Molecular and computational tools for investigating genomic imprinting

在过去的十年中，生物研究从高通量基因组技术的部署中受益匪浅。我们能够快速而廉价地对细胞中的所有DNA进行测序，这使得将变异与身体特征联系起来比以往任何时候都更容易。由于DNA是通过几代人传递的，它传统上被认为是遗传性的基本手段。表观遗传学是对遗传性的研究，它基于不涉及DNA序列的机制。这通常涉及对DNA或与DNA相关的蛋白质的化学修饰，并通过调节基因表达表现为可观察的性状。虽然存在几种工具来绘制被认为是表观遗传学基础的化学修饰，但要理解这些特征如何以高通量方式引起可遗传的表型效应，将需要开发新的技术和方法。我们的研究项目集中在基因组印记，这是表观遗传学最具特色的例子之一，其中一些基因是沉默的，这取决于它们是从母亲还是父亲遗传的。每个基因的两个拷贝被认为可以确保一个基因中的有害突变被从另一个父母那里遗传来的“健康”拷贝所掩盖。为什么一个物种会进化出一种机制来沉默特定的基因，而且总是以起源的方式？这个问题激发了30多年的研究，最终在人类和小鼠中发现了100多个已知的印记基因。我们最近发表了一种高通量方法，在一个实验中概括了25年的发现。此后，我们改进了这种方法，并用它来研究组织特异性印记;这项工作最终为解释印记起源的特定进化理论提供了强有力的支持。从这些努力中显而易见的是，仅仅绘制印记基因的图谱是不够的，我们需要知道特定基因在其进化历史中何时被印记，以及印记基因的功能是什么。我们正在正面解决这些问题，通过扩展我们对跨物种，发育和解剖学的基因组印记广度的知识，我们将能够推断这种现象是如何以及为什么进化的。这也将使我们能够直接询问脊椎动物中单等位基因表达的后果。这项工作和我们正在开发的工具将在进化生物学、健康科学以及研究表观遗传学在塑造生命多样性方面的潜在巨大贡献方面有许多应用。 这里所要求的NSERC支持大部分用于培训HQP。**

Over the last decade biological research has benefitted tremendously from deployment of high-throughput genomic technologies. Our ability to quickly and cheaply sequence all of the DNA in our cells has made it easier than ever to link variation to physical traits. Since DNA is transmitted through generations, it is traditionally regarded as the basic means of heritability. Epigenetics is the study of heritability that is based on mechanisms that do not involve DNA sequence. This typically involves chemical modifications to the DNA or the proteins associated with DNA, and manifests as observable traits by regulating gene expression. Although several tools exist for mapping the chemical modifications thought to underlie epigenetics, understanding how these features cause heritable phenotypic effects in a high-throughput manner will require development of new technologies and methods. Our research program focuses on genomic imprinting one of the best characterized examples of epigenetics where some genes are silenced depending on whether they were inherited from mother or father. Two copies of each gene are thought to ensure that a deleterious mutation in one gene is masked by the “healthy” copy inherited from the other parent. Why would a species evolve a mechanism to silence specific genes, and always in a parent-of-origin manner? This question has fuelled over 30 years of research that culminated in just over 100 known imprinted genes in humans and mouse. We recently published a high-throughput method that recapitulated 25 years of discovery in a single experiment. We have since improved on the method and used it to investigate tissue-specific imprinting; work that has culminated in strong support for a specific evolutionary theory explaining the origins of imprinting. What has become obvious from these efforts is that simply generating maps of imprinted genes is insufficient, and that we need to know when specific genes became imprinted in their evolutionary history and what the functions of imprinted genes are. We are tackling these questions head-on, by extending our knowledge of the breadth of genomic imprinting across species, development, and anatomy, we will be able to infer how and why the phenomenon evolved. It will also enable us to directly ask what are the consequences of monoallelic expression in vertebrates. This work and the tools we are developing will have many applications in evolutionary biology, health sciences, and in investigating the potentially large contribution of epigenetics in shaping the diversity of life. The bulk of the NSERC support requested here is for training HQP.**