The evolution of genomic imprinting

基因组印记的进化

• 批准号: 10080036
• 负责人: Jeffrey Good
• 金额: $ 28.97万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10080036
• 关键词: Alleles; Atlases; Biodiversity; Biological Models; Candidate Disease Gene; Chromatin Structure; Complex; Congenital Disorders; DNA Methylation; Data; Development; Developmental Process; Disease model; Dwarfism; Dysplasia; Embryonic Development; Epigenetic Process; Evolution; Failure; Fetal Development; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetic study; Genome; Genomic Imprinting; Genomic approach; Genotype; Goals; Growth; Growth Disorders; Hamsters; House mice; Human; Hybrids; Knowledge; Link; Mammals; Modeling; Molecular Genetics; Mus; Parents; Pathology; Pathway interactions; Phenotype; Placenta; Placentation; Play; Recurrence; Regulation; Regulator Genes; Regulatory Pathway; Research; Research Project Grants; Rodent; Rodent Model; Role; Series; Syndrome; System; Testing; Variant; X Chromosome; comparative; comparative genomics; developmental disease; epigenetic silencing; epigenomics; experimental study; fascinate; follow-up; genetic approach; genetic architecture; genome-wide; genomic data; imprint; insight; interest; mammalian genome; novel; programs; reproductive; trait; transcriptomics

Genomic imprinting is a form of epigenetic gene regulation that plays a key role in placental development. Imprinted expression is highly enriched within developmental pathways and, as a consequence, the disruption of imprinted pathways results in a range of congenital developmental disorders in humans and other mammals. Mammalian hybrids often manifest many of the same placental growth abnormalities, raising the intriguing possibility that recurrent developmental syndromes within and between species may reflect the disruption of common regulatory pathways. However, surprisingly little is known about the evolution of imprinted regulatory networks, and the contribution of disrupted genomic imprinting to the evolution of reproductive barriers between species remains unresolved. The proposed research will begin to overcome these fundamental gaps in knowledge by generating novel comparative genomic data on placental gene expression and genomic imprinting among closely related species and their reciprocal hybrids. Specific Aims 1 and 2 will use a series of hybrid rodent systems to generate an atlas of genome-wide placental transcription, DNA methylation, and chromatin structure across five species and two major lineages of rodents (house mice and dwarf hamsters). These unprecedented comparative data will allow us to resolve the basic epigenetic mechanisms controlling genomic imprinting and quantify how placental expression and imprinting has evolved over 30 million years of divergence. Specific Aim 3 will use a systems genetics approach to examine the genetic architecture of hybrid overgrowth, placental expression, and imprinting in dwarf hamsters and mice. These experiments will allow us to understand the mechanistic and genetic underpinnings of a common form of placental dysplasia and test the novel hypothesis the X chromosome plays a central role in the regulation of imprinted autosomal regulatory networks. The long-term goals of this research program are to (1) illuminate the basic epigenetic mechanisms controlling genomic imprinting, (2) provide insights into the evolutionary tempo and theoretical drivers of imprinting and other aspects of placental expression, (3) test hypotheses on the causal connection between disrupted imprinting and abnormal placental development, (4) understand the organization and evolution of imprinted expression networks, and (5) link these conceptual advances to understand the contribution of genomic imprinting to the origin of biological diversity.

基因组印迹是表观遗传基因调控的一种形式，在胎盘中起着关键作用 发展。印记表达在发育过程中高度丰富，作为一种 结果，印迹通路的破坏导致了一系列先天性 人类和其他哺乳动物的发育障碍。哺乳动物的混血儿经常表现出 许多相同的胎盘生长异常，增加了耐人寻味的复发可能性 物种内部和物种之间的发育综合征可能反映了共同的 调控途径。然而，令人惊讶的是，人们对印记的进化知之甚少。 调控网络，以及被破坏的基因组印记对人类进化的贡献 物种之间的生殖障碍仍然没有解决。拟议的研究将开始 通过产生新的比较基因组数据来克服知识中的这些根本差距 近缘物种胎盘基因表达和基因组印迹的研究 互惠的混血。特定目标1和2将使用一系列杂交啮齿动物系统来产生 全基因组胎盘转录、DNA甲基化和染色质结构图谱 涉及五种和两种主要的啮齿动物(家鼠和矮小仓鼠)。这些 史无前例的比较数据将使我们能够解决基本的表观遗传机制 控制基因组印迹并量化胎盘表达和印迹如何 经过3000万年的分化进化而来。《特定目标3》将使用一种系统遗传学 研究杂交种过度生长的遗传结构、胎盘表达和 在矮小仓鼠和小鼠身上留下印记。这些实验将使我们能够理解 一种常见形式的胎盘发育不良的机制和遗传学基础 新的假说X染色体在印记常染色体的调节中起中心作用 监管网络。这项研究计划的长期目标是：(1)阐明 表观遗传机制控制基因组印迹，(2)提供对进化的洞察 胎盘表达的节奏和理论驱动因素及其他方面，(3)检验 印迹中断与胎盘异常之间因果关系的假说 发展，(4)了解印记表达网络的组织和演变， 以及(5)将这些概念性进展联系起来，以了解基因组印记对 生物多样性的起源。