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

背景：个体间表型变异在种群成员中的持续分布是所有生物的普遍特征。虽然经典遗传学可以很容易地解释稀有等位基因孟德尔遗传导致的二元性状，但数量性状的连续分布更难解释。环境可以在改变数量性状中发挥作用，这一点也得到了很好的证实，但对此负责的机制尚不清楚。了解在生物系统中产生数量性状的基本机制对生物学具有基础性的理论意义和实践意义。DNA甲基化是DNA的一种共价修饰，它在不改变基因序列的情况下沉默基因的表达，与所有细胞和组织中相同的生殖系突变不同，即使在同一组织中，基因的甲基化状态也可能因细胞而异，从而增加了持续变异的可能性。因此，DNA甲基化很好地创造了数量性状的分布。与我的合作者Ehab Abouheif一起，我们利用蚂蚁社会解决了这个问题，并提供了DNA甲基化可以通过定量调节表皮生长受体的转录在复杂性状中产生数量变异的原理证明(Alvarado等人，自然通讯)。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，因为它们是天然动物，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，轻松地操纵环境，并且它们的基因组紧凑，可以进行高通量的深度测序。*具体目标：我们的研究将首先检查，在许多基因组座位上，弯曲线虫蚂蚁的DNA甲基化是否存在自然的个体间变异，其次，这是否对一系列数量性状的连续个体间分布负责，第三，DNA甲基化的这些变异是否是环境驱动的；第四，环境操作是否会改变这些特征的分布，使用全基因组亚硫酸氢盐测序、行为和形态计量学表型以及环境和遗传操作来测试原因。*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，这种对话的表型结果是自然的个体间表型变异，创造了活着的种群的异质性。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对生物技术渔业、农场动物和农业产生影响的有针对性的干预铺平道路。**

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. **