续个体间分布的原因，第三，DNA甲基化的这些变化是否是环境驱动的，第四，这些特征的分布是否可以通过使用基因组的环境操纵来改变，广泛的亚硫酸氢盐测序行为和形态表型以及环境和遗传操作来测试因果关系。* 重要性：这项研究将测试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，这种对话的表型结果是自然的个体间表型变异，这种变异创造了生活群体的异质性。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铺平道路，这将对生物技术渔业、农场动物和农业产生影响。**

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. **